HIV: Low Risk for Drug Resistance From PrEP

Lara C. Pullen, PhD

April 02, 2015

Drug resistance in individuals who acquire human immunodeficiency virus (HIV) while receiving preexposure prophylaxis (PrEP) is rare, but can occur, according to the results of a randomized clinical trial of single- or dual-agent PrEP.

In the study, emtricitabine plus tonofovir disoproxil fumarate was associated with a greater frequency of resistant mutations than PrEP with tonofovir alone.

The results of the study were published in the April 15 issue of the Journal of Infectious Disease.

"The risk of resistance was highest in those with unrecognized acute infection at PrEP initiation, suggesting that careful screening is important in PrEP implementation," write Dara A. Lehman, PhD, from Fred Hutchinson Cancer Research Center, in Seattle, Washington, and colleagues.

In addition, the authors report that the resistance arising in individuals who acquire HIV while taking PrEP is predominately a result of an emtricitabine-selected mutation.

The Partners PrEP Study

Standard genotypic and phenotypic assays are not sensitive enough to detect low-frequency mutations within a viral population. Therefore, the researchers used a highly sensitive assay to detect low-frequency resistance among HIV seroconverters from the Partners PrEP Study in Africa.

The study was a placebo-controlled trial of PrEP in uninfected men and women who are partnered with an individual who is HIV-positive. The investigators measured levels of tenofovir in serum samples every 3 months and used this as an objective measure of PrEP use. The sampling also had the advantage of minimizing the duration of PrEP exposure after infection.

The research team documented a total of 121 seroconverters, 25 of whom received the dual-agent therapy, 38 of whom received tenofovir alone, and 58 of whom received placebo. The investigators estimated that 123 infections were prevented during the course of the study.

Only 7 of 25 seroconverters in the dual-therapy group and 19 of 38 seroconverters in the single-therapy group had detectable levels of tenofovir during HIV infection. There were only five cases of PrEP-selected resistance among 63 seroconverters in the active PrEP group.

The rate of resistance in the emtricitabine plus tonofovir disoproxil fumarate group (4 [57%] of 7) was significantly higher than the rate of resistance in the group of patients treated with tenofovir only (1 [5.3%] of 19; P = .01).

The results confirm previous findings that resistance occurs in only a minority of seroconverters. Moreover, resistance appears to occur primarily in individuals who have systemic HIV infection when PrEP is started. The results suggest that increased rate of resistance in patients receiving emtricitabine must be weighed against the added efficacy of adding the agent to tenofovir for PrEP.

The threat of drug resistance is on the mind of clinicians and public health officials who advocate antiretroviral use as a means of controlling the HIV epidemic. As PrEP use is increasing, so is the fear of drug resistance.

"There are ways to minimize the risk of drug resistance during PrEP use," Robert M. Grant, MD, MPH, and Teri Liegler, PhD, from the University of California, San Francisco, write in an accompanying editorial, including using highly sensitive viral tests that can rule out acute infection before starting PrEP.

Dr Grant and Dr Liegler caution against "fomenting fear of drug resistance," saying it is "misguided if it distracts us from fear of HIV itself, by far the greater threat to human health."

PrEP is frequently coupled with regular monitoring, and thus has the added benefit of detecting breakthrough HIV-1 infection within months of infection.

The authors have disclosed no relevant financial relationships. Gilead Sciences donated study drug for Dr Grant's research on PrEP. Dr Liegler has disclosed no relevant financial relationships.

J Infect Dis. 2015;211:1211-1218. Article full text, Editorial full text

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