Tuesday, February 2, 2016

Tenofovir Resistance Alarmingly Common; Ongoing HIV Replication Replenishes Reservoirs; and More

By Warren Tong

From TheBodyPRO.com

January 29, 2016

This week, we read a study that finds a high rate of resistance to tenofovir disoproxil fumarate (TDF, Viread) among individuals on treatment but without undetectable viral loads. We also read a study that highlights how HIV continues to replicate and replenish the viral reservoir, despite effective antiretroviral therapy. And we also see how the size of the viral reservoir may predict how fast viral rebound occurs after treatment interruption. To beat HIV, you have to follow the science!


Resistance to tenofovir disoproxil fumarate, a popular HIV drug taken as part of both treatment and pre-exposure prophylaxis (PrEP), is alarmingly common, according to a study published in The Lancet Infectious Diseases. Researchers followed 1,926 individuals living with HIV around the world who were prescribed treatment but did not have undetectable viral loads. They found tenofovir-resistant strains of HIV in 60% of participants living in sub-Saharan Africa and 20% of participants living in Europe. Even more concerning, about two-thirds of those who had developed tenofovir resistance also developed resistance to both other drugs in their regimen, indicating complete treatment failure. "Tenofovir is a critical part of our armamentarium against HIV, so it is extremely concerning to see such a high level of resistance to this drug," explains lead author Ravi Gupta, M.P.H., Ph.D., according to the study press release. "It is [a] very potent drug with few side effects, and there aren't any good alternatives that can be deployed using a public health approach. Tenofovir is used not only to treat HIV but also to prevent it in high-risk groups, so we urgently need to do more to combat the problem of emerging resistance." Drug resistance typically develops with suboptimal treatment adherence, which translates to at least 85-90% doses taken regularly, according to the study. Resistant strains of virus can be transmitted to others, which would only exacerbate the problem.

HIV Persistence

HIV continues to replicate in lymphoid tissues, which helps maintain the hidden HIV reservoirs, despite effective antiretroviral therapy and an undetectable viral load, according to a study published in the journal Nature. Researchers from Northwestern University examined viral DNA from cells in the lymph nodes and blood cells of three HIV-positive individuals, following the patients before and during the first six months of treatment. Despite the patients achieving undetectable viral loads in the blood, the researchers discovered that ongoing low-level HIV replication in lymphoid tissues replenishes the viral reservoir. Even with this ongoing replication, drug resistance does not necessarily develop. The investigators used a mathematical model to explain that drug-sensitive strains of HIV tend to flourish over drug-resistant strains in areas where the drug concentrations are low, such as the viral reservoirs. In areas with intermediate levels of drug concentration, drug-resistant strains start to flourish more. And in areas with high levels of concentration, such as the blood, HIV cannot grow. "We now have a path to a cure," said corresponding author Steven Wolinsky, M.D., according to the study press release. "The challenge is to deliver drugs at clinically effective concentrations to where the virus continues to replicate within the patient." Size of HIV Reservoir Predicts Timing of Viral Rebound After Treatment Interruption The bigger the size of the viral reservoir, as measured by levels of HIV expression, the faster the viral rebound after treatment interruption, according to a study published in the journal AIDS. Researchers in the U.S. analyzed data from 235 participants across six studies on analytic treatment interruption (ATI) to identify possible predictors of viral rebound. They measured the active viral reservoir by measuring cell-associated HIV DNA (CA-DNA) and RNA (CA-RNA). Higher levels of CA-RNA before treatment interruption were significantly associated with shorter times to viral rebound. Patients who started treatment during acute or early HIV infection and those who were on a regimen containing a non-nucleoside reverse transcriptase inhibitor had longer times to viral rebound. "Quantification of the active HIV reservoir may provide a biomarker of efficacy for therapies that aim to achieve [antiretroviral therapy]-free HIV remission," the authors concluded.

Warren Tong is the senior science editor for TheBody.com and TheBodyPRO.com.
Follow Warren on Twitter: @WarrenAtTheBody.

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