Although drug resistance may linger for months or even years when individuals become infected with a drug resistant virus, evidence from a large European study does not suggest that these individuals have a poorer response to first line therapy, according to findings presented at the Eleventh Conference on Retroviruses and Opportunistic Infections in San Francisco this week.
A range of studies from North America and Europe presented at the conference have shown that drug resistance mutations are far more persistent than previously assumed in individuals followed after acquisition of drug-resistant virus. In particular, resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs) can persist for at least two years after infection, researchers reported.
Susan Little of University of California, San Diego, reported on twelve individuals infected with drug-resistant virus who were identified an average of 56 days after exposure to HIV. Ten had acquired virus with genotypic evidence of NNRTI resistance, five had PI-resistant virus and five had nucleoside analogue resistant virus (two had multidrug resistant virus, resistant to agents in all three drug classes, and three had virus resistant to at least one drug in two drug classes).
Only one individual with NNRTI-resistant virus experienced any increase in drug susceptibility during a median follow-up period of 310 days, and the mean time to the emergence of any variants without the acquired NNRTI mutation (wild type) was 375 days. No protease inhibitor mutations disappeared during the follow-up period, whilst viruses with nucleoside analogue mutations did not begin to be replaced by wild-type viruses until an average follow-up of one year had elapsed. The M184V mutation associated with 3TC treatment was identified in two patients, and reverted to wild type after 181 days and 327 days respectively.
Only one patient totally reverted to wild type virus, after follow-up of 2.8 years.
Multidrug resistance has been associated with low replication capacity, and hence less harm to CD4 cell counts, in other studies, but in this sample, replication capacity was high, leading Susan Little to suggest that drug-resistant variants with higher replication capacity will tend to be favoured for transmission. She also warned that persistence may amplify the transmission of drug-resistant virus.
“Persistence provides a window of opportunity for onward transmission at a time when replication capacity and viral load are high, during early HIV infection,” she told the conference.
Pat Cane of the UK-based Health Protection Agency Antiviral Susceptibility Unit reported that mutations associated with AZT and NNRTI resistance persisted for up to 33 months in individuals identified through a UK study of newly infected individuals. Participants were followed prospectively after identification and tested on a regular basis to identify patterns of genotypic resistance.
Eighteen patients with drug resistance were identified in this study. The M41L mutation associated with AZT treatment was found in five, and persisted to the last sample in the study, taken between 7 and 33 months post-seroconversion. Six patients had mutations at codon 215, also associated with AZT treatment. A variety of amino acid patterns were noted at this codon; in four cases the amino acid pattern remained stable, whilst in two cases a switch from T215Y to T215C was observed.
Non-nucleoside reverse transcriptase inhibitor resistance was seen in five patients, three of whom had acquired multidrug resistant viruses. Two patients experienced loss of NNRTI resistance after 23 and 25 months, but those with multidrug resistance exhibited unchanged resistance patterns at last follow-up (17, 24 and 18 months after seroconversion). These patients also had protease inhibitor resistance mutations which remained unchanged throughout the follow-up period.
Clinical implications
Two predominant patterns of acquired resistance were seen in the two studies reported here. One was acquisition of resistance to NNRTIs, with little if any reversion of resistance. The other was resistance to agents in more than one drug class, potentially presenting more complex difficulties in prescribing a first-line regimen.
UK guidelines recommend resistance testing in all patients presenting with HIV infection for the first time, to establish a baseline resistance pattern. However, the effects of resistance on response to first-line treatment have not been systematically examined in large numbers of patients.
Researchers from the international CASCADE collaboration presented an analysis of response to first-line treatment in 20 patients who had acquired HIV resistant to at least one drug, and compared them to 132 patients without evidence of resistance and known dates of seroconversion from European seroconverter cohorts. They found no significant difference in the time taken to achieve a viral load below 500 copies between individuals who were not fully sensitive to all agents in their first regimen and those who were judged fully sensitive by genotypic resistance test. They also found no evidence that transmitted resistance to a particular class of drug conferred a disadvantage, but they did suggest that transmitted resistance could affect response to second- and third-line regimens, since it may narrow the range of available drugs that could be used after the failure of the first regimen.
Cane P et al. Persistence of primary genotypic resistance following HIV-1 seroconