Conference 19th Conference on Retroviruses and Opportunistic Infections

Science can seem to move along at an achingly slow pace, especially when curing HIV is the goal. Even though there has been extraordinary progress in understanding the virus and identifying targets for therapy, there is still much to learn about how HIV can be cured. One of HIV’s survival mechanisms is to hide from our own immune system’s response and to antiviral drugs that slow its progression. But new research is beginning to frame HIV cure science while we watch the developments unfold.

There were several oral sessions and posters dedicated to viral latency, eradication, and cure strategies in pre-clinical and animal studies, and some very encouraging early phase clinical trials. The HIV Latency and Eradication: Clinical Perspectives symposium was so popular that there were two overflow rooms for attendees that could not fit into the main session room.

Trying to understand HIV latency and attempts to activate or wake up so-called sleeper cells harboring the virus are in very early research stages. This is a critical HIV reservoir in which scientists are trying to figure ways to wake up the CD4 memory cell so that the dormant virus can complete its replication process. Then, theoretically, antiviral therapy can move in to do its job. But there are many barriers to completely understanding this process, and uncovering safe and effective ways that may lead to a functional cure (stopping HIV without the use of long-term drugs).

Scientists must agree on the best way to measure virus inside the CD4 memory cell before and after attempts at activation. It is also difficult to find these cells with dormant HIV inside. Also, finding the best monkey model to test the latency and activation hypothesis is in progress, but access to study animals continues to be problematic.

In an elegant proof of concept clinical study from the University of North Carolina, David Margolis, MD, a leading cure researcher, showed for the first time that HIV can be purged from resting cells using one dose of an anti-cancer drug called vorinostat (known as SAHA for suberoylanilide hydroxamic acid). The drug is from a large class of drugs known as HDAC (histone deacetylase inhibitors). Histone deacetylase is an important enzyme that contributes to maintaining latency of HIV genetic material integrated into human cells.

The UNC study looked at six HIV-positive men who had been on stable antiretroviral regimens with viral load less than 50 copies/mL (undetectable) and CD4 cell counts above 500 cells/mm3. First, CD4 cells were removed and tested to establish baseline virus levels inside the cell. Then the cells were exposed to vorinostat, and HIV RNA was measured to show whether HDAC was inhibited. The cells were compared before and after the single dose of vorinostat. There was a two-fold increase in histone deacetylation after eight hours of the dose. All six participants had a response from 1.5- to 10-fold HIV RNA increase inside the cell, showing that one dose of the study drug could activate the sleeping virus. Even though only one dose was used there were no drug-related adverse events or toxicities. “This proves for the first time that there are ways to specifically treat viral latency, the first step towards curing HIV infection,” Margolis stated.

PABLO TEBAS, MD

Other drugs such as pegylated interferon-alpha-2a, used as one of the backbone treatments for hepatitis C, and disulfiram (Antabuse—used for treating alcoholism) were presented at CROI with varying results. Still, the field is moving ahead as indicated by the number of positive results in pre-clinical, animal, and clinical studies presented. In time, the activation pathway combined with other approaches such as vaccines and immune modulators may all contribute to a functional cure. One remaining question is whether these or other approaches can target other HIV reservoirs such as the central nervous system.

Pablo Tebas, MD, showed additional data from the first zinc finger nuclease (SB-728) cohorts at UPenn and Quest/San Francisco presented at CROI and ICAAC last year. The two cohorts were immunologic responders with CD4 cells greater than 450 and immunologic non-responders with CD4 cells less than 500 who all were given one infusion of SB-728. There have been no serious adverse events except one transfusion reaction that went away after a few days. After about one year, dramatic CD4 increases were seen in both groups that investigators think was related to increases in IL-2, IL-7, and IL-15, cytokines associated with CD4 expansion. CD4:CD8 T-cell ratios normalized in the majority of participants. After infusion, SB-728 was detected in peripheral blood from 90 to 700 days thus far. The modified cells also traffic to the rectal mucosa, showing that the modified cells are reaching other important HIV reservoirs.

