HIV Treatment, Cure Discussed at CROI

A trio of experimental antiretroviral drugs and research toward a cure for HIV were among the more than 1,000 presentations at the recent Conference on Retroviruses and Opportunistic Infections in Seattle.

With current HIV treatment being highly effective and easy to use, the pipeline for new antiretrovirals has slowed to a trickle. But there is still room for new drugs that are better tolerated and attack the virus by novel mechanisms.

ART Old and New

David Cooper from the University of New South Wales in Australia kicked off the confab with a rundown of the history of antiretroviral therapy (ART), following a tribute to AIDS researcher Joep Lange. Lange and several colleagues were killed last July enroute to the International AIDS Conference in Melbourne when Malaysian Airlines flight MH17 was shot down by a missile near the Russia-Ukraine border.

Cooper discussed the ongoing controversy about whether to start treatment immediately after HIV diagnosis - an approach adopted by the San Francisco Department of Public Health and UCSF in early 2010, and now part of national treatment guidelines -- or to wait until immune function declines.

Starting treatment early reduces immune activation and inflammation, leads to lower viral reservoirs in resting T-cells, and viral suppression nearly eliminates the risk of HIV transmission. But antiretroviral drugs can cause long-term toxicities and so far there is little evidence from randomized trials showing that starting treatment with a CD4 T-cell count over 500 offers a survival advantage.

Currently 13.6 million people are receiving antiretroviral therapy worldwide -- a "remarkable achievement in scaling up" -- but there are still 28.6 million more who need treatment.

"It's hard to see how current flat levels of funding can allow for a doubling of people on ART," Cooper said. "We simply need to tell civil society that these funds cannot be flat-lined... that is unacceptable and we need to finish the job."

New Tenofovir in the Pipeline

Researchers presented results from a pair of studies looking at Gilead's tenofovir alafenamide or TAF, a new version of the widely used tenofovir disoproxil fumarate or TDF. A component of several combination pills including Truvada - used for both HIV treatment and pre-exposure prophylaxis, or PrEP -- TDF is generally safe and effective, but it can cause kidney and bone problems in some people. TAF reaches higher levels in HIV-infected cells but lower levels in the blood, meaning less drug exposure for the kidneys, bones, and other organs.

David Wohl from the University of North Carolina reported that a TAF coformulation works as well as the current TDF coformulation sold as Stribild. In two studies that together enrolled more than 1,700 people starting HIV treatment for the first time, 92 percent of participants in the TAF group and 90 percent in the TDF group achieved undetectable viral load by 48 weeks.

While the overall safety profiles of the two drugs were similar, Paul Sax from Brigham and Women's Hospital in Boston reported that TAF has less detrimental effects on the kidneys and bones than TDF. People taking TAF had fewer kidney-related side effects and DEXA scans showed less bone loss in the spine and hips.

"Efficacy was very comparable and clearly TAF held its own against TDF," Wohl said at a CROI press conference. Sax added that his team's findings "strongly suggest [TAF] will be safer in the long run for the kidneys and bones than TDF."

Gilead has submitted TAF for approval in the U.S. and Europe and it is currently undergoing FDA review, with a decision expected by November.

It is not yet known whether TAF will be effective for PrEP, but Marshall Fordyce from Gilead told the Bay Area Reporter that the company is collaborating with the Centers for Disease Control and Prevention on a study of TAF plus emtricitabine for HIV prevention in monkeys.

Novel Viral Targets

Researchers also presented data on two new drugs being developed by Bristol-Myers Squibb that attack HIV in new ways, interfering with different steps of the viral lifecycle than current antiretrovirals. Drugs that work in novel ways could be particularly beneficial for treatment-experienced people with HIV who have extensive drug resistance.

As HIV replicates, it first attaches to receptors on the cell surface. Once it enters a cell, it uses the cell's machinery to produce large poly-proteins that are cut up by protease enzymes and assembled into new virus particles. The final steps include forming a capsid around newly produced viral genetic material and budding out through the cell's outer membrane.

BMS-663068 or fostemsavir is the first HIV attachment inhibitor. It binds to "spikes" on HIV's outer envelope and prevents the virus from latching onto T-cells.

A Phase 2b study with 254 treatment-experienced patients showed that BMS-663068 worked as well as a widely used HIV protease inhibitor, with up to 82 percent achieving viral suppression by 48 weeks. This drug was also generally safe and well tolerated at all doses tested. Bristol-Myers Squibb announced in a press release that a Phase 3 clinical trial of BMS-663068 started February 23.

A bit further back in the pipeline, BMS-955176 is a maturation inhibitor that interferes with protease, cutting newly produced HIV poly-proteins into usable pieces. This leads to the assembly of immature virus particles that cannot complete their lifecycle and are not infectious.

Max Lataillade from Bristol-Myers Squibb reported results from a Phase 2a proof-of-concept study that enrolled 60 previously untreated participants in Germany. BMS-955176 at various doses taken alone for 10 days produced large declines in HIV viral load. This drug was again safe and well tolerated, with no major side effects. A Phase 2b study is expected to start by the middle of this year.

"Today, due to tremendous advancements in therapy, many patients living with HIV are able to remain healthier and live longer; however, this means that they are usually exposed to multiple therapies over time, and may often develop drug resistance," said Jay Lalezari of Quest Clinical Research, an investigator for BMS-663068 study. "Treatment-experienced patients represent an important patient subset, for whom ongoing research and development of new drug classes is being actively pursued."

Search for a Cure

Several sessions at the conference provided updates on the state of HIV cure research, after a year of disappointments including the return of HIV in a Mississippi child and two Boston bone marrow transplant patients who researchers hoped might have been cured. Researchers have gone back to the drawing board, realizing there is still much to learn about how HIV establishes reservoirs in the body where it can hide during antiretroviral therapy, only to come roaring back if treatment is stopped.

Matt Sharp, who works with Shanti and Let's Kick ASS (AIDS Survivor Syndrome), was among a panel of speakers presenting at this year's Martin Delaney lecture, honoring the late Project Inform founder who catalyzed immune-based therapy and cure research.

Sharp introduced the new "CUREiculum," developed by the group known as AVAC, which is a set of tools for community educators, media, and others that offers simple, accessible information on HIV cure research developed by scientists, community educators, and several advocacy groups.

"A cure [for HIV] is going to be possible, but it will take a combination of approaches, sustained and increased funding, and growing collaborations, all of which will inevitably take more time," Sharp predicted.

A community cure workshop and a session on HIV persistence and latency showcased the latest research in these areas. Several researchers summarized their findings at a CROI press conference.

James Whitney from Harvard Medical School described work on a TLR7 agonist, GS-9620, being developed by Gilead. The drug is designed to reverse viral latency, or pull latent HIV out of hiding. It looks safe and promising in monkey studies and will be entering human clinical trials this month.

Jonathan Li, also from Harvard, discussed how HIV reservoir size predicts the timing of viral rebound after stopping antiretroviral treatment, while John Frater from the University of Oxford described his team's search for biomarkers to predict viral rebound after stopping antiretroviral therapy.

"The cure field started with enthusiasm, and enthusiasm is still there, but progress will be slow," said John Mellors. "It will wind out over years or decades before we have functional cure applicable to many people with HIV."