Articles. Definitions. Board and Staff. november 2014 ISSN gay or straight couples Most HIV-positive people in US not having sex

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1 The Center for AIDS Information & Advocacy A program of Legacy Community Health Services P.O. Box 66308, Houston, TX Combined HIV prevention strategies work best for 3 gay or straight couples Most HIV-positive people in US not having sex 8 without condoms Normal life expectancy with CD4 count above 200 and 12 low viral load after 1 year of ART AIDS deaths down, cancer deaths up in large 16 US/European HIV group Liver and heart deaths down in Europe/US HIV study, 21 but not non-aids cancers Higher CD4 count during antiretroviral therapy tied to 24 lower virus-related cancer rate Smoking lies behind higher risk of virus-related cancers 27 in people with HIV Web-based smoke-ending program doubles quitting rate 31 in people with HIV Changes in CD4 count and viral load before antiretroviral 35 therapy begins Stroke rate higher with than without HIV but not if 38 viral load low or CD4s high High blood pressure, high cholesterol often not well 42 controlled in large HIV group Osteoporosis and fracture risk higher with HIV plus 46 HCV than without Definitions 50 Board and Staff 52 ISSN Articles november 2014 A publication of

2 MISSION The Center for AIDS Information & Advocacy empowers people living with HIV to make informed decisions about their health care by providing the latest research and treatment information and by advocating for accessible, affordable, and effective treatment options until there s a cure. About HIV Treatment Alerts! HIV Treatment Alerts! is a publication of The Center for AIDS Information & Advocacy (The CFA). This newsletter is intended for those affected by HIV and their caregivers. The statements and opinions expressed in this newsletter do not impy recommendations or endorsement. Always consult your doctor before altering a prescribed drug regimen or taking any drug or supplement. HIV Treatment Alerts! is published twice a year. The print version of the newsletter is available for free at the L. Joel Martinez Information Center at Legacy Montrose Clinic, 1415 California Street, Houston, TX Access to the newsletter is available online from The CFA website ( The CFA also publishes Research Initiative/Treatment Action! (RITA!), a literature-review journal that covers issues in HIV research and policy. This and other publications are available on The CFA website ( HIV Teatment ALERTS! thanks Marie Helleberg, Suzanne Ingle, Arielle Lasry, Julia Marcus, Christine Mattson, Margaret May, Merle Myerson, Fumiyo Nakagawa, Jonathan Shutter, Michael Silverberg, Colette Smith, Richard Wolitski, Elizabeth Yanik, and Michael Yin for reviewing the reports on their research. The Center for AIDS Information & Advocacy A program of Legacy Community Health Services P.O. Box 66308, Houston, TX California Street, Houston, TX Phone Fax Website Editor Mark Mascolini Publications Coordinator Paul Simmons, MSN, NP-C Graphics Teresa B. Southwell 2 November 2014 HIV Treatment Alerts

3 Article 1 Combined HIV prevention strategies work best for gay or straight couples Combining HIV prevention strategies such as antiretroviral therapy* and condoms offers the best long-term protection against HIV transmission in gay or heterosexual couples with one HIV-positive partner and one HIV-negative partner, according to a mathematical analysis by researchers at the Centers for Disease Control and Prevention (CDC). 1 The study also confirmed that anal sex greatly increases HIV transmission risk when compared with vaginal sex. Throughout the world, most new HIV infections result from sex between an HIV-positive person and an HIVnegative person. Often couples with positive and negative partners are in long-term relationships, so the risk of HIV transmission continues as long as they keep having sex. But how HIV transmission risk accumulates in couples over the years is poorly understood. Since early in the HIV epidemic, gay and straight couples have used condoms to stop HIV from passing from a positive partner to a negative partner during sex. In recent years, several well-planned studies found that other strategies also cut the risk of HIV transmission. Male circumcision lowers the risk that a heterosexual man will get infected by a female partner about 54%. In separate studies, PrEP (the term for HIV-negative people taking daily antiretroviral pills to prevent infection) lowered HIV infection risk by 75% in a study of heterosexual women and men and by 44% in gay men. When an HIV-positive person starts antiretroviral therapy, the risk of sexual HIV transmission to a negative partner drops by 96%. Until this CDC study, no one had tried to figure out the long-term protection from HIV offered by these four strategies condoms, circumcision, PrEP, and antiretroviral therapy alone or together as couples continue to have sex over time. CDC researchers conducted this study to address that question. They aimed to see how different HIV risk-reduction strategies and sex behaviors in gay and straight couples affect chances that the HIV-positive partner will infect the HIVnegative partner. How the study worked. The researchers considered four sex acts: insertive vaginal sex (by the heterosexual man), receptive vaginal sex (by the heterosexual woman), insertive anal sex (by the gay top ), and receptive anal sex (by the gay bottom ). They considered three types of committed couples: M+/M-: An HIV-positive gay man and his HIV-negative gay partner F+/M-: An HIV-positive heterosexual woman and her HIV-negative male partner M+/F-: An HIV-positive heterosexual man and his HIV-negative female partner The researchers evaluated four strategies that could lower the risk of HIV transmission: condom use, PrEP, male circumcision, and antiretroviral therapy. Using findings from well-conducted studies, the CDC team figured the risk ratio for each of the four strategies, that is, how much each strategy lowers the risk of HIV infection for each of the four sex acts. Whenever possible, the researchers based their calculations on findings from studies involving people in the United States and other high-income countries, because they wanted their results to apply to a US population of men and women. Using data from completed studies and accepted statistical methods, the CDC team figured the probability of HIV transmission for each of the four sex acts when couples did not use a condom: Insertive vaginal sex: 0.08% per sex act Receptive vaginal sex: 0.08% per sex act Insertive anal sex: 0.62% per sex act Receptive anal sex: 1.4% per sex act Then the researchers calculated how much each HIV prevention strategy lowered the HIV transmission rate for these sex acts: HIV-positive partner taking antiretrviral therapy: 96% *Words in bold are defined in the Technical Word List at the end of this issue of HIV Treatment Alerts. November 2014 HIV Treatment Alerts 3

4 Consistent condom use: 80% Circumcision of an HIV-negative man when having insertive anal sex: 73% PrEP in a heterosexual couple: 71% Circumcision of a negative man in a heterosexual couple: 54% PrEP in a gay couple: 44% The CDC investigators assumed that all couples would have sex 6 times monthly: 3 insertive anal and 3 receptive anal sex acts for each gay man, and 6 vaginal sex acts for each heterosexual man or woman. For the heterosexual couples, the researchers varied the analysis to assume 5 vaginal sex acts plus 1 anal sex act monthly. What the study found. Among people in steady couples who did nothing to prevent transmission of HIV, chances of transmission were higher in gay couples (52% at 1 year and 99.9% at 10 years) than in straight couples who did not have anal sex (6% at 1 year and 44% at 10 years with no anal sex) (Figure 1). In HIV-negative heterosexual women who had receptive anal sex once a month and used no prevention strategy, the probability of becoming infected with HIV rose to 20% in 1 year and to 89% in 10 years (Figure 1). In HIV-negative heterosexual men who had insertive anal sex once a month and used no prevention strategy, the probability of becoming infected with HIV rose to 12% at 1 year and to 71% at 10 years (Figure 1). Considering all these factors, the CDC team then calculated cumulative probability of HIV transmission within a couple over 1 year and over 10 years. HIV transmission risk to HIV-negative partners in 1 year and 10 years Figure 1. Risk of HIV transmission in steady couples was higher in gay men than in women or men in straight (St) couples through 1 and 10 years. Transmission risk rose substantially in straight couples who had anal sex. 4 November 2014 HIV Treatment Alerts

5 In gay couples, circumcision alone lowered the 10-year HIV transmission risk from 99.9% to only 99.7% (Figure 2), having no receptive anal sex lowered the risk to 99%, using PrEP cut the risk to 98%, and PrEP plus circumcision cut the risk to only 96%. Consistent condom use alone lowered the 10-year HIV transmission risk from 99.9% to 76%, and antiretroviral therapy for the positive partner cut the 10-year risk to 25%. For gay couples, only four combination prevention strategies decreased the 10-year HIV transmission risk below 10%: antiretroviral therapy plus consistent condom use (6%), antiretroviral therapy, condoms, and circumcision (4%), antiretroviral therapy, condoms, and PrEP (3%), and antiretroviral therapy, condoms, PrEP, circumcision, and no receptive anal intercourse (1%). strategies to 15% with PrEP alone, to 11% with consistent condom use alone, and to 2% with only antiretroviral therapy for the HIV-positive partner (Figure 3). Tenyear transmission risk in couples with an HIV-negative woman was lowest when combining antiretroviral for the positive partner with PrEP for the HIV-negative partner (1%), combining antiretrovirals with consistent condom use (0.5%), or combining antiretrovirals with condoms plus PrEP (0.5%). Prevention impact on 10-year transmission risk to HIV-negative woman in straight couples In heterosexual couples with an HIV-negative woman, 10-year probability of HIV transmission without receptive anal sex dropped from 44% with no prevention Prevention impact on 10-year transmission risk in gay couples Figure 2. Risk of HIV transmission in gay couples with one HIV-positive partner and one HIV-negative partner reached almost 100% over 10 years. Circumcision alone, giving up receptive anal sex alone, and PrEP alone barely lowered the 10-year transmission risk. Consistent condom use cut 10-year transmission risk to 76%, antiretroviral therapy (ART) for the positive partner cut it to 25%, and antiretroviral therapy plus consistent condom use cut it to 6%. Figure 3. Risk of HIV transmission in straight couples with an HIV-negative woman stood at 44% over 10 years in couples who did not have anal sex. That rate dropped to 15% with PrEP alone, to 11% with consistent condom use alone, to 2% with antiretroviral therapy (ART) for the HIV-positive man, and to 1% with antiretroviral therapy for the HIV-positive man plus PrEP for the HIV-negative woman. In heterosexual couples with an HIV-negative man, 10-year probability of HIV transmission without insertive anal sex fell from 44% with no prevention strategies to 23% with circumcision alone, to 15% with PrEP November 2014 HIV Treatment Alerts 5

6 Prevention impact on 10-year transmission risk to HIV-negative man in straight couples Figure 4. Risk of HIV transmission in straight couples with an HIV-negative man stood at 44% over 10 years in couples that did not have anal sex. That rate dropped to 23% with circumcision alone, to 15% with PrEP alone, to 11% with consistent condom use alone, and to 2% with antiretroviral therapy (ART) for the HIV-positive woman. alone, and to 11% with consistent condom use alone (Figure 4). Antiretroviral therapy for the HIV-positive woman cut the 10-year transmission risk to the HIVnegative man to 2%. Adding one other prevention strategy to antiretroviral therapy lowered the 10-year transmission risk to 1% or less. The lowest 10-year transmission risk, 0.1%, came with antiretroviral therapy plus condoms plus PrEP. Decreasing the number of times a couple had sex every month lowered HIV transmission risk from the positive partner to the negative partner. And increasing the number of sex acts monthly raised the HIV transmission risk. For example, gay couples who had 2 instead of 6 episodes of anal sex monthly cut the 1-year probability of HIV transmission from 52% to 22%. In contrast, gay couples who had 20 instead of 6 bouts of anal sex monthly raised the 1-year probability of HIV transmission from 52% to 91%. What the results mean for you. This mathematical analysis of data available from previous studies made several important findings about the risk that an HIVpositive partner in a steady couple would pass HIV to the HIV-negative partner during sex: 1. Although chances of HIV transmission from one partner to another during a single sex act are small (see second bullet list above), transmission risk reaches high levels over 1 to 10 years if couples have sex regularly. 2. Because of this high HIV transmission risk over time, using only one HIV prevention strategy may not be enough to protect the HIV-negative partner. 3. Combining two or three prevention strategies has the biggest impact on HIV transmission risk. 4. Antiretroviral therapy taken by the HIV-positive partner has the greatest impact of any single 6 November 2014 HIV Treatment Alerts

7 strategy on preventing transmission in these couples. But antiretroviral therapy always works better when combined with one or more other prevention strategies. 5. Even one anal sex act monthly greatly raises the risk of HIV transmission in straight couples. 6. Anal sex by gay or straight couples carries a much higher HIV transmission risk than vaginal sex by straight couples. According to this analysis, gay couples could keep the 10- year risk of HIV transmission below 10% by combining antiretroviral therapy with consistent condom use. Adding a third prevention strategy lowered the HIV transmission risk even more for gay couples. The strong link between HIV prevention and antiretroviral therapy taken by the HIV-positive partner fits with US guidelines on antiretroviral use by adults and adolescents. Those guidelines recommend antiretroviral therapy for all HIV-positive people regardless of CD4 count, partly because therapy prevents HIV transmission to negative sex partners. 2 Couples with an HIV-positive partner not taking antiretrovirals should strongly consider this recommendation. The CDC researchers cautioned that other factors not considered in their analysis such as sex outside the couple, type of sex act, and having other sexually transmitted infections could affect their estimates of HIV transmission risk. In addition, the researchers noted that people who take PrEP daily (versus less often) will have much higher levels of protection from HIV. For these reasons, the HIV transmission risk estimates cannot be considered absolute. Still, this study offers the first thorough look at how today s proven HIV prevention strategies may affect transmission risk in couples. So couples with one HIV-positive partner and one HIV-negative partner should consider these findings when planning how to protect the negative partner from HIV. References 1. Lasry A, Sansom SL, Wolitski RJ, et al. HIV sexual transmission risk among serodiscordant couples: assessing the effects of combining prevention strategies. AIDS. 2014;28: Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. May 1, November 2014 HIV Treatment Alerts 7

8 Article 2 Most HIV-positive people in US not having sex without condoms About three quarters of HIV-positive people in care in the United States are not having sex without condoms, according to a nationwide analysis by the Centers for Disease Control and Prevention (CDC). 1 But 12% of people in this group had sex without a condom and with an HIV-negative partner or a partner whose HIV status they did not know, and half of that 12% had sex with a detectable viral load.* Having sex without a condom and with a detectable viral load poses a risk of passing HIV to sex partners, but this study found that a large majority of HIV-positive people in care in the United States do not fall into this high-risk group. In 2010 an estimated 47,500 people in the United States became infected with HIV. 2 This new-infection rate has remained constant for several years. By far the largest proportion of new HIV infections in the United States (and across the world) results from sex involving one HIV-positive partner. One study estimated that 4 of every 100 HIV-positive people in the United States passes HIV to a sex partner every year. 3 Research clearly shows that taking antiretroviral therapy lowers the risk of passing HIV to a sex partner, especially when treatment makes the viral load low or undetectable. But studies from around the world have produced mixed results on whether people taking antiretroviral therapy are more or less likely to have sex without condoms and thus more or less likely to infect sex partners with HIV. To get a better idea of condom use and sex behavior among HIV-positive people in care in the United States, CDC researchers conducted this study. How the study worked. This analysis involved 4094 HIV-positive adults in care in the United States in These people completed a face-to-face interview that gathered basic information like age and race and information about behaviors such as number of sex partners and sexually transmitted infections. The analysis focused on self-reported behaviors in the 12 months before the patient interviews. The CDC team collected data from medical records of participants including viral load and antiretroviral use. They defined viral suppression as all viral loads below 200 copies in the past 12 months. The CDC team divided the group into men who have sex with men (MSM), men who have sex with women (MSW), and women who have sex with men (WSM). They considered three separate types of sexual behavior in the past 12 months: (1) any vaginal or anal sex, (2) vaginal or anal sex without a condom, and (3) vaginal or anal sex without a condom and with an HIV-negative partner or a partner whose HIV status was not known. The CDC team used standard statistical methods to translate the findings collected into data representing the US population of HIV-positive people in care. They did this by studying people in different regions of the country, in areas with high, low, and medium HIV rates, in both urban and rural clinics, and in both public and private clinics. The main goals of the analysis were to determine how many people had vaginal or anal sex without a condom, how many people were virally suppressed, and how viral suppression affected chances of sex without a condom. What the study found. The CDC project staff interviewed and analyzed medical records of 4094 people diagnosed with HIV infection for at least 12 months and receiving care for their infection. This group included 1897 gay/bisexual men (MSM) (46%), 1016 MSW (24%), and 1093 WSM (27%). The largest proportion of participants (40%) were 40 to 49 years old, while 36% were 50 or older, and 24% were younger than 40. By race or ethnicity, 41% of the group were black, 35% white, 19% Hispanic, and 5% multiracial or with another race. Just under half of the group, 44%, lived at or below the US poverty level. More than three quarters, 78%, had been diagnosed with HIV for at least 5 years, 89% had prescriptions for combination antiretroviral therapy, and 59% were virally suppressed (all viral loads in past year below 200 copies). Almost two thirds of these people, 62%, said they had oral, anal, or vaginal sex in the past 12 months. *Words in bold are defined in the Technical Word List at the end of this issue of HIV Treatment Alerts. 8 November 2014 HIV Treatment Alerts