One remaining question was whether HIV RNA would be affected by SB-728. To show this, participants went on a treatment interruption during the trial. After increase in viral load levels, all had significant drops in virus levels before resuming ARVs again. One man who dropped to undetectable levels was found to be heterozygous for the delta 32 mutation, making him an “elite controller,” one whose HIV is controlled without ART. Because of this finding, a study has been enrolled to look at this very population to see if the antiviral effect is real. Another study is using a single infusion of a chemotherapy drug in order to make room for more expansion of the CCR5-modified CD4 cells.

AIDS treatment activists have been at the table in the latest developments in cure research since Martin Delaney stumbled upon the Timothy Brown “Berlin patient” poster several years ago. At CROI, that tradition continued in a one-day workshop organized by activists. Leading cure researchers, the FDA, the IAS (International AIDS Society), and pharmaceutical companies developing eradication molecules joined activists in a robust discussion. Issues addressed were how to better inform the community about cure research and clinical trials, including revision of the cumbersome informed consent process. Also, the challenge researchers have in gaining access to experimental drugs from other companies for use in their experiments and the continuing problem of development of the best assays and animal models were all discussed. Sangamo, the biotech company developing zinc finger technology, is now scheduling a meeting with a few cure research activists. Investigators from UCSF, UNC, and the Fred Hutchinson Cancer Center presented programs being developed for the Martin Delaney Collaboratory. Activists are also working to create community advisory positions with this groundbreaking research.

The game changer at CROI was that cure research has reached the main stage. While no one knows how long it is going to take to find a cure for HIV, everyone agrees that a lot of work remains.

Diagnosed with HIV in 1988, Matt Sharp’s long history as an AIDS advocate includes belonging to ACT UP Golden Gate; directing the education programs at Test Positive Aware Network in Chicago and Project Inform in San Francisco; and helping to found the AIDS Treatment Activists Coalition. Currently, he acts as an international consultant.

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Prevention study results yield more good news

After two years of landmark studies, HIV prevention continued to dominate research news at CROI.

The Partners PrEP study enrolled nearly 5,000 heterosexual couples where one partner had HIV and the other didn’t. “PrEP” stands for pre-exposure prophylaxis (prevention), and is taken by HIV-negative people to prevent sexual transmission of HIV.

Final primary results from Partners PrEP showed a 67% reduction in risk of HIV infection with Viread and a 75% reduction with Truvada (considered not to be a statistically significant difference). The two HIV medications were compared against placebo (fake pill) in couples in Kenya and Uganda.

“They worked approximately the same,” said presenter Jared Baeten, MD, MPH, of the University of Washington in Seattle, in a press conference. “This was definitive protection for people at high risk of HIV because of a known HIV-positive partner.” He added that the results were consistent no matter the viral load in the positive partner. For the HIV-negative partners who took the prevention medications, side effects included mild fatigue and nausea.

Asked about treatment as prevention (TasP), in which successful anti-HIV treatment of a positive partner has been shown to greatly reduce transmission of HIV to a negative partner, Baeten said a need for PrEP remains. Some HIV-positive individuals prefer to delay therapy, he said, but at the same time, heterosexual couples are concerned about conceiving children. Still, “we’ve been very aggressive about making sure infected partners are treated when eligible.” In some resource-poor countries, HIV-positive people are not eligible for government-sponsored antiviral treatment until their medical condition meets certain requirements, such as a CD4+ T-cell count under 200. “We can use PrEP as a bridge until a partner starts treatment,” he said.

Of the 27 individuals who seroconverted in Partners PrEP, none developed drug resistance to Viread or Truvada, the drugs studied for PrEP. The development of drug resistance is a concern for individuals taking PrEP who become infected because HIV treatment is heavily dependent on the use of Viread or Truvada (in wealthier countries, at least). But more and more, prevention studies with HIV medications are showing that where they fail, it’s because the drugs are not being taken as prescribed. A person’s virus can develop drug resistance when medications are being taken inconsistently (missing doses).

