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More iPrEx and OLE Data Published: Adherence Higher in U.S.

Participants enrolled at the U.S. study sites of the global iPrEx trial of Truvada pre-exposure prophylaxis (PrEP) achieved better adherence than those in other countries, reaching 90% in San Francisco, researchers reported in the September 16 advance edition of Journal of Acquired Immune Deficiency Syndromes. Findings from the iPrEx open-label extension (OLE) were also recently published.

Studies in different populations have found that once-daily Truvada (tenofovir plus emtricitabine) is highly effective in preventing HIV infection among people who take it consistently, but overall adherence rates can be quite low.

The global iPrEx trial is the pivotal study of Truvada PrEP for gay and bisexual men, which also included a small number of transgender women. The study enrolled a total of 2499 HIV negative participants at 11 sites in 6 countries (Brazil, Ecuador, Peru, South Africa, Thailand, and the U.S.).

Participants were randomly assigned to take either Truvada or an inactive placebo once-daily, and everyone also received regular HIV testing and prevention services including risk-reduction counseling and free condoms. After the main study ended, participants had the option to continue receiving Truvada in the iPrEx open-label extension.

As previously reported in the December 30, 2010, New England Journal of Medicine, the risk of HIV infection in the main randomized iPrEx study was 44% lower overall in the Truvada arm compared with the placebo arm in an intent-to-treat analysis of all participants. For people that self-reported taking Truvada most of the time, the risk fell by 73%. Among people with detectable blood drug level, risk reduction was 92%. A mathematical model later estimated that risk reduction could reach 99% with daily use.

Adherence in iPrEx

Albert Liu from the San Francisco Department of Public Health and fellow iPrEx investigators performed a more thorough assessment of adherence patterns in the trial, looking at subgroups broken down by age, study site location, and other factors. Using blood concentrations of tenofovir or emtricitabine as an objective measure of consistent use, they evaluated frequency and factors associated with adherence in a random sample of 470 participants at week 8 and a longitudinal cohort of 303 participants through 72 weeks of follow-up.

About half the participants who received Truvada in the active treatment arm and who were included in the week 8 and longitudinal samples were over age 25 and 13% were transgender. About 60% reported having receptive anal sex without a condom at study entry and about one-quarter had sexually transmitted infections. Nearly half reported being concerned about having a place to live and 70% worried about having a job. Reported methamphetamine and cocaine use was uncommon (7%).

More than two-thirds in the active treatment arm were from Ecuador or Peru, 15% were from Brazil, 9% were from the U.S., 5% were from Thailand, and 4% were from South Africa. Participants from Ecuador and Peru were somewhat under-represented in the 8-week sample (44%) and the longitudinal cohort (56%), while people from the other countries were somewhat over-represented.

Results

• Overall, 55% of participants tested at week 8 had detectable blood drug levels.
• In the longitudinal analysis, 31% of participants never had detectable drug levels, 30% always had detectable levels, and 39% had an inconsistent pattern.
• Overall drug detection rates declined over time in the longitudinal cohort, from 59% at week 12 to 44% at week 72.
• Drug detection at some or all visits was associated with older age, having receptive anal sex without condoms, and being uncertain about the efficacy of PrEP.
• Participants over age 30 were nearly 5 times more likely to sometimes have and 33 times more likely to always have detectable drug levels compared to those under age 20.
• Drug detection at week 8 varied substantially across study site:

o   Lima and Inquitos in Peru: 35% and 55%, respectively;

o   Guayaquil, Ecuador: 60%;

o   Cape Town, South Africa: 68%;

o   Chiang Mai, Thailand: 72%;

o   Rio de Janeiro and Sao Paolo in Brazil: 71% and 77%, respectively;

o   Boston and San Francisco in the U.S.: 72% and 90%, respectively.

• In the longitudinal cohort, far more participants in Peru and Ecuador sometimes had detectable drug levels (37%-64%) than those who always had detectable drug (17%-21%).
• The opposite was seen in San Francisco, where 27% sometimes had detectable drug levels and 67% always did so.

