Back HIV/AIDS

HIV / AIDS

CROI 2016: Botswana Close to Reaching 90-90-90 HIV Testing and Treatment Targets

Botswana is already close to reaching the 90-90-90 target for HIV testing, treatment, and viral suppression, and is ahead of the United States and most European countries in its efforts to improve treatment coverage, Tendani Gaolathe of the Botswana-Harvard AIDS Institute Partnership reported at the Conference on Retroviruses and Opportunistic Infections (CROI 2016) this week in Boston.

alt

CROI 2016: People with HIV Considerably Overestimate Their Chances of Infecting Someone

Only a small proportion of HIV-positive people in a large U.S. treatment study, ACTG A5257, regarded themselves as non-infectious after up to 3 years on antiretroviral therapy (ART), and a third of participants regarded their chance of infecting a partner as still "high," even though only 10% of participants actually had a detectable viral load, according to a report at the Conference on Retroviruses and Opportunistic Infections (CROI 2016) in Boston.

alt

[Produced in collaboration with Aidsmap.com]

The study showed that there was no correlation between a person’s actual viral load and their belief about how infectious they were, Raphael Landovitz of the University of California in Los Angeles told the conference.

ACTG A5257 was a large drug-comparison study in which 1809 participants were randomized to receive either raltegravir (Isentress), boosted atazanavir (Reyataz), or boosted darunavir (Prezista), plus tenofovir/emtricitabine (Truvada). The 96-week results were presented at the CROI 2014 conference.

The trial enrolled participants between 2009 and 2011 and patients were asked about their infectiousness beliefs 1, 2, and 3 years after starting ART, so this study includes responses up to 2014.

A quarter of the study population was women, the mean age was 37, and ethnicity was distributed quite evenly, with 34% white, 42% African-American, and 22% Hispanic. The median viral load at baseline was 40,000 copies/mL, with 30% having a viral load over 100,000 copies/mL.

The participants were asked the question "How likely would you be to give someone HIV if you had unprotected sex with them today?"

They rated how infectious they thought they were on a visual analog scale, from "not infectious at all" (zero) to "highly infectious" (100). They were then divided into 4 categories: those who thought they were not infectious, and those who thought their risk of infecting another person was "low" (score 1-33), "medium" (34-66), or "high" (67-100).

As the start of the study, 58% of participants thought they were highly infectious and 26% placed themselves in the "medium" category. This left 16% who thought -- at this point inaccurately -- that their risk of infecting another person was "low" (10%) or zero (6%).

After a year on ART, a higher proportion -- just under one-third -- thought their risk of infecting someone was low. But 38% still thought their infectiousness was high. The percentage who thought they were not infectious at all had increased slightly to 10%. (Incidentally, 8.1% of this 10% -- just 8 individuals – were actually mistaken in their belief at this point, did have a detectable viral load, and were, to at least some extent, infectious.)

This hardly changed at all in the subsequent 2 years. At week 96, when 90% of trial participants were in fact virally suppressed, 36% still thought they were highly infectious and 19% were in the "medium" category. The proportion who thought their chance of infecting others was low had gone up just 1 point to 33%, and the proportion who thought they were not infectious to 12%.

By week 144, after 3 years on ART, 34% still thought they were highly infectious and a majority (52%) thought they were highly or somewhat infectious. The "low" category had increased by 2 points to 35%, and the non-infectious by 2 points to 14%.

In other words, after 3 years on largely suppressive antiretroviral therapy, the proportion who thought they were highly infectious had roughly halved and the proportion who believed they were not infectious had roughly doubled, but these figures in no way reflected the actual proportions who were infectious, and had no relationship with people’s actual viral load.

At week 48, young people under age 30 were somewhat more likely than average to regard their infectiousness as having fallen. Black people, people with lower educational attainment, and people who entered the study with a very low CD4 count were less likely to do so.

Women and Hispanic people were more likely to put themselves in the "not infectious" category at week 48, and users of recreational drugs and those who at baseline had seen themselves as highly infectious were less likely.

