HIV that is resistant to the non-nucleoside drugs (NNRTIs) efavirenz and nevirapine is efficiently transmitted between members of sexual networks, a study from Canada has found. The proportion of NNRTI-resistant HIV could even be amplified by rapid, ‘chain reaction’ transmission between members of large networks, the study finds.
In contrast, other types of HIV drug resistance are more likely to appear within isolated cases of infection and seem to be ‘filtered out’ by such chain transmission.
An important study last year of HIV transmission in Quebec, Canada, in which people (largely gay men) recently infected with HIV had their virus subjected to extremely precise analysis of its entire polymerase gene, found that half of HIV infections in the province occurred in smaller or larger clusters of anything between two and 17 people, where a ‘cluster’ was defined as the occurrence of HIV viruses that were genetically identical or near-identical in different people.
Estimating the dates of transmission and the rate of change in the HIV polymerase gene showed that about half of all infections were transmitted by people in primary HIV infection, in the first six weeks or so when people’s viral loads are high.
Subsequent studies from other parts of the world including the UK have confirmed that a high proportion (25%-50%) of HIV infections is acquired from people who are themselves in primary infection.
Dr Mark Wainberg of the team at the McGill AIDS Centre in Montreal that conducted the initial study undertook a further evaluation of the same cohort to establish the frequency of transmission of drug-resistant virus.
They found worrying evidence that clustering of transmissions and therefore rapid-fire ‘cascades’ of transmission were getting more common, with the proportion of infections that were in a cluster increasing from 49% in December 2005 to 56% by June 2007. The average number of people in transmission clusters had also increased, from 6.6 to 10.3. People infected in clusters were also younger, with an average age of 30 as opposed to 40 in unique infections.
Wainberg’s team found 64 small clusters (defined as having four members or fewer) and 31 large ones (five or more members). Infection with virus resistant to the nucleoside analogue (NRTI) drugs – AZT, tenofovir, abacavir, 3TC and the like – was more common in one-off infections than in ones in clusters. Nine per cent of unique infections had NRTI resistance compared with 3.8% in small clusters and only 2.1% in large clusters.
In contrast NNRTI resistance was no more common in small clusters than in unique infections (5.9% and 6.7% respectively), but it was a lot more common within large clusters, at 15.5% of all virus acquired by large-cluster members. Individual NNRTI mutations were also more common in large clusters while individual NRTI mutations were less common. Protease inhibitor (PI) resistance was also less common in clusters than in unique infections (2.4% versus 4.0%).
Why is this happening? NRTI and PI resistance tends to make the virus carrying it less fit. It reproduces more poorly and people carrying it tend to have lower viral loads than people with NNRTI-resistant virus, so it is transmitted less often. This also means it tends to decrease as a proportion of the total virus carried by people with multiple strains. so, if they transmit HIV, they tend to transmit fitter, non-resistant virus.
NNRTI resistance on the other hand exacts no fitness penalty and also persists longer in the body. In a group of people who are rapidly transmitting HIV to each other and where people are infected with genetically near-identical strains, therefore, any introduction of NNRTI-resistant virus into the group results in a high likelihood that it will be transmitted to multiple individuals in the group. In this way transmission clusters can act as amplifiers of NNRTI resistance.
“NNRTIs [in combination therapy] may be more fragile than long term clinical trials suggest,” said Wainberg. “It is only logical that the transmission of NNRTI mutations will continue to increase in settings in which they are used extensively in first-line therapy.”
However he also added that he was hopeful that the new-generation NNRTIs, etravirine and the yet-to-be-license rilpivirine, which do not acquire resistance so easily, would not show the same pattern of cluster amplification.
The findings have particular relevance for resource-limited settings where first-line therapy is almost entirely dependent on NNRTIs, and where treatment failure may not be detected for months or even years due to the lack of viral load testing. In these settings recently reported evidence suggests that anywhere from 30-90% of patients failing NNRTI-containing regimens have NNRTI resistance by the time that treatment failure is detected.
The World Health Organization is working with national AIDS programmes to develop surveillance systems in resource-limited settings that can detect if NNRTI resistance is becoming a serious problem in newly-infected people.
Further information about the transmission of drug-resistant HIV can be found here on aidsmap.com
Brenner BG et al (presenter Wainberg MA). NNRTI mutations are efficiently transmitted within clusters of new infections. Ninth International Congress on Drug Therapy in HIV Infection, Glasgow. Abstract O114. 2008.