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and Hepatitis.com Coverage of the
XVIII International AIDS Conference (AIDS 2010) July 18 - 23, 2010, Vienna, Austria
Cure for HIV Is Feasible and Necessary, Experts Say
Antiretroviral therapy has dramatically reduced illness and increased survival of people with HIV, but they still do not achieve a normal life expectancy compared with the HIV negative general population.
HIV persists in the body even with the best existing antiretroviral therapy (ART) and, as Steven Deeks from the University of California at San Francisco explained at the IAS meeting, low-level virus can contribute to a host of problems associated with excessive immune activation and chronic inflammation.
These include cardiovascular disease, liver and kidney problems, neurocognitive impairment, and immune senescence, leading to an overall state akin to accelerated aging. "There's some sort of HIV-related problem that's causing people to get sick earlier than they otherwise would have," he said.
Furthermore, while they are much better tolerated than earlier drugs, today's antiretroviral medications still have toxicities and can lead to resistance with long-term use.
Lewin, from Monash University in Melbourne, also emphasized the financial drawbacks of providing everyone worldwide with standard-of-care ART according to current treatment guidelines -- currently 350 CD4 cells/mm3 according to World Health Organization (WHO) global guidelines and 500 cells/mm3 according to U.S. federal guidelines.
Treating 40% of HIV positive people in low- and middle-income countries (the current rate of coverage) starting at the prior WHO threshold of 200 cells/mm3 would cost $25 billion by 2030, she noted. Expanding coverage to 80% would increase the cost to $35 billion -- equal to half the entire U.S. foreign aid budget by 2016.
"I don't think we should accept that HIV is a chronic illness requiring life-long treatment ," Lewin said. "In the absence of an effective vaccine, we must seriously pursue the possibility of a cure."
But, as researchers discussed in detail during the 2-day IAS meeting, many barriers to a cure remain. Long-lived resting T-cells containing integrated HIV genetic material are resistant to current treatments, but have the potential to "wake up" at any time and beginning producing infectious new virus. In addition, hidden HIV persists in anatomical reservoirs such as the brain and gut, impervious to antiretroviral drugs.
Researchers do not yet fully understand how HIV evades the body's immune responses and establishes itself in resting cells, but various signalling molecules and transcription factors appear to play a role.
Participants in the IAS meeting described a range of potential eradication therapies, which Lewin summarized for a non-specialist audience during her AIDS 2010 plenary.
The problem of HIV persistence and potential therapies to overcome it were also discussed in an extensive review article by some of the top experts in the field published in the July 9, 2010 issue of Science.
To date, studies looking at ART intensification, or adding extra drugs to a suppressive regimen to try drive down the last bit of virus, have not proven very effective. Such findings suggest that HIV is not continuing to replicate -- since current drugs are very good at halting replication -- but rather that new virus is escaping from resting cells to re-seed the blood and tissues.
This conclusion, however, is subject to controversy. Some researchers, for example, found that adding raltegravir led to an increase in 2-LTR circles, a by-product of replicating virus that is unable to integrate its genetic material into a host cell due to the effects of integrase inhibitors. This finding, they argued, suggests that HIV is indeed continuing to reproduce at a low level.
Some research indicates that starting current combination ART very early -- during acute infection, before the virus has fully established itself throughout the body -- is a promising approach, but again study data have been mixed.
Many experts think the most promise lies with a strategy of activating resting cells and their integrated HIV genes to force them to begin producing virus that can be eliminated by antiretrovirals; once activated, infected T-cells quickly die.
A variety of agents have been proposed for activating latent cells and flushing out the virus, including the natural cytokine interleukin 7 (IL-7), histone deacetylase inhibitors, and methylation inhibitors. Some agents in these classes have already been extensively tests in humans -- for example as cancer therapies -- and appear safe and well-tolerated, Lewin explained.
At the IAS meeting, Daria Hazuda from Merck Research Labs reported that her company has screened millions of potential compounds for this indication, finding several dozen that warrant further investigation.
Further in the future, researchers might one day alter cells to make them resistant to HIV infection. The experience of the "Berlin Patient" -- a man who received a bone marrow stem cell transplant for leukemia from a donor with a naturally occurring HIV-resistant CCR5 mutation and has remained virus-free for 3 years -- shows that in principle such an approach could work. More recently, researchers demonstrated that mouse stem cells could be altered using gene therapy to make them resistant to infection.
While widespread bone marrow transplantation is not realistic, both due to its exorbitant cost and the lack of potential donors with the protective CCR5-delta32 mutation, Lewin said these proof-of-concept studies can provide clues about HIV entry, latency, and immune response that could lead to simpler, more feasible approaches.
At both the IAS meeting and AIDS 2010, researchers and advocates stressed the need for increased funding and collaborations between basic scientists, clinicians, pharmaceutical companies and funders.
AmfAR recently announced such an initiative, and earlier this month the National Institute of Allergy and Infectious Diseases (NIAID) and the National Institute of Mental Health (NIMH) launched a new public/private HIV cure collaboratory named after Project Inform founder Martin Delaney.
While procedures costing tens of thousands of dollars may be a hard sell at a time when HIV treatment budgets are shrinking and millions of people worldwide lack access even to basic combination ART, Lewin made a convincing case that HIV eradication could be a smart financial move.
Today and for the foreseeable future, ART remains the cornerstone of HIV treatment, and the right to universal access must be guaranteed, Lewin concluded. But just as the 2006 International AIDS Conference marked the start of the ART era, she expressed hope that Vienna "will mark the beginning of a future where we seriously prioritize finding a cure."