Factors not associated with likelihood of detectable drug levels included being transgender, education level, substance use, and concerns about housing or jobs, and the researchers emphasized that such factors "should not exclude these potential PrEP users." Experiencing early side effects also did not affect likelihood of having detectable drug levels later on.

"Distinct patterns of study-product use were identified, with a significant proportion demonstrating no drug detection at any visit," the study authors concluded. "Research literacy may explain greater drug detection among populations having greater research experience, such as older [men who have sex with men] in the U.S."

The good news, they suggested, is that, "Greater drug detection among those reporting highest-risk sexual practices is expected to increase the impact and cost-effectiveness of PrEP."

iPrEx OLE

Robert Grant from the Gladstone Institutes and colleagues published results from the iPrEx open-label extension in the September 2014 edition of The Lancet Infectious Diseases. Grant previously reported OLE findings at the 20th International AIDS Conference this summer in Melbourne.

After the main randomized portion of the iPrEx study ended, participants were given the option to receive open-label Truvada for 72 weeks. A total of 1603 participants joined iPrEx OLE, with 76% choosing to take Truvada and the rest serving as an untreated control group. At this point the recipients knew they were getting the active drug, not placebo. Also, partway through the OLE participants were informed about the main iPrEx findings, so they knew PrEP worked if taken consistently. People who reported condomless receptive anal sex were more likely to chose to take Truvada in the OLE (81%), as were those with herpes (77%).

The researchers measured drug concentrations in plasma and dried blood spots for people who seroconverted and a random sample of those who remained HIV negative. They assessed PrEP uptake, adherence, sexual practices, and HIV incidence.

Results

• Among people taking PrEP, HIV incidence was 1.8 new infections per 100 person-years, compared with 2.6 per 100 person-years among those who opted not to take PrEP in the OLE and 3.9 per 100 person-years among those assigned to the original placebo group -- about a 50% risk reduction (hazard ratio 0.51 and 0.49, respectively).
• Infection rates were 2.3 per 100 person-years for people with drug concentrations suggesting they took Truvada 2 or fewer times per week, 0.6 per 100 person-years for those taking it 2-3 times per week, and 0 per 100 person-years -- or 100% efficacy -- for those taking PrEP 4 or more times per week.
• Older participants and those with more education had higher blood drug concentrations.
• People who reported condomless receptive anal sex, more sexual partners, and a history of syphilis or herpes also had drug levels indicating better adherence.
• No evidence of risk compensation -- or an increase in risky sexual practices -- was observed during open-label access to PrEP.

"PrEP uptake was high when made available free of charge by experienced providers," the researchers concluded. "The effect of PrEP is increased by greater uptake and adherence during periods of higher risk."

"People who more often engaged in risky sexual practices and who had sexually transmitted infections were more likely to join the study, more likely to choose PrEP, and more likely to have sustained protective levels of PrEP use," they continued in their discussion. "Such preferential use of PrEP during times of greater risk is expected to increase the effect and cost-effectiveness of PrEP services, and shows people's capacity to recognize and respond appropriately to risks when given attractive options."

Transgender women had lower concentrations of active tenofovir, which might have resulted from lower adherence or different pharmacokinetics -- an issue that requires further study, they noted.

"Although oral PrEP with [Truvada] is recommended for daily use, which helps foster dosing habits, the drug concentrations achieved with daily dosing...were substantially higher than the protective threshold for men and transgender women who have sex with men, providing protection against HIV infection even if a few doses are missed," they wrote. "This relation between drug concentrations in blood and protection from HIV apply to this cohort for whom anal intercourse was the primary risk factor; the minimum required adherence to PrEP and the relation between blood drug concentrations and protection from vaginal or other viral exposure might be different."

9/26/14

References

A Liu, DV Glidden, PL Anderson, R Grant, et al. Patterns and Correlates of PrEP Drug Detection among MSM and Transgender Women in the Global iPrEx Study. Journal of Acquired Immune Deficiency Syndromes. September 16, 2014 (Epub ahead of print).

RM Grant, PL Anderson, V McMahan, et al. Uptake of pre-exposure prophylaxis, sexual practices, and HIV incidence in men and transgender women who have sex with men: a cohort study. The Lancet Infectious Diseases 14(9):820-829. September 2014.