Deborah Donnell, PhD, of the University of Washington and the Fred Hutchinson Cancer Research Center in Seattle, illustrated this issue with a Partners PrEP sub-study showing that only nine of the 27 infected individuals had any tenofovir in their blood at all at the time of seroconversion. (Tenofovir is the generic name of Viread, and it is also found in Truvada.) “Tenofovir detected in blood was highly correlated with protection from HIV infection,” she said. “I think our results are clearly proof of concept that daily use of tenofovir can substantially reduce the risk of HIV infection.”

Lut Van Damme, MD, of Family Health International, illustrated the same concept with the FEM-PrEP study, which disappointed HIV advocates when a daily Truvada pill failed to prevent HIV in women. However, Van Damme reported that the medication was found in blood levels of less than half of the 33 infected women who had been given it, as well as in less than half of the uninfected women in a matched control group. According to the FEM-PrEP abstract, studies will need to focus on what determines adherence to preventative medicine in people at high risk of infection. Also of importance in this study was that the infected women perceived themselves to be at “little or no risk of HIV infection.” They were actually at high risk of infection and didn’t know it.

There was more welcome data on the potential problem of resistance. The CAPRISA 004 research team reported no resistance in either the blood or the genital tracts of women who became infected during the study. “This is a good news result,” said Will Fischer of the Los Alamos National Laboratory. “There was only one case of high-level resistance and this was from a woman on placebo, so it was presumably a transmitted resistance [she picked up a drug-resistant virus from a sex partner].” CAPRISA 004 used a tenofovir gel applied vaginally.

“I guess this decade will be remembered as the tenofovir decade,” said Linda-Gail Bekker of the University of Capetown, while co-facilitating a session on the use of HIV drugs for the prevention of sexually transmitted HIV. She noted that her research team has used tenofovir in all of its prevention studies.

Other encouraging tenofovir data: a small study from the Microbicide Trials Network with a re-formulated tenofovir gel was found to be safe and acceptable as a rectal microbicide used daily for seven days. A previous formulation was safe but bothersome. The new reduced-glycerin formulation of 1% tenofovir gel is moving into a Phase 2, eight-week study.

Tenofovir and Truvada are ahead of the game now, but other HIV antivirals are also being tested for prevention. A small, early study with the new non-nucleoside rilpivirine (Edurant) was shown to penetrate vaginal and rectal tissue and fluids in an amount needed to inhibit HIV infection. Rilpivirine was used in a long-acting, injectable form in this research (used intramuscularly). The use of the HIV entry inhibitor drug Selzentry (maraviroc) is also being explored with a vaginal ring that releases maraviroc into the genital tract. The hope is that such medications will help counter the adherence problems found with prevention research to date.

Said Susan Buchbinder, of the San Francisco Department of Public Health and the University of California, San Francisco, “Lots of data was presented this morning—[showing that] HIV infections occur during periods of low blood exposure.” See her talk on the possibilities for intermittent PrEP (not taken daily) in the Wednesday symposium “Next Steps in Using ARV for Prevention” at www.retroconference.org, along with a talk from Baeten, “What Can the Twisted Tale of PrEP Results Teach Us?” and two other presentations.

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ART plus new drugs coming soon

We often hear that there’s not much new coming down the HIV drug development pipeline, but there were several presentations and plenty of posters on new HIV drugs in development at this year’s CROI, including two new integrase inhibitors set to be approved in 2012, elvitegravir and dolutegravir, plus a reinvention of the popular HIV drug tenofovir (Viread), also found in Truvada (emtricitabine/tenofovir). There was also information regarding already approved drugs that will help inform us on how to make better use of the drugs that are currently in use. Go to retroconference.org.

The Quad

In a Phase 3 study, the once-daily single tablet regimen (STR) of elvitegravir, cobicistat, emtricitabine, and tenofovir, known as the “Quad,” was found to be non-inferior to the gold standard Atripla (efavirenz/emtricitabine/tenofovir) at 48 weeks. This is the first large head-to-head study of two single-tablet-regimens. 700 treatment-naïve individuals were randomized to receive either the “Quad” or Atripla, with 88% of those on the “Quad” achieving undetectable viral load (less than 50 copies) compared to 84% of those on Atripla. Side effects differed between the two groups, with higher rates of nausea in those on the “Quad” compared to Atripla (21% vs. 14%), while increased rates of CNS side effects and rash were seen in those taking Atripla versus the “Quad”—abnormal dreams (27% vs. 15%), insomnia (14% vs. 9%), dizziness (24% vs. 7%), and rash (12% vs. 6%). Both groups showed similar low rates of discontinuation due to side effects (4–5%), and similar low rates of virologic failure (7%).

