Information, inspiration and advocacy for people with HIV/AIDS and hepatitis C p1 p5 p6 p7 HIV CARE NEWS New drugs: dolutegravir, MK-1439, cenicriviroc, and HIV and heart health. HIV PrEP NEWS Disappointing results of PrEP in women. HIV CURE NEWS Functional cure of baby is making news. HEPATITIS C CARE NEWS Interferon-free regimen cures 100% in small study of mono-infected individuals. P.I. perspective MARCH 2013 273 Ninth Street, San Francisco, CA 94103 www.projectinform.org Reportback from the 2013 CROI (Conference on Retroviruses & Opportunistic Infections) In this issue of PI Perspective, Project Inform reports on data that was presented at this year s CROI in Atlanta, GA, from March 3 6. HIV Care News Several new experimental treatments for HIV coming forth by David Evans, Director of Research Advocacy At this year s Conference on Retroviruses and Opportunistic Infections (CROI) in Atlanta, there were several presentations about new treatments or treatment strategies that could benefit both those new to treatment as well as treatment veterans. Merck presented data on a new NNRTI (non-nucleoside reverse transcriptase inhibitor); Tobira offered new information about their entry inhibitor cenicriviroc; and researchers also suggested that NRTIs (nucleoside reverse transcriptase inhibitors) might not be needed for salvage therapy. Here s how it all stacked up. u CONTINUED: page 2 New integrase inhibitor dolutegravir continues to do well By Alan McCord, Director of Education At the 2013 Conference on Retroviruses and Opportunistic Infections (CROI), early study results show this new integrase inhibitor may be more advantageous over the current Isentress (raltegravir) and the experimental elvitegravir. The advantages include once daily dosing (Isentress is taken twice a day) and no need for a boosting drug (as it is with elvitegravir). Earlier study has shown that dolutegravir is effective against strains of HIV that are resistant to the other two integrase inhibitors. u CONTINUED: page 3
Project inform PERSPECTIVE MARCH 2013 www.projectinform.org 2 HIV Care News u CONTINUED: from page 1 Several new HIV experimental treatments coming forth MK-1439 The drug company Merck, which makes the first FDAapproved integrase inhibitor raltegravir (Isentress), now has a new second-generation NNRTI in the works called MK-1439. They presented phase Ib data at CROI. MK- 1439 may have less neurological side effects than the top-selling first-line therapy drug efavirenz (Sustiva) and also be effective against virus that has become resistant to either Sustiva or nevirapine (Viramune). The new study compared multiple doses of MK-1439 for seven days to placebo in HIV-positive study volunteers. Doses ranged from 25mg to 200mg once daily. Non-serious side effects included headache and loss of appetite. It should be noted that these kinds of side effects are commonly found with nearly any drug tested in humans. In terms of viral suppression, HIV levels were reduced almost equally by just over 1.25 logs in those taking the 25mg and the 200mg doses compared with no suppression in those taking the placebo. Further studies will be started by Merck in the near future. In a couple of years this drug may prove to become a potent first-line therapy, especially in those infected with HIV that is resistant to efavirenz or nevirapine or those who are treatment experienced. Cenicriviroc Cenicriviroc is an entry inhibitor that works against two immune co-receptors on CD4 cells, one of which HIV uses to enter cells, called CCR5, and a second called CCR2 that is not involved in cell infection. HIV uses CCR5 to infect many CD4 cells. CCR2 is implicated in many inflammatory diseases including rheumatoid arthritis. This 48-week phase IIb study compared cenicriviroc to efavirenz (found in Sustiva and Atripla). A total of 143 people who were new to treatment were randomized into one of three groups: 100mg cenicriviroc + Truvada; 200mg cenicriviroc + Truvada; or efavirenz + Truvada (Atripla). The dosing schedule was called double-dummy since the people who took cenicriviroc also took a dummy efavirenz dose and those on efavirenz also took a dummy cenicriviroc dose. Overall, the three arms of the study were quite similar. After 24 weeks, 76% of those who took 100mg cenicriviroc, 73% of those on 200mg cenicrivoric and 71% taking efavirenz had undetectable viral loads <50 copies. There was a slight difference in efficacy based on how high a person s starting viral load was, but the overall numbers in the high viral load group are too small to make strong conclusions. For those with a viral load <100,000, cenivcriviroc was about 80% effective regardless of dose compared with 71% effective with efavirenz. For those with viral loads >100,000, efavirenz had higher numbers with 75% reaching undetectable compared to 60% on 100mg of cenicriviroc and 50% on 200mg of cenicriviroc. Protocol defined treatment failures were 12% with 100mg cenicriviroc and 16% with 200mg cenicriviroc and 11% with efavirenz. While people who stopped the study due to side effects were 0% with 100mg cenicriviroc and 2% in the 200mg cenicriviroc arm, it climbed to 18% in the efavirenz arm. In terms of the CCR2 activity, which deals with HIVrelated activation, there was a