Clinical Policy Title: Pre-exposure prophylaxis for HIV prevention

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1 Clinical Policy Title: Pre-exposure prophylaxis for HIV prevention Clinical Policy Number: Effective Date: May 1, 2016 Initial Review Date: February 17, 2016 Most Recent Review Date: November 16, 2017 Next Review Date: November 2018 Related policies: None. Policy contains: Acquired Immunodeficiency Syndrome (AIDS) Human Immunodeficiency Virus (HIV) Pre-exposure prophylaxis for HIV/AIDS prevention Highly active antiretroviral therapy (HAART) ABOUT THIS POLICY: Select Health of South Carolina has developed clinical policies to assist with making coverage determinations. Select Health of South Carolina s clinical policies are based on guidelines from established industry sources, such as the Centers for Medicare & Medicaid Services (CMS), state regulatory agencies, the American Medical Association (AMA), medical specialty professional societies, and peerreviewed professional literature. These clinical policies along with other sources, such as plan benefits and state and federal laws and regulatory requirements, including any state- or plan-specific definition of medically necessary, and the specific facts of the particular situation are considered by Select Health of South Carolina when making coverage determinations. In the event of conflict between this clinical policy and plan benefits and/or state or federal laws and/or regulatory requirements, the plan benefits and/or state and federal laws and/or regulatory requirements shall control. Select Health of South Carolina s clinical policies are for informational purposes only and not intended as medical advice or to direct treatment. Physicians and other health care providers are solely responsible for the treatment decisions for their patients. Select Health of South Carolina s clinical policies are reflective of evidence-based medicine at the time of review. As medical science evolves, Select Health of South Carolina will update its clinical policies as necessary. Select Health of South Carolina s clinical policies are not guarantees of payment. Coverage policy Select Health of South Carolina considers the use of pre-exposure prophylaxis for prevention of Human Immunodeficiency Virus (HIV) / Acquired Immunodeficiency Syndrome (AIDS) to be clinically proven and therefore medically necessary when (Günthard 2016, Centers for Disease Prevention and Control 2014, Molina 2015, Buchbinder 2014, Baeten 2012, Plosker 2013): Daily tenofovir disoproxil fumarate and emtricitabine are used singly or in combination therapy as preexposure prophylaxis to prevent HIV/AIDS in persons at high risk defined as follows: Individual is in an ongoing sexual relationship with an HIV-infected partner. Gay or bisexual men who have had sex without a condom or been diagnosed with a sexually transmitted infection within the past six months, and not in a mutually monogamous relationship with a partner who recently tested HIV-negative. A heterosexual man or woman who does not always use condoms when having sex with partners known to be at risk for HIV (for example, injecting drug users or bisexual male partners of unknown HIV status), and is not in a mutually-monogamous relationship with a partner who recently tested HIV-negative. Anyone who has, within the past six months, injected illicit drugs and shared equipment or been 1

2 in a treatment program for injection drug use. Limitations: All other uses of pre-exposure prophylaxis for HIV prevention are not medically necessary. Alternative covered services: Routine patient evaluation and management by a network healthcare provider Background Human Immunodeficiency Virus (HIV)/Acquired Immunodeficiency Syndrome (AIDS) has killed more than 25 million people since it was first diagnosed in 1981, and despite significant strides in its management remains a major threat to human health worldwide. However, with the introduction of greater public awareness, the expanded use of preventive measures, and the introduction of highly active antiretroviral therapy (HAART) the prevalence and incidence of HIV has declined globally over the last decade. Antiretroviral chemoprophylaxis before exposure is a promising approach for the prevention of human immunodeficiency virus (HIV) acquisition. Conflicting results have been reported among studies, probably due to challenges of adherence to a daily regimen. Even though combination antiretroviral therapy provides stable viral suppression, it is not devoid of undesirable side effects, especially in persons undergoing long-term treatment. It also has limitations with respect to the emergence of multidrug resistance. Some experts believe that for maximum effect pre-exposure prophylaxis should be targeted to the subpopulations that account for the largest proportion of infections (population-attributable fraction) and for whom the number needed to treat to prevent infection is lowest (e.g., the Pre-Exposure Prophylaxis Initiative trial). Others claim that increased sexual risk taking by individuals using effective HIV prevention strategies, like pre-exposure prophylaxis (e.g., the Pre-Exposure Prophylaxis study), could offset the benefits of HIV prevention. Finally, natural products such as plant-originated compounds and plant extracts may offer novel anti-hiv compounds with new modes of action, acceptable toxicity and less likelihood of agent resistance. The World Health Organization (WHO) has suggested there is a need to evaluate traditional medicine, particularly medicinal plants and other natural products that may yield effective and affordable therapeutic and prophylactic agents for HIV/AIDS. Although there are many instances of traditional uses of plants to treat various diseases, knowledge of herbal remedies used to manage HIV/AIDS are as yet still scanty, vague and poorly documented. Searches 2