9 Sex behavior in national sample of adults in care with HIV Figure 1. Estimated US sample of adults diagnosed with HIV for at least 12 months and (1) in care for HIV infection and proportions reporting (2) vaginal or anal sex, (3) sex without a condom, (4) sex without a condom and with a partner negative for HIV or with an unknown HIV status, and (5) sex with a detectable viral load, without a condom, and with a partner negative for HIV or with an unknown HIV status. With standard statistical methods, the CDC used these findings to create a nationally representative sample of 408,092 HIV-positive adults diagnosed with HIV for at least 12 months and receiving care for their HIV. Of that group, an estimated 224,112 (56%) had any vaginal or anal sex (Figure 1), 98,022 (24%) had condom-free vaginal or anal sex, 50,953 (12%) had condom-free vaginal or anal sex with a partner negative for HIV or with an unknown HIV status, and 23,933 (6%) had condom-free vaginal or anal sex with a negative or statusunknown partner when they had a detectable viral load. The last two estimates mean that about half of all people in care for HIV and having condom-free sex with an HIV-negative or HIV status-unknown partner do so with a detectable viral load. In other words, this half runs a risk of passing HIV to a sex partner not already infected with HIV. Among MSM (gay or bisexual men) in care for HIV in the United States, an estimated 30% had condom-free anal or vaginal sex, 13% did so with an HIV-negative partner or HIV-status-unknown partner, and 6% did so with an HIV-negative or status-unknown partner while having a detectable viral load. MSM were significantly more likely than MSW or WSM to have sex without a condom. And WSM were significantly more likely than MSW to have condom-free sex. About half of an estimated 3212 transgender people had vaginal or anal sex in the past 12 months. Compared with people who had a detectable viral load, those with an undetectable viral load were 12% less likely to have vaginal or anal sex, 15% less likely to have condom-free vaginal or anal sex, and 21% less likely to have condom-free vaginal or anal sex with an HIVnegative partner or a partner whose HIV status they did not know (Figure 2). November 2014 HIV Treatment Alerts 9

10 Relationship of undetectable viral load to sexual risk taking Figure 2. In a nationally representative sample of US adults in care for HIV infection, those who had an undetectable viral load were significantly less likely than people with detectable HIV to (1) have vaginal or anal sex, (2) have vaginal or anal sex without a condom, or (3) have vaginal or anal sex without a condom with an HIV-negative partner or a partner whose HIV status they did not know. Compared with MSM (gay or bisexual men) with a detectable viral load, those with an undetectable viral load were 13% less likely to have anal or vaginal sex, 22% less likely to have condom-free anal or vaginal sex, and 24% less likely to have condom-free anal or vaginal sex with an HIV-negative partner or a partner whose HIV status they did not know. Having an undetectable viral load was not linked to chances of condom-free sex or condom-free sex with an HIV-negative partner among MSW or WSM. Compared with people taking antiretroviral therapy, those not taking antiretroviral therapy were significantly more likely to have vaginal or anal sex, to have condomfree vaginal or anal sex, and to have condom-free vaginal or anal sex with an HIV-negative partner or a partner whose HIV status they did not know. What the results mean for you. This is the first US analysis in the current antiretroviral treatment era that looks at sexual risk behavior by adults in care for HIV infection. The good news from this analysis of a nationally representative sample of HIV-positive people is that three quarters of them are not having vaginal or anal sex without a condom. Only an estimated 12% of people in the whole group analyzed had condom-free sex with at least one partner who did not have HIV or whose HIV status was unknown. The bad news is that half of this 12% (or 6% of the group overall) had a detectable viral load when having sex without a condom. Vaginal or anal sex without a condom and with a detectable viral load poses a risk that the HIVpositive partner will transmit HIV to the sex partner. HIV-positive people should always use condoms during sex, regardless of whether they think their sex partner is HIV-positive or negative, and regardless of whether they believe they or their partner has an undetectable viral load because of taking antiretroviral therapy. Viral loads can jump to detectable levels if someone misses a few antiretroviral doses. Even people who take their antiretrovirals regularly can have little jumps in viral load that may pose a risk of HIV transmission during sex. In addition, using condoms prevents transmission of other sexually transmitted infections. This CDC analysis also found that compared with people who had a detectable viral load those with an undetectable viral load were less likely to have vaginal or anal sex, to have sex without a condom, and to have condom-free sex with an HIV-negative partner or a partner whose HIV status they did not know. Also, people taking antiretrovirals were less likely to have condomfree sex than were people not taking antiretrovirals regardless of whether they had a detectable viral load or an undetectable load. 10 November 2014 HIV Treatment Alerts

11 Some experts had feared that people taking antiretroviral therapy especially those who reach an undetectable viral load would feel less concern about passing HIV to a partner during sex. But results of this CDC analysis, and of previous studies, 4,5 indicate that taking antiretrovirals does not result in more sexual risk taking. When the CDC team divided this HIV group into MSM, MSW, and WSM, they found that the link between an undetectable viral load and less sexual risk taking held true for MSM. But those links were much less consistent for heterosexual men and women. The smaller size of the heterosexual male and female groups could explain why the link between an undetectable viral load and less sexual risk taking did not hold true for them. Or it could mean there really is no link between an undetectable load and risk behavior in heterosexuals with HIV. The CDC project staff stresses that HIV providers should discuss HIV transmission risk regularly with their patients. Clinicians play a vital role in HIV prevention, they noted, and should use medical visits to discuss sexual risk behavior, reinforce prevention messages, diagnose and treat sexually transmitted infections, and emphasize medication adherence. References 1. Mattson CL, Freedman M, Fagan JL, et al. Sexual risk behaviour and viral suppression among HIV-infected adults receiving medical care in the United States. AIDS. 2014;28: Centers for Disease Control and Prevention. Estimated HIV incidence in the United States, HIV Surveillance Supplemental Report ;17(No. 4) Centers for Disease Control and Prevention. Monitoring selected national HIV prevention and care objectives by using HIV surveillance data: United States and 6 U.S. dependent areas HIV Surveillance Supplemental Report. 2012;17 (No. 3, part A) Crepaz N, Hart TA, Marks G. Highly active antiretroviral therapy and sexual risk behavior: a meta-analytic review. JAMA. 2004;292: Crepaz N, Marks G, Liau A, et al. Prevalence of unprotected anal intercourse among HIV-diagnosed MSM in the United States: a meta-analysis. AIDS. 2009;23: November 2014 HIV Treatment Alerts 11

12 Article 3 Normal life expectancy with CD4 count above 200 and low viral load after 1 year of ART HIV-positive 35-year-old men and women in the United Kingdom (Great Britain) can expect to live about as long as people in the general population, if they have a CD4 count* above 200 and a viral load below 400 copies after 1 year of antiretroviral therapy. 1 But people with a CD4 count below 200 when they start antiretroviral therapy have a lower expected age at death than people in the general population. As HIV-positive people live longer thanks to antiretroviral therapy, studies show that they can expect to live about as long as people without HIV. 2-5 Longer life with HIV depends on gaining CD4 cells and reaching an undetectable viral load. But previous studies have not looked closely at how many CD4 cells an HIV-positive person has to gain to live as long as an HIV-negative person the same age. Reaching an undetectable viral load is another signal of a good response to antiretroviral therapy. But the impact of viral load on life expectancy remains unclear. To address the questions of how changes in CD4 count and viral load affect life expectancy, researchers in the United Kingdom (UK) conducted a large study of HIVpositive people in care between 2000 and How the study worked. This analysis involved people at least 20 years old in a large, ongoing study of HIVpositive people in care in the UK. Participants in the lifeexpectancy analysis began combination antiretrovirals between January 1, 2000 and December 31, The analysis did not include people who became infected with HIV while injecting drugs or who became infected around the time of birth. The researchers used national records to determine how many people died from the time they entered this study through December 31, They recorded the last CD4 count before people started antiretroviral therapy and the last CD4 count in the first, second, third, fourth, and fifth years of treatment. The investigators also determined which study participants had a viral load below 400 copies in the previous year. The research team used a standard statistical method to estimate mortality (the death rate) from the start of antiretroviral therapy through 1, 2, 3, 4, and 5 years of treatment. This analysis figured mortality by gender, age, latest CD4 count (under 200, 200 to 349, or over 349), and viral load (below or above 400 copies). Next the researchers estimated life expectancy for 5-year age groups 20 to 24, 25 to 29, and so on up to age 85. They defined life expectancy as the average number of additional years a person of a specific age could expect to live. To make their findings easier to understand, they translated life expectancy into expected age at death. For example, for a 35-year-old with a life expectancy of 40 years, the expected age at death is 75. Finally, the investigators compared expected age at death in the HIV group with expected age at death in the general population, according to gender and age group. What the study found. The analysis focused on 21,388 antiretroviral-treated people, 14,742 (69%) men and 6646 (31%) women. Two thirds of the men were white, while three quarters of the women were black African. Most men (73%) and most women (64%) were between 30 and 49 years old. Similar proportions of men and women started antiretroviral therapy in (21% and 22%), (26% and 30%), (32% and 30%), and (22% and 18%). Over the study period, 961 people (4.5%) died. Overall mortality was higher in men than women (9.0 versus 7.9 per 1000 person-years). But among people younger than 45, men and women had the same mortality (7.9 per 1000 person-years, meaning about 8 of every 1000 people died every year). Expected ages at death from the start of antiretroviral therapy for men 20, 35, and 50 years old were 68, 73, and 77, compared with 77, 78, and 79 years in the general population of the UK. Expected ages at death from the start of antiretroviral therapy for women 20, 35, and 50 *Words in bold are defined in the Technical Word List at the end of this issue of HIV Treatment Alerts. 12 November 2014 HIV Treatment Alerts

13 Impact of initial CD4 count on expected age at death in 35-year-old men Figure 1. Compared with 35-year-old men in the general population of the UK, 35-year-old HIV-positive men who started antiretroviral therapy with a CD4 count of 200 or more had a similar expected age at death. Expected age at death was lower in men who started antiretroviral therapy with a CD4 count below 200. years old were 69, 74, and 78 years, compared with 81, 82, and 83 years in the general population. Expected age at death for men and women with HIV differed according to CD4 count when antiretroviral therapy began. For example, for 35-year-old men starting antiretroviral therapy, expected ages at death were 71 for men with a CD4 count below 200 (versus 78 in the general population), 78 for men with a CD4 count of 200 to 349, and 77 for men with a CD4 count above 349 (Figure 1). These numbers mean that 35-year-old men in the UK who start antiretroviral therapy with a CD4 count of 200 or higher can expect to live as long as men in the general population if those men did not get infected with HIV while injecting drugs. For 35-year-old women starting antiretroviral therapy, expected ages at death were 68 for those starting treatment with a CD4 count below 200 (compared with 82 in the general population), 76 for those starting with 200 to 349 CD4 cells, and 74 for those starting with more than 349 CD4 cells (Figure 2). Thus women starting antiretroviral therapy at a CD4 count above 200 can expect to live longer than women starting therapy with a lower CD4 count but not as long as women in the general population. Impact of initial CD4 count on expected age at death in 35-year-old women Figure 2. Women in the UK who started antiretroviral therapy at age 35 with a CD4 count of 200 or more had a later expected age at death than women who started therapy with a CD4 count below 200. But expected age at death was lower in all groups of 35-year-old HIV-positive women than in 35-year-old women in the general population. November 2014 HIV Treatment Alerts 13

14 HIV-positive women whose CD4 counts rose above 200 during the first 5 years of antiretroviral therapy and who reached a viral load below 400 copies began to catch up with women in the general population in expected age at death. For example, 35-year-old HIV-positive women whose CD4 count remained below 200 after 3 years of antiretroviral therapy could expect to live only to 67, compared with 82 in the general population of 35-yearold UK women, even if their viral load fell below 400 copies (Figure 3). But 35-year-old women whose CD4 stood between 200 and 349 after 3 years of antiretroviral therapy and who had a viral load below 400 could expect to live to 79. And 35-year-old women whose CD4 count stood above 349 after 3 years of therapy and who had a viral load below 400 could expect to live to 81, virtually the same as the expected age at death among women in the general population. HIV-positive 35-year-old men whose viral load fell below 400 copies after 3 years of antiretroviral therapy but whose CD4 count remained below 200 could expect to live only to 65, compared with an expected age at death of 78 among 35-year-old men in the general population of the UK (Figure 3). But 35-year-old men whose CD4 count stood between 200 and 349 after 3 years of therapy and who had a viral load below 400 copies could expect to live to 77. And 35-year-old men whose CD4 count climbed above 349 after 3 years of therapy and who had a viral load below 400 could expect to live to 80. Among 35-year-old women and men who had a CD4 count above 200 and a viral load below 400 copies after 1 year of antiretroviral therapy, expected age at death (81 for women and 78 for men) was similar to expected age at death for women and men in the general population of the UK (82 and 78). In both men and women, CD4 counts rose as time taking antiretroviral therapy increased. The proportion of people with a CD4 count of 350 or more climbed sharply in the first year of antiretroviral therapy and continued to rise through 5 years of treatment. When antiretroviral therapy began, only 19% of this study group had a CD4 count above 350. After 5 years of therapy, 79% of the group had a CD4 count above 350. Impact of 3 years of ART on expected age of death Figure 3. Among 35-year-old men and women who reached a viral load below 400 copies and a CD4 count above 200 after 3 years of antiretroviral therapy (ART), expected age at death was similar to that of 35-year-old men and women in the general population of the UK. Expected age at death was much lower in both men and women whose CD4 count remained below 200 after 3 years of antiretroviral therapy. 14 November 2014 HIV Treatment Alerts