greater reduction in soluble CD14, an indication of HIV-related inflammation and relocation of gut bacteria into the bloodstream, in those taking cenivriviroc compared to those on efavirenz. ACTG OPTIONS Study In the AIDS Clinical Trials Group (ACTG) OPTIONS study, the aim was to determine if the standard practice of keeping people with multiclass drug resistance on a backbone of NRTI therapy was even necessary, even if their virus was largely resistant to those drugs. A total of 360 people enrolled in the study from 2009 to 2011. Three-quarters were male and most were black or Hispanic. Everyone had multiclass drug resistance. All of the participants had genotypic resistance tests and were guided to a regimen that seemed optimal against their strains of virus. The new regimens had to include darunavir (Prezista), enfuvirtide (Fuzeon), etra- u CONTINUED: page 3
3 HIV Care News u CONTINUED: from page 2 Several new HIV experimental treatments coming forth virine (Intelence), maraviroc (Selzentry), raltegravir (Isentress) or boosted tipranavir (Aptivus). People were then randomized to whether they would include NRTIs in their new regimen or not. Overall success rates were fairly high and statistically similar in both arms. Only 26% of those without an NRTI in their regimen had treatment failure, while 30% in those with NRTIs in their regimen failed treatment. Of note, there was a statistically significant difference in the number of deaths while on therapy. Among those who included an NRTI in their regimen, six people died, while none in the NRTI-free regimen died. In a couple of cases where people were taking NRTIs the researchers judged that the NRTIs could have contributed to the deaths. In all, this study could substantially change the way we look at treatment of multi-class resistant HIV. u CONTINUED: from page 1 New integrase inhibitor dolutegravir continues to do well This small study in 205 people who had never been on treatment compared three doses of dolutegravir (50mg, 25mg, 10mg) to Sustiva. Average CD4 count was 324 and about 20% had viral loads above 100,000. After 96 weeks, average CD4 count gains were similar between the dolutegravir arms (339) and Sustiva (301). Undetectable viral loads were seen at 88% on the 50mg dose, 78% on 25mg, 79% on 10mg and 72% on Sustiva. Fewer general side effects occurred on dolutegravir (11%) compared to Sustiva (24%). No resistance was seen in any of the participants. Although these results come from the dose-ranging studies of dolutegravir, the drug is now in later-stage studies of treatment-experienced people and those going on treatment for the first time. It s possible that we could see this drug approved by the FDA in 2013, and perhaps combined into a full-regimen pill. HIV and your heart by David Evans, Director of Research Advocacy There were a number of presentations and posters on HIV and the heart this year at the Conference on Retroviruses and Opportunistic Infections (CROI) in Atlanta. These ranged from studies showing that a common scoring system for heart attack risk may under-estimate risk in people with HIV; studies showing higher rates of heart disease in younger HIV-positive people; data about whether cholesterol-lowering statin drugs can reduce mortality; and the fact that people with HIV aren t taking aspirin to protect their hearts to the same degree as similar HIV-negative people. HIV and Cardiovascular Disease (CVD) One of the most common ways to score your risk of having a heart attack comes from the years long Framingham heart study. The Framingham Risk Score (FRS) takes into account your weight, blood pressure, cholesterol levels and smoking history among other things. People with a lower score (under 10%) have a lower risk of having a heart attack in the coming 10 years than people with a higher score (usually 20% or more). Previous studies have found that people with HIV might be more prone to heart attacks than HIV-negative people who have similar heart attack risks and that HIV itself may play a role in this. What hasn t been known is whether the FRS is adequate at predicting which people with HIV are at the highest risk of a heart attack. There are also concerns that people with hepatitis C virus (HCV) may also be missed by the FRS. To determine this, researchers looked at data from an arce of male veterans enrolled in a Veterans Affairs study from 2001 through 2009. Veterans with HIV and u CONTINUED: page 4
4 HIV Care News u CONTINUED: from page 3 HIV and your heart HCV were more likely to have drug and alcohol abuse histories than those without either disease. They were also less likely to use cholesterol lowering drugs. In short, researchers found that the FRS was about equally good at predicting heart attack risks in men infected with HCV alone and in non-infected men, but that it under-estimated the risk in men with either HIV alone or those co-infected with both HIV and HCV. This is not the only study to find that the FRS may be underestimating heart attack risks in HIV-positive individuals. To date, a replacement or modification of the FRS specific to people with either HIV or HCV has not been widely validated though some newer scoring systems exist. A different study among HIV-positive veterans involved in