3 Select Health of South Carolina searched PubMed and the databases of: UK National Health Services Center for Reviews and Dissemination. Agency for Healthcare Research and Quality s National Guideline Clearinghouse and other evidence-based practice centers. The Centers for Medicare & Medicaid Services (CMS). We conducted searches on October 11, Searched terms were: "HIV pre-exposure prophylaxis (MeSH)"," protection against HIV-1 infection (MeSH)" and "HIV prevention." We included: o Systematic reviews, which pool results from multiple studies to achieve larger sample sizes and greater precision of effect estimation than in smaller primary studies. Systematic reviews use predetermined transparent methods to minimize bias, effectively treating the review as a scientific endeavor, and are thus rated highest in evidence-grading hierarchies. o Guidelines based on systematic reviews. o Economic analyses, such as cost-effectiveness, and benefit or utility studies (but not simple cost studies), reporting both costs and outcomes sometimes referred to as efficiency studies which also rank near the top of evidence hierarchies. Findings Günthard (2016), writing on behalf of the International Antiviral Society-USA Panel offered consensus recommendations for the use of antiretroviral drugs to prevent HIV infection in adults aged 18 years. Daily tenofovir disoproxil fumarate/emtricitabine was recommended for use as preexposure prophylaxis to prevent HIV infection in persons at high risk (CDC 2014); and when indicated, postexposure prophylaxis should be started as soon as possible after exposure. Preexposure prophylaxis, when used effectively, can sustain HIV suppression and can prevent new HIV infection. With these treatment regimens, survival rates among HIV-infected adults who are retained in care can approach those of uninfected adults. The Centers for Disease Prevention and Control issued guidelines for pre-exposure prophylaxis for HIV prevention in The guidelines urge consideration of the practice where: Individual is in an ongoing sexual relationship with an HIV-infected partner. Gay or bisexual men who have had sex without a condom or been diagnosed with a sexually transmitted infection within the past six months, and not in a mutually monogamous relationship with a partner who recently tested HIV-negative. A heterosexual man or woman who does not always use condoms when having sex with partners known to be at risk for HIV (for example, injecting drug users or bisexual male partners of unknown HIV status), and is not in a mutually-monogamous relationship with a partner who recently tested HIV-negative. 3

4 Anyone who has, within the past six months, injected illicit drugs and shared equipment or been in a treatment program for injection drug use. Seidman (2016) studied the use of pre-exposure prophylaxis for women who were at substantial risk of HIV preconception and during pregnancy and lactation. Twenty-seven women (median age 27 years) made up the study cohort. One-half of the women had unstable housing, 22 percent of the women had ongoing intimate partner violence, and 22 percent of the women had active substance use. Twenty-six women had a male partner living with human immunodeficiency virus, and 1 woman had a male partner who had sex with men. Of the partners who were living with HIV, 73 percent (19/26) were receiving antiretroviral therapy, and 42 percent (11/26) had documented viral suppression. Of the women who presented and were offered pre-exposure prophylaxis, 67 percent women (16/24) chose to take it. Median length of time on pre-exposure prophylaxis was 30 weeks (interquartile range, 20-53). The authors noted that women frequently chose to use pre-exposure prophylaxis for HIV prevention when it was offered preconception and during pregnancy and lactation; but there remain deficiencies in screening for women who are at risk of HIV for pre- and postexposure prophylaxis eligibility and gaps in care before and during pregnancy and lactation. Postpartum women are particularly vulnerable in this regard. A randomized, placebo-controlled trial (Marrazzo 2015) to assess daily treatment with oral tenofovir disoproxil fumarate, oral tenofovir emtricitabine, or 1% tenofovir vaginal gel as preexposure prophylaxis against HIV-1 infection in women in South Africa, Uganda, and Zimbabwe. HIV-1 testing was performed monthly, and plasma tenofovir disoproxil fumarate levels were assessed quarterly. Of 12,320 women who were screened, 5029 were enrolled in the study. The rate of retention in the study was 91% during 5509 person-years of follow-up. A total of 312 HIV-1 infections occurred; the incidence of HIV-1 infection was 5.7 per 100 person-years. In the modified intention-to-treat analysis, the effectiveness was 49.0% with tenofovir disoproxil fumarate (hazard ratio for infection, 1.49; 95% confidence interval [CI], 0.97 to 2.29), 4.4% with tenofovir emtricitabine (hazard ratio, 1.04; 95% CI, 0.73 to 1.49), and 14.5% with tenofovir gel (hazard ratio, 0.85; 95% CI, 0.61 to 1.21). In a random sample, tenofovir was detected in 30%, 29%, and 25% of available plasma samples from participants randomly assigned to receive tenofovir disoproxil fumarate, tenofovir emtricitabine, and tenofovir gel, respectively. Independent predictors of tenofovir detection included being married, being older than 25 years of age, and being multiparous. Detection of tenofovir in plasma was negatively associated with characteristics predictive of HIV-1 acquisition. Elevations of serum creatinine levels were seen more frequently among participants randomly assigned to receive oral tenofovir emtricitabine than among those assigned to receive oral placebo (1.3% vs. 0.2%, P=0.004). The authors observed no significant differences in the frequencies of other adverse events; however, none of the drug regimens evaluated reduced the rates of HIV-1 acquisition in an intention-to-treat analysis. Adherence to study drugs was low. A double-blind, randomized trial (Molina 2015) studied antiretroviral therapy for preexposure HIV-1 prophylaxis among men who have unprotected anal sex with men. Participants were randomly assigned to take a combination of tenofovir disoproxil fumarate and emtricitabine or placebo before and after sexual activity. All participants received risk-reduction counseling and condoms and were regularly 4

