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Reaching UNAIDS HIV Treatment Targets Could Avert Millions of Deaths and New Infections

Achieving UNAIDS 90-90-90 targets for getting more people with HIV diagnosed and on antiretroviral therapy (ART) in 2 of the hardest-hit countries -- Nigeria and South Africa -- could avert more than 3 million deaths, according to a study published in the July 6 edition of PLoS ONE. The new Fast-Track Cities Initiative aims to help make this goal a reality in the highest-burden cities.

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Study Sheds Light on How Tenofovir is Processed in Different Body Tissues

Tenofovir, which is widely used for HIV treatment and prevention, is activated in a tissue-specific manner, being processed by different enzymes in immune cells, the vagina, and the colon, according to a study published in the July 19 advance edition of EBioMedicine. These findings have implications for the effectiveness of tenofovir for pre-exposure prophylaxis (PrEP).

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Tenofovir disoproxil fumarate or TDF (Viread, also in the Truvada, Atripla, Complera, and Stribild coformulations) is among the most widely used antiretroviral drugs for HIV treatment. A new formulation under development, tenofovir alafenamide or TAF, reaches higher levels in HIV-susceptible immune cells when taken at lower doses that are easier on the kidneys and bones.

Oral Truvada is the only agent currently approved for HIV PrEP. Other tenofovir formulations are under study including gels and vaginal rings. The iPrEx trial of mostly gayand bisexual men showed that once-daily Truvada reduced the risk of HIV infection by 44% overall, rising to 92% among participants with blood drug levels indicating consistent use.

Truvada PrEP also performed well in the Partners PrEP and TDF2 studies of heterosexual couples in Africa. But the Fem-PrEP and VOICE trials of young women were unable to show a protective effect of Truvada or tenofovir vaginal gel. This has primarily been attributed to poor adherence, but animal and human studies suggest that there are also physiological reasons why tenofovir may be less effective against vaginal compared to rectal HIV exposure.

Julie Lade and colleagues fromJohns Hopkins University School of Medicine performed a laboratory study to analyze the chemical processing required to convert tenofovir to its pharmacologically active form in the body.

Tenofovir requires 2 phosphorylation steps (addition of phosphate groups), being converted first to tenofovir monophosphate then to the active form tenofovir diphosphate. But the specific kinase enzymes that activate tenofovir in cells and tissues susceptible to HIV infection have not yet been identified, the study authors noted as background.

In this study the researchers examined peripheral blood mononuclear cells (PBMC) and vaginal and colon-rectal tissue samples that were transfected with siRNA targeting nucleotide kinases and incubated with tenofovir in the laboratory. As explained in a Johns Hopkins press release, this had the effect of "knock[ing] out genes for phosphate-adding enzymes one by one."

They also genetically sequenced clinical samples from 142 women who participated in Microbicide Trials Network study MTN-001, which tested oral tenofovir and 1% tenofovir vaginal gel.

Results

  • Adenylate kinase 2 (AK2) performed the first phosphorylation step -- converting tenofovir to tenofovir monophosphate-- in PBMCs, vaginal tissue, and colon tissue.
  • Both pyruvate kinase isoenzymes -- muscle (PKM) and liver/red blood cell (PKLR) versions -- were able to phosphorylate tenofovir monophosphateto tenofovir diphosphatein PBMCs and vaginal tissue.
  • However, the creatine kinase muscle isoenzyme (CKM) performed this conversion in colon tissue.
  • Sequencing of MTN-001 clinical samples detected 71 previously unreported variants in the genes encoding these kinases, several of which could make the enzymes ineffective.
  • 8% of the women had genetic variants that would likely to make them unable to convert tenofovir to its activated form.

"[O]ur results demonstrate that tenofovir is activated in a compartment-specific manner," the authors concluded. "Further, genetic variants have been identified that could negatively impact tenofovir activation, thereby compromising tenofovir efficacy in HIV treatment and prevention."

"Because these enzymes are polymorphic and may be dysfunctional in some individuals, these findings suggest that tenofovir-based HIV PrEP may not be protective for all individuals," they added.

"Tenofovir has been shown in trials to be very effective, so when it doesn’t work, researchers and clinicians tend to assume the individual just wasn’t taking the drug as directed," coauthor Namandje Bumpus explained in the press release. "That is probably true in most cases, but in others, it’s possible that genetic variation is actually at fault."

"If confirmed by further studies, our results suggest that in the future, before prescribing tenofovir to a patient, a doctor could order genetic testing and know in advance if it works, and prescribe a different drug if it won’t," she added.

7/16/15

Reference

JM Lade, EE To, CW Hendrix, and NN Bumpus. Discovery of Genetic Variants of the Kinases That Activate Tenofovir in a Compartment-specific Manner. EBioMedicine. July 10, 2015 (Epub).

Other Source

Johns Hopkins. New Evidence that Genetic Differences May Help Explain Inconsistent Effectiveness of Anti-HIV Drug. Press release. July 9, 2015.

San Francisco Sees Declines in New HIV Infections and Deaths of People with HIV

The number of new HIV cases diagnosed in San Francisco decreased by more than 18% between 2013 and 2014, and deaths among people with HIV also fell during the same period, according to a progress report on the city's "Getting to Zero" initiative presented to the San Francisco Health Commission last week.

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IAS 2015: International AIDS Society Conference Starts this Weekend in Vancouver

The 8th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention (IAS 2015) starts this Sunday and runs July 19-22 in Vancouver. HIV prevention -- including treatment-as-prevention and pre-exposure prophylaxis (PrEP) -- will be a major focus of the meeting. Other topics will include antiretroviral drugs in development, expanding access to treatment and retention in care, and HIV/hepatitis coinfection. HIVandHepatitis.com will be on site covering the latest news.

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People with HIV Still at Risk for Opportunistic Illness Death Despite Dramatic Survival Gains

The risk of death due to opportunistic illnesses (OIs) has declined dramatically since the advent of combination antiretroviral therapy (ART) in the mid-90s, but even in the era of effective ART about a third of people diagnosed with a first OI died within 5 years, according to an analysis of more than 20,000 people living with HIV in San Francisco.

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Goal of 15 Million People with HIV on Treatment Met Ahead of Schedule, says UNAIDS

The Millennium Development Goal (MDG) of getting 15 million HIV-positive people worldwide onto antiretroviral therapy (ART) by 2015 -- a goal many once considered impossible -- has been reached 9 months sooner than projected, according to a new report from UNAIDS. Other MDG target have also been achieved or exceeded, as new HIV infections have decreased by 35% and AIDS-related deaths by 41%, and more than 80 countries have halted or reversed their epidemics.

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Drug Levels Are Key to Effectiveness of Tenofovir Vaginal Gel for HIV Prevention

Although the VOICE study failed to show an overall protective effect for tenofovir vaginal gel, further analysis suggests that women who had detectable blood drug levels were at lower risk of HIV infection, according to an analysis described in the June 29 advance edition of Journal of Infectious Diseases. Another recent analysis from the CAPRISA 004 trial showed that higher levels of tenofovir in the genital tract were associated with greater reduction in risk.

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