15 What the results mean for you. This large study of HIV-positive people in care in the United Kingdom (Great Britain) found that women and men who have a CD4 count above 200 and a viral load below 400 copies after 1 year of antiretroviral therapy can expect to live as long as women and men in the general population. But people who start antiretroviral therapy after their CD4 count falls below 200 and people who fail to reach a CD4 count above 200 after 1 or more years of therapy have an earlier expected age at death than people in the general population of the UK. All of these findings apply only to people infected with HIV during sex not to people infected while injecting drugs or infected around the time of birth. These encouraging findings about life expectancy in people who respond well to antiretroviral therapy 1 reflect results of other recent studies in the United States and Canada, 2 two international antiretroviral trials, 3 the Netherlands, 4 and France. 5 Together these studies show that, in general, HIV-positive people who reach an undetectable viral load and gain CD4 cells with antiretroviral therapy can expect to live about as long as people the same age and gender in the general population. It s important to realize that a normal life span with HIV depends on several factors, as the researchers who conducted the British study explained: 1 3. Starting antiretroviral therapy 4. Taking antiretroviral pills on schedule, as your HIV provider directs 5. Remaining in care Taking your antiretroviral drugs on time is necessary to reach an undetectable viral load and a high CD4 count. As this study shows, both an undetectable viral load and a high CD4 count are essential to achieving a normal life span with HIV. Talk to your HIV clinician if you have trouble taking your pills regularly. There are many successful strategies to remind people to take pills on time. Sometimes your antiretroviral combination can be changed to make pill taking easier or to avoid side effects. It s also important to realize that studies like this calculate life expectancy for a whole group of people with HIV not for individuals within that group. High proportions of HIV-positive people have other life-threatening illnesses (like hepatitis, heart disease, diabetes, and cancer) and life-shortening habits (like smoking, drinking alcohol, and using illegal drugs). People with more of these illnesses and more of these bad habits face a greater challenge in living long with HIV. HIV-positive people should work with their providers to avoid or control life-threatening illnesses and to give up or control life-threatening habits. 1. Diagnosis of HIV infection before the CD4 count falls too low 2. Promptly starting care for HIV infection after diagnosis References 1. May MT, Gompels M, Delpech V, et al. Impact on life expectancy of HIV-1 positive individuals of CD4+ cell count and viral load response to antiretroviral therapy. AIDS. 2014;28: Samji H, Cescon A, Hogg RS, et al. Closing the gap: increases in life expectancy among treated HIV-positive individuals in the United States and Canada. PLoS One. 2013;8:e Rodger AJ, Lodwick R, Schechter M, et al. Mortality in well controlled HIV in the continuous antiretroviral therapy arms of the SMART and ESPRIT trials compared with the general population. AIDS. 2013;27: van Sighem AI, Gras LA, Reiss P, Brinkman K, de Wolf F, ATHENA national observational cohort study. Life expectancy of recently diagnosed asymptomatic HIV-infected patients approaches that of uninfected individuals. AIDS. 2010;24: Lewden C, Chene G, Morlat P, et al. HIV-infected adults with a CD4 cell count greater than 500 cells/mm 3 on long-term combination antiretroviral therapy reach same mortality rates as the general population. J Acquir Immune Defic Syndr. 2007;46: November 2014 HIV Treatment Alerts 15

16 Article 4 AIDS deaths down, cancer deaths up in large US/European HIV group AIDS deaths fell in 65,000 HIV-positive adults taking antiretroviral therapy* in the United States, Canada, and Europe during the period 1996 to But deaths from non-aids cancers rose over the same period. A lower CD4 count and a detectable viral load after starting antiretroviral therapy were linked to higher rates of death from AIDS, non-aids infections, and other illnesses. Since HIV-positive people started taking combination antiretroviral therapy, the death rate with HIV has dropped sharply. Today, many people taking a successful antiretroviral combination can expect to live as long as people in the general population (see the article starting on page 12 of this issue of HIV Treatment Alerts). But overall mortality the death rate is still higher in people with HIV than in HIV-negative people. 2-4 As people live to an older age with HIV infection and take antiretroviral therapy for a longer time, rates of death from specific causes are changing. For example, rates of deaths from AIDS are down, although AIDS remains the leading cause of death in many study groups. At the same time, heart disease and certain non- AIDS cancers now cause a higher proportion of deaths in HIV populations than in the general population. Understanding these trends in causes of death and identifying factors linked to specific causes of death can help people with HIV and their providers anticipate and address death risk factors. Researchers working with the Antiretroviral Therapy Cohort Collaboration conducted this analysis to examine these issues. How the study worked. The Antiretroviral Therapy Cohort Collaboration (ART-CC) is an ongoing analysis of data from several HIV study groups in the United States, Canada, and Europe. This cause-of-death analysis used data from 16 study groups that included adults who had never taken antiretrovirals before entering the study and who then began treatment with a standard antiretroviral combination. Causes of death were recorded in a uniform way in all 16 study groups. ART-CC researchers classified causes of death into 11 groups: AIDS Non-AIDS infections Liver-related (hepatitis and liver failure) Non-AIDS, nonhepatitis cancer Cardiovascular disease (myocardial infarction, ischemic heart disease, stroke) Heart/vascular disease (heart failure, other heart diseases, nonspecific heart diseases) Lung disease Kidney failure Central nervous system disease Unnatural deaths (accidental, violent, suicide, overdose) Other The research team calculated follow-up time as the time from starting antiretroviral therapy until death or the last clinic visit plus 3 months. They determined mortality (death rate) for each cause of death according to time since starting antiretroviral therapy. Hazard ratios indicating death risk from specific causes considered age, pretreatment CD4 count, and HIV transmission group (sex between men, heterosexual sex, injection drug use, or other). To evaluate changes in causes of death according to time on treatment, the researchers used a standard statistical method to calculate hazard ratios for death in the first year of antiretroviral therapy and in all later years for each person. These calculations accounted for sex (male or female), HIV transmission group, current age, pretreatment CD4 count, pretreatment viral load, pretreatment AIDS, and year when antiretroviral treatment began ( , , and ). The research team calculated hazard ratios for death after the first year of antiretroviral therapy according to CD4 count and AIDS status 12 months after treatment began. *Words in bold are defined in the Technical Word List at the end of this issue of HIV Treatment Alerts. 16 November 2014 HIV Treatment Alerts

17 What the study found. The study included 65,121 people in care for at least 1 year from 1996 through Almost three quarters of study participants (72%) were men, and most were 30 to 39 years old (42.5%) or 40 to 49 (25.2%). Most people became infected with HIV during sex (41% heterosexual, 32.5% sex between men). About one third of study participants started antiretrovirals in each of the three study periods ( , , and ). Median age stood at 37 years. Median CD4 count when antiretroviral therapy began was 217, meaning almost half of the study group began therapy with a CD4 count below 200. Median viral load stood at 70,000 copies when treatment began. During a median follow-up time of 4.5 years, 4237 people (6.5%) died to yield an overall mortality of 12.9 deaths per 1000 person-years (meaning about 13 of every 1000 people died every year). Mortality was higher in the first year of antiretroviral therapy than in later years (20.0 versus 11.3 deaths per 1000 person-years). The most frequent cause of death was AIDS (in 42%), followed by non-aids cancers (13%), and unnatural causes (10%). People who had a CD4 count at or above 200 when they started antiretroviral therapy had an overall 50% lower death rate than people who started therapy with a lower CD4 count (Figure 1). The AIDS death rate was 80% lower in people who started antiretrovirals with a CD4 count of at least 200. Non-AIDS death rates were also significantly lower in the group with an initial CD4 count of at least 200 for all non-aids deaths (40% lower), non-aids cancers (40% lower), non-aids infections (60% lower), liver disease (40% lower), cardiovascular disease (30% lower), kidney disease (80% lower), and other causes of death. Median CD4 count at the time of death was lowest in people who died of AIDS and highest in people who died of cardiovascular disease (48 versus 360). Initial CD4 count impact on death rates Figure 1. Starting antiretroviral therapy with a CD4 count of at least 200 lowered death rates from all causes, AIDS, all non-aids causes, non-aids cancers, non-aids infections, and other causes in a 65,000-person study in North America and Europe. November 2014 HIV Treatment Alerts 17

18 Gay and bisexual men had death rates similar to those of heterosexuals for all causes of death except unnatural causes of death and AIDS cancers, which were 50% lower in heterosexuals. People who became infected with HIV when injecting drugs had higher death rates than people who became infected during sex for all causes of death, particularly for non-aids infection (4.3 times higher than in gay/bisexual men), liver disease (10.6 times higher), and substance abuse (13.1 times higher). Death from any cause fell from 24.3 per 1000 personyears in the first 6 months of antiretroviral therapy to 10.2 per 1000 after 5 years of therapy. In these same two treatment periods, the AIDS death rate dropped from 13.2 to 2.4 per 1000 person-years, and the non- AIDS infection rate fell from 1.8 to 0.9 per In contrast, the rate of death from a non-aids cancer rose from 1.1 per 1000 person-years in the first 6 months of antiretroviral therapy to 1.5 per 1000 after 5 years of therapy. The researchers calculated that the death rate from non-aids cancer rose 4% with each additional year of antiretroviral therapy. In the first year of antiretroviral therapy, women had a lower death rate than men, mostly because of a 70% lower rate of non-aids cancer and a 50% lower rate of death from liver disease. This mortality difference between women and men diminished as treatment continued past the first year. Compared with men infected with HIV during sex with other men, people infected while injecting drugs had higher death rates from all causes, particularly liver-related death (18.1 times higher), substance abuse (16.3 times higher), and heart/vascular disease (6.8 times higher). AIDS before starting antiretroviral therapy was linked to a higher death rate from AIDS (4.3 times higher), non-aids infection (2.8 times higher), and liver-related death (1.9 times higher) in the first year of antiretroviral therapy. An AIDS diagnosis before people had taken antiretroviral therapy for 1 year meant a higher death rate from AIDS (2.3 times higher) and from non-aids infection (1.5 times higher). Where the CD4 count stood after the first year of antiretroviral therapy had a strong impact on death rates from AIDS, non-aids cancer, non-aids infection, and liver-related death (Figure 2). Compared with people who had an undetectable viral load after 1 year of antiretroviral therapy, those with a detectable viral load had higher rates of death from AIDS, non-aids infection, liver disease, heart/vascular disease, and suicide (Figure 3). Impact of CD4 count after 1 year of ART on death rates 350 to 499 CD4 cells versus under 200 Figure 2. A CD4 count of 350 to 499 (versus under 200) after 1 year of antiretroviral therapy (ART) was linked to lower rates of death from AIDS, non-aids cancers, non-aids infections, and liver disease. 18 November 2014 HIV Treatment Alerts

19 Impact of detectable viral load after 1 year of ART on death rates Versus an undetectable viral load Figure 3. Having a detectable viral load after 1 year of antiretroviral therapy (ART) was linked to higher rates of death from AIDS and several non- AIDS conditions in a large North American/European study. Compared with men who became infected with HIV during sex with other men, people infected during sex between men and women had higher death rates after the first year of antiretroviral therapy for non-aids cancer (1.3 times higher) and non-aids infections (2.2 times higher). After 1 year of antiretroviral therapy, heterosexuals had a 24% lower death rate from AIDS than did gay/bisexual men. Compared with men who became infected during sex with other men, people infected while injecting drugs had higher death rates after the first year of antiretroviral therapy for liver-related death (9 times higher), substance abuse (5.9 times higher), non-aids infection (4.8 times higher), accidental or violent deaths (2.7 times higher), cardiovascular disease (1.9 times higher), non-aids cancer (1.7 times higher), and AIDS (1.5 times higher). What the results mean for you. This large and thorough study of North Americans and Europeans taking antiretroviral therapy produced many important findings about death rates and factors that influence those rates. Many of the findings fall into four groups: (1) the impact of CD4 count before and during antiretroviral therapy, (2) the impact of viral load during antiretroviral therapy, (3) the impact of injection drug use, and (4) changing death rates during antiretroviral therapy. All of the CD4 count and viral load findings point in the same direction: People who started antiretroviral therapy with a lower CD4 count or had lower CD4 counts during therapy (Figure 2) ran a higher risk of death from AIDS and non-aids diseases. People who failed to reach an undetectable viral load during treatment also had higher rates of death from AIDS and certain non-aids diseases (Figure 3). Together, these findings underline two points: First, starting antiretroviral therapy earlier in the course of HIV infection (with a higher CD4 count) lowers the risk of death not only form AIDS, but also from key non-aids diseases. That means people with a risk of HIV infection including any sexually active person and anyone who injects drugs should get tested for HIV, as the Centers for Disease Control and Prevention (CDC) advises. People with a high risk of HIV infection including men who have sex with men should get tested regularly. Second, once antiretroviral therapy begins, gaining CD4 cells and reaching an undetectable viral load November 2014 HIV Treatment Alerts 19

20 are critical goals. Studies show that for most people CD4 counts continue to climb year after year with antiretroviral therapy and may reach normal levels. And most well-planned antiretroviral combinations will make the viral load undetectable. To achieve and maintain these goals, people with HIV must take their antiretrovirals regularly, as directed by their provider. Don t skip doses if you think your antiretrovirals are causing side effects or if you find them hard to take for any reason discuss the problem with your provider. There are ways to avoid side effects or lessen their impact, sometimes by switching to other antiretrovirals. In this large study people who became infected with HIV while injecting drugs had higher death rates from AIDS and many non-aids diseases. They also had higher rates of accidental death or drug overdose. Sometimes these higher death rates can be explained by continuing drug injection, which threatens overall health in many ways. People taking antiretrovirals while struggling with drug use can forget to take their antiretrovirals and lose control of their HIV infection. For all these reasons, drug injectors should try to break their habit through programs recommended by their HIV provider or other professionals involved in their care. Good news from this study included the falling overall death rate and falling AIDS death rate as antiretroviral therapy continues. But AIDS remained the leading cause of death by far. The persistence of death from AIDS largely reflects the high proportion of people who started antiretroviral therapy with a low CD4 count. The study also found that the rate of death from non- AIDS cancer rose slowly over the years as antiretroviral therapy continued. (The study reviewed on page 21 of this issue of HIV Treatment Alerts found falling death rates from heart and liver disease in HIV-positive people, but no drop in deaths from non-aids cancer.) This stable or rising cancer death rate partly reflects the aging of the study group people with and without HIV run a higher risk of cancer as they get older. But the slowly climbing cancer risk also reflects the high smoking rate in people with HIV and high rates of infection with other sexually transmitted viruses that can cause cancer. Quitting smoking and protecting yourself from sexually transmitted infections are critical in preventing cancer and some other major killers. References 1. Ingle SM, May MT, Gill J, et al. Impact of risk factors for specific causes of death in the first and subsequent years of antiretroviral therapy among HIV-infected patients. Clin Infect Dis. 2014;59: Leone S, Gregis G, Quinzan G, et al. Causes of death and risk factors among HIV-infected persons in the HAART era: analysis of a large urban cohort. Infection. 2011;39: Galli L, Spagnuolo V, Salpietro S, et al. Mortality of HIV-infected patients with or without cancer: comparison with the general population in Italy. Antivir Ther. 2012;17: Aldaz P, Moreno-Iribas C, Egues N, et al. Mortality by causes in HIV-infected adults: comparison with the general population. BMC Public Health. 2011;11: November 2014 HIV Treatment Alerts