5 tested for HIV-1 and HIV-2 and other sexually transmitted infections. Of the 414 participants who underwent randomization, 400 who did not have HIV infection were enrolled (199 in the tenofovir emtricitabine group and 201 in the placebo group). All participants were followed for a median of 9.3 months (interquartile range, 4.9 to 20.6). A total of 16 HIV-1 infections occurred during follow-up, 2 in the tenofovir emtricitabine group (incidence, 0.91 per 100 person-years) and 14 in the placebo group (incidence, 6.60 per 100 person-years), a relative reduction in the tenofovir emtricitabine group of 86% (95% confidence interval, 40 to 98; P=0.002). Participants took a median of 15 pills of tenofovir emtricitabine or placebo per month (P=0.57). The rates of serious adverse events were similar in the two study groups. In the tenofovir emtricitabine group, as compared with the placebo group, there were higher rates of gastrointestinal adverse events (14% vs. 5%, P=0.002) and renal adverse events (18% vs. 10%, P=0.03). The authors concluded that the use of tenofovir emtricitabine before and after sexual activity provided protection against HIV-1 infection in men who have sex with men. The treatment was associated with increased rates of gastrointestinal and renal adverse events. The iprex study (Buchbinder 2014) was a randomized controlled efficacy trial of pre-exposure prophylaxis with coformulated tenofovir disoproxil fumarate and emtricitabine in 2499 men who have sex with men and transgender women. Participants aged 18 years or older who were male at birth were enrolled from 11 trial sites in Brazil, Ecuador, Peru, South Africa, Thailand, and the USA. Participants were randomly assigned (1:1) to receive either a pill with active pre-exposure prophylaxis or placebo, taken daily. The aim of the study was to establish the association between demographic and risk behavior during screening and subsequent seroconversion among placebo recipients and to calculate the population-attributable fraction and the number needed to treat for risk behavior subgroups. Patients were enrolled between July 10, 2007, and Dec 17, 2009, and were followed up until Nov 21, Of the 2499 men who have sex with men and transgender women in the Pre-Exposure Prophylaxis Initiative trial, 1251 were assigned to pre-exposure prophylaxis and 1248 to placebo. 83 of 1248 patients in the placebo group became infected with HIV during follow-up. Participants reporting receptive anal intercourse without a condom seroconverted significantly more often than those reporting no anal sex without a condom. The overall population-attributable fraction for men who have sex with men and transgender women reporting receptive anal intercourse without a condom was 64% (prevalence 60%). Most of this risk came from receptive anal intercourse without a condom with partners with unknown serostatus; by contrast, the population-attributable fraction for receptive anal intercourse without a condom with an HIV-positive partner was 1 percent. The overall number needed to treat per year for the cohort was 62 (95% CI ). Numbers needed to treats were lowest for men who have sex with men and transgender women self-reporting receptive anal intercourse without a condom (number needed to treat 36), cocaine use (12), or a sexually transmitted infection (41). Having one partner and insertive anal sex without a condom had the highest number needed to treats (100 and 77, respectively). The authors concluded that pre-exposure prophylaxis may be most effective at a population level if targeted toward men who have sex with men and transgender women who report receptive anal intercourse without a condom, even if they perceive their partners to be HIV negative. Substance use history and testing for sexually transmitted infection may inform individual decisions to start pre-exposure prophylaxis. 5

6 A randomized, three-arm trial (Baeten 2012) of oral antiretroviral Pre-Exposure Prophylaxis studied heterosexual couples from Kenya and Uganda in which one member was HIV-1 seronegative and the other HIV-1 seropositive. Seronegative partners were randomly assigned to once-daily tenofovir, combination emtricitabine/tenofovir, or matching placebo and followed monthly for up to 36 months. At enrollment, HIV-1 seropositive partners were not eligible for antiretroviral therapy under national guidelines. All couples received standard HIV-1 treatment and prevention services, including individual and couples risk-reduction counseling and condoms. In all, 4758 couples were enrolled; for 62%, the HIV-1 seronegative partner was male. For HIV-1 seropositive participants, the median CD4 count was 495 cells/μl (interquartile range ). Of 82 post-randomization HIV-1 infections, 17 were among those assigned tenofovir (incidence 0.65 per 100 person-years), 13 among those assigned emtricitabine/tenofovir (incidence 0.50 per 100 person-years), and 52 among those assigned placebo (incidence 1.99 per 100 person-years), indicating a 67% relative reduction in HIV-1 incidence for tenofovir (95% CI 44 to 81, p<0.001) and 75% for emtricitabine/tenofovir (95% CI 55 to 87, p<0.001). HIV-1 protective effects of emtricitabine/tenofovir and tenofovir were not significantly different (p=0.23), and both study medications significantly reduced HIV-1 incidence in both men and women. The rate of serious medical events was similar across the study arms. The authors concluded that oral tenofovir and emtricitabine/tenofovir provided substantial protection against HIV-1 acquisition in heterosexual men and women, with comparable efficacy of tenofovir and emtricitabine/tenofovir. A narrative review (De Man 2013) examined pre-exposure prophylaxis and its role in a comprehensive HIV/AIDS prevention strategy. The authors noted that several trials demonstrated the safety and the efficacy of pre-exposure prophylaxis in HIV prevention; however two large trials failed to show such efficacy. The authors opined that this was likely due to poor adherence in these trials. Pre-exposure was noted as cost-effective within certain cohorts, and could be a useful additional tool for the prevention of HIV in specific high-risk groups. The authors stated also that preventative interventions should be implemented in a way that deals with issues such as ensuring high adherence and ensuring that preexposure prophylaxis does not detract from, but complements, other more fundamental elements of HIV prevention programs. Pre-Exposure Prophylaxis (Mugwanya 2013) undertook a longitudinal analysis of data from a doubleblind, randomized, placebo-controlled trial of daily oral pre-exposure prophylaxis among HIV-uninfected partners of heterosexual HIV-serodiscordant couples (n=3163, 18 years of age). Efficacy for HIV prevention was publicly reported in July 2011, and participants continued monthly follow-up thereafter. The authors used regression analyses to compare the frequency of sex-unprotected by a condom-during the 12 months after compared with the 12 months before July 2011, to assess whether knowledge of pre-exposure prophylaxis efficacy for HIV prevention caused increased sexual risk behavior. Data was collected over person-months from 3024 HIV-uninfected individuals (64% male). The average frequency of unprotected sex with the HIV-infected study partner was 59 per 100 person-months before unmasking versus 53 after unmasking; and demonstrated no immediate change (p=0.66) or change over time (p=0.25) after July, The authors identified a significant increase in unprotected sex with outside partners after July, 2011, but the effect was small (average of 6.8 unprotected sex acts per year 6