the Veterans Aging Cohort Study (VACS) looked not only at heart attacks, but also end-stage kidney disease and non-aids related cancers. As for heart attacks, there was evidence that HIV-positive veterans had an 81% increased risk compared to similar HIV-negative veterans. HIV-positive men also had greater amounts of plaque in their arteries. Researchers associated with the study hypothesized that HIV-related inflammation might be driving the increased risk. Given a study earlier in the year showing that smoking alone outweighs HIV in terms of risk of death, it is even more critical that people with HIV seek to quit smoking, moderate their alcohol use, eat healthfully and get ongoing exercise. Statins to Reduce Death Risk? Though one study at CROI found that statins were effective at reducing markers of immune inflammation something that should be helpful in reducing the risk of CVD and other illnesses two larger studies of statin use by HIV-positive individuals did not find a statistically significant improvement in CVD or all-cause mortality from statin use. In both cases, especially with more potent statins such as atorvastatin and rosuvastatin, there was a trend toward lower rates of heart disease, but not quite large enough to be truly meaningful. Other studies, however, have suggested beneficial effects of statins on heart disease in HIV-positive people. In the larger study, from the Veterans cohort, using statin therapy showed a trend toward both a decreased risk of non-aids cancers and death. Is HIV More Potent Than Aspirin? Finally, one study looked into aspirin use and its effects in people living with HIV in a large Boston health system. Although aspirin has well-proven beneficial effects on heart health in HIV-negative people, less is known about its effect in HIV-positive individuals. Researchers in this study looked at two things. First, they examined how often aspirin was used by study participants. Second, they analyzed whether low-dose aspirin had a beneficial effect on heart attacks. The results moved in opposite directions. While aspirin use was much lower among HIV-positive men than HIV-negative men or women (HIV-positive women had similar rates to HIV-negative women), there didn t seem to be any positive influence of aspirin on the risk of having a heart attack. Experts say that what s needed is a randomized study of aspirin in HIVpositive people at risk of CVD or inclusion of more people with HIV in CVD studies. Fair Pricing Coalition Panel Discussion from the 2013 CROI For a wrap-up of the most notable news from CROI, check out FPC s video at www.youtube.com/ watch?v=sgh4mteizsq.
5 PrEP News Disappointing results of PrEP for women by David Evans, Director of Research Advocacy A second clinical trial studying pre-exposure prophylaxis (PrEP) in women in Africa has found that the intervention was no more helpful than a placebo in preventing new HIV infections, but that once again this was highly likely due to the fact that very few women were using the products as directed. These results were reported at the 2013 Conference on Retroviruses and Opportunistic Infections (CROI) in Atlanta. As with the previous trial showing poor results, called FEM PrEP, the VOICE trial enrolled women of childbearing age in several African countries. With VOICE, just over 5,000 women were enrolled in three African countries. The women, with an average age of 25 and with nearly 80% being unmarried, were randomized to one of the following arms: take Truvada [tenofovir (TDF) + emtricitabine (FTC)] take TDF pill alone take a placebo pill take a vaginal TDF gel take a vaginal placebo gel The gel and tenofovir arms were stopped early for futility, meaning that the results were already so poor as to render efficacy unlikely, in 2011. The Truvada arms continued through the end of the study in August 2012. In the final analysis, VOICE researchers found that there were 15% fewer infections in the TDF gel arm than the placebo arm. There were 4% more infections in the Truvada arm than the placebo arm and nearly 50% more infections in the TDF arm. None of these reached statistical significance, however. Though 90% of the women in all of the arms claimed that they took their pills or used their gel, an analysis of blood and vaginal fluids revealed that less than 30% were using the drugs at any time point. What s more, because the blood and vaginal results only meant that the pills or gels were used within the last several days there is no way to know whether those with adequate blood or vaginal fluid levels were using the products daily as directed. In all, both poor adherence and infections were more likely in younger women and unmarried women. Attention must now turn to both better technologies for PrEP, including long-acting formulations available by injection or in vaginal rings. These would be far less vulnerable to poor adherence. Research focus must also be directed at better understanding adherence challenges and technology preferences of women in Africa. We should be cautious, however, about assuming that these results can be extrapolated to all women or to women in the United States. Both the PARTNERS PrEP and TDF2 studies found relatively high rates of adherence and efficacy in women in Africa.