21 Article 5 Liver and heart deaths down in Europe/US HIV study, but not non-aids cancers Death rates from any cause and from AIDS, cardiovascular disease, or liver disease dropped from 1999 through 2011 in a large group of HIV-positive people in Europe, the United States, and Australia. 1 But the death rate from non-aids cancers stayed about the same. Among people responding well to antiretroviral therapy,* research shows that life expectancy is now similar to life expectancy in the general population. (See the article starting on page 12 of this issue of HIV Treatment Alerts.) With a falling proportion of HIV-positive people dying of AIDS, rising proportions are dying from common non-aids diseases like cardiovascular disease, liver disease, and non-aids cancers. (Non-AIDS cancers are all cancers except Kaposi sarcoma, non-hodgkin lymphoma, and cervical cancer.) As people live to older ages with antiretroviral therapy, it is important to determine how causes of death are changing. Knowing which diseases are causing more deaths in people taking antiretroviral therapy can help HIV-positive people and their providers remain alert to risk factors for these diseases, and to avoid or control those risk factors. Researchers who conducted the study described here noted that certain non-aids diseases may be more common in people with HIV than without HIV for three reasons: (1) Many HIV-positive people have important risk factors for such diseases, such as smoking and infection with hepatitis viruses (HBV or HCV) that affect the liver. (2) The impact of HIV on the immune system and general inflammation in the body can increase risk of some non-aids diseases, even in people taking effective antiretroviral therapy. (3) Side effects of antiretrovirals, which must be taken for life to keep HIV under control, also contribute to the risk of key non-aids diseases. To learn more about changing causes of death in antiretroviral-treated people, these researchers analyzed death rates in almost 50,000 people with HIV. They also wanted to detect any unexpected increases in death from specific causes and to learn how factors like changing CD4 count and viral load affect death rates. How the study worked. The study group, called DAD, includes almost 50,000 HIV-positive people taking antiretroviral therapy at 212 clinics in Europe, the United States, and Australia. As part of the ongoing DAD study, individual clinics report important health-related developments including death to the central DAD database. All participating clinics use the same method to classify deaths. The researchers divided causes of death into five groups: (1) AIDS, (2) cardiovascular disease, (3) liver disease, (4) non-aids cancers, and (5) other causes. The DAD team tracked individual patients from the time they entered the DAD study (starting in 1999) until (1) death, (2) 6 months after their last clinic visit, or (3) February 1, 2011, whichever came first. The researchers used sophisticated statistical analysis to calculate death rates for all deaths combined and for the five types of death, comparing rates in to rates in , , , , and This analysis accounted for several factors that can change death risk, such as age when entering the DAD study, sex (male or female), ethnic origin, smoking, certain non-aids diseases, current viral load, and current CD4 count. What the study found. The study included 49,731 people, 74% of them men. Median age stood at 38 years. While 44% of the study group became infected with HIV during sex between men, 33% became infected during sex between men and women and 15% when injecting drugs. Current smokers made up 35% of the group and former smokers 17%. During the study period 3909 people died, 29% from AIDS, 15% from non-aids cancer, 13% from liver disease, 11% from cardiovascular disease, and 32% from *Words in bold are defined in the Technical Word List at the end of this issue of HIV Treatment Alerts. November 2014 HIV Treatment Alerts 21

22 other causes (such as bacterial infection, suicide, drug overdose, and accident). Overall mortality (death rate) stood at 12.7 per 1000 person-years, meaning about 13 of every 1000 people in this group died every year. Overall mortality fell by almost half from 17.5 per 1000 person-years in to 9.1 per 1000 in Mortality also fell from to for AIDS, liver disease, and cardiovascular disease, but mortality for non-aids cancer stayed about the same (Figure 1). Non-AIDS cancers are now the leading cause of non-aids death in this DAD study group. decreasing death rates over time. The same analysis adjusted for key death-risk factors did not continue to show a drop in AIDS deaths over time. That finding probably reflects the impact of improving CD4 counts over time on AIDS mortality. From to , the percentage of all deaths caused by AIDS fell from 34% to 22% and the percentage caused by liver disease dropped from 16% to 10% (Figure 2). But in the same period, the percentage of deaths caused by non-aids cancers rose from 9% to 23%. Change in mortality in DAD study group over past decade Percentage of deaths from AIDS, liver disease, and non-aids cancer over time Figure 1. From to , death rates per 1000 person-years (p-y) for AIDS, liver disease, and cardiovascular disease all fell, while the death rate from non-aids cancer stayed about the same in a large group of antiretroviral-treated people. Figure 2. In a large European-US-Australian group of antiretroviral-treated people, percentage of deaths caused by AIDS and liver disease fell from to But percentage of deaths caused by non-aids cancer rose over the same period. When the DAD researchers adjusted this analysis for key factors that might affect death risk,* they continued to see sizeable drops in mortality from all causes, liver disease, and cardiovascular disease. That probably means changes in these factors do not explain the Finally the DAD team limited the analysis to people with a viral load below 400 copies, in other words, people who had good HIV control because of antiretroviral therapy. The overall death rate in that group was 9.6 per 1000 person-years (compared with the overall rate of 12.7 per *Adjusted for sex, age, ethnic origin, HIV infection risk, hepatitis B virus status, hepatitis C virus status, smoking status, diabetes, hypertension, current viral load, current body mass index, and current CD4 count. 22 November 2014 HIV Treatment Alerts

23 1000 in the analysis that included all study participants). In people with a viral load below 400 copies, the AIDS death rate was only 1.4 per 1000 person-years. What the results mean for you. This large and careful study in the United States, Europe, and Australia has much good news for people taking antiretroviral therapy. From to , the researchers charted falling rates of death from all causes, AIDS, liver disease, and cardiovascular disease (heart and blood vessel disease). Over that period, the study found no increase in death risk from any cause. And the study produced no evidence that side effects of long-term antiretroviral therapy increase the risk of death from any cause. Indeed, the study adds to earlier findings that good control of HIV with antiretrovirals lowers death rates from AIDS and several non-aids diseases. Falling AIDS mortality across the study period, the DAD team believes, largely reflects rising CD4 counts resulting from successful antiretroviral therapy. But AIDS remained the leading cause of death, accounting for more than one quarter of all deaths. The researchers suggested that earlier diagnosis of HIV infection and good antiretroviral pill-taking habits by people with HIV might further decrease the AIDS death rate. Non-AIDS cancers were the only cause of death that did not drop during the study period. In a US/European study reviewed on page 16 of this issue of HIV Treatment Alerts, non-aids cancers were the only cause of death that did not fall from 1996 to The DAD researchers pointed out that cancer deaths in the general population have dropped over the period of their study. They noted that higher proportions of people with HIV than without HIV have cancer risk factors such as smoking, drinking alcohol, hepatitis, and infection with cancer-causing viruses like human papillomavirus (HPV). Avoiding or controlling these risk factors, the researchers suggested, could lower the cancer death rate in people with HIV. Several factors that may contribute to the falling cardiovascular disease death rate: (1) greater awareness of heart disease and stroke (see page 38) by people with HIV and their providers, (2) better management of related conditions like high cholesterol and hypertension, and (3) better prevention through diet, exercise, and quitting smoking. The drop in liver-disease deaths could reflect better care for viral hepatitis, which affects the liver. Most people who died of liver disease in this study had hepatitis, caused by either HBV or HCV infection. The DAD researchers noted that effective treatment for HCV remained uncommon in HIV-positive people during this study period. Recent availability of several strong anti-hcv drugs could lead to further drops in liver deaths among people with HIV. The overall dramatic drop in death from AIDS and certain non-aids diseases found in this study should give people with HIV further encouragement to begin antiretroviral therapy and to take their antiretroviral drugs regularly, as directed by their providers. References 1. Smith CJ, Ryom L, Weber R, et al. Trends in underlying causes of death in people with HIV from 1999 to 2011 (D:A:D): a multicohort collaboration. Lancet. 2014;384: Ingle SM, May MT, Gill J, et al. Impact of risk factors for specific causes of death in the first and subsequent years of antiretroviral therapy among HIV-infected patients. Clin Infect Dis. 2014;59: November 2014 HIV Treatment Alerts 23

24 Article 6 Higher CD4 count during antiretroviral therapy tied to lower virus-related cancer rate A higher CD4 count* 6 months after antiretroviral therapy began and a higher latest CD4 count lowered chances that a virus-related cancer (such as anal cancer or Hodgkin lymphoma) would develop in a large US study. 1 The findings suggest that low CD4 counts play a role in development of these cancers. Three cancers (non-hodgkin lymphoma, cervical cancer, and Kaposi sarcoma) are called AIDS cancers because they developed often in people with HIV infection in the early years of the HIV epidemic before people started taking strong antiretroviral combinations. In more recent years, research shows that so-called non-aids cancers became more frequent in HIV-positive people, despite antiretroviral therapy. 2 Researchers who conducted the new cancer study 1 suggested three reasons for the high rate of non-aids cancers in people with HIV: Longer life with HIV infection (and a resulting rise in age-related cancers). High rates of behaviors linked to cancer, such as smoking, drinking alcohol, and sex (leading to infection with cancer-causing viruses). Lower-than-normal CD4 counts because of HIV infection (and a resulting weakness of immune system defenses against cancer). Because antiretroviral therapy restores the immune system, it should lower the risk of some cancers. Although research shows this is true for some people with HIV and certain cancers, taking antiretroviral therapy does not always prevent cancer. This lack of protection against cancer might be explained partly by difference in the effectiveness of antiretroviral therapy from person to person. For example, some people gain CD4 cells slowly or not at all after they start antiretrovirals. People whose CD4 count stays low despite antiretroviral therapy might continue to run a higher risk of certain non-aids cancers. To gain a better understanding of how response to a first antiretroviral combination affects cancer risk, a team of US researchers conducted this study. How the study worked. CNICS is a network of eight US HIV clinics that collect data on basic patient information (like age and race), antiretroviral therapy, laboratory measures (like CD4 count and viral load), and newly developing illnesses, including cancer. Researchers combine findings from HIV-positive people in all eight clinics to create a large database they can analyze to address questions about HIV infection. This study included CNICS participants at least 18 years old who started their first antiretroviral combination between January 1, 1996 and August 30, Everyone (1) had their CD4 count and viral load measured within the 12 months before starting antiretroviral therapy, (2) had a CD4 count and viral load measured during the first 6 months of therapy, and (3) were alive more than 6 months after starting therapy. CNICS researchers calculated three CD4-cell responses to antiretroviral therapy: Six-month CD4 count, defined as the latest CD4 count measured in the first 6 months of antiretroviral therapy Latest CD4 count measured during care of each person CD4 cell count-years, a total CD4 count over time defined in note 3 Monitoring of study participants continued for each person until (1) their first non-aids cancer diagnosis, (2) the last date that people were checked for cancer at each CNICS site, (3) a gap of 12 months without a clinic visit, (4) 10 years after antiretroviral therapy began, or (5) death. People stayed in the study group even if they switched or interrupted their antiretrovirals. *Words in bold are defined in the Technical Word List at the end of this issue of HIV Treatment Alerts. 24 November 2014 HIV Treatment Alerts

25 Table 1. Virus-related non-aids cancers considered in a study of 9389 people with HIV Virus Virus-related non-aids cancer Human papillomavirus (HPV) Anal cancer, squamous cell cancer of the mouth or pharynx, penis cancer, cancer of the vagina or vulva Epstein-Barr virus (EBV) Hodgkin lymphoma (cancer of the lymph nodes, spleen, liver, bone marrow, and other sites) Hepatitis B virus or hepatitis C virus (HBV, HCV) Liver cancer The researchers divided non-aids cancers into virusrelated cancers and nonviral cancers. Table 1 lists virusrelated cancers. 63,000 copies. Almost two thirds of study participants (64%) had an undetectable viral load within 6 months of starting antiretroviral therapy. Study participants were considered at risk for non-aids cancer after the first 6 months of antiretroviral therapy to avoid including cancers that started developing before antiretroviral therapy began. Researchers used sophistical statistical methods to determine the impact of the three CD4 count measures 6 months and 12 months after the measure was made. This 6-month or 12-month lag helps ensure the cancer itself did not lower CD4 counts. What the study found. The study included 9389 HIVpositive people, 1900 of them (20%) women and 5192 (55%) gay or bisexual men. Similar proportions of study participants were white (43%) or black (41%), and 11% were Hispanic. Median CD4 count when antiretroviral therapy began was 200, while median viral load was During a median 3.8 years of care, 164 non-aids cancers developed, including 65 virus-related cancers and 99 nonviral cancers. Anal cancer was the most frequent virus-related cancer, developing in 25 people, followed by Hodgkin lymphoma in 16 people, liver cancer in 13, oral/pharyngeal cancer in 8, and other virus-related cancers in 3. Median CD4 count rose from 200 before antiretroviral therapy to 260 in the first 6 months of treatment, to 324 in the second 6 months, and to 358 in months 12 to 18. All three CD4-count measures indicated that greater CD4-cell gains with treatment lowered chances of virusrelated non-aids cancers (Figure 1) but not chances of nonviral cancers. With the 6-month lag between Impact of CD4 gains on virus-related non-aids cancer risk Figure 1. Greater CD4-cell gains with antiretroviral therapy measured three ways were linked to lower risk of virus-related non- AIDS cancers in a US study of 9389 people with HIV. November 2014 HIV Treatment Alerts 25

26 CD4 measure and cancer development, every 100-cell higher CD4 count 6 months after antiretrovirals began was linked to a 31% lower risk of virus-related cancer (Figure 1). Every 100-cell higher latest CD4 count was linked to a 15% lower risk of virus-related cancer. And every 200-cell higher CD4 cell count-years 3 was linked to a 13% lower non-aids cancer risk. Results were almost identical when the researchers used the 12-month lag for their analysis. These links between CD4 count and lower cancer risk were independent of CD4 count when antiretroviral therapy began, viral load response to therapy, age, and other factors. Greater CD4 gains after starting antiretroviral therapy were linked to progressively lower rates of virus-related non-aids cancers. For example, compared with CD4 cell count-years of 600, count-years between 600 and 1600 lowered chances of virus-related cancer 17%. And CD4 cell count years above 1600 lowered chances of virus-related cancer 70%. The researchers found similar results when they looked at improving responses by 6-month CD4 count or latest CD4 count. These links between better CD4 gains and lower cancer risk did not hold true for nonviral cancers. What the results mean for you. This large and carefully conducted study adds to earlier evidence indicating that higher latest CD4 counts are linked to lower rates of virus-related non-aids cancers (Table 1). 4-6 The new study found that links between three CD4-count measures and lower non-aids cancer rates were so strong that they were not affected by age, CD4 count when antiretroviral therapy began, or viral load change during antiretroviral therapy. Because of these findings, the US researchers suggested that a drop in a person s most recent CD4 count may be a useful signal that the person should be monitored more closely for non-aids cancers. They proposed that a longer time with a low CD4 count could provide a greater opportunity for infection with cancer-causing viruses and for persistence of those viruses in the infected person. The result may be development of non- AIDS cancers caused by these viruses. These findings underline the importance of (1) starting antiretroviral therapy before the CD4 count falls too low and (2) taking all antiretrovirals every day, as instructed by your HIV provider. Regular antiretroviral pill taking will boost CD4 counts faster. And a higher CD4 count may prevent development of virus-related non-aids cancers, such as anal cancer, liver cancer, and Hodgkin lymphoma. References 1. Yanik EL, Napravnik S, Cole SR, et al. Relationship of immunologic response to antiretroviral therapy with non-aids defining cancer incidence. AIDS. 2014;28: Simard EP, Pfeiffer RM, Engels EA. Cumulative incidence of cancer among individuals with acquired immunodeficiency syndrome in the United States. Cancer. 2011;117: CD4 cell count-years are calculated by multiplying the average of two consecutive CD4 counts by the time between the two counts and then adding values for all intervals between CD4 counts. For example, a person with a CD4 count of 200 for the first 6 months of antiretroviral therapy and a count of 400 for the second 6 months would have CD4 cell count-years of 300 for the first year of therapy. 4. Silverberg MJ, Chao C, Leyden WA, et al. HIV infection, immunodeficiency, viral replication, and the risk of cancer. Cancer Epidemiol Biomarkers Prev. 2011;20: Reekie J, Kosa C, Engsig F, et al. Relationship between current level of immunodeficiency and nonacquired immunodeficiency syndrome-defining malignancies. Cancer. 2010;116: Kesselring A, Gras L, Smit C, et al. Immunodeficiency as a risk factor for non-aids-defining malignancies in HIV-1-infected patients receiving combination antiretroviral therapy. Clin Infect Dis. 2011;52: November 2014 HIV Treatment Alerts