7 vs 6.2 acts in a predicted counterfactual scenario had patients remained masked, p=0.04). Compared with before July, 2011, the authors noted no significant increase in incident sexually transmitted infections or pregnancy after July, A narrative review (Plosker 2013) noted that once-daily administration of emtricitabine/tenofovir was approved in the United States for pre-exposure prophylaxis in conjunction with safer sex practices to reduce the risk of sexually acquired HIV-1 in high-risk adults who are not infected. The authors noted, that to date, results of four large, randomized, double-blind, placebo-controlled, multicentre trials with emtricitabine/tenofovir as pre-exposure prophylaxis have been published and three of these studies showed statistically significant reductions in the number of individuals with emergent HIV-1 infection when emtricitabine/tenofovir was compared with placebo over the 1 2-year study periods. Efficacy (i.e., risk reduction relative to placebo) was 44% in the Pre-Exposure Prophylaxis Initiative trial in men who have sex with men, 75 % in the Partners Pre-Exposure Prophylaxis study in heterosexual HIV-1- serodiscordant couples and 62 % in the tenofovir-2 trial in heterosexual men and women. The fourth study in heterosexual women did not show a statistically significant difference between emtricitabine/tenofovir and placebo, although low adherence rates may have been a factor. No unexpected adverse events were reported in the trials. The authors also offered that it is important to monitor the long-term safety of emtricitabine/tenofovir (e.g. renal function, bone mineral density) as well as adherence, cost and the potential for development of drug resistance. They concluded that, if used appropriately in selected high-risk individuals, preexposure prophylaxis with emtricitabine/tenofovir represents an important additional strategy to reduce the spread of HIV-1 infection. A randomized, double-blind, placebo-controlled trial (Van Damme 2012), assigned 2120 HIV-negative women in Kenya, South Africa, and Tanzania to receive either a combination of tenofovir disoproxil fumarate and emtricitabine or placebo once daily. The primary objective was to assess the effectiveness of tenofovir disoproxil fumarate and emtricitabine in preventing HIV acquisition and to evaluate safety. HIV infections occurred in 33 women in the tenofovir disoproxil fumarate and emtricitabine group (incidence rate, 4.7 per 100 person-years) and in 35 in the placebo group (incidence rate, 5.0 per 100 person-years), for an estimated hazard ratio in the tenofovir disoproxil fumarate and emtricitabine group of 0.94 (95% confidence interval, 0.59 to 1.52; P=0.81). The proportions of women with nausea, vomiting, or elevated alanine aminotransferase levels were significantly higher in the tenofovir disoproxil fumarate and emtricitabine group (P=0.04, P<0.001, and P=0.03, respectively). Rates of drug discontinuation because of hepatic or renal abnormalities were higher in the tenofovir disoproxil fumarate and emtricitabine group (4.7%) than in the placebo group (3.0%, P=0.051). Less than 40% of the HIV-uninfected women in the tenofovir disoproxil fumarate and emtricitabine group had evidence of recent pill use at visits that were matched to the HIV-infection window for women with seroconversion. The study was stopped early, on April 18, 2011, because of lack of efficacy. The authors concluded that prophylaxis with tenofovir disoproxil fumarate and emtricitabine did not significantly reduce the rate of HIV infection and was associated with increased rates of side effects, as compared with placebo. Despite 7