In a related poster (#627) the “Quad” showed non-inferiority to boosted Reyataz (atazanavir/ritonavir) in combination with Truvada at 48 weeks, with 90% of those on the “Quad” achieving undetectable viral load compared to 87% of those using boosted Reyataz plus Truvada. This Phase 3 study is being conducted in parallel with the Quad vs. Atripla study discussed above.

An FDA advisory committee meeting on the “Quad” is scheduled for May 11.

New integrase inhibitor dolutegravir

SPRING-1 is a Phase 2b dose-ranging study of dolutegravir, a once-daily unboosted integrase inhibitor, in approximately 200 treatment-naïve individuals. The study looked at 10, 25, and 50 mg doses of dolutegravir compared to Sustiva (efavirenz), both in combination with two NRTIs. Fewer participants on dolutegravir (3%) discontinued therapy due to adverse events compared to Sustiva (10%). The study was not designed to demonstrate non-inferiority; however, the proportion of those with undetectable viral load was 88% for the dolutegravir group (using the 50 mg dose) compared to 72% for the Sustiva group, with no integrase inhibitor resistant mutations detected at 96 weeks. Two Phase 3 studies are currently enrolling for both treatment-naïve and -experienced individuals using the selected 50 mg dose, and an expanded access program (EAP) is now open for those failing or resistant to Isentress (raltegravir) or elvitegravir and who need access to dolutegravir now (see Briefly, page 8).

GS-7340—son of tenofovir

GS-7340 is a pro-drug (a substance that becomes activated after entering the body) of tenofovir (Viread). Peter Ruane, MD, and colleagues conducted a 10-day monotherapy study which was to compare three different doses of GS-7340 (8, 25, and 40 mg once daily), 300 mg tenofovir, and GS-7340 placebo. The drop in viral load was greater in the GS-7340 groups compared to Viread, while blood levels of tenofovir were lower in all GS-7340 groups compared to those on Viread. This newer version of the popular drug Viread (also contained in Truvada, Atripla, and Complera) achieves greater concentration of the active form of the drug within the cells, and lower levels in the bloodstream, while allowing for smaller doses—in other words, greater antiviral activity, potentially less toxic, and a smaller pill (making it easier to co-formulate with other drugs). Gilead is also planning to explore use of GS-7340 as a treatment for hepatitis B.

PETER RUANE, MD

Other studies

BMS-626529 (poster #725) is the first in its drug class, an oral attachment inhibitor, which blocks the first step in viral entry, using a different target than entry inhibitors. In a brief study, monotherapy with BMS-663068, a pro-drug of “529,” did not appear to select for BMS-626529 resistance for as long as eight days.

Rilpivirine (Edurant) is the newest non-nuke that was approved in 2011, and is also co-formulated with Truvada in a single-tablet regimen known as Complera. The ECHO and THRIVE studies compared rilpivirine versus efavirenz (Sustiva) in combination with Truvada, Epzicom, or Combivir. In a pooled analysis from both Phase 3 studies of 1,368 individuals, in those with a baseline CD4 count of 50 and above, responses were high and similar between the rilpvirine and efavirenz groups. There were lower responses for those on rilpivirine with a baseline CD4 count less than 50. Responses seen with rilpivirine were significantly higher than with efavirenz with both baseline viral load of less than 100,000 and CD4 cell count of 200 and greater. Overall responses were lower with rilpivirine compared to efavirenz with baseline viral load greater than 100,000, although non-inferiority between the groups was still met. Another poster (#617) demonstrated that rilpivirine 25 mg once daily and raltegravir (Isentress) 400 mg twice daily can be co-administered without dose modifications.

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