27 Article 7 Smoking lies behind higher risk of virus-related cancers in people with HIV HIV-positive people have almost a 3 times higher risk of smoking-related cancers than HIV-negative people, according to results of a nationwide study in Denmark. 1 And people with HIV have more than an 11 times higher risk of cancers caused by viruses (such as anal cancer and lymphoma). HIV-positive people who did not smoke did not run a higher risk of smoking-related cancers or cancers not related to smoking or to viruses. As people with HIV infection live longer thanks to antiretroviral therapy,* cancer is emerging as a major cause of death. Three cancers have long been classified as AIDS cancers cervical cancer, non-hodgkin lymphoma, and Kaposi sarcoma. But several studies show that socalled non-aids cancers are now developing at a faster pace than the three AIDS cancers in HIV-positive people. It remains unclear how much of this higher risk can be explained by (1) the negative impact of HIV on the immune system and (2) the negative impact of lifestyle factors, such as smoking, substance abuse, and sexual behavior. Denmark maintains detailed records on all HIV-positive people in care across the country. As a result, researchers can conduct studies that compare the country s entire HIV population with similar HIV-negative people throughout Denmark. Recently, a research team in Denmark found that smoking shortens life in HIVpositive people more than HIV itself. 2 Those researchers conducted a new study to weigh the impact of (1) smoking by itself, (2) HIV infection by itself, and (3) a low CD4 count by itself on development of non-aids cancers and smoking-related cancers in people with HIV compared with HIV-negative people. How the study worked. The study focused on all HIVpositive people at least 16 years old in Denmark who were receiving care 1 year after their HIV diagnosis in the period from January 1995 through December Study participants had to have a known smoking status, being (1) a current smoker, (2) a previous smoker, or (3) a person who never smoked. The researchers matched the HIV group to 2 or more HIV-negative people by gender and age. The non-hiv group was picked at random from members of an ongoing study of people in the Copenhagen area. Denmark records all cancer cases in everyone throughout the country. The researchers used this national cancer database to determine how often cancer developed in the HIV-positive and HIV-negative people they studied. They classified cancer as (1) smoking-related cancers (lung cancer, head and neck cancer, esophagus cancer, and bladder cancer), (2) virus-related cancers (lymphomas, Kaposi sarcoma, liver cancer, anal cancer, cervical cancer, cancer of the vulva, and cancer of the penis), or (3) all other cancers. Incidence is the new-diagnosis rate of a disease. Incidence rate ratios determined in this study indicate cancer incidence in people with HIV compared with incidence in people without HIV. The research team calculated incidence rate ratios for each of the three groups of cancers according to (1) HIV status (positive or negative), (2) smoking status, and (3) CD4 count (lowest-ever CD4 count below 200 and CD4 count below 200 for at least 2 years before the study period began). When calculating incidence rate ratios, the researchers used statistical methods that accounted for the potential impact of factors like age, gender, and (in people with HIV) route of HIV infection and time taking antiretroviral therapy. By comparing cancer rates in the HIV group versus the HIV-negative group, the researchers also calculated population-attributable fractions, that is, the proportions of cancers in the HIV-positive population in Denmark that could be attributed to (1) smoking, (2) HIV infection, and (3) a lowest-ever CD4 count below 200. What the study found. The study involved 3503 adults with HIV and 12,979 HIV-negative people matched to the HIV group by age and gender. Three quarters of HIV-positive people were taking antiretroviral therapy for more than 90% of the study period. Median CD4 count when HIV-positive people *Words in bold are defined in the Technical Word List at the end of this issue of HIV Treatment Alerts. November 2014 HIV Treatment Alerts 27

28 entered the study was 450. The HIV-positive group included a larger proportion who ever smoked than did the HIV-negative group (67% versus 53%). Among people who ever smoked, the HIV group included a much larger proportion of people who currently smoked (76% versus 39%). When the researchers looked at all cancers (except skin cancer), they calculated that HIV-positive people had a 2 times higher cancer risk than the matched group without HIV (Figure 1). Compared with the HIVnegative group, HIV-positive people had almost a 3 times higher risk of smoking-related cancers (Figure 1). And the HIV-positive group had an 11.5 times higher risk of virus-related cancers (Figure 1). For all other cancers, people with HIV did not have a higher risk than people without HIV. When the research team looked only at people who never smoked, HIV-positive people had a 2.3 times higher risk of all cancers than HIV-negative people and a 17 times higher risk of virus-related cancers. But among people who never smoked, the HIV group did not have a higher risk of smoking-related cancers than people without HIV. Compared with HIV-positive people who never smoked, those who smoked had a 74% higher risk of cancer. Compared with HIV-negative people who never smoked, those who smoked had a 92% higher risk of cancer. HIVpositive current smokers had a 21 times higher risk of smoking-related cancers than HIV-positive people who never smoked. HIV-negative current smokers had a 4 times higher risk of smoking-related cancers than HIV-negative people who never smoked. Those last two findings mean smoking boosts the risk of smokingrelated cancers in people with and without HIV but the cancer risk linked to smoking is much greater in HIV-positive people than HIV-negative people. HIV-positive smokers whose CD4 count fell below 200 before they started antiretroviral therapy had a 2.3 times higher risk of smoking-related cancers than HIVpositive people whose CD4 count never fell that low. HIV-positive smokers whose CD4 count fell below 200 before they started antiretroviral therapy had a 3.5 times higher risk of lung cancer than HIV-positive people whose CD4 count never fell below 200. Cancer risk with versus without HIV Figure 1. Compared with HIV-negative people the same age and gender, HIV-positive people in Denmark had a doubled risk of cancers overall, almost a tripled risk of smoking-related cancers, and an 11.5 times higher risk of virus-related cancers. 28 November 2014 HIV Treatment Alerts

29 Proportion of cancers explained by smoking and HIV Figure 2. Comparing 3503 adults with HIV and 12,979 HIV-negative people matched to the HIV group by age and gender, researchers in Denmark found that high proportions of all cancers, virus-related cancers, and smoking-related cancers could be explained by HIV infection or by smoking. Smoking-related cancers made up 23% of all cancers in HIV-positive people, and virus-related cancers made up 43% of all cancers in people with HIV. Thus smoking-related cancers and virus-related cancers combined accounted for two thirds of all cancers in people with HIV. The researchers estimated that 27% of cancers in people with HIV could be explained by smoking, and 49% could be explained by HIV infection (Figure 2). They figured that 91% of cancers classified as smoking-related in people with HIV could be explained by smoking. And 91% of virus-related cancers in people with HIV could be explained by HIV infection. What the results mean for you. This large and carefully planned study adds to what is already known about the impact of smoking and HIV infection on cancer risk. Smoking raised the risk of smoking-related cancers in people with and without HIV, but the impact of smoking was much greater in HIV-positive people. HIV infection raised the risk of virus-related cancers. These key findings stand out: HIV-positive people had an overall 2 times higher cancer risk than a group of HIV-negative people the same age and gender. Compared with the HIV-negative group, people with HIV had almost a 3 times higher risk of smoking-related cancers (lung cancer, head and neck cancer, esophagus cancer, bladder cancer). Compared with the HIV-negative group, people with HIV had an 11.5 time higher risk of virus-related cancers (lymphomas, Kaposi sarcoma, liver cancer, anal cancer, cervical cancer, cancer of the vulva, cancer of the penis). Smoking raised the risk of smoking-related cancers more in people with HIV than in people without HIV. Compared with HIV-negative people who never smoked, HIV-positive people who never smoked had more than a 17 times higher risk of virus-related cancers but not a higher risk of smoking-related cancers. HIV-positive people whose CD4 count fell below 200 before they started antiretroviral therapy had more than a doubled risk of smoking-related cancers than HIV-positive people whose CD4 count never fell that low. About 90% of smoking-related cancers in people with HIV could be explained by smoking, and about 90% of virus-related cancers in people with HIV could be explained by HIV infection. November 2014 HIV Treatment Alerts 29

30 Overall, these results hold two important messages for people with HIV: 1. HIV infection itself boosts the risk of many deadly cancers. Therefore HIV-positive people should do their best to avoid other cancer risk factors, including smoking, substance abuse, and sex without condoms. Sex without condoms can lead to infection with non- HIV viruses that make certain cancers more likely. 2. Smoking raises the risk of certain cancers more in people with HIV than in HIV-negative people. Nonsmokers should not start smoking, and people who already smoke should quit. Among HIV-positive people in this study, the risk of any cancer was not higher in former smokers than in people who never smoked. The risk of smoking-related cancers was higher in former HIV-positive smokers than in HIV-positive people who never smoked, but not nearly as high as the risk in current HIV-positive smokers compared with HIVpositive people who never smoked (4 times higher versus 21 times higher). People who smoke should talk to their HIV provider about finding a way to quit. Several strategies including nicotine replacement, drug therapy, and support groups can help people quit smoking (click on the link at reference 3 below). The next article in this issue of HIV Treatment Alerts explains an internet-based smoke-ending strategy for people with HIV. 4 Don t be discouraged if you already tried to quit smoking and failed. Many people manage to quit smoking after several failed attempts. More than half of adult smokers in the United States give up smoking. 3 Quitting not only cuts cancer risk, it also lowers the risk of heart disease, noncancer lung disease, and other illnesses. HIV-positive people have almost a 3 times higher risk of smoking-related cancers than HIV-negative people, according to results of a nationwide study in Denmark. References 1. Helleberg M, Gerstoft J, Afzal S, et al. Risk of cancer among HIV-infected individuals compared to the background population: impact of smoking and HIV. AIDS. 2014;28: Helleberg M, Afzal S, Kronborg G, et al. Mortality attributable to smoking among HIV-1-infected individuals: a nationwide, population-based cohort study. Clin Infect Dis. 2013;56: Centers for Disease Control and Prevention. Smoking and tobacco use. How to quit Shuter J, Morales DA, Considine-Dunn SE, An LC, Stanton CA. Feasibility and preliminary efficacy of a web-based smoking cessation intervention for HIV-infected smokers: a randomized controlled trial. J Acquir Immune Defic Syndr. 2014;67: November 2014 HIV Treatment Alerts

31 Article 8 Web-based smoke-ending program doubles quitting rate in people with HIV A study comparing an online program with usual advice on quitting smoking by people with HIV found that the Web-based program doubled quitting rates. 1 Quitting rates were higher in HIV-positive people who logged into all eight online sessions, and higher still in women who logged into all eight sessions. Throughout the world, higher proportions of people with HIV than without HIV smoke. A recent nationwide US study by the Centers for Disease Control and Prevention (CDC) found that 42% of HIV-positive people smoke, compared with 21% of people in the general US population. 2 Smoking is a major cause of heart disease, cancer, and lung disease in people with and without HIV. All health experts agree that quitting smoking would have a huge impact on the health and survival of people with HIV. But the best ways to help people with HIV stop smoking remain unknown. Researchers who conducted this new study 1 worked with HIV-positive smokers, HIV specialists, psychologists, graphic artists, and software designers to develop an eight-session 7-week online program called Positively Smoke Free on the Web to help people with HIV quit. The study compared Positively Smoke Free on the Web with standard smoke-ending advice in HIVpositive smokers. Positively Smoke Free on the Web *Words in bold are defined in the Technical Word List at the end of this issue of HIV Treatment Alerts. November 2014 HIV Treatment Alerts 31

32 How the study worked. The HIV clinic at Montefiore Medical Center in the Bronx, New York, cares for more than 2800 HIV-positive people. From March 2012 through April 2013, researchers invited HIV-positive smokers with an interest in quitting to enter this study. Participants had to be members of the HIV clinic, had to confirm that they smoked nicotine-containing products in the past 5 days, and had to confirm their interest in quitting in the next 6 months. Everyone had to have access to an online computer. People could not enter the study if they could not use nicotine-replacement therapy (like a nicotine patch), if they were pregnant, or if they had a low score on a reading test in English or Spanish. The researchers randomly assigned participants to standard care or to Positively Smoke Free on the Web. The standard-care group got less than 5 minutes of advice on how to quit, a self-help brochure on quitting, and an offer of a 3-month supply of nicotine patches to help them break their addiction to nicotine. All study participants had health insurance to cover the full cost of nicotine patches. People in the Positively Smoke Free on the Web group got an offer of a 3-month supply of nicotine patches and an access code to the online program, which they could view in English or Spanish. The online program included eight sessions, each containing four to seven Web pages with interactive clickable features. One new online session became available each week. People received up to four electronic messages ( or text messages) reminding them when a new session became available. People who did not log into the session after receiving reminders were called by clinic staff and encouraged to access the new session. Positively Smoke Free on the Web is designed to educate users about quitting, to motivate them to quit, and to strengthen their belief that they have the ability to quit. All study participants completed a self-administered questionnaire with questions about basic individual information (like age and race), questions about nicotine addiction and motivation to quit, and questions about depression, loneliness, anxiety, and stress. People completed the questionnaire at their first study visit and 6 weeks and 3 months after all online sessions were supposed to be completed. All participants received travel vouchers to cover transportation to the clinic and $30 for each study visit. The main goal of the study was to measure rates of 7-day abstinence from smoking 3 months after the online sessions were supposed to be finished. The researchers confirmed self-reports of abstinence by measuring carbon monoxide exhaled by study participants. What the study found. The study included 138 people, 69 assigned to Positively Smoke Free on the Web and 69 assigned to standard smoke-ending care. Both groups averaged about 46 years in age. There were 76 men, 60 women, and 2 transgendered people. About three quarters of study participants were black and most of the rest white. Ethnically, just under half were Latino or Latina. About three quarters of participants were single, 90% had stable housing, and 86% were unemployed or disabled. Most recent CD4 count averaged 578 in the online group and 595 in the standard-care group. The most recent viral load lay below 40 copies in about two thirds of both study groups. Nicotine dependence scores and motivation to quit were almost identical in the two groups. Twenty-eight of 69 people (41%) in the online group logged into all eight sessions, 46 (67%) logged into 6 or more sessions, and 8 (12%) logged into no sessions. Sixty-five of 69 people in the online group (94%) needed 32 November 2014 HIV Treatment Alerts