8 substantial counseling efforts, drug adherence appeared to be low. A randomized controlled study (Grant 2010) assigned 2499 HIV-seronegative men or transgender women who have sex with men to receive a combination of two oral antiretroviral drugs, emtricitabine and tenofovir disoproxil fumarate, or placebo once daily. All subjects received HIV testing, risk-reduction counseling, condoms, and management of sexually transmitted infections. The study subjects were followed for 3324 person-years (median, 1.2 years; maximum, 2.8 years). Of these subjects, 10 were found to have been infected with HIV at enrollment, and 100 became infected during follow-up (36 in the emtricitabine/tenofovir group and 64 in the placebo group), indicating a 44% reduction in the incidence of HIV (95% confidence interval, 15 to 63; P = 0.005). In the emtricitabine/tenofovir group, the study drug was detected in 22 of 43 of seronegative subjects (51%) and in 3 of 34 HIV-infected subjects (9%) (P<0.001). Nausea was reported more frequently during the first 4 weeks in the emtricitabine/tenofovir group than in the placebo group (P<0.001). The two groups had similar rates of serious adverse events (P = 0.57). Detectable blood levels strongly correlated with the prophylactic effect. The authors concluded that oral emtricitabine/tenofovir provided protection against the acquisition of HIV infection among the subjects. Summary of clinical evidence: Citation Günthard (2016) Antiretroviral Drugs for Treatment and Prevention of HIV Infection in Adults Centers for Disease Prevention and Control (2014) Pre-exposure prophylaxis for the prevention of HIV infection in the United States Content, Methods, Recommendations The International Antiviral Society-USA Panel offered consensus recommendations for the use of antiretroviral drugs to prevent HIV infection in adults aged 18 years. Daily tenofovir disoproxil fumarate/emtricitabine was recommended for use as preexposure prophylaxis to prevent HIV infection in persons at high risk; and when indicated, postexposure prophylaxis should be started as soon as possible after exposure. Preexposure prophylaxis, when used effectively, can sustain HIV suppression and can prevent new HIV infection. With these treatment regimens, survival rates among HIV-infected adults who are retained in care can approach those of uninfected adults. The Centers for Disease Prevention and Control issued guidelines for pre-exposure prophylaxis for HIV prevention in The guidelines urge consideration of the practice where: o Individual is in an ongoing sexual relationship with an HIV-infected partner. o Gay or bisexual men who have had sex without a condom or been diagnosed with a sexually transmitted infection within the past six months, and not in a mutually monogamous relationship with a partner who recently tested HIV-negative. o A heterosexual man or woman who does not always use condoms when having sex with partners known to be at risk for HIV (for example, injecting drug users or bisexual male partners of unknown HIV status), and is not in a mutuallymonogamous relationship with a partner who recently tested HIV-negative. 8

9 Citation Seidman (2016) Use of HIV preexposure prophylaxis during the preconception, antepartum and postpartum periods at two United States medical centers. Marrazzo (2015) Tenofovir-Based Preexposure Prophylaxis for HIV Infection among African Women. Content, Methods, Recommendations o Anyone who has, within the past six months, injected illicit drugs and shared equipment or been in a treatment program for injection drug use. Trial of the use of pre-exposure prophylaxis for women who were at substantial risk of HIV preconception and during pregnancy and lactation. Twenty-seven women (median age 27 years) made up the study cohort. One-half of the women had unstable housing, 22 percent of the women had ongoing intimate partner violence, and 22 percent of the women had active substance use. Twenty-six women had a male partner living with human immunodeficiency virus, and 1 woman had a male partner who had sex with men. Of the partners who were living with human immunodeficiency virus, 73 percent (19/26) were receiving antiretroviral therapy, and 42 percent (11/26) had documented viral suppression. Of the women who presented and were offered pre-exposure prophylaxis, 67 percent women (16/24) chose to take it. Median length of time on pre-exposure prophylaxis was 30 weeks (interquartile range, 20-53). A randomized, placebo-controlled trial to assess daily treatment with oral tenofovir, oral tenofovir emtricitabine, or 1% tenofovir vaginal gel as preexposure prophylaxis against HIV-1 infection in women in South Africa, Uganda, and Zimbabwe. HIV-1 testing was performed monthly, and plasma tenofovir gel levels were assessed quarterly. Of 12,320 women who were screened, 5029 were enrolled in the study. The rate of retention in the study was 91% during 5509 person-years of follow-up. A total of 312 HIV-1 infections occurred; the incidence of HIV-1 infection was 5.7 per 100 person-years. In the modified intention-to-treat analysis, the effectiveness was 49.0% with tenofovir (hazard ratio for infection, 1.49; 95% confidence interval [CI], 0.97 to 2.29), 4.4% with tenofovir emtricitabine (hazard ratio, 1.04; 95% CI, 0.73 to 1.49), and 14.5% with tenofovir gel (hazard ratio, 0.85; 95% CI, 0.61 to 1.21). In a random sample, tenofovir gel was detected in 30%, 29%, and 25% of available plasma samples from participants randomly assigned to receive tenofovir tenofovir emtricitabine, and tenofovir gel, respectively. Independent predictors of tenofovir gel detection included being married, being older than 25 years of age, and being multiparous. Detection of tenofovir gel in plasma was negatively associated with characteristics predictive of HIV-1 acquisition. Elevations of serum creatinine levels were seen more frequently among participants randomly assigned to receive oral tenofovir emtricitabine than among those assigned to receive oral placebo (1.3% vs. 0.2%, P=0.004). The authors observed no significant differences in the frequencies of other adverse events; however, none of the drug regimens evaluated reduced the rates of HIV-1 acquisition in an intention-to-treat analysis. Adherence to study drugs was low. 9

