Brian Risley, M.F.A., and Mark Katz, M.D.
The recent 19th Conference on Retroviruses and Opportunistic Infections (CROI), the major international HIV science gathering of the year, featured promising developments in HIV cure and general HIV/AIDS-related research. For the first time in years, researchers reported compelling news about recent cell-mediated studies, where the body’s immune system is re-armed through the benefit of gene therapies, stem cell therapies or prime boosted vaccines to both attack and fend off HIV and disease progression.
Conference presenters also revealed new strategies for viral eradication or activation of virus from latent reservoirs and destruction of it. In one of the opening talks, there was serious discussion of what vaccine researchers have been searching for—the discovery and potential of broadly neutralizing antibodies against HIV.
Another major topic of conference discussion was the use of antiretroviral (ARV) therapy in preventing HIV transmission.
Researchers reported conflicting results in some of the recent studies on this HIV prevention strategy, which is known as “PrEP” (pre-exposure prophylaxis, when a healthcare provider gives an anti-HIV medication to someone who is HIV-negative but at risk for the disease as a means to prevent infection) studies. Four completed PrEP trials demonstrated efficacy while two trials in women showed high HIV incidence and disappointing results either in the entire study or its individual arms.
In 2010, the 39 percent efficacy obtained in the CAPRISA 004 trial was, though modest, a significant triumph. That breakthrough has been followed by encouraging, if mixed, results from more recent studies of daily, oral PrEP, as well as vaginal microbicides containing ARVs. The HIV prevention value of ARVs was supported in 2010 by the results of the HPTN 052 study, which found that earlier treatment of HIV-infected individuals in relationships with HIV-uninfected people reduced HIV transmission to their partners by a stunning 96 percent.
The lessons learned from all these studies, and for the two trials for women that had disappointing results, prove that adherence is critical; that those on a PrEP regimen must have high enough levels of the drug to achieve protection; and that genital inflammation increases the risk of acquiring HIV.
These lessons are very applicable to oral PrEP regimens, as well. Findings from a host of studies presented at CROI suggest that adherence is an important determinant of PrEP efficacy. Such factors are likely to be a major focus of future studies, as researchers try to develop a more comprehensive picture of when, where and how PrEP might best be used.
The need for PrEP demonstration trials in different cities that will potentially benefit people at high risk for HIV infection was also discussed. In Los Angeles, a citywide demonstration project is about to be implemented that would provide PrEP as one pill, Truvada (which actually contains two different medications), taken once a day to prevent HIV infection. The pill, along with HIV testing and risk reduction counseling and adherence support, will be provided to all participants. This biomedical strategy is not for everyone, but researchers will study the importance of its role as a part of the prevention toolkit. Stay tuned for more information about the Los Angeles-based PrEP demonstration study.
Another study that underscored the importance of adherence was the Partners PrEP trial of 4,758 heterosexual, serodiscordant (where one partner was HIV-positive and the other HIV-negative) couples in Kenya and Uganda. Results from that trial revealed in 2011 that a daily dose of tenofovir (one of the components of Truvada) reduced the risk of HIV infection by 62 percent, and a similar regimen of Truvada cut that risk by as much as 73 percent.
Recent findings indicate that individuals who remained HIV-negative in the tenofovir and full Truvada arms of the study had detectable levels of the drug on 83 percent and 81 percent of their study visits, respectively.
While ARV-based prevention strategies was one focus of the conference, news on the surging field of HIV cure research really packed the vast conference halls. One scientist compared the state of cure research to the state of antiretroviral research 15 years ago, when Highly Active AntiRetroviral Therapy (known as HAART ) was about to revolutionize AIDS care.
Scientists believe one possible way to cure HIV would be to locate and drain reservoirs of latent HIV-carrying cells. A reservoir of “resting” cells in every HIV-infected person harbors the virus in a dormant state. These resting cells have long lives and fly under the immune system’s radar as long as HIV’s genes remain hidden inside chromosomes. Such reservoirs persist even in people whose circulating HIV has been effectively suppressed by ARVs.
One study, presented by David Margolis, director of the School of Medicine at the University of North Carolina, who led one of the first major, cure-related clinical trials, used a cancer drug called vorinostat to activate latent cells, forcing the hiding HIV to reveal itself. Scientists also found that disulfiram proved to be among the most effective drugs currently available that can reactivate latent HIV. And because disulfiram is a drug already approved by the FDA, experts know it is safe for use in humans
One of the more surprising presentations at the conference dealt with basic science—namely the race to fully understand the structure and weaknesses of HIV’s so-called “envelope protein.” This molecular complex juts out like a spike from HIV’s surface and plays a key role in its infection of target cells.
The keynote address covered advances in the identification and analysis of antibodies that can neutralize a broad spectrum of HIV variants. These antibodies open a door to developing an effective HIV vaccine.
Researchers presented data on promising new pipeline drugs, advancing these drugs further toward FDA approval. A new one-pill, once-daily treatment, known as the “QUAD” drug, met its primary objective. The drug combines a new integrase inhibitor, elvitegravir, with a new boosting agent, cobicistat, and the two drugs that make up Truvada—emtricitabine and tenofovir disoproxil fumarate.
The drug being evaluated for HIV-1 infection in treatment-naïve patients met non-inferiority at week 48 as compared to ritonavir-boosted atazanavir plus Truvada, based on the proportion of subjects who achieved HIV RNA levels (viral load) of less than 50 copies. The 90 percent response rate observed on the QUAD arm in this study is an impressive result and speaks to the potency, safety and convenience of an integrase-based, single-tablet regimen.
Study results also show that dolutegravir, a new integrase inhibitor, may be more advantageous over the current Isentress (raltegravir) and the experimental elvitegravir while offering once-daily dosing and no need for a boosting drug. An earlier study has shown that dolutegravir is effective against strains of HIV that are resistant to the other two integrase inhibitors.
In summary, the advanced state of HIV protein and drug research, the promise of biomedical prevention and the monetary and scientific investment in an HIV cure make this an exciting time of discovery and real hope toward ending this 30-year-old epidemic.