The study team will now analyze the data further to find if people’s beliefs about their infectiousness had any impact on their sexual risk behavior and choices of partners.

Given that people’s beliefs about their infectiousness, although changing somewhat after starting treatment, had little relationship to whether they were infectious, Landovitz was asked whether patients were taking over-cautious messages from healthcare professionals to heart, or felt, due to HIV stigma, that they still had to profess a belief in their own infectiousness.

Landovitz commented that ACTG A5257 spanned the period during which, in May 2011, the results were announced from the HPTN 052 study, which confirmed that people with HIV who were on ART were rarely infectious. This result appears to have had little impact on the ACTG A5257 participants.

However the trial finished around the time that the even more persuasive PARTNER study, which found no transmissions from anyone with an undetectable viral load, announced its interim findings. Landovitz commented that if this same sub-study was repeated today, people’s beliefs about their infectiousness might be different.

Asked what message we should give to patients about viral load and infectiousness, he commented: "Don’t give them a dumbed-down message and talk in absolutes. In my experience, people want nuanced information about their risk of infecting others and want to be able to make up their own minds."

2/26/16

Reference

RJ Landovitz, TT Tran, SE Cohn, et al. Perception of Infectiousness in HIV-Infected Persons After Initiating ART: ACTG A5257Conference on Retroviruses and Opportunistic Infections. Boston, February 22-25, 2016. Abstract 55.

CROI 2016: Almost-Certain Case of Truvada PrEP Failure Due to Drug Resistance Reported

A case report of a man in Toronto who became infected with a multidrug-resistant strain of HIV despite apparently very consistent adherence to PrEP using tenofovir/emtricitabine (Truvada) was presented at the 2016 Conference on Retroviruses and Opportunistic Infections this week in Boston.

alt

Coverage of the 2016 Conference on Retroviruses and Opportunistic Infections

HIVandHepatitis.com coverage of the 2016 Conference on Retroviruses and Opportunistic infections (CROI 2016), February 22-25, 2016, in Boston.

Conference highlights include PrEP and other HIV prevention innovations, new HIV treatment strategies, HIV cure research, the cascade of care, HIV-related conditions, and optimizing therapy for hepatitis C.

HIVandHepatitis.com coverage by topic

CROI website

2/26/16

alt

CROI 2016: TAF/FTC Maintains Viral Suppression as Well as TDF with Less Bone and Kidney Toxicity

A fixed-dose coformulation of tenofovir alafenamide (TAF) and emtricitabine (FTC), combined with a variety of third antiretroviral agents, maintained undetectable viral load in people who switched from similar regimens containing the older tenofovir disoproxil fumarate (TDF), according to a report presented at the Conference on Retroviruses and Opportunistic Infections (CROI 2016)this week in Boston. The study also showed improvement in kidney function biomarkers and bone density gains in the group taking TAF/FTC.

alt

CROI 2016: HIV in the Brain -- New Tools and Treatment Options to Keep Your Mind Beautiful

In the future, HIV-related neurocognitive disorder (HAND) may become less common because of the earlier use of antiretroviral therapy (ART), but neurological disease -- caused by a number of different factors -- will remain an important issue as people with HIV live longer, according to several presentations in a symposium called "A beautiful Mind, Keeping It," held at the annual Conference on Retroviruses and Opportunistic Infections (CROI 2016) in Boston.

alt

CROI 2016: TAF PrEP Protects Monkeys, But Levels in Humans May Be Too Low

A proof-of-concept study showed that the new tenofovir alafenamide (TAF) plus emtricitabine (FTC) protects macaque monkeys from infection with an HIV-like virus, with a degree of protection similar to that previously seen with the older tenofovir disoproxil fumarate (TDF), researchers reported at the Conference on Retroviruses and Opportunistic Infections (CROI 2016)this week in Boston. But another study looking at TAF concentrations in rectal and genital tissue samples from women found lower than expected levels, which could mean it won't be as effective as TDF/FTC (Truvada) for pre-exposure prophylaxis, or PrEP.

alt

Gilead Sciences' Truvada is currently the only agent approved for HIV prevention in the U.S., France, and a few other countries. Studies have shown that it dramatically reduces the risk of HIV infection when used consistently, with around 90% or better efficacy among gay men. TDF is generally considered safe and well-tolerated, but it can cause modest bone loss and kidney problems in susceptible individuals. 

