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IAS 2015: New NNRTI Doravirine Suppresses HIV as Well as Efavirenz But with Fewer CNS Side Effects

Merck's next-generation NNRTI doravirine (formerly known as MK-1439) was found to be as effective as efavirenz at suppressing HIV replication, but half as many study participants taking doravirine experienced drug-related adverse events -- in particular central nervous system (CNS) side effects -- and were less likely to stop treatment prematurely, according to study findings reported this week at the at the 8th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention this week in Vancouver.

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IAS 2015: No HIV Infections from Partners with Fully Suppressed Virus in Landmark Trial

Final follow up of the HPTN 052 study of treatment as prevention shows no evidence of HIV transmission from people with fully suppressed viral load to their partners, 4 years after the first results from thestudy demonstrated that early HIV treatment reduced the risk of HIV transmission by 96%, according to a report by Professor Myron Cohen at the 8th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention this week in Vancouver.

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IAS 2015: Non-Daily PrEP Provides Extra Options, But Adherence Often Better with Daily Dosing

For some people in some settings, less frequent pre-exposure prophylaxis (PrEP) regimens with doses linked to sexual activity are feasible, with high numbers of sexual acts protected by PrEP, according to studies presented Monday at the 8th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention in Vancouver. This may give people who want to use PrEP and their doctors additional options, allowing people to find a pattern of taking PrEP that best suits them. But the studies also found that more people are able to adhere to daily PrEP than non-daily regimens. Further, the actual effectiveness of non-daily regimens remains uncertain.

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The studies presented Monday were in part inspired by the French Ipergay study, so far the only study to demonstrate that a schedule of non-daily PrEP, with Truvada (tenofovir/emtricitabine) doses taken before and after sex, could be effective (there were 86% fewer infections). However, Ipergay was conducted in a population of gay men who tended to have sex quite frequently. To prevent transmission during anal sex, 4 doses a week appear to be almost equivalent to 7 doses. But it's possible that people who have sex less frequently -- and so take pills less frequently -- will have lower levels of the drug in the body that are not protective.

Presented in Vancouver in a late-breaker session on Monday afternoon, HPTN 067/ADAPT is a trio of 3 randomized trials investigating the feasibility and acceptability of different PrEP regimens with 3 distinct populations in Bangkok, Harlem (New York City), and Cape Town. The studies give insights into patterns of PrEP use and adherence, but were not designed to answer questions about effectiveness. Larger Phase 3 trials would be needed to do that.

The researchers found that in a group of well-educated, motivated Thai gay men, each of the 3 PrEP regimens tested were feasible, acceptable, and likely to protect against most exposures to HIV. The non-daily regimens required far fewer pills to be taken.

Challenging social circumstances were more commonly experienced by participants in Harlem and Cape Town. Adherence was generally not as good in these 2 locations. Moreover, the daily regimen resulted in better adherence and likely protection against HIV than the non-daily options.

The HPTN 067 Studies

In each city, around 180 participants were recruited and randomly allocated to receive 3 TruvadaPrEP regimens:

  • Daily dosing;
  • Twice-weekly dosing + an extra dose after sex;
  • Event-driven dosing (1 dose up to 48 hours before sex, another 2 hours after sex).

Follow up continued for 6 months. Adherence was measured by providing PrEP in pill bottles, which send an electronic signal when they are opened. Weekly phone calls to the participants collected information about recent sexual activity, which was correlated with the data on when pills were taken.

The populations in the 3 cities had different social, cultural, and demographic characteristics. The researchers expected these to influence the acceptability of different regimens -- they did not expect to find one regimen that would be appropriate everywhere.

  • Bangkok, Thailand: 176 men who have sex with men and 2 transgender women. Most were university educated, few were unemployed, and the average age was 31. Participants had sex an average of once a week.
  • Harlem, New York City: 176 men who have sex with men and 3 transgender women. Over two-thirds were unemployed and over two-thirds were black. Average age was 30. Participants had sex an average of once a week.
  • Cape Town, South Africa: 179 women. Four-fifths were unemployed, a similar proportion were unmarried, and the average age was 26.

Results

Across all sites, adherence was somewhat higher for the daily rather than the non-daily Truvada doses. For example, in Bangkok, 85% of daily doses, 79% of twice-weekly doses, and 65% of event-driven doses were taken as prescribed. In Harlem, the respective figures were 65%, 46%, and 41%.

The primary analysis was of the percentage of reported sexual acts which were protected by PrEP, with doses taken both before and after sex.

  • In Bangkok, the daily regimen protected 85% of sexual acts, the twice-weekly regimen protected 84%, and the event-driven regimen protected 74%.
  • In Harlem, the daily regimen protected 66% of sexual acts, the twice-weekly regimen protected 47%, and the event-driven regimen protected 52%.
  • In Cape Town, the daily regimen protected 75% of sexual acts, the twice-weekly regimen protected 56%, and the event-driven regimen protected 52%.

The missed doses were most often those that were meant to be taken after sex, both in the twice-weekly and event-driven regimensA. Participants often found it difficult to take this dose when they were still with a sexual partner or were away from home.