6 HIV Cure News Researchers report functional cure of baby, but questions remain by David Evans, Director of Research Advocacy Researchers reported a case of a functional cure of a small child on Monday at the 2013 Conference on Retroviruses and Opportunistic Infections (CROI) in Atlanta. Dr. Deborah Persaud from Johns Hopkins University explained that a child, who appeared to be infected 30 hours after birth, and started on antiretroviral (ARV) therapy, has now been off therapy for roughly 12 months without the return of virus. The child s HIV status was confirmed at 30 and 31 hours with both a DNA and an RNA test and at this time point it had nearly 20,000 copies of HIV in blood. Dr. Persaud explained that when children have virus at this early state it is strongly assumed that the baby was infected before the birth process. The child was started immediately on a prophylactic regimen of ARVs and once infection was confirmed switched to a treatment regimen including lopinavir/ritonavir (Kaletra). The child remained on treatment until 18 months of age, at which point the child s guardian withdrew treatment and disappeared from care. Case workers tracked down the child several months later and the baby reentered care at 23 months. At that time point viral load tests and an antibody test were performed. The viral load test was undetectable and the antibody test was negative. The baby had remained off therapy since. Subsequent analysis revealed small traces of HIV DNA in cells taken from the blood. Dr. Persaud, during her presentation, stated that while the available evidence suggested a functional cure, there is still a chance that the baby s virus will return eventually. During the session, one researcher complained about the term functional cure, because in adults this usually is accompanied by detectable immune cells that are strongly oriented toward recognizing and killing HIV. In this case, the baby has none of those cells. Another presentation earlier in the conference also suggested that when the viral reservoir is reduced to a very small size, but not eliminated, it could result in the virus remaining undetectable in blood for many months before climbing again. In subsequent conversations with researchers and activists after the session, they expressed some skepticism that a functional cure can ever be resolutely proved in this case, in part, because lingering questions will remain about whether the baby was ever truly productively infected with HIV before clearing most of the virus without the need for ARV control. There was also some consternation about announcing this as a cure of any type at this early time point. Nevertheless, this is an encouraging case report and further cases are now being sought and discussions are beginning on how best to test the theory that very early therapy in infants may result in a cure of some kind.
7 hcv Hepatitis C Care News Interferon-free HCV regimen with sofosbuvir cures 100% in small study By Alan McCord, Director of Education On Monday at the 2013 Conference on Retroviruses and Opportunistic Infections (CROI), results from the ELEC- TRON study showed 100% of its participants who had hepatitis C (but not HIV) had a sustained virologic response (SVR) from taking two new drugs (sofosbuvir, ledipasvir) along with ribavirin for 12 weeks. A total of 25 people new to treatment and 9 who were null responders (NPs, never reached undetectable HCV on earlier treatment) have so far maintained undetectable viral loads up to 4 weeks after treatment. Given the significant side effects from regimens with interferon, this all-oral combination offers people with hepatitis C a simpler and shorter regimen with fewer side effects. Everyone who enrolled had genotypes 1a and 1b and showed no signs of cirrhosis. About half were male, average age was 48, and nearly all were Caucasian. Average HCV viral loads were high at the start of the study and ranged between 6 and 7 logs. Surprisingly, only 9 of the treatment-naïve and none of the NPs had the favorable IL28B genotype of CC a genetic mutation that favors a person reaching an SVR. As seen in the chart below, all but 1 person had reached an undetectable HCV viral load by week 4. The study will continue to follow these individuals through 12 weeks after stopping treatment to see if the SVRs continue. Common side effects included headache (4%), depression (8%) and mild-to-moderate anemia (20%). More troublesome side effects included bloody urine (36%, mostly women), severe anemia (20%) and increased coagulation (8%). One person stopped the study due to severe side effects. Moving forward, the company that s developing these two new drugs will study them combined as a single-dose pill. Other studies will look at the optimal duration of treatment and the possibility of taking ribavirin out of the regimen as well as treating people with cirrhosis. The results to undetectable HCV viral load: Time of treatment New to treatment (25) Null responders (9) Week 1 11 (44%) 0 Week 2 22 (88%) 4 (44%) Week 4 25 (100%) 8 (88%) Week 12 25 (100%) 9 (100%) SVR at week 4 25 (100%) 9 (100%)