33 phone-call reminders to log into the next session. Individuals in the online group got an average of seven reminder calls. Only 3 people logged into all 8 sessions without any phone-call reminders. People with a highschool education or more education logged into more sessions than people with less education (average 6.0 versus 3.9). Overall, the online group spent an average 60 minutes logged into Positively Smoke Free on the Web and viewed an average 26 pages. Factors linked to viewing all 41 Web pages, more interactive clicks, or more total time logged in were (1) at least a high school education, (2) higher anxiety score, (3) lower stress score, (4) getting online at home, and (5) not being infected with HIV during sex between men. About three quarters of people randomized to Positively Smoke Free on the Web said they found the program met their expectations, was helpful, and was personally relevant. Three months after the target date for finishing Positively Smoke Free on the Web, 10% in the online group and 4% in the standard-care arm had quit smoking (Figure 1). Statistical analysis determined that the online group had a 2.5 times higher chance of quitting. Quitting rates were higher in certain subgroups who used Positively Smoke Free on the Web (Figure 1), including (1) people who logged into all eight sessions (18%), (2) people who visited all 41 Web pages (22%), (3) women (12%), (4) women who logged into all eight sessions (31%), and women who visited all 41 Web pages (40%). Race or ethnicity did not affect quitting rates. Use of the nicotine patch or other nicotine-replacement agents or smoke-ending drugs did not affect quitting differences between the online group and the standardcare group. Of the 51 people who used any therapy to help quit, 24 were in the online group and 27 in the standard-care group. Quitting rates with an online program versus standard care Figure 1. An interactive Web-based program helped more HIV-positive people quit smoking than standard quitting advice (10.1% versus 4.3%). Quitting rates were higher for women than men (11.7% versus 2.7%) and higher for people who logged into all eight Web sessions or viewed all 41 Web pages. November 2014 HIV Treatment Alerts 33

34 What the results mean for you. This well-planned study of a Web-based smoke-ending strategy suggested that an online program does better than standard counseling in helping HIV-positive people quit. Quitting rates were more than twice higher in the group using the online program, Positively Smoke Free on the Web, than in the group receiving standard care with no online component. People who logged into more of the eight online sessions and viewed more online pages quit at higher rates than people who logged in less. This was especially true for women. Smoking is more common among people with HIV than in the general population, and it causes high rates of disease and death. One recent study determined that 61% of deaths in people with HIV can be traced directly to smoking and that smoking takes an average 12 years off the lives of people with HIV. 3 For these reasons, finding a way to stop smoking should be a high priority for HIV-positive smokers. Different people will respond better to different smoke-ending strategies. This study shows that a Web-based program may be a good approach for some people with internet access and a desire to quit. The researchers who conducted this study noted that over half of HIV-positive people in certain US HIV group have a home computer and internet access. And they observed that Web-based smoking programs have worked well for non-hiv populations. Log-in rates in this HIV study were much higher than attendance rates at smoke-ending group meetings in the same HIV clinic. 4 Compared with live group sessions, an online program offers the advantages of convenience, privacy, and working at one s own pace. Although the overall quitting rate in the online group 10% sounds low, it s important to remember that quitting smoking is difficult. Only a small proportion of any group trying a specific smoking-ending strategy will manage to quit, and quitting rates have been lower with other strategies in people with HIV. In this study, people who logged into more sessions and viewed more Web pages had quitting rates ranging from 18% to 40%. If you try any quitting strategy and aren t able to quit, don t give up. Many people have to try several times before they can quit. This study was small and included HIV-positive people seen at a single clinic. Still, this study group is typical of other city-based HIV populations in the United States, including a high proportion of blacks and Hispanics. The racial make-up of this group had little impact on quitting rates. What mattered most was logging into the program regularly and interacting with more Web pages. Positively Smoke Free on the Web is free and can be accessed by anyone at the link given on page 31. References 1. Shuter J, Morales DA, Considine-Dunn SE, An LC, Stanton CA. Feasibility and preliminary efficacy of a web-based smoking cessation intervention for HIV-infected smokers: a randomized controlled trial. J Acquir Immune Defic Syndr. 2014;67: Mdodo R, Frazier E, Mattson C, Sutton M, Brooks J, Skarbinski J. Cigarette smoking among HIV+ adults in care: Medical Monitoring Project, US, th Conference on Retroviruses and Opportunistic Infections. March 3-6, Atlanta. Abstract Helleberg M, Afzal S, Kronborg G, et al. Mortality attributable to smoking among HIV-1-infected individuals: a nationwide, population-based cohort study. Clin Infect Dis. 2013;56: Moadel AB, Bernstein SL, Mermelstein RJ, et al. A randomized controlled trial of a tailored group smoking cessation intervention for HIV-infected smokers. J Acquir Immune Defic Syndr. 2012;61: November 2014 HIV Treatment Alerts

35 Article 9 Changes in CD4 count and viral load before antiretroviral therapy begins CD4 counts* fell by an average 78 cells yearly in a large study of Europeans who had not started antiretroviral therapy. 1 Every 10-fold higher current viral load meant a person lost an additional 38 CD4 cells yearly. Race and gender did not affect CD4 decreases or viral load increases in this study group. Before HIV-infected people start antiretroviral therapy, the CD4 count almost always keeps falling and the viral load almost always keeps rising. In almost everyone who does not start therapy, AIDS diseases eventually develop and those untreated people die. But researchers have not pinned down how much CD4 count and viral load change over time in people not taking antiretrovirals. And they have not figured out how falling CD4 count and rising viral load may be related to each other or what factors affect CD4 and viral load changes. Getting a better grasp on these changes in untreated people with HIV can lead to a better understanding of when to start antiretroviral therapy. And better understanding of CD4 count and viral load changes in people who have not begun therapy can help researchers plan future studies. For these reasons, a team of HIV researchers conducted this study. How the study worked. COHERE is a large ongoing study that combines findings from 36 groups of people living in Europe with HIV infection. This particular analysis considered all available viral loads and CD4 counts from any person in those groups who was more than 16 years old and who had not begun antiretroviral therapy. The researchers focused on pairs of CD4 counts and viral loads measured between 60 and 365 days apart. In each pair, viral load had to be measured within 1 week of its paired CD4 count. The research team called the first CD4 count/viral load measurement in the pair time 0 and the second measurement in the pair time 1. Every person considered for the study had to have another CD4 count/viral load pair before the time 0 measurement. The researchers excluded CD4 count/viral load pairs if (1) the CD4 count at time 0 was below 100 or (2) the viral load change from one pair to the next was greater than 0.8 on the log10 scale (about 6.3-fold). The COHERE team used standard statistical methods to identify factors linked to changes in CD4 count and viral load. Factors considered were current gender, race, current age, getting HIV infection when injecting drugs, CD4 count (for the viral load analysis), and viral load (for the CD4 count analysis). What the study found. The study involved 34,348 people who had 158,385 pairs of CD4 counts and viral loads measured from 1984 through Three quarters of the study group were men; 47% became infected during sex between men, 34% during sex between men and women, and 12% while injecting drugs. At the date of their first CD4-cell and viral load measures, study participants had a median age of 34 years, a median CD4 count of 477, and a median viral load of 10,000 copies (Figure 1). CD4 counts fell by an average 78 cells yearly, while viral loads rose an average 23% yearly (Figure 1). The 78- cell yearly drop in CD4 count means someone starting with a CD4 count of 477 will have a count of 243 after 3 years without antiretroviral therapy and a count of 87 after 5 years (Figure 1). The 23% yearly rise in viral load with untreated HIV infection means someone with a viral load of 10,000 copies will have a load of 12,300 copies 1 year later and 28,100 copies 5 years later (Figure 1). Someone who starts with a viral load of 50,000 copies will have a load of 61,500 copies 1 year later and 140,765 copies 5 years later. *Words in bold are defined in the Technical Word List at the end of this issue of HIV Treatment Alerts log10 copies/ml or 1.23-fold. November 2014 HIV Treatment Alerts 35

36 Average yearly change in CD4 count and viral load with untreated HIV infection CD4 count ,900 28, ,000 12,300 15,100 18, Start 1 y 2 y 3 y 4 y 5 y Viral load 40,000 20,000 10,000 Figure 1. In a large European HIV group that had not begun antiretroviral therapy, initial CD4 count stood at 477 and initial viral load at 10,000 copies. CD4 count dropped by an average 78 cells yearly, meaning the CD4 count would be 321 after 2 years without antiretrovirals and 87 after 5 years. Viral load rose 23% yearly during untreated HIV infection, meaning viral load would be up to 15,100 copies after 2 years without treatment and up to 28,100 copies after 5 years. Gender, race, and HIV infection while injecting drugs did not affect changes in viral load over time. But statistical analysis linked every 10 years of age to a 5% greater viral load increase before antiretroviral therapy began. The impact of age on viral load change differed between men and women. For example, in untreated women over 55 years old, viral load rose an average 44.5% yearly, while in untreated men over 55 years old, viral load rose an average 29% yearly. Statistical analysis determined that viral load at time 0 was the single strongest predictor of CD4-count change before antiretroviral therapy began: Every 10-fold greater viral load at time 0 meant an additional 37.6-cell yearly drop in CD4 cells without treatment. If viral load was less than 200 copies at time 0, CD4 counts dropped by only an average 5 cells yearly. If viral load lay above 1 million copies at time 0, CD4 counts dropped by an average 225 cells yearly. Gender, race, and getting HIV infection when injecting drugs did not affect CD4-count change before antiretroviral therapy began. Older age had a small impact on CD4-count change: Every additional 10 years of age meant an additional 1.7-cell per year drop in CD4 count. What the results mean for you. The carefully calculated changes in CD4 count and viral load in a large group of people with untreated HIV infection provide reliable average yearly changes for these two important markers of HIV disease progression. These findings based on more than 150,000 pairs of CD4 counts and viral loads show how rapidly HIV disease can get worse before a person starts antiretroviral therapy. For example, someone starting with a CD4 count of 477 (as in this study group) would have a count of only 243 after 3 years and only 87 after 5 years. And 36 November 2014 HIV Treatment Alerts

37 someone with an initial viral load of 50,000 copies would have 93,000 copies after 3 years of untreated infection and 140,765 copies after 5 years. Letting the CD4 count drop and the viral load rise without treatment is dangerous for several reasons. When the CD4 count falls below 400, the immune system begins to weaken and allows development of diseases normally prevented by a healthy immune system. When the CD4 count drops below 200, several severe and life-threatening AIDS illnesses may develop. It takes longer for a person with a lower CD4 count to reach a healthy CD4 count after starting antiretrovirals, and it takes longer for a higher viral load to become undetectable after starting antiretrovirals. During that longer recovery phase, people may remain vulnerable to illnesses that would not develop if they had started antiretrovirals at a higher CD4 count and a lower viral load. In addition, trials of individual antiretrovirals show that some of them control HIV in a lower proportion of people who start treatment with a viral load above 100,000 copies. When HIV remains uncontrolled by antiretroviral therapy, the body endures ongoing inflammation, as well as activation of immune system cells. Continuing inflammation and immune-cell activation contribute to some important non-aids diseases, including heart disease and cancer. Starting antiretroviral therapy at a higher CD4 count and lower viral load could help prevent some deadly diseases. The study also found that viral load rises faster in older people who have not started antiretroviral therapy. And a higher current viral load meant a faster yearly drop in CD4 count in this large study group. Previous studies also found a strong link between older age and a faster CD4-cell fall. 2-4 Finally, results of this study do not support the idea the viral load levels off at a certain point after the first few weeks of HIV infection and remains at that level for some time. Instead, this study shows that viral load keeps rising during untreated HIV infection. HIV experts in the United States now recommend antiretroviral therapy for everyone diagnosed with HIV infection, regardless of CD4 count. 5 HIV-positive people who have not started antiretroviral therapy should discuss treatment options with their HIV provider. References 1. The Natural History Project Working Group for the Collaboration of Observational HIV Epidemiological Research Europe (COHERE) in EuroCoord. Factors associated with short-term changes in HIV viral load and CD4+ cell count in antiretroviral-naive individuals. AIDS. 2014;28: CASCADE Collaboration. Short-term risk of AIDS according to current CD4 cell count and viral load in antiretroviral drug-naïve individuals and those treated in the monotherapy era. AIDS. 2004;18: Langford S, Ananworanich J, Cooper D. Predictors of disease progression in HIV infection: a review. AIDS Res Ther. 2007;4: Touloumi G, Hatzakis A, Rosenberg PS, O Brien TR, Goedert JJ. Effects of age at seroconversion and baseline HIV RNA level on the loss of CD4+ cells among persons with hemophilia. AIDS. 1998;12: Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. May 1, November 2014 HIV Treatment Alerts 37

38 Article 10 Stroke rate higher with than without HIV but not if viral load low or CD4s high Compared with HIV-negative people in a large California group, HIV-positive people had a higher stroke* rate over But stroke rates were similar in HIVnegative and HIV-positive people if people with HIV had (1) a viral load below 500 copies or (2) a recent CD4 count above 500 cells. Strokes occur when blood to the brain gets cut off. That can happen when blood vessels in the brain get blocked (Figure 1) or when a weakened blood vessel in the brain breaks. 2 The California study focused on strokes involving blood vessel blockage, called ischemic stroke. Research over the past decade shows that HIV-positive people run a higher risk of cardiovascular disease including stroke than people the same age without HIV. Several factors probably contribute to this higher risk, including HIV-related inflammation and behavioral risk factors such as smoking. Also, as people live longer because of effective antiretroviral therapy, their risk of age-related conditions like stroke increases. But risk of non-aids conditions like stroke changes all the time in HIV-positive people for a number of reasons. Stroke risk could change, for example, because HIV-positive people and their physicians have become more aware of heart and blood vessel risks and are avoiding or controlling factors that may lead to those problems. In addition, people in the United States and other countries now start antiretroviral therapy with less advanced HIV infection (at a higher CD4 count), and earlier HIV control could affect non-aids disease risk. Figure 1. Blockage of an artery leading to the brain can cut off blood to the brain and cause a stroke. (Illustrations from Servier Medical Art. *Words in bold are defined in the Technical Word List at the end of this issue of HIV Treatment Alerts. 38 November 2014 HIV Treatment Alerts

39 Also, antiretroviral combinations have become easier to take and less toxic factors that contribute to better pilltaking habits and thus better HIV control. Researchers with the Kaiser Permanente healthcare system in California conducted this study with three major goals: (1) to compare stroke rates in people with and without HIV, (2) to determine the impact of CD4 count and viral load on stroke rates, and (3) to pinpoint stroke risk factors in people with HIV. How the study worked. The Kaiser Permanente system cares for almost one third of insured people in California. This study focused on people at least 18 years old who were members of the Kaiser system at some point between 1996 and For every 1 person diagnosed with HIV infection, the researchers picked 10 HIV-negative people matched to the HIV-positive person by age, sex, medical center, and first year in the Kaiser system. The analysis excluded anyone who had an ischemic stroke in the 2 years before they entered the study period. Using electronic medical records, the researchers tracked each person until they had an ischemic stroke, died, or dropped out of the Kaiser system, or until December 31, They also used electronic medical records to collect data on each person that might be useful in this analysis, such as age, sex, race, smoking, diabetes, high blood pressure, and use of lipid-lowering drugs. For people with HIV, the researchers collected data on CD4 count, viral load, time taking antiretroviral therapy, types of antiretrovirals taken, and other factors. The researchers used standard statistical methods to determine the new stroke rate (incidence) in the HIV group and the HIV-negative group, meausred as number of people with a stroke per 100,000 person-years. Then the investigators determined the stroke rate in HIVpositive people compared with HIV-negative people. They repeated that comparison in male and female subgroups and in subgroups with different CD4 counts and viral loads. Finally, the Kaiser team used accepted statistical methods to identify stroke risk factors in the HIV group according to recent CD4 count, lowest-ever CD4 count, recent viral load, and several other factors. What the study found. The study included 24,768 people with HIV and 257,600 without HIV. Age averaged 41 in the HIV group and 40 in the HIVnegative group when they first entered the study period, and 91% in each group were men. Higher proportions of people with than without HIV ever smoked (45% versus 31%), abused alcohol (11% versus 7%), or abused drugs (16% versus 5%). Rates of other stroke risk factors such as overweight or obesity, high blood pressure, and diabetes did not differ much between the HIV group and the non-hiv group. Among people with HIV infection, 75% became infected during sex between men, 16% during sex between men and women, and 7% while injecting drugs. Slightly fewer than half of HIV-positive people (46%) had taken antiretroviral therapy when the study period began. CD4 count averaged 410 and viral load averaged 59,802 copies. From 1996 through 2011, the stroke rate was 125 per 100,000 person-years in the HIV group and 74 per 100,000 person-years in the non-hiv group. Those rates mean 125 of every 100,000 people with HIV had a stroke every year, compared with 74 of every 100,000 HIV-negative people. Based on those numbers, statistical analysis that took into account standard stroke risk factors determined that HIV-positive people had a 40% higher stroke rate than people without HIV. Focusing only on men, a similar analysis accounting for standard stroke risk factors found that men with HIV had a 40% higher stroke rate than men without HIV. The next statistical analysis taking into account traditional stroke risk factors compared stroke rates in HIV-negative people and HIV-positive people with different CD4 counts and viral loads (Figure 2). HIVpositive people with a recent CD4 count above 500 or a recent viral load below 500 copies had the same stroke rate as HIV-negative people. In contrast, HIV-positive people with a recent CD4 count below 200 or between 200 and 499 had a higher stroke rate than HIV-negative people. Also, HIV-positive people with a lowest-ever (nadir) CD4 count below 200 had a higher stroke rate than HIV-negative people. HIV-positive people with a recent viral load between 500 and 9999 copies had November 2014 HIV Treatment Alerts 39