The researchers also tested blood samples twice during the study to see if tenofovir could be detected, restricting the analysis to those participants who reported having sex in the previous week. In Bangkok, over 90% of participants in each arm had detectable drug, with no significant differences between arms.

In contrast, Harlem and Cape Town participants were more likely to have detectable drug if they had been asked to take PrEP daily.

A total of 6 people prescribed PrEP became HIV positive -- 5 in Cape Town, 1 in Harlem -- but each had low or negligible levels of drug in their body.

One hoped-for advantage with non-daily regimens is that by reducing the number of pills, side effects may be less frequent. However, the data so far do not show statistically significant differences in the experience of side effects between arms. This may be partly due to the limited number of people in each arm and the short period of follow up. The side effects that were reported (dizziness, headaches, nausea, diarrhea etc.) were mild and mostly experienced during the first 2 months of taking PrEP.

But the non-daily regimens did require considerably fewer Truvada tablets, which could make providing PrEP more affordable. Sexual behavior did not differ between PrEP regimens.

Conclusions

Presenting the Bangkok data, Timothy Holtz summed up several advantages of daily regimens: clearly proven to be effective, likely to offer more protection, more forgiving of missed doses, and helping people develop habits of daily pill-taking.

But he said that non-daily PrEP could be an option for those men who have sex somewhat infrequently and know in advance when they are likely to do so. The findings suggest some flexibility in the way in which PrEP can be prescribed.

Robert Grant, who led the HPTN 067/ADAPT studies, told a press conference that PrEP needs to be adaptable to the different circumstances of people’s lives. And non-daily use is happening anyway: "People do choose how to use PrEP, when to take it and when not to take it," he said.

SEE ALSO:

IAS 2015: Pros and Cons of PrEP -- Volunteers Recount their Experiences in ADAPT Study

IAS 2015: ADAPT Study Shows PrEP Feasibility [VIDEO]

7/21/15

References

T Holtz, Achitwarakor, ME Curlin,et al. HPTN 067/ADAPT study: a comparison of daily and non-daily pre-exposure prophylaxis dosing in Thai men who have sex with men, Bangkok, Thailand. 8th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention. Vancouver, July 19-22, 2015.Abstract MOAC0306LB.

S Mannheimer, Y Hirsch-Moverman, A Loquere, et al. HPTN 067/ADAPT study: a comparison of daily and intermittent pre-exposure prophylaxis (PrEP) dosing for HIV prevention in men who have sex with men and transgender women in New York City. 8th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention. Vancouver, July 19-22, 2015. Abstract MOAC0305LB.

R Grant et al. HPTN 067 ADAPT methods and results from women in Cape Town. 8th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention. Vancouver, July 19-22, 2015. MOSY0103.

IAS 2015: Opioid Substitution Therapy Combined with HIV Treatment Saves More Lives

Providing opioid substitution therapy (OST) along with antiretroviral therapy (ART) to people who inject drugs results in a significantly greater reduction in deaths compared to providing either intervention alone, according to a study by Bohdan Nosyk and colleagues from the University of British Columbia Centre of Excellence in HIV/AIDS at the 8th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention this week in Vancouver. Research from Ukraine, also presented at the conference, showed that people receiving opioid substitution therapy had better engagement with HIV care.

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IAS 2015: Vancouver Consensus Calls for Early Access to HIV Treatment and PrEP Worldwide

Leading figures in the HIV response field have endorsed a call for immediate access to antiretroviral therapy for all people upon diagnosis with HIV on the opening day of the 8th International AIDS Society Conference on HIV Pathogenesis, Treatment in Prevention (IAS 2015) taking place this week in. The Vancouver Consensus statement -- intended to place pressure on donors and governments to support expanded HIV treatment and prevention -- has been endorsed by leaders of major agencies including UNAIDS, the Global Fund to Fight AIDS, Tuberculosis and Malaria, and the U.S. President's Emergency Plan for AIDS Relief (PEPFAR).

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IAS 2015: Young Woman Stays Undetectable for 12 Years Off Treatment After Early HIV Therapy

The 8th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention (IAS 2015) heard on Monday of a case of a young woman who was infected with HIV at birth and received very early antiretroviral therapy as a child, and has stayed off therapy since the age of 6 with a viral load well below the detectability limit of standard tests. Such "post-treatment controllers" are models for a "functional cure," which is one of the goals of HIV treatment research.

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IAS 2015: Maturation Inhibitor BMS-955176 Shows Good Antiviral Activity with Atazanavir

The next-generation HIV maturation inhibitor BMS-955176 was well-tolerated and suppressed HIV viral load as well as standard antiretroviral therapy (ART) when used in a combination with atazanavir (Reyataz) in a 28-day study, according to late-breaking results from a small study presented at the 8th International AIDS Society Conference this week in Vancouver.