TAF is a new tenofovir pro-drug that delivers the active agent, tenofovir diphosphate, more efficiently to cells. TAF produces high intracellular drug levels with a 10-fold lower dose than TDF (25 mg vs 300 mg), which means about 90% lower drug concentrations in the blood plasma and less exposure for the kidneys, bones, and other organs and tissues.

Gilead has requested approval of a dual coformulation of TAF/FTC, which could be a successor to Truvada (to be marketed as Descovy). Several studies -- including one presented this week at CROI -- found that antiretroviral regimens containing TAF/FTC maintain viral suppression as well as those containing TDF/FTC when used for HIV treatment, but with less detrimental effects on kidney function and bone density.

Kidney and bone side effects among HIV-negative people using TDF/FTC for PrEP are not fully understood. Most clinical trials -- which excluded people with pre-existing kidney problems -- did not see significant kidney toxicity or bone loss, but these have been reported in PrEP demonstration projects and "real world" clinical use.

Some researchers and advocates have suggested that TAF could potentially be a safer alternative to TDF for PrEP, but it is not yet known whether it will be equally effective, given that it is distributed differently in the body.

TAF/FTC Protects Monkeys

Gerardo Garcia-Lerma from the U..S Centers for Disease Control and Prevention (CDC) presented findings from a study evaluating whether TAF/FTC would prevent rectal infection in macaques exposed to an HIV-like virus called SHIV. Garcia-Lerma's team previously conducted much of the animal research showing that TDF/FTC is effective for PrEP.

The study consisted of 2 parts. In the first part, Indian rhesus macaques were given a single dose of TAF to determine a human-equivalent dose. TAF was administered orally at 3 different doses -- 0.5, 1.5 and 4.5 mg/kg -- to 4 animals per dose. Tenofovir and tenofovir diphosphate (TFV-DP) concentrations were then measured in blood plasma, peripheral blood mononuclear cells such as T-cells (PBMCs), and rectal biopsy samples.

The researchers found that a 1.5 mg/kg TAF dose produced TFV-DP levels in PBMCs that were within the range achieved with 25 mg once-daily dosing in humans. As seen in humans, a low 1.5 mg/kg TAF dose (about one-tenth the TDF dose) produces about 90% lower plasma tenofovir exposure. Biopsies suggested that TFV-DP levels were lower in rectal tissue with TAF than with TDF.

In the second part of the study 6 macaques were treated with TAF/FTC (1.5 and 20 mg/kg) while another 6 received a placebo. After 1 to 24 hours the animals were exposed to rectally administered SHIV (strain SHIV162p3), with repeated weekly exposures for up to 19 weeks to simulate people at high risk for HIV infection.

Garcia-Lerma said the study design and procedures were the same as those previously used to demonstrate the effectiveness of TDF/FTC in monkeys in a prior study that showed 5 of 6 animals were protected after 14 SHIV exposures, for an efficacy of 94%.

In the current study none of the TAF/FTC-treated macaques became infected after 19 SHIV exposures. In contrast, all the placebo-treated monkeys were eventually infected after 1 to 10 exposures.

"We show that [TAF/FTC] prevents rectal SHIV infection in macaques to a degree similar to that previously found with [TDF/FTC] but with a substantially reduced TAF dose," the researchers concluded. "High protection [was] achieved despite lower rectal TFV-DP exposure with TAF than with TDF."

These findings, they added, "suggest that [TAF/FTC] may be a feasible alternative to [TDF/FTC] for PrEP against rectal HIV infection, and support the clinical development of [TAF/FTC] as a PrEP agent."

