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Tenofovir Resistance May Develop in More than Half of Patients Failing Treatment

More than half of people who experienced failure of a tenofovir-based antiretroviral regimen in sub-Saharan Africa had resistance to tenofovir, a meta-analysis of drug resistance studies published in the January 28 online edition of Lancet Infectious Diseases has shown. The study found that the prevalence of tenofovir resistance after first-line treatment failure ranged from 20% in Western Europe and North America to 56%-60% in sub-Saharan Africa.

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Long-term Tenofovir Use Associated with Increased Risk of Serious Liver Disease

Long-term therapy with the antiretroviral drug tenofovir (Viread, also in several coformulations including Truvada and Atripla) increases the risk of end-stage liver disease and liver cancer, according to data from the D:A:D study published in the January 18 online edition of AIDS. Researchers found that 5-year cumulative use of the drug increased the relative risk of serious liver disease by 46%.

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ViiV and Janssen To Collaborate on Long-Acting Injectable HIV Treatment

ViiV Healthcare and Janssen have announced a plan to work together on the development of long-acting injectable HIV treatment using ViiV's investigational integrase inhibitor cabotegravir and an injected formulation of Janssen's currently available oral NNRTI rilpivirine (Edurant).

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Study Sheds Light on Ongoing HIV Replication in Lymph Node Reservoirs

HIV may continue to replicate in sanctuary sites in lymphoid tissues despite antiretroviral therapy, and may not necessarily develop drug resistance mutations, researchers reported in the January 27 online edition of Nature. While the existence of HIV reservoirs is well known, further characterizing the behavior of the virus in these sites could suggest new approaches to a cure.

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HIV Patients with Rapid Disease Progression May Have Worse Immune Recovery

People with HIV who experience fast disease progression with a rapid drop in their CD4 T-cell count may be less likely to regain a normal CD4 level after starting antiretroviral therapy (ART), according to research from the CASCADE Collaboration published in the November 2015 edition of AIDS.

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Updated Antiretroviral Therapy Guidelines Emphasize Benefits of Early HIV Treatment

The U.S. Department of Health and Human Services has updated itsGuidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents to reflect findings from the START and TEMPRANO trials demonstrating the clinical benefits of early initiation of antiretroviral therapy (ART) with a pre-treatment CD4 T-cell count above 500 cells/mm3.

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New amfAR/UCSF Institute Aims to Advance Basic Science of HIV Cure Research

UCSF researchers gave an overview of their latest work at a community forum last month launching a new Institute for HIV Cure Research, funded by a $20 million grant from amfAR, the Foundation for AIDS Research, will aims to develop the scientific basis of a cure for HIV by the end of 2020. The new institute will focus on 4 key areas: learning how latent viral reservoir are formed and persist in the body, determining the precise locations of these reservoirs, quantifying the amount of virus in them, and eradicating the reservoirs from the body.

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"We recognize that realistically we're not talking about delivering a cure to everyone who needs it by 2020," amfAR CEO Kevin Frost said at the HIV Cure Summit on World AIDS Day (December 1). "We believe a cure is evolutionary -- we want to build the foundations and understand the science of what it takes." Frost stressed that the $20 million allocated for the first 5 years is "a floor, not a ceiling."

"The San Francisco area has a higher concentration of scientific thought leaders in HIV than anywhere else in the world," said amfAR vice president and director of research Rowena Johnston. "The Bay Area has consistently led the way in developing and implementing scientific advances in HIV prevention and treatment, and the potential for this team of researchers to develop a cure is unparalleled."

UCSF was chosen to host the institution in a national competition. It will involve collaborations with the Gladstone Institute of Virology and Immunology and Blood Systems Research Institute, the University of California at Berkeley, Oregon Health and Science University, the Infectious Disease Research Institute in Seattle, Gilead Sciences, RainDance Technologies, and Monogram Biosciences.

"San Francisco has a long and storied history of response to the HIV epidemic," said USCF Center For AIDS Research director Paul Volberding, who will also head the new institute. "This will bring together a broad team of leading scientists who believe a cure is possible, and that it will happen here. We're ready to end this epidemic."

Scientific Foundations for a Cure

Effective combination antiretroviral therapy, which debuted in the mid-1990s, has made HIV a chronic manageable disease for most people with access to treatment -- in many cases using once-daily single-tablet regimens. But the drugs are not a cure, and if they are discontinued the virus soon starts to multiply. Even during treatment, inactive HIV genetic material remains hidden in the body, and this low-level virus can cause inflammation that contributes to conditions such as cardiovascular disease and cancer.