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Combination ART consists of agents that target different steps of the HIV lifecycle, but none of the currently approved drugs inhibit viral assembly, maturation, and release from host cells. If larger studies confirm its safety and efficacy, BMS-955176 could be the first drug in a new class of antiretrovirals that may offer an important treatment option for people with HIV who have developed extensive resistance to existing drug classes.

HIV uses an infected cell's machinery to produce complex polyproteins that are then cut up by protease enzymes and assembled into new virus particles. The final steps include forming a capsid around new viral genetic material and "budding" out through the cell's membrane, resulting in a mature infectious virion. Maturation inhibitors like BMS-955176 interfere with protease cleavage between the viral p24 capsid protein and a smaller peptide in the Gag polyprotein, leading to the release of immature virus that cannot infect other cells.

An older maturation inhibitor candidate, bevirimat (PA-457), initially showed promising antiviral activity, but it was hampered by formulation problems. Worse, more than half of study participants had reduced susceptibility to bevirimat due to naturally occurring HIV Gag variations.

In early studies the newer maturation inhibitor BMS-955176 showed activity against HIV that was not susceptible to bevirimat, as well as virus with resistance to nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), NNRTIs, protease inhibitors, and integrase inhibitors.

BMS-955176 has a long half-life in the body, allowing for once-daily dosing, and no significant safety issues have been identified so far. In a proof-of-concept study presented at this year's Conference on Retroviruses and Opportunistic Infections, BMS-955176 reduced HIV RNA by about 1.6 log when used as monotherapy for 10 days.

Carey Hwang from the Bristol-Myers Squibb HIV Global Development Team and colleagues conducted a Phase 2a study to evaluate BMS-955176 used in conjunction with atazanavir for 28 days.

Due to the proximity of their sites of inhibition in the viral lifecycle, the drugs may have synergistic activity, the researchers noted as background. This combination could potentially offer a NRTI-sparing regimen for people who cannot tolerate or are resistant to NRTIs.

Study AI468002 (NCT01803074) enrolled 28 adults with HIV subtype B. Participants could be either treatment-naive or previously treated with drugs other than HIV protease inhibitors or maturation inhibitor candidates. All were men and most were white. At baseline the median CD4 T-cell count was approximately 500 cells/mm3 and the median viral load was about 4.2 log.

Study participants were randomly assigned to receive once-daily oral BMS-955176 at doses of either 40 mg or 80 mg plus either 300 mg atazanavir boosted with 100 mg ritonavir, or 400 mg unboosted atazanvir. A control group received standard therapy using tenofovir/emtricitabine (the drugs in Truvada) plus boosted atazanavir. Treatment continued for 28 days, with follow-up through day 42.

Results

  • Viral load rapidly declined in all treatment arms. Median declines in HIV RNA the day after the last dose ranged from -1.66 to -2.18 log in the 3 BMS-955176 arms, comparable to the -2.22 logdrop seen in the standard therapy arm.
  • Maximum median viral load declines were -2.02 logfor people taking 40 mg BMS-955176 with boosted atazanavir, -1.86 logfor those taking 40 mg BMS-955176 with unboosted atazanavir, and -2.23 logfor those taking 80 mg BMS-955176 with unboosted atazanavir, compared with -2.39 logusing standard therapy.
  • Short-term treatment with BMS-955176 was generally safe and well-tolerated, with no serious adverse events or study discontinuations due to adverse events. One person in the 80 mg arm developed transient neutropenia (low white blood cells).
  • A majority of people who used ritonavir-boosted atazanavir, either with 40 mg BMS-955176 or in the standard-of-care regimen, experienced grade 3-4 bilirubin elevations -- a known side-effect of atazanavir; however, this occurred in just 2 of the 16 people using unboosted atazanavir.
  • Bilirubin increased by a median of 60.0 mcmol/L in the 40 mg BMS-955176 plus boosted atazanavir arm and 41.8 in the standard therapy arm, compared with 11.8 and 7.7 mcmol/L, respectively, in the 40 mg and 80 mg BMS-955176 arms with unboosted atazanavir.

BMS-955176 80 mg plus atazanavir or BMS-955176 40 mg plus atazanavir and ritonavir "demonstrated similar antiviral activity compared to the standard of care control over the 28-day treatment period," the researchers concluded. "BMS-955176 plus unboosted atazanavir was associated with lower median changes from baseline in bilirubin levels compared to the arms with boosted atazanavir."

Bristol-Myers Squibb announced in a press release that a pair of Phase 2b studies of BMS-955176 have started this year: a traditional dose-finding study (NCT02415595) for treatment-naive people and a study evaluating a NRTI- and booster-sparing regimen for treatment-experienced patients.

7/21/15

Reference

C Hwang, D Schürmann, C Soboths, et al. Second-generation HIV-1 maturation inhibitor BMS- 955176: antiviral activity and safety with atazanavir +/- ritonavir. 8th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention. Vancouver, July 19-22, 2015. Abstract TUAB0106LB.

Bristol-Myers Squibb. Second-Generation Investigational HIV-1 Maturation Inhibitor Demonstrates Positive New Phase IIa Results, Supporting Continued Development. Press release. July 21, 2015.