Is what we know about transmitted drug resistance just ‘the tip of the iceberg?’

Drug-resistant HIV dominates, and persists for longer, in semen compared to blood, increasing the likelihood that onward sexual transmission will occur, according to a small Californian study published in the August 1^st issue of The Journal of Infectious Diseases. An accompanying editorial notes that the prevalence – and transmission – of low-level resistance may be much higher and that this study may be “giving us a warning about a metaphorical HIV drug-resistance iceberg.”

The prevalence of transmitted drug resistance (TDR), also known as primary resistance, varies between countries and within different populations. The most recent data from the United Kingdom suggest that prevalence of transmitted drug resistance amongst antiretroviral-naive individuals declined from a peak of 14% in 2001-2002 to 8% in 2004.

Previous studies have suggested that TDR may persist for a considerable amount of time, in some cases up to seven years following initial infection.

Davey Smith and colleagues from the University of California, San Diego have previously reported that transmitted drug resistance can persist not only in plasma but also in seminal fluid for longer than three years. This study had included five newly HIV-infected gay men enrolled in the San Diego cohort of the Acute Infection and Early Disease Research Program (AIEDRP). All had acquired HIV with NNRTI-associated mutations.

In this paper, the investigators also evaluate the transmissibility of drug-resistant HIV from the male genital tract, by using phylogenetic analysis to investigate three events of drug-resistant HIV transmission after reported sexual exposure, using two of the participants in the AIEDRP.

(The paper does not mention the spectre of civil liability or of criminal prosecutions for HIV transmission, both of which are possible in California, but does note, “each partner agreed to participate and was enrolled pursuant to local institutional board standards.”).

They asked one participant – who joined the study “probably within 12 weeks of HIV infection” – to recruit the sex partner by whom he thought he had been infected with HIV. This man – who was recruited two weeks later – had acquired multi-drug resistance following a history of suboptimal drug regimens.

The investigators took blood and semen samples from both men within weeks of the alleged transmission events, and utilised rigorous phylogenetic analysis methods (using pol sequences). They found the viruses in the two men were “very closely related (

Interestingly, although the circulating viral population in the partner’s blood had a mixture of drug-resistant and drug-sensitive virus, only drug-resistant virus could be identified in his semen.

An accompanying editorial by Joanne Stekler and Robert Coombs of the University of Washington, Seattle, discusses the implications. This case study, they write, “is a counterexample to the supposition that different selection pressures exist between the blood and genital tract of individuals who receive ARV therapy and that HIV drug-resistance mutations may confer low transmission fitness, compared with wild-type virus, in individuals infected with a mixture of mutant and wild-type viruses.”

They argue that “further study of transmission pairs is essential to assess whether the transmission of resistant virus is dependent on the quantity of virus in the genital tract, whether transmission fitness is correlated with the replication capacity of virus in the blood or genital tract, and what other factors may be associated with a relative advantage for the transmission of a drug-resistant virus.”

Are individuals with primary infection more likely to pass on TDR?

A second participant in the AIEDRP study recruited two sexual partners who had developed acute HIV infection nine days after ‘high risk’ sexual exposure. Both men were found to have TDR within four weeks of becoming infected.

Again, phylogenetic analysis found that all three men had “very closely related” virus that also had the same resistance mutation (K103N). This was found to be “consistent with reported sexual transmission”.

In the accompanying editorial, Stekler and Coombs ponder the issue of serial or horizontal transmission of TDR and cite recent studies suggesting that individuals with primary HIV infection are more likely to transmit HIV. “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,” they write.

“If the risk of transmission of HIV drug resistance is associated with increasing HIV RNA levels in the genital tract, then perhaps this transmission risk provides an additional impetus for HIV prevention efforts to identify individuals with acute HIV infection using pooled nucleic acid testing algorithms [such as STARHS].”

Tip of the iceberg?

The investigators note that they have now demonstrated that drug-resistant HIV persists for at least as long in the male genital tract as in the blood, which, they suggest, “allows for a prolonged opportunity to transmit drug-resistant virus.”

In addition, the two case studies of transmission events “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.”

However, most clinical drug resistance data – including those obtained in this study – are based on standard genotypic resistance testing which can typically only measure drug-resistant HIV that makes up 30% or more of the entire population. Consequently, the true prevalence of transmitted resistance may be underestimated and, the investigators note, drug-resistant HIV in the male genital tract may last for much longer than the three years they have observed so far.

The theme is taken up by Stekler and Coombs. “Captain Edward John Smith ignored several warning about icebergs and went down with the RMS Titanic,” they write. “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?”

However, utilising more sensitive resistance testing may be counterproductive, they argue. “If sensitive resistance assays become more widely available and are used without appropriate clinical validation, there could be some unanticipated consequences. For example, HIV care providers might avoid convenient first-line agents that require fewer pills and less-frequent dosing. This might lead to a decrease in adherence because of the greater complexity of initial ARV regimens. As a consequence, the best intentions could lead to a paradoxical increase in the prevalence of HIV drug resistance.”

Instead, they write, “given the potential risks and lack of clear benefits, we should confirm that the use of highly sensitive resistance testing improves immunological and virological outcomes before a new standard of care is implemented.”

“Ultimately,” they conclude, “our therapeutic task is to stop HIV transmission as early as possible, to mitigate the transmission of drug-resistant HIV, and to avoid the epidemiological drug-resistance iceberg. Should we screen patients for high levels of genital HIV RNA and for viral resistance in genital secretions, to counsel patients about the potential risk for transmission of drug-resistant HIV? Should we be more diligent about prescribing ARVs with good penetration into genital fluids? Will the use of ARVs to prevent HIV transmission in serodiscordant couples decrease HIV transmission but eventually increase the risk of transmission of resistant virus? These and many other important questions remain unanswered but warrant further discussion and study.”