Drug Resistance in People on PrEP Who Acquire HIV

While a small subset of individuals acquired HIV despite being in a pre-exposure prophylaxis (PrEP) program, many of those people had mutations resistant to antiretroviral drugs, according to a study from the Global Evaluation of Microbicide Sensitivity (GEMS) project.

Breakthrough HIV infections occurred in 204 individuals in GEMS, out of more than 104,000 people in sub-Saharan Africa who enrolled in the program, reported Urvi Parikh, PhD, of the Microbicides Trials Network and the Virology Core Laboratory at the University of Pittsburgh.

Of those people who experienced breakthrough infections, 175 gave blood samples for analysis, and 104 of those samples were successfully genotyped, with at least one HIV drug-resistant (HIVDR) mutation detected in 47 of those samples, or 45% of that subgroup, GEMS co-director Parikh said at a press conference at the International AIDS Society (IAS) virtual meeting. She noted that 35% of the samples could not be genotyped, mainly because of insufficient HIV RNA.

"Daily pre-exposure prophylaxis is very effective in preventing HIV, but when someone becomes HIV-positive while using PrEP, there is a risk that they will get drug resistance," Parikh explained. "The goal of our GEMS study was to figure out how many people who became HIV-positive while taking PrEP had drug-resistant HIV. This is important because the same drugs are used for treatment and prevention, and drug resistance could undermine the important progress that has been made towards ending the HIV epidemic globally."

"Improved identification of acute infection before initiating PrEP, and HIVDR monitoring on PrEP is essential for PrEP rollout programs to preserve antiretroviral options for both treatment and prevention," she added. "The study was done in real-world settings as national PrEP programs were rolled out in Zimbabwe, Kenya, and Eswatini, and through PrEP demonstration projects in South Africa. This was a huge coordinated effort with ministries of health and PrEP delivery partners, funded by USAID and PEPFAR."

Of the 175 individuals (median age 24; 74% female) who provided drug samples, 41% were from South Africa, 33% were from Kenya, 16% were from Zimbabwe, and 10% were from Eswatini.

About 21% of the breakthrough infections occurred in HIV serodiscordant partnerships, while about 10% occurred among female sex workers, and 9% occurred in men who have sex with men (MSM), as well as 6% in transgender individuals, Parikh reported. She pointed out that 26% of infections occurred within 60 days of PrEP initiation, suggesting that some of the participants had been acutely infected with HIV before they entered GEMS.

Most of the resistance mutations were unrelated to PrEP use, and they had originated from antiretroviral therapy in the partner who transmitted HIV, according to the researchers. Transmitted non-nucleoside reverse transcriptase inhibitor mutations unrelated to PrEP included K101E (1%), K103NS (13%), V106IM (5%), Y181C (2%), and G190A (7%).

The majority of mutations (23 of 27 cases) were due to M184I/V, the emtricitabine/FTC mutation, and there were four cases of tenofovir-resistant HIV (mutations K65R and K70EN).

"Taking PrEP every day is very effective at preventing HIV," Parikh stressed in a press release. "The number of reported infections on PrEP was very small compared to the number of PrEP users, which tells us that the benefit of PrEP in preventing HIV far outweighs the risk of drug resistance."

The findings "reinforce the need for PrEP rollout programs to check for acute infections before starting people on PrEP, and to conduct ongoing HIV drug-resistance monitoring," stated press conference co-moderator Hendrik Streeck, MD, of the University of Bonn in Germany.

"Drug resistance in PrEP breakthrough infections could threaten treatment effectiveness, contribute to spread of resistance and undermine efforts to prevent HIV, and...undermine prevention programs used in pre-exposure prophylaxis to prevent HIV infections," he noted.

Another PrEP-related IAS study demonstrated that event-driven HIV prevention regimens seemed to have a better protective effect than daily regimens in a real-world setting among MSM in China.

Comment