10 Citation Molina 2015 On-Demand Preexposure Prophylaxis in Men at High Risk for HIV-1 Infection Buchbinder 2014 Content, Methods, Recommendations A double-blind, randomized trial studied antiretroviral therapy for preexposure HIV-1 prophylaxis among men who have unprotected anal sex with men. Participants were randomly assigned to take a combination of tenofovir disoproxil fumarateand emtricitabine or placebo before and after sexual activity. All participants received risk-reduction counseling and condoms and were regularly tested for HIV-1 and HIV-2 and other sexually transmitted infections. Of the 414 participants who underwent randomization, 400 who did not have HIV infection were enrolled (199 in the tenofovir - emtricitabine group and 201 in the placebo group). All participants were followed for a median of 9.3 months (interquartile range, 4.9 to 20.6). A total of 16 HIV-1 infections occurred during follow-up, 2 in the tenofovir - emtricitabine group (incidence, 0.91 per 100 person-years) and 14 in the placebo group (incidence, 6.60 per 100 person-years), a relative reduction in the tenofovir - emtricitabine group of 86% (95% confidence interval, 40 to 98; P=0.002). Participants took a median of 15 pills of tenofovir - emtricitabine or placebo per month (P=0.57). The rates of serious adverse events were similar in the two study groups. In the TDF-FTC group, as compared with the placebo group, there were higher rates of gastrointestinal adverse events (14% vs. 5%, P=0.002) and renal adverse events (18% vs. 10%, P=0.03). The authors concluded that the use of tenofovir - emtricitabine before and after sexual activity provided protection against HIV-1 infection in men who have sex with men. The treatment was associated with increased rates of gastrointestinal and renal adverse events. HIV pre-exposure prophylaxis in men who have sex with men and transgender women The Pre-Exposure Prophylaxis Initiative study was a randomized controlled efficacy trial of pre-exposure prophylaxis with coformulated tenofovir disoproxil fumarate and emtricitabine in 2499 men who have sex with men and transgender women. Participants aged 18 years or older who were male at birth were enrolled from 11 trial sites in Brazil, Ecuador, Peru, South Africa, Thailand, and the United States. Participants were randomly assigned (1:1) to receive either a pill with active pre-exposure prophylaxis or placebo, taken daily. The aim of the study was to establish the association between demographic and risk behavior during screening and subsequent seroconversion among placebo recipients and to calculate the population-attributable fraction and number needed to treat for risk behavior subgroups. Patients were enrolled between July 10, 2007, and Dec 17, 2009, and were followed up until Nov 21, Of the 2499 MSM and transgender women in the Pre-Exposure Prophylaxis Initiative trial, 1251 were assigned to pre-exposure prophylaxis and 1248 to placebo. 83 of 1248 patients in the placebo group became infected with HIV during follow-up. Participants reporting receptive anal intercourse without a condom seroconverted significantly more often than those reporting no anal sex without a condom. The overall population-attributable fraction for men who have sex with men and transgender women reporting receptive anal intercourse without a condom was 64% 10

11 Citation Baeten 2012 Antiretroviral Prophylaxis for HIV-1 Prevention among Heterosexual Men and Women De Man 2013 Content, Methods, Recommendations (prevalence 60%). Most of this risk came from receptive anal intercourse without a condom with partners with unknown serostatus; by contrast, the population-attributable fraction for receptive anal intercourse without a condom with an HIV-positive partner was 1 percent. The overall number needed to treat per year for the cohort was 62 (95% CI ). Number needed to treat were lowest for men who have sex with men and transgender women self-reporting receptive anal intercourse without a condom (number needed to treat 36), cocaine use (12), or a sexually transmitted infection (41). Having one partner and insertive anal sex without a condom had the highest number needed to treat (100 and 77, respectively). The authors concluded that pre-exposure prophylaxis may be most effective at a population level if targeted toward men who have sex with men and transgender women who report receptive anal intercourse without a condom, even if they perceive their partners to be HIV negative. Substance use history and testing for sexually transmitted infection may inform individual decisions to start pre-exposure prophylaxis. Randomized, three-arm trial of oral antiretroviral Pre-Exposure Prophylaxis studied heterosexual couples from Kenya and Uganda in which one member was HIV-1 seronegative and the other HIV-1 seropositive. Seronegative partners were randomly assigned to once-daily tenofovir, combination emtricitabine/tenofovir, or matching placebo and followed monthly for up to 36 months. At enrollment, HIV-1 seropositive partners were not eligible for antiretroviral therapy under national guidelines. All couples received standard HIV-1 treatment and prevention services, including individual and couples risk-reduction counseling and condoms. In all, 4758 couples were enrolled; for 62%, the HIV-1 seronegative partner was male. For HIV-1 seropositive participants, the median CD4 count was 495 cells/μl (interquartile range ). Of 82 post-randomization HIV-1 infections, 17 were among those assigned tenofovir (incidence 0.65 per 100 person-years), 13 among those assigned emtricitabine/tenofovir (incidence 0.50 per 100 person-years), and 52 among those assigned placebo (incidence 1.99 per 100 person-years), indicating a 67% relative reduction in HIV-1 incidence for tenofovir (95% CI 44 to 81, p<0.001) and 75% for emtricitabine/tenofovir (95% CI 55 to 87, p<0.001). HIV-1 protective effects of emtricitabine/tenofovir and tenofovir were not significantly different (p=0.23), and both study medications significantly reduced HIV-1 incidence in both men and women. The rate of serious medical events was similar across the study arms. The authors concluded that oral tenofovir and emtricitabine/tenofovir provided substantial protection against HIV-1 acquisition in heterosexual men and women, with comparable efficacy of tenofovir and emtricitabine/tenofovir. What is the place of pre-exposure prophylaxis in HIV A narrative review examined pre-exposure prophylaxis and its role in a comprehensive HIV/AIDS prevention strategy. 11