40 CD4 and viral load factors affecting stroke rate with vs without HIV Figure 1. Blockage of an artery leading to the brain can cut off blood to the brain and cause a stroke. (Illustrations from Servier Medical Art. Figure 2. A comparison of 24,768 people with HIV and 257,600 without HIV found no difference in stroke rate over time in HIV-negatives and HIV-positives with a recent CD4 count above 500 or a recent viral load (VL) below 500 copies. But a recent CD4 count below 200, a recent count of 200 to 499, and a lowest-ever CD4 count below 200 were linked to a higher stroke rate in HIV-positive people than HIV-negative people. And a recent viral load of 500 to 9999 copies or above 9999 was linked to a higher stroke rate in HIV-positive people than HIV-negative people. almost a twice higher stroke rate than HIV-negative people. And HIV-positive people with a recent viral load at or above 10,000 copies had more than a twice higher stroke rate than people without HIV. Focusing just on people with HIV, the researchers linked three HIV-related factors to a higher stroke rate, independently of other stroke risk factors: Recent CD4 count below 200 versus 500 or higher: 2.5 times higher stroke rate HIV infection for 10 or more years versus under 5 years: 40% lower stroke rate HIV infection for 5 to 9 years versus under 5 years: 40% lower stroke rate Recent use of protease inhibitors or nonnucleosides (two types of antiretrovirals) did not affect the stroke rate. Length of treatment with protease inhibitors or nonnucleosides did not affect the stroke rate. In the same analysis, several traditional risk factors independently affected stroke rates in people with HIV: Age 50 to 64 versus 18 to 39: 5.2 times higher stroke rate Age 65 or older versus 18 to 39: 11.2 times higher stroke rate Ever abusing alcohol or drugs: 2 times higher stroke rate Having high blood pressure in the past: 3.3 times higher stroke rate Ever being overweight or obese: 50% lower stroke rate What the results mean for you. This large California study covering the years 1996 through 2011 found that people with HIV infection had a higher stroke rate than people without HIV, even after researchers took into account traditional stroke risk factors like age, race, smoking, and high blood pressure. But when 40 November 2014 HIV Treatment Alerts

41 the researchers compared HIV-negative people with subgroups of HIV-positive people, they found that HIVpositive people with a recent CD4 count above 500 or a recent viral load below 500 copies had the same stroke rate as HIV-negative people. These important findings suggest that HIV-positive people responding well to antiretroviral therapy do not have a higher stroke risk than people without HIV. Related findings include the lack of any link between protease inhibitors or nonnucleosides (two types of antiretrovirals) and stroke rate. In addition, length of time taking protease inhibitors or nonnucleosides did not affect stroke rate. Along the same lines, this study found that a recent CD4 count below 200 versus above 500 was linked to a 2.5 times higher stroke rate. Together these findings should assure HIV-positive people and their providers that effective antiretroviral combinations help protect people from stroke. The lower stroke rate in overweight or obese people was surprising since overweight and obesity are typically considered risk factors for cardiovascular diseases such as stroke. In people with HIV, greater weight could be a signal of better overall health, and that may partly explain the lower stroke rate in this HIV group. But this finding is hard to interpret and certainly does not justify overweight or obesity, which pose many health risks. About 795,000 people in the United States have a stroke every year, according to the American Stroke Association. 3 Strokes kill more than 137,000 people in the United States every year. When a stroke is not deadly, it can permanently damage basic functions like movement and speech. Older age, black race, and being a woman raise the risk of stroke. The California study found that HIV infection is also a stroke risk factor but only when the CD4 count is low or the viral load is high. Age, race, and gender are risk factors can t be changed, but many other risk factors can be changed: 4 High blood pressure Cigarette smoking High cholesterol Poor diet Physical inactivity and obesity Diabetes Carotid artery disease or other artery disease Heart rhythm disorders Sickle-cell disease HIV-positive people with any of these conditions should work with their HIV provider to treat or control them. And people with HIV should take their antiretrovirals regularly as directed by their provider to reach a high CD4 count and an undetectable viral load. This study shows that doing so could lower stroke risk, in addition to the many other health benefits that come with good control of HIV infection. References 1. Marcus JL, Leyden WA, Chao CR, et al. HIV infection and incidence of ischemic stroke. AIDS. 2014;28: American Stroke Association. Types of stroke American Stroke Association. Impact of stroke (stroke statistics) American Stroke Association. What stroke risk factors can be changed, treated, or controlled? SubHomePage.jsp November 2014 HIV Treatment Alerts 41

42 Article 11 High blood pressure, high cholesterol often not well controlled in large HIV group A high percentage of HIV-positive people in a New York City HIV clinic with high blood pressure (hypertension*) and high low-density lipoprotein (LDL) cholesterol were getting treated for those two important heart disease risk factors. 1 But much lower percentages of these people reached blood pressure or LDL cholesterol targets with treatment. As people with HIV infection live longer because of antiretroviral therapy, age-related illnesses like cardiovascular disease have become an important cause of sickness and death. Research shows that people with HIV infection have a twice higher heart attack rate than people without HIV. 2 Researchers who conducted this new study of hypertension and LDL cholesterol (sometimes called bad cholesterol ) suggested three reasons why people with HIV have a higher cardiovascular disease rate than people without HIV: Changes in body functions caused by HIV itself, such as body fat changes, insulin resistance, high blood pressure, and abnormal lipids (including LDL cholesterol) Abnormal lipids (including LDL cholesterol) resulting from treatment with certain antiretrovirals Longer life with HIV infection, so people with HIV are living to an age at which cardiovascular disease is more common Over the past 10 years, more research has focused on cardiovascular disease rates and risk factors in HIVpositive people. But little work has addressed two important questions: (1) how often are HIV-positive people with high blood pressure or high LDL cholesterol treated for those conditions, and (2) how often do HIVpositive people treated for high blood pressure or high LDL cholesterol reach treatment targets? To address those questions, researchers conducted this study of more than 4000 HIV-positive adults in care at a large New York City HIV center. How the study worked. The study took place at New York City s Mount Sinai Roosevelt and St. Luke s Institute for Advanced Medicine HIV Clinics, which treat many thousands of people with HIV infection. This study involved HIV-positive people at least 20 years old who were not pregnant or transgendered. The study excluded pregnant and transgendered people because lipid and blood pressure levels may change during pregnancy or gender reassignment treatment. People were receiving care at some point from 2008 through For each study participant, the researchers reviewed electronic medical records to collect basic information (like age and race) and data on clinical conditions, medications, and lab values. They used the most recent lab values for this analysis, most importantly blood pressure and LDL cholesterol. The research team used standard methods to classify all study participants as having a low, medium, or high cardiovascular risk (see note 3). LDL cholesterol goals were below 160 mg/dl for low-risk people, below 130 mg/dl for medium-risk people, and below 100 mg/dl for high-risk people. The researchers defined hypertension as taking drugs for hypertension or having blood pressure at or above 140/90 mm Hg. They set the treatment goal as a blood pressure reading below 140/90 mm Hg. Finally, the investigators used standard statistical methods to identify predictors of reaching the LDL cholesterol goal and the blood pressure goal. *Words in bold are defined in the Technical Word List at the end of this issue of HIV Treatment Alerts. 42 November 2014 HIV Treatment Alerts

43 What the study found. The study involved 4278 people with HIV infection, 1083 (25%) of them women. Age averaged 46 years and ranged from 20 to 87. While 45% of participants in this New York City group were black, 35% were Hispanic, and 14% white. Most people (60%) used Medicaid, the government health insurance for low-income people. Most got infected with HIV during sex either between men (42%) or between men and women (34%); 9% got infected while injecting drugs. Only 117 people (2.7%) had heart disease in the past, but 311 (7.3%) had diabetes. Almost one third of study participants (31%) were overweight, while 30% were obese. The researchers classified 73% of people as having low cardiovascular risk, while 23% had medium risk and only 4% had high risk. Most people (87.5%) were taking antiretroviral therapy. Among people taking antiretrovirals, 67% had a viral load below 200 copies. CD4 count for all study participants averaged 468. About one third of study participants (35%) had high LDL ( bad ) cholesterol, including 37% of men and 31% of women. High LDL cholesterol was somewhat more frequent in Hispanics (40%) and whites (37%) than in blacks (30%). Almost everyone with high LDL cholesterol (90%) received treatment for this condition, and 75% of those treated reached the treatment target. Similar proportions of men and women (76% and 74%) reached their LDL cholesterol treatment goal (Figure 1). Hispanics (78%) and whites (78%) reached their target somewhat more often than blacks (70%). People with a low cardiovascular risk (90%) reached their LDL cholesterol treatment target more often than people at medium risk (75%) or high risk (56%). LDL cholesterol treatment targets are lower (harder to reach) with medium cardiovascular risk than with low cardiovascular risk. And people with high cardiovascular risk have the toughest LDL treatment goal. Overall, 43% of study participants including 43% of men and 43% of women had high blood pressure. Rates of high blood pressure were similar in blacks (47%), whites (43%), and Hispanics (40%). Among people with hypertension, 75% got treated; a higher proportion of women than men got treated (82% versus 73%). While 77% of blacks and Hispanics with hypertension got treated, 65% of whites with hypertension received treatment. Only 57% of people treated for hypertension reached their treatment goal (Figure 2), including 45% of women and 42% of men. Hypertension treatment goals were reached by 49% of Hispanics, 42% of whites, and 39% of blacks. Goals were reached by 54% of people with high cardiovascular risk, 59% with medium risk, and 56% with low risk. HIV-positive people who reached LDL cholesterol treatment goal Figure 1. High proportions of HIV-positive people in a New York City group with high LDL cholesterol reached treatment targets. Compared with Hispanics and whites, blacks had a lower response rate. And people with high cardiovascular (CVD) risk had lower response rates than people with low or medium cardiovascular risk. November 2014 HIV Treatment Alerts 43

44 HIV-positive people who reached blood pressure treatment goal Figure 2. Only 57% of HIV-positive people in a large New York City group reached blood pressure treatment targets. Response rates were best in Hispanics, lower in whites, and lowest in blacks. Cardiovascular (CVD) risk (low, medium, or high) did not affect response to high blood pressure treatment. Statistical analysis that considers several risk factors at the same time identified five independent predictors of reaching the LDL cholesterol target with treatment and two predictors of reaching the blood pressure target with treatment. Factors predicting reaching LDL cholesterol goal: Every 1 year older age: 2% lower chance Smoking: 42% lower chance Previous coronary heart disease: 53% lower chance Previous coronary heart disease equivalent 3 : 46% lower chance Viral load at or above 200 copies: 66% higher chance Factors predicting reaching blood pressure goal: Viral load at or above 200 copies: 27% lower chance Taking antiretrovirals: 66% higher chance What the results mean for you. This study found that one third to almost one half of adults in a New York City HIV clinic had high LDL cholesterol or high blood pressure. Although most people with high LDL cholesterol or high blood pressure were getting treated for these conditions, 25% had not reached established LDL cholesterol goals and 43% had not reached blood pressure goals. High blood pressure (hypertension) and high LDL cholesterol make serious heart disease more likely in people with and without HIV infection. The Centers for Disease Control and Prevention (CDC) estimates that one third of people in the United States have high blood pressure and about one third have high cholesterol. Thus the high blood pressure rate in this New York City HIV group is similar to the rate in the whole US population, but the high LDL cholesterol rate in this HIV group is much higher than in the general population. Because people with HIV infection have a higher risk of cardiovascular disease than people in the general population, 2 they should make a special effort to control conditions that can lead to heart disease, like high blood pressure and high LDL cholesterol. The CDC lists several heart disease risk factors (Table 1), most of which can be avoided or treated. 44 November 2014 HIV Treatment Alerts

45 Table 1. Heart disease risk factors Conditions High cholesterol High blood pressure Diabetes LDL cholesterol in this New York City HIV group reached the LDL goal set by US experts. But proportions reaching these goals differed by overall heart disease risk. While 90% of people with low risk reached their goal, 75% with medium risk reached their goal, and only 56% with high risk reached their goal. Behavior Smoking Diets with too much fat, cholesterol, or salt Physical inactivity Obesity Drinking too much alcohol Heart disease in close family member Father, mother, brother, or sister It is important to note that the classification system used to determine cardiovascular risk level for these patients was based on the general public and was not specific to people with HIV. The researchers believe that if HIV status were considered, more people with HIV would be classified as having medium and high risk. Older people, smokers, and people who already had heart disease or a heart-related disease like diabetes were all less likely to reach their LDL cholesterol target. And these people are among those with the greatest need for controlling cholesterol along with risk factors like smoking and diabetes. Source: Centers for Disease Control and Prevention. Heart disease risk factors. Overall only 57% of people treated for high blood pressure reached the goal of blood pressure below 140/90 mm Hg. Results of this study underline the importance of (1) getting tested for cholesterol and blood pressure, (2) getting treated if cholesterol or blood pressure levels are too high, and (3) reaching treatment goals for cholesterol and blood pressure. Three quarters of people with high Several drug therapies and nondrug therapies effectively lower LDL cholesterol and blood pressure. It s very important for all HIV-positive people especially those with other heart disease risk factors to work with their provider to get LDL cholesterol and blood pressure levels down to goal levels. References 1. Myerson M, Poltavskiy E, Armstrong EJ, Kim S, Sharp V, Bang H. Prevalence, treatment, and control of dyslipidemia and hypertension in 4278 HIV outpatients. J Acquir Immune Defic Syndr. 2014;66: Grinspoon SK, Grunfeld C, Kotler DP, et al. State of the science conference: initiative to decrease cardiovascular risk and increase quality of care for patients living with HIV/AIDS: executive summary. Circulation. 2008;118: Low risk = 0 or 1 cardiovascular risk factors plus a 10-year risk below 10%; medium risk = 2 or more cardiovascular risk factors plus a 10-year risk below 10% or 10% to 20%; high risk = coronary heart disease or coronary heart disease equivalent (diabetes, peripheral artery disease, ischemic stroke, carotid artery disease, and abdominal aortic aneurysm) or 10-year risk above 20%. (Goff DC Jr, Bertoni AG, Kramer H, et al. Dyslipidemia prevalence, treatment, and control in the Multi-Ethnic Study of Atherosclerosis (MESA): gender, ethnicity, and coronary artery calcium. Circulation. 2006;113: ) November 2014 HIV Treatment Alerts 45

