Drug-resistant HIV can remain detectable in the male genital tract, and potentially transmissible to others, for an extended period of time, according to a study published in the August 1 issue of the Journal of Infectious Diseases (JID). The new findings, reported by Davey Smith, MD, of the University of California, San Diego, and his colleagues, also confirm that drug-resistant HIV can be spread by individuals who are newly infected and may not know that they are harboring a difficult-to-treat strain of the virus.

The study involved five San Diego men participating in the Acute Infection and Early Disease Research Program (AIEDRP). The five subjects were all newly infected with HIV upon enrolling in the international cohort and listed sex with other men as their only transmission risk factor.

At the time of study entry, all five men had non-nucleoside reverse transcriptase inhibitor (NNRTI)-resistant HIV detected in their blood and semen samples, suggesting that they had been infected by someone else with NNRTI-resistant virus. Additionally, two of the men had evidence of HIV resistance to drugs in all three classes of oral HIV medications.

The first goal of the study was to determine how long NNRTI-resistant HIV could be detected in the patients’ blood and semen samples after their estimated dates of infection. For as long as drug-resistant virus remains detectable in the male genital tract, Dr. Smith’s team suggests, sexual transmission of the virus remains a possibility.

At the time of the paper’s submission for publication in JID, three of the five men (subjects 1, 2, and 5) – none of whom had received any antiretrovirals – had detectable NNRTI-resistant HIV in their blood and semen samples (between 102 and 444 days).

One individual (subject 3) had NNRTI-resistant HIV in his blood and semen samples collected approximately 475 days after his estimated date of infection. According to samples collected on day 875, NNRTI-resistant HIV was still detectable in semen, but had been replaced by drug-sensitive (wild-type) virus in the blood. Only in samples collected on day 1193 was drug-sensitive virus detectable in both blood and semen. In other words, NNRTI-resistant HIV may have persisted in his semen for almost a year after it reverted to wild-type in his blood.

Another individual (subject 4) had a mixture of drug-resistant and drug-sensitive virus in blood samples collected 1179 days after his estimated date of infection, whereas drug-resistant HIV remained the only detectable virus in his semen sample.

The second goal of the study was to evaluate the transmissibility of drug-resistant HIV from the male genital tract. To do this, Dr. Smith and his colleagues investigated three events of drug-resistant HIV transmission involving two of the five original study participants.

One of the individuals (subject 1) asked a former sex partner – who he believed to be the likely source of his infection (called source 1) – to participate in the study.

Another individual (subject 2) invited two sex partners to join the study. Subject 2 thought that he likely infected these two individuals (dubbed recipients 2A and 2B), as they both experienced symptoms of acute HIV infection approximately nine days after engaging in sexual activity with him.

After interviewing the transmission pairs and studying the virus’s genetic structure in the blood and seminal fluid of the men, the researchers confirmed that subject 1 was infected with an NNRTI-resistant form of HIV from source 1, and that subject 2 had gone on to infect recipients 2A and 2B with NNRTI-resistant HIV.

Dr. Smith and his team write that these two cases “demonstrate how the persistence of drug resistance in the [male genital tract] allows the transmission of drug resistance from source partners with either acquired resistance…or transmitted resistance.”

Previous studies have shown that, over time, drug-resistant strains of HIV in the blood eventually revert to become drug-susceptible wild-type virus. But this study shows that the male genital tract acts as a reservoir where drug-resistant virus persists at least as long as in the blood. In these cases, it persisted longer, but Dr. Smith and colleagues note, “given the small number of participants, the actual delay cannot be extrapolated to all individuals with [transmitted drug resistance].”

An editorial accompanying the study in JID, authored by Joanne Stekler, MD, and Robert Coombs, MD, of the University of Washington in Seattle, raises important questions. It remains unclear, they write, as to which group of HIV-positive people are contributing most to the spread of drug-resistant HIV. Is it HIV-positive people who know they’re infected and have acquired drug-resistant HIV as a result of treatment experience? Or is it HIV-positive people who were infected with drug-resistant virus themselves and do not yet know they are carrying the virus?

“It is intriguing to consider whether individuals with primary HIV infection (PHI) are not only more likely to transmit HIV infection but also may contribute disproportionately to the transmission of HIV drug resistance,” Drs. Stekler and Coombs write. “[Viral load] levels in [semen] are highest during the first few months after HIV acquisition, and sexual transmission from source partners with PHI contributes to a significant proportion of overall HIV incident infections.”

Ominously, Drs. Stekler and Coombs write that “Captain Edward John Smith ignored several warnings about icebergs and went down with the RMS Titanic; are Davey M. Smith and colleagues giving us a warning about a metaphorical HIV drug-resistance iceberg that we should heed to avoid a similar fate?”