12 Citation Content, Methods, Recommendations prevention? The authors noted that several trials demonstrated the safety and the efficacy of preexposure prophylaxis in HIV prevention; however two large trials failed to show such efficacy. The authors opined that this was likely due to poor adherence in these trials. Pre-exposure was noted as cost-effective within certain cohorts, and could be a useful additional tool for the prevention of HIV in specific high-risk groups. The authors stated also that preventative interventions should be implemented in a way that deals with issues such as ensuring high adherence and ensuring that pre-exposure prophylaxis does not detract from, but complements, other more fundamental elements of HIV prevention programs. Mugwanya 2013 Sexual behavior of heterosexual men and women receiving antiretroviral preexposure prophylaxis for HIV prevention Plosker 2013 Pre-Exposure Prophylaxis undertook a longitudinal analysis of data from a double-blind, randomized, placebo-controlled trial of daily oral pre-exposure prophylaxis among HIVuninfected partners of heterosexual HIV-serodiscordant couples (n=3163, 18 years of age). Efficacy for HIV prevention was publicly reported in July 2011, and participants continued monthly follow-up thereafter. The authors used regression analyses to compare the frequency of sex-unprotected by a condom-during the 12 months after compared with the 12 months before July 2011, to assess whether knowledge of pre-exposure prophylaxis efficacy for HIV prevention caused increased sexual risk behavior. Data was collected over person-months from 3024 HIV-uninfected individuals (64% male). The average frequency of unprotected sex with the HIV-infected study partner was 59 per 100 person-months before unmasking versus 53 after unmasking; and evidenced no immediate change (p=0.66) or change over time (p=0.25) after July, The authors identified a significant increase in unprotected sex with outside partners after July, 2011, but the effect was small (average of 6.8 unprotected sex acts per year vs 6.2 acts in a predicted counterfactual scenario had patients remained masked, p=0.04). Compared with before July, 2011, the authors noted no significant increase in incident sexually transmitted infections or pregnancy after July, Emtricitabine/tenofovir disoproxil fumarate: a review of its use in HIV-1 pre-exposure prophylaxis A narrative review noted that once-daily administration of emtricitabine/tenofovir was approved in the United States for pre-exposure prophylaxis in conjunction with safer sex practices to reduce the risk of sexually acquired HIV-1 in high-risk adults who are not infected. The authors noted, that to date, results of four large, randomized, double-blind, placebocontrolled, multicentre trials with emtricitabine/tenofovir as pre-exposure prophylaxis have been published and three of these studies showed statistically significant reductions in the number of individuals with emergent HIV-1 infection when emtricitabine/tenofovir was compared with placebo over the 1 2-year study periods. Efficacy (i.e., risk reduction relative to placebo) was 44% in the Pre-Exposure Prophylaxis Initiative trial in men who have sex with men, 75 % in the Partners Pre-Exposure Prophylaxis study in heterosexual HIV-1-serodiscordant couples and 62 % in the tenofovir-2 trial in heterosexual men and women. 12

13 Citation Van Damme 2012 Preexposure Prophylaxis for HIV Infection among African Women Grant 2010 Preexposure Chemoprophylaxis for HIV Prevention in Men Who Have Sex with Men Content, Methods, Recommendations The fourth study in heterosexual women did not show a statistically significant difference between emtricitabine/tenofovir and placebo, although low adherence rates may have been a factor. No unexpected adverse events were reported in the trials. The authors also offered that it is important to monitor the long-term safety of emtricitabine/tenofovir (e.g. renal function, bone mineral density) as well as adherence, cost and the potential for development of drug resistance. They concluded that, if used appropriately in selected high-risk individuals, pre-exposure prophylaxis with emtricitabine/tenofovir represents an important additional strategy to reduce the spread of HIV-1 infection. A randomized, double-blind, placebo-controlled trial assigned 2120 HIV-negative women in Kenya, South Africa, and Tanzania to receive either a combination of tenofovir disoproxil fumarate and emtricitabine or placebo once daily. The primary objective was to assess the effectiveness of tenofovir disoproxil fumarate and emtricitabine in preventing HIV acquisition and to evaluate safety. HIV infections occurred in 33 women in the tenofovir disoproxil fumarate and emtricitabine group (incidence rate, 4.7 per 100 person-years) and in 35 in the placebo group (incidence rate, 5.0 per 100 person-years), for an estimated hazard ratio in the tenofovir disoproxil fumarate and emtricitabine group of 0.94 (95% confidence interval, 0.59 to 1.52; P=0.81). The proportions of women with nausea, vomiting, or elevated alanine aminotransferase levels were significantly higher in the tenofovir disoproxil fumarate and emtricitabine group (P=0.04, P<0.001, and P=0.03, respectively). Rates of drug discontinuation because of hepatic or renal abnormalities were higher in the tenofovir disoproxil fumarate and emtricitabine group (4.7%) than in the placebo group (3.0%, P=0.051). Less than 40% of the HIV-uninfected women in the tenofovir disoproxil fumarate and emtricitabine group had evidence of recent pill use at visits that were matched to the HIVinfection window for women with seroconversion. The study was stopped early, on April 18, 2011, because of lack of efficacy. The authors concluded that prophylaxis with tenofovir disoproxil fumarate and emtricitabine did not significantly reduce the rate of HIV infection and was associated with increased rates of side effects, as compared with placebo. Despite substantial counseling efforts, drug adherence appeared to be low. A randomized controlled study assigned 2499 HIV-seronegative men or transgender women who have sex with men to receive a combination of two oral antiretroviral drugs, emtricitabine and tenofovir disoproxil fumarate, or placebo once daily. All subjects received HIV testing, risk-reduction counseling, condoms, and management of sexually transmitted infections. The study subjects were followed for 3324 person-years (median, 1.2 years; maximum, 2.8 years). Of these subjects, 10 were found to have been infected with HIV at enrollment, and 100 became infected during follow-up (36 in the emtricitabine/tenofovir group and 64 in the 13