TAF Levels in Human Tissue

A second study, however, gives reason for caution about whether these promising animal findings will apply to humans.

Katy Garrett from the University of North Carolina at Chapel Hill and colleagues from Gilead analysed tenofovir and TFV-DP concentrations in genital and rectal tissue and fluid samples obtained from 8 healthy women. Most were white and the median age was 27.5 years. Although all participants were cisgender women, the rectal tissue results may also hold for men (and the vaginal results for trans men).

As background, Garrett noted that the efficacy of oral TDF/FTC PrEP has been low in clinical trials of women compared with the high levels of protection seen in studies of men who have sex with men. Social and cultural factors play a role, especially regarding adherence, but biological factors also appear to be important.

TFV-DP concentrations with TDF are lower in the female genital tract than in rectal tissue and the protective effect does not last as long. One analysis suggested that while rectal protection could be achieved with just 2 doses of TDF/FTC per week -- though the usual recommended minimum for gay men is 4 doses -- female genital tract protection would require 7 doses.

In this study women were treated with a single 25 mg dose of TAF, and tenofovir and TFV-DP concentrations were measured in cervical tissue, vaginal tissue, cervicovaginal fluid, and colorectal tissue over 14 days.

Since a 25 mg dose of TAF produces TFV-DP levels 7-fold higher in PBMCs than a 300 mg dose of TDF, the researchers hypothesised that TFV-DP concentrations in cervical, vaginal, and rectal mucosal tissue would also be 7 times higher with TAF than with TDF.

Instead, they found that drug concentrations were lower in genital and rectal tissue than predicted, even though levels in plasma and cells were consistent with prior studies. Tenofovir levels in plasma were 19-fold lower with TAF than with TDF, while TFV-DP levels in PBMCs were 9-fold higher.

But tenofovir levels in genital tissue (cervical and vaginal combined) were about 2-fold lower with TAF than with TDF. Levels peaked at 12 hours after dosing and became undetectable by day 10. TFV-DP levels were below the level of detection in 75% of the genital samples after TAF dosing compared with 25% of samples after TDF dosing. Tenofovir levels in cervicovaginal fluid were about 11-fold lower with TAF.

Tenofovir concentrations in rectal tissue were about 10-fold lower with TAF than with TDF. Here, levels peaked by day 3 and remained detectable through the end of the 14-day study period. TFV-DP levels were undetectable in 63% of the rectal samples after TAF dosing but always detectable after TDF dosing.

"Over 48 hours, tenofovir exposure in mucosal tissues was 2-10 fold lower after TAF than TDF" and "TFV-DP exposure was 13-fold lower in rectal tissue and 1-fold lower in the female genital tract," the researchers summarized.

Garrett said additional research is needed to better understand the pharmacology of TAF in mucosal tissues and to determine pharmacological targets or surrogate markers that consistently predict what drug levels confer adequate protection against HIV infection.

In addition, we still do not know whether protection depends on tenofovir or TFV-DP levels in plasma, in genital or rectal tissues, or both.

Until more is known, both Garrett and Garcia-Lerma stressed that TAF should not be used for PrEP until clinical trials are complete and it is approved for this indication.

If TAF/FTC for HIV treatment is approved in the U.S. in the coming months, as expected, it will be important to educate potential users that they should not substitute the new coformulation for Truvada on an off-label basis.

2/24/16

References

I Massud, J Mitchell, D Babusis, G Garcia-Lerma, et al. Chemoprophylaxis with Oral FTC/TAF Protects Macaques from Rectal SHIV Infection. Conference on Retroviruses and Opportunistic Infections. Boston, February 22-25, 2016. Abstract 107.

KL Garrett, ML Cottrell, HM Price, et al. Concentrations of TFV and TFVdp in Female Mucosal Tissues after a Single Dose of TAF. Conference on Retroviruses and Opportunistic Infections. Boston, February 22-25, 2016. Abstract 102LB.