46 Article 12 Osteoporosis and fracture risk higher with HIV plus HCV than without People infected with both HIV and hepatitis C virus (HCV) had higher risks of osteoporosis* (low bone mineral density) and fracture (a broken bone) than people infected only with HIV or infected with neither HIV nor HCV, according to a combined analysis of 15 studies. 1 Traditional risk factors including smoking and drinking alcohol also made osteoporosis or fractures more likely. Previous research links both HIV infection and HCV infection to lower bone mineral density and to fracture. The authors of this new study noted that 184 million people across the world have HCV infection, and 35 million have HIV. In studies of HIV-infected individuals in the United States and Europe, 20% to 30% also had HCV infection. 2-4 Some research shows that infection with both HIV and HCV boosts the risk of fracture more than HIV or HCV alone. 5,6 To get a better understanding of the risk of osteoporosis and fracture with HIV plus HCV, a US team searched for studies that addressed these issue and analyzed their combined results. How the study worked. The authors of this study searched three electronic databases for studies on osteoporosis or fracture in people with both HIV and HCV infection. They also searched for studies presented at key meetings on HIV, HCV, and bone disease up to Studies had to focus on people at least 18 years old and had to have a comparison group of people infected only with HIV or people with neither HIV nor HCV infection. Studies had to establish osteoporosis by bone mineral density measured by DXA scans. Next the investigators analyzed relevant findings from studies that met their requirements for being included in this study. The analysis had several goals: (1) establish the prevalence of osteoporosis in HIV/HCV-coinfected people, (2) calculate an odds ratio to determine chances of osteoporosis in HIV/HCV-coinfected people compared with uninfected people or people infected only with HIV, (3) establish the incidence (new-diagnosis rate) of fracture in HIV/HCV-coinfected people, (4) calculate an incidence rate ratio to determine fracture risk in HIV/HCV-coinfected people compared with uninfected people or people infected only with HIV. Finally, the researchers analyzed the individual studies they found to identify risk factors for osteoporosis and fracture in people coinfected with HIV and HCV. What the study found. The researchers found 15 studies that met their requirements for being included in this analysis. Nine studies focused on osteoporosis in people with HIV/HCV, and 6 studies focused on fractures. Of the 15 studies, 9 took place in the United States, 2 in France, and 1 each in Denmark, Italy, Spain, and Taiwan. Four studies included only women and 1 included only men. The number of people in each study ranged from 22 in a study of women past the menopause to 36,950 in a study of the US Medicaid population. Among HIV/HCV-infected people in the 9 osteoporosis studies, from 5.4% to 45% had osteoporosis. When the researchers combined results, they determined a combined osteoporosis prevalence of 22%. The combined odds ratio figuring chances of osteoporosis in people with HIV/HCV versus people with only HIV was That means people with HIV/HCV had a 63% greater chance of osteoporosis than people infected only *Words in bold are defined in the Technical Word List at the end of this issue of HIV Treatment Alerts. 46 November 2014 HIV Treatment Alerts

47 Fracture risk with HIV/HCV vs HIV alone or neither HIV nore HCV Figure 1. Combining results of 6 studies, researchers calculated fracture (Fx) risk with HIV/HCV coinfection versus (1) HIV alone (first five cones) and (2) neither HIV nor HCV (last cone). They figured fracture risk in all studies addressing one comparison or the other. For the comparison of HIV/HCV with HIV alone, they also figured fracture risk for studies that included (1) all fractures, (2) only traumatic fractures, and (3) only fragility fractures. with HIV. The researchers repeated that analysis after excluding the study of 22 postmenopasual women, and results were about the same. Combining results of the 6 fracture studies, the researchers determined that overall fracture incidence was 1.77 times higher with HIV/HCV coinfection than with HIV infection alone (Figure 1). In studies that considered all fractures or just traumatic/high-energy fractures, the combined fracture rate was twice higher with HIV/HCV coinfection than with HIV alone (Figure 1). In studies of fragility/low-energy fractures, the combined fracture rate was 1.7 times higher with HIV/HCV coinfection than with HIV alone (Figure 1). In studies that compared fracture incidence in people with HIV/HCV versus people with neither infection, the overall combined fracture rate was almost 3 times higher with HIV/HCV than with neither infection (Figure 1). Next the researchers went through all 15 studies to pick out independent predictors of osteoporosis or fracture in people with HIV/HCV infection. Independent predictors are risk factors linked to a higher or lower chance of osteoporosis or fracture regardless of whatever other risk factors a person has. Older age and lower body mass index (weight measured as kilograms per height in meters squared) predicted both osteoporosis and fracture in several studies (Table 1). Other frequent predictors of osteoporosis were infection with HCV or hepatitis B virus (HBV), smoking, using heroin or methadone, and being past the menopause. Other frequent predictors of fracture were HCV, white race, alcohol or substance abuse, and advanced liver disease indicated by cirrhosis (liver scarring) or hepatic decompensation. November 2014 HIV Treatment Alerts 47

48 Table 1. Independent predictors of osteoporosis or fracture in 15 studies of people with HIV/HCV Osteoporosis predictors Fracture predictors Lower BMI: 5 studies Older age: 4 studies HCV or HBV: 4 studies Heroin or methadone use: 3 studies Smoking: 2 studies Being past menopause: 2 studies Protease inhibitor or antiretroviral use: 2 studies HCV: 4 studies Older age: 4 studies White race: 2 studies Lower BMI: 2 studies Alcohol or substance abuse: 2 studies Advanced liver disease: 2 studies BMI, body mass index (weight in kilograms divided by height in meters squared). (Illustrations from Servier Medical Art. What the results mean for you. This combined analysis of 15 studies found that infection with both HIV and HCV raises the risk of osteoporosis or fracture more than 60% compared with people infected only with HIV. Fracture risk was even higher in HIV/HCV-coinfected people when compared with people who have neither HIV nor HCV infection. The osteoporosis rate of 22% in HIV/HCV-infected people when the researchers combined 9 osteoporosis studies is much higher than rates of 5% to 15% in people infected only with HIV or only with HCV. A high proportion of HIV-positive people in the United States from 20% to 30% also have HCV infection. 2-4 Because declining bone mineral density and broken bones are more frequent with than without HIV, everyone with HIV infection should avoid or modify risk factors for osteoporosis or fracture (Table 1). Findings of this study underline the special importance of avoiding or modifying those risk factors by people infected with both HIV and HCV. Some risk factors like older age and white race cannot be changed. But others can. Among the independent risk factors in Table 1, those that can be changed are lower body mass index (a person can be too thin), smoking cigarettes, and abusing alcohol or illegal drugs like heroin. People not already infected with hepatitis B virus (HBV) can avoid infection by getting the HBV vaccine. The researchers who did this study also advised HIV providers to counsel their patients about getting enough calcium and vitamin D, exercising, and preventing falls. 7 HCV infection affects the liver and causes severe liver damage if left untreated. This analysis confirmed that advanced liver disease raises the fracture risk in people with HCV and HIV. Research shows that treatment of HCV infection increases bone mineral density and decreases fracture risk, 8,9 but this has not been studied in people with HIV. Several new HCV drugs have become available in the past few years, and studies show that these drugs can cure HCV infection in people with HIV as often as in people without HIV. Everyone with HIV should be tested for HCV, and HCV-positive people should discuss HCV therapy with their provider. US experts on HIV and bone disease recommend DXA scanning (a painless test like an x-ray) for all HIVpositive people over 50 years old. 10 The researchers who conducted this HIV/HCV study believe their findings confirm that recommendation for people with HIV and for those with both HIV and HCV. 48 November 2014 HIV Treatment Alerts

49 References 1. Dong HV, Cortés YI, Shiau S, Yin MT. Osteoporosis and fractures in HIV/hepatitis C virus coinfection: a systematic review and meta-analysis. AIDS. 2014;28: Rockstroh JK, Mocroft A, Soriano V, et al. Influence of hepatitis C virus infection on HIV-1 disease progression and response to highly active antiretroviral therapy. J Infect Dis. 2005;192: Sherman KE, Rouster SD, Chung RT, Rajicic N. Hepatitis C virus prevalence among patients infected with human immunodeficiency virus: a cross-sectional analysis of the US adult AIDS Clinical Trials Group. Clin Infect Dis. 2002;34: Staples CT Jr, Rimland D, Dudas D. Hepatitis C in the HIV (human immunodeficiency virus) Atlanta V.A. (Veterans Affairs Medical Center) Cohort Study (HAVACS): the effect of coinfection on survival. Clin Infect Dis. 1999;29: Lo Re V 3rd, Guaraldi G, Leonard MB, et al. Viral hepatitis is associated with reduced bone mineral density in HIV-infected women but not men. AIDS. 2009;23: Young B, Dao CN, Buchacz K, Baker R, Brooks JT, Investigators HIVOS. Increased rates of bone fracture among HIV-infected persons in the HIV Outpatient Study (HOPS) compared with the US general population, Clin Infect Dis. 2011;52: National Osteoporosis Foundation. Clinician s guide to prevention and treatment of osteoporosis. Washington, DC: National Osteoporosis Foundation Hofmann WP, Kronenberger B, Bojunga J, et al. Prospective study of bone mineral density and metabolism in patients with chronic hepatitis C during pegylated interferon alpha and ribavirin therapy. J Viral Hepat. 2008;15: Arase Y, Suzuki F, Suzuki Y, et al. Virus clearance reduces bone fracture in postmenopausal women with osteoporosis and chronic liver disease caused by hepatitis C virus. J Med Virol. 2010;82: McComsey GA, Tebas P, Shane E, et al. Bone disease in HIV infection: a practical review and recommendations for HIV care providers. Clin Infect Dis. 2010;51: November 2014 HIV Treatment Alerts 49

50 Adherence means taking medications, such as antiretrovirals, according to the schedule set by your healthcare provider. Antiretrovirals are drugs used to treat HIV infection. Antiretroviral therapy (often abbreviated ART) usually means treatment with three or more antiretrovirals. Cardiovascular disease includes diseases that affect the heart and vascular (blood vessel) system. Common cardiovascular diseases are myocardial infarction (heart attack) and stroke. CD4 cells are one type of cell necessary to fight infection. HIV attacks CD4 cells, so CD4 counts fall when a person is not taking antiretrovirals to control HIV or when treatment fails. CD4 count measures the number of CD4 cells in a cubic millimeter of blood. People with CD4 counts below 500 have a harder time controlling infections. The risk of uncontrolled infection gets higher as the CD4 count gets lower. Diabetes is a lifelong disease in which there are high levels of sugar in the blood. Diabetes can be caused by too little insulin, resistance to insulin, or both. Hypertension is high blood pressure against artery walls as blood circulates through the body. Blood pressure below 120/80 mm Hg (millimeters of mercury) is considered normal; /80-89 is considered prehypertension; and 140/90 or higher is considered hypertension. The immune system is the collection of cells and organs that help the body fight infections and cancers. Incidence is the rate at which an event (such as infection with a virus) occurs over a defined period of time (such as 1 year). Insulin is a hormone that helps the body use glucose for energy. When the body does not produce enough insulin or the cells ignore insulin (insulin resistance), glucose builds up in blood instead of going into cells and may cause diabetes. (American Diabetes Association. Diabetes basics. Type 2. Insulin resistance is the inability of body cells to let insulin help them take up glucose from the blood. Insulin resistance can lead to high glucose levels in blood, which can result in diabetes. A median is the number above which half of all the numbers recorded lie, and below which half of all the numbers recorded lie. A median age of 45 years mean half of the people being studied are under 45 and half are over 45. The median number differs from the average (or mean) number. For example, in the series 1, 3, 8, 9, and 14, the median is 8 because half of the other numbers lie above it and the remaining half lie below. But the average of 1, 3, 8, 9, and 14 is 7. MSM are men who have sex with men (gay or bisexual men). MSW are men who have sex with women (heterosexual men) Myocardial infarction, or heart attack, is heart cell damage or death caused by lowered blood supply to the heart. Artery blockage with plaques can lower blood supply to the heart. Osteoporosis is a condition characterized by progressive loss of bone density, thinning of bone tissue and increased vulnerability to fractures, according to the National Institutes of Health. A person-year is a measure of time used in medical studies. A single person-year is 1 year lived by 1 person. An HIV infection rate of 2 per 100 person-years means 2 of 100 people are infected within a year. PrEP stands for pre-exposure prophylaxis, which means taking antiretroviral drugs before becoming infected with HIV to protect the body from HIV. Prevalence is a rate measured at a single point in time, for example, at the beginning of a study. A stroke occurs when blood stops flowing to part of the brain. Viral load is the number of HIV particles in a milliliter of blood or another body fluid, such as semen or cerebrospinal fluid. WSM are women who have sex with men (heterosexual women). 50 November 2014 HIV Treatment Alerts

51 If you have HIV, what are the 25 most important things to know? And do! The Center for AIDS Information & Advocacy (a program of Legacy Community Health Services) answers those questions in an easy-to-read booklet prepared with the help of some of the best HIV providers working today. Get your copy online at

52 Bryan Hlavinka, Chairperson Beth Bruce, Vice-Chairperson Jani C. Lopez, Secretary Glen Bauguss, Treasurer Ian Rosenberg, At-Large/Executive Committee Sehba Ali Beryl Basham Glen Bauguss Beth Bruce Dr. Abigail Caudle Victor Cordova Shaun Davis David L. Fox, Ph.D Cyndy Garza Roberts Bryan Hlavinka Alton LaDay Jani C. Lopez Glenna Pierpont Ian Rosenberg Jay Sears Lauren Soliz John C. Sheptor Executive Director Katy Caldwell Chief Medical Officer Ann Barnes, M.D., M.P.H. Chief Development Officer Chree Boydstun Chief Financial Officer Ben Glisan Chief Strategy Officer Michael Kopper Chief Marketing & Communications Officer Kimberly Paulus A publication of The Center for AIDS Information & Advocacy A program of Legacy Community Health Services P.O. Box 66308, Houston, TX Articles Combined HIV prevention strategies work best for 3 gay or straight couples Most HIV-positive people in US not having sex 8 without condoms Normal life expectancy with CD4 count above 200 and 12 low viral load after 1 year of ART AIDS deaths down, cancer deaths up in large 16 US/European HIV group Liver and heart deaths down in Europe/US HIV study, 21 but not non-aids cancers Higher CD4 count during antiretroviral therapy tied to 24 lower virus-related cancer rate Smoking lies behind higher risk of virus-related cancers 27 in people with HIV Web-based smoke-ending program doubles quitting rate 31 in people with HIV Changes in CD4 count and viral load before antiretroviral 35 therapy begins Stroke rate higher with than without HIV but not if 38 viral load low or CD4s high High blood pressure, high cholesterol often not well 42 controlled in large HIV group Osteoporosis and fracture risk higher with HIV plus 46 HCV than without Definitions 50 Board and Staff 52 NOVEMBER 2014 ISSN Chief Operating Officer Jeff Perry