14 Citation Content, Methods, Recommendations placebo group), indicating a 44% reduction in the incidence of HIV (95% confidence interval, 15 to 63; P = 0.005). In the emtricitabine/tenofovir group, the study drug was detected in 22 of 43 of seronegative subjects (51%) and in 3 of 34 HIV-infected subjects (9%) (P<0.001). Nausea was reported more frequently during the first 4 weeks in the emtricitabine/tenofovir group than in the placebo group (P<0.001). The two groups had similar rates of serious adverse events (P = 0.57). Detectable blood levels strongly correlated with the prophylactic effect. The authors concluded that oral emtricitabine/tenofovir provided protection against the acquisition of HIV infection among the subjects. References Professional society guidelines/other: Günthard HF, Saag MS, Benson CA, et al. Antiretroviral Drugs for Treatment and Prevention of HIV Infection in Adults: 2016 Recommendations of the International Antiviral Society-USA Panel. JAMA. 2016;316(2): Centers for Disease Prevention and Control. Pre-exposure prophylaxis for the prevention of HIV infection in the United States. U.S. Public Health Service, Rockville MD; Peer-reviewed references: Baeten J, Donnell D, Ndase P, et al. Partners PrEP Study Team. Antiretroviral Prophylaxis for HIV-1 Prevention among Heterosexual Men and Women. N Engl J Med. 2012; 367(5): Buchbinder SP, Glidden DV, Liu AY, et al.hiv pre-exposure prophylaxis in men who have sex with men and transgender women: a secondary analysis of a phase 3 randomised controlled efficacy trial. Lancet Infect Dis. 2014;14(6): De Man J, Colebunders R, Florence E, Laga M and Kenyon C. What is the place of pre-exposure prophylaxis in HIV prevention? AIDS Rev. 2013;15(2): Grant R, Lama J, Anderson P, et al. For the iprex Study Team: Preexposure Chemoprophylaxis for HIV Prevention in Men Who Have Sex with Men. N Engl J Med. 2010; 363(27): Kesavo R, Kurapati K, Atluri V, Samikkannu T, Garcia G, and Nair M. Natural Products as Anti-HIV Agents and Role in HIV-Associated Neurocognitive Disorders (HAND): A Brief Overview. Front Microbiol. 2015; 6: Marrazzo J, Ramjee G, Richardson B, et al. For the VOICE Study Team. Tenofovir-Based Preexposure 14

15 Prophylaxis for HIV Infection among African Women. N Engl J Med 2015; 372: Molina M and Capitant D. For the ANRS IPERGAY Study Group.On-Demand Preexposure Prophylaxis in Men at High Risk for HIV-1 Infection. N Engl J Med 2015; 373: Mugwanya KK, Donnell D, Celum C, et al. Partners PrEP Study Team. Sexual behavior of heterosexual men and women receiving antiretroviral pre-exposure prophylaxis for HIV prevention: a longitudinal analysis. Lancet Infect Dis. 2013;13(12): Plosker GL. Emtricitabine/tenofovir disoproxil fumarate: a review of its use in HIV-1 pre-exposure prophylaxis. Drugs. 2013;73(3): Seidman DL, Weber S, Timoney MT, Oza KK, Mullins E, Cohan DL, Wright RL. Use of HIV pre-exposure prophylaxis during the preconception, antepartum and postpartum periods at two United States medical centers. Am J Obstet Gynecol. 2016;215(5):632.e1-632.e7. Terrazas-Aranda K, Van Herrewege Y, Lewi PJ, Van Roey J and Vanham G. In vitro pre- and post-exposure prophylaxis using HIV inhibitors as microbicides against cell-free or cell-associated HIV-1 infection. Antivir Chem Chemother. 2007;18(3): Van Damme L, Corneli A, Ahmed K, et al. Preexposure Prophylaxis for HIV Infection among African Women. N Engl J Med 2012; 367: CMS National Coverage Determination (NCDs): No NCDs identified as of the writing of this policy. Local Coverage Determinations (LCDs): No LCDs identified as of the writing of this policy. Commonly submitted codes Below are the most commonly submitted codes for the service(s)/item(s) subject to this policy. This is not an exhaustive list of codes. Providers are expected to consult the appropriate coding manuals and bill in accordance with those manuals. CPT Code Description Comment 4276F Potent antiretroviral therapy prescribed (HIV) 4271F Patient receiving potent antiretroviral therapy for less than 6 months or not receiving potent antiretroviral therapy (HIV) 4270F Patient receiving potent antiretroviral therapy for 6 months or longer (HIV) 15

16 CPT Code Description Comment 4293F Patient screened for high-risk sexual behavior (HIV) ICD-10 Code Description Comment Z11.4 Encounter for screening for human immunodeficiency virus [HIV] Z20.6 Contact with and (suspected) exposure to human immunodeficiency virus [HIV] Z29.8 Encounter for other specified prophylactic measures Z71.7 Human immunodeficiency virus [HIV] counseling Z70.0 Counseling related to sexual attitude Z72.52 High risk homosexual behavior Z72.53 High risk bisexual behavior Z Other long term (current) drug therapy HCPCS Level II Code N/A Description No applicable codes Comment 16