"I don't talk to any patient who wouldn't rather be cured than take one pill once a day," Volberding said at the summit.

The past couple years have seen set-backs in the cure field, including the return of HIV in the Mississippi Baby, a child infected before birth who started antiretrovirals very early and was thought by many to be cured.

This leaves only 1 person -- Timothy Brown, known as the Berlin Patient -- who appears to have been truly cured of HIV. Brown has no detectable HIV in his blood or tissues more than 8 years after receiving bone marrow transplants from a donor with a natural mutation (CCR5-delta-32) that makes T-cells resistant to infection because they lack receptors the virus needs to enter cells.

Researchers have tried various approaches to cure HIV, including very early antiretroviral treatment, mimicking Brown's cure by protecting cells from infection, flushing the virus out of hiding and destroying it -- a strategy known as "shock and kill" -- and strengthening natural immune responses against the virus.

Many researchers now speak of a "functional cure" or remission, rather than completely eliminating HIV from the body, and most experts think a combination of approaches will be necessary.

"Let's get to a place where we don't have to take medications every day, where we don't have to experience the side effects of the medications, and where we can get our immune systems to a state where we're not at a risk of early aging," said long-time AIDS survivor and advocate Matt Sharp, speaking on a KQED program announcing the new institute. "But overall, of course, I'd like to see HIV completely eradicated from my body."

The HIV Cure Summit featured an overview by Johnston, followed by UCSF researchers who will lead the 4 teams comprising the new institute.

Warner Greene, director of the Gladstone Institute of Virology and Immunology, will head an effort to study how hidden HIV reservoirs are established and persist in the body.

"Our strategy will be to exploit the innate immune system to help flush the virus out of hiding and ultimately to eliminate its ability to bounce back when drug treatment ends," said Greene, who is investigating how molecules known as TLR agonists set off immune activation, including activation of the T-cells that harbor latent HIV.

"We need not only to shock [latent virus] but also to have a good kill strategy," he stressed. "Shock without kill is a failed strategy -- in fact it could make matters worse -- we need to make sure activated cells die. We may not be able to get every last virus, but maybe we can get to a low enough level that the immune system can control it."

Mike McCune and his team aim to figure out precisely where HIV hides within specific tissues in the body -- including how viral reservoirs differ between men and women -- while Satish Pillai's group will work on better ways to measure hidden virus that is capable of replicating.

"The population of latently infected cells is what stands between us and a cure, but our knowledge of the reservoir is still rather nebulous," said Pillai. "The Mississippi Baby showed that virus was lurking somewhere but our tools were not sensitive enough to find it. We will find more needles by sampling much more of the haystack."

Finally, Steven Deeks and his team will study how TLR agonists affect HIV reservoirs in the tissues of patients on antiretroviral treatment. So far, Gilead's experimental TLR7 agonist GS-9620 has shown "remarkable latency reversal in monkeys," he said.

"With the support of the community in San Francisco, I think we have a responsibility to take these [ideas] quickly into the clinic, to quickly identify approaches that we can safely bring into human trials," said Deeks. "We're doing this differently than the traditional academic approach, where you study something deeply and write a paper. I'm tired of that. We want to make an impact, so we're using a bit of an industry approach to move things into the clinic within next 4-5 years."

Deeks predicted that the "next big game changer" will be long-acting injectable antiretrovirals that last 1-2 months. "This will have a huge impact on people who cannot take pills on a daily basis," he said, "but it will not be a substitute for a cure."

Ultimately, Greene concluded, a cure has to be "simple, safe, effective, and scalable to the 36 million people in the world who are infected with HIV."

More Cure Research at CROI

Cure research will be among the topics of this year's Conference on Retroviruses and Opportunistic Infections, which will take place February 22-25 in Boston. The Community Cure Research Workshop on February 21, co-sponsored by the AIDS Treatment Activists Coalition, European AIDS Treatment Group, AVAC, Treatment Action Group, and Project Inform, will feature an overview for advocates of recent advances in the field and community strategy sessions to discuss how to promote cure research.

1/13/16

Sources

AmfAR. amfAR Establishes San Francisco-Based Institute for HIV Cure Research. Press release. November 30, 2015.

UCSF. $20 Million Grant from amfAR Funds Institute for HIV Cure Research. Press release. November 30, 2015.