Ethical considerations regarding oral preexposure prophylaxis in HIV prevention trials

Abstract

Purpose of review Although substantial evidence supports oral pre-exposure prophylaxis with tenofovir disoproxil fumarate and emtricitabine (OPTF) for the primary prevention of HIV infection in certain settings, assessing whether other promising HIV prevention interventions are safe and effective as well as determining optimal prevention strategies necessitates research. However, given the established safety and efficacy of OPTF, it is necessary to determine when and how is it ethically acceptable to conduct this research, which is the focus of this review. Recent findings Although they are somewhat intertwined, questions regarding OPTF in research can be considered in two broad categories: use in a comparison arm and as a standard of prevention. Major statements addressing these issues are described and recent literature directed at the particular issue of OPTF in research is reviewed and critiqued. Summary There is now arguably a rebuttable presumption for the use of OPTF as a comparator or as part of the standard of prevention in much future HIV prevention research. However, making such determinations necessitates taking into account scientific considerations, the modality being evaluated, acceptability, adherence and the local context. Doing so should be optimized by robust stakeholder engagement.

The promise and pitfalls of long-acting injectable agents for HIV prevention

“…Considerations for the design of phase 3 efficacy studies for prevention are complex and nuanced now that daily oral TDF/FTC has a robust supportive body of evidence for HIV prevention; the results of upcoming dapivirine ring studies, if positive, may additionally complicate these issue for women. A detailed discussion of the ethics of phase 3 efficacy study designs for HIV prevention is provided in an additional article in this issue [28]. …”

Estimation of new HIV diagnosis rates among high‐risk, PrEP‐eligible individuals using HIV surveillance data at the Metropolitan Statistical Area level in the United States

“…This approach may also be useful in the design and interpretation of active comparator noninferiority trials for HIV prevention. Since a true placebo arm is often excluded in modern PrEP clinical trials , trial design and interpretation rely on historical placebo and prior active comparator efficacy data. This approach assumes that the active comparator is similarly effective compared to prior clinical trials, and thus the interpretation of the trial may be incorrect if the active comparator performs significantly better (or worse) than it has previously.…”

“…Such community‐level data are important to guide local prevention efforts tailored to each community's specific needs. It is equally important to understand local HIV diagnosis rates in PrEP‐eligible individuals when designing and interpreting clinical trials involving PrEP and novel HIV prevention strategies, especially when placebo arms must be omitted for ethical reasons . As F/TDF efficacy is high when taken as directed, the lack of a placebo or control arm can make it challenging to determine whether a new drug for PrEP is effective .…”

A strategic action framework for multipurpose prevention technologies combining contraceptive hormones and antiretroviral drugs to prevent pregnancy and HIV

“…Regulatory requirements in recent studies for comparator trial designs have been devised to show non-inferiority or superiority of new products relative to oral pre-exposure prophylaxis [46,47]. This is a departure from placebocontrolled trials for HIV prevention, in light of the ethical implications of conducting new trials when effective HIV prevention already exists [48,49]. It is likely that future MPT trials will be required to have similar comparator designs for the HIV prevention indication.…”