www.hivandhepatitis.com

CROI 2012: Drug Levels Predict Efficacy in PrEP Trials, Highlighting Importance of Adherence

Two analyses of PrEP studies presented at the 19th Conference on Retroviruses and Opportunistic Infections (CROI 2012) this week in Seattle found that drug levels -- and by implication, adherence -- were strongly correlated with protection against HIV infection.

Pre-exposure prophylaxis (PrEP) refers to the use of antiretroviral drugs by HIV negative people to prevent HIV infection. In recent years several studies have shown PrEP to between 42%-76% effective. However, one study, called FEM-PrEP, was halted early when it failed to show any protective effect. Researchers are keen to understand why some study populations benefit greatly from PrEP, while others do not.

Partners PrEP

Partners PrEP enrolled almost 4758 couples in Uganda and Malawi. In each couple, 1 member was HIV positive and the other was HIV negative (called serodiscordance). The HIV negative partner was randomly assigned to receive 1 of 2 PrEP regimens -- tenofovir (Viread) alone or tenofovir/emtricitabine (Truvada) -- or placebo. Overall PrEP reduced new infections by approximately 70%.

In an oral session at CROI, Deborah Donnell of the Fred Hutchinson Cancer Res Center in Seattle presented results from a study of people who became infected during Partners PrEP, while taking active drugs.

Results

• In total there were 29 new HIV infections among people in the 2 PrEP active drug arms.
• In the tenofovir monotherapy arm, only 35% of people who became infected had detectable levels of the drug in their blood.
• In the tenofovir/emtricitabine combination arm, 25% had detectable drug levels.
• New infections were reduced by 86% in the tenofovir arm when tenofovir drug concentrations were > 70 ng/mL.
• In the tenofovir/emtricitabine arm there was a 90% reduction.

iPrEx

iPrEx was a randomized, controlled clinical trial which enrolled 2499 men who have sex with men (MSM) and transgender women at 11 sites on 4 continents. Participants were randomly assigned to take either Truvada PrEP or a matching placebo once-daily. All participants were counseled about safer sex practices, provided with free condoms, and tested for HIV infection every 12 weeks.

The main results from iPrEx were presented at the 2011 International AIDS Society meeting in Rome.

There were 132 total new HIV infections in the study -- 84 in the placebo arm and 48 in the tenofovir/emtricitabine PrEP arm -- indicating that PrEP was 42% effective in an overall intent-to-treat analysis. PrEP was 92% effective, however, among participants with detectable drug in their blood.

During the same oral session at CROI 2012, Peter Anderson of the University of Colorado Denver presented detailed results looking at intracellular tenofovir concentrations and the risk of HIV infection in iPrEx. They did not evaluate emtricitabine concentrations.

Results

• A total of 48 patient samples were tested.
• When samples had  tenofovir levels of > 15.6 fmol/mL, there was a 90% reduction in risk of infection.

Based on these findings, the researchers also looked at how different dosing schedules might affect infections. Using data from the STRAND study, they estimated that taking tenofovir:

• 2 times per week would result in a 76% reduction in infections;
• 4 times per week would result in a 97% reduction;
• 7 times per week would result in a 99% reduction.

PrEP has received significant attention in the past few years. As researchers and community activist advocated for more and better strategies to reduce the rate of new HIV infections, PrEP has stood out for its potential. The drugs used in most PrEP studies are easy to take (once-daily, no food restrictions) and tend to be well tolerated. The hope is that PrEP use by people at elevated risk for HIV infection could help reduce the stubbornly high rates of infection.

Taken together, these studies highlight the importance of adherence when using PrEP. While individuals do metabolize drugs differently, the magnitude of the differences in drug concentrations in these analyses is likely related to adherence.

Most research on medical adherence shows that people struggle to take medicine regularly for long periods of time. This is especially the case when people do not feel sick. Given this, some have questioned the wisdom of giving healthy people HIV drugs, when we expect that a number of them will fail to strictly adhere to their regimens.

Complicating things further, there are many people already infected with HIV who need these drugs and do not have access to them. In the U.S. alone, there are over 4000 people on ADAP (AIDS Drug Assistance Program) waiting lists. Worldwide the picture is worse. Medical, economic, and ethical factors complicate matters, and people are working hard to address these issues.

The research presented at CROI shows something not at all surprising: Medicines generally only work if you take them regularly. We know this is true for people living with HIV, where numerous studies have demonstrated the strong link between adherence and a range of positive outcomes (undetectable viral load, high CD4 count, lower rates of death). Issues around adherence will need to be hashed out -- with a particular focus on adherence support systems -- if PrEP is ever to meet its promise.

3/8/12

References

D Donnell, J Baeten, C Hendrix, et al. Tenofovir Disoproxil Fumarate Drug Levels Indicate PrEP Use Is Strongly Correlated with HIV-1 Protective Effects: Kenya and Uganda. 19th Conference on Retroviruses and Opportunistic Infections (CROI 2012). Seattle, WA. March 5-8, 2012. Abstract 30.

P Anderson, A Liu, S Buchbinder, and the iPrEx Study Team. Intracellular Tenofovir-DP Concentrations Associated with PrEP Efficacy in MSM from iPrEx. 19th Conference on Retroviruses and Opportunistic Infections (CROI 2012). Seattle, WA. March 5-8, 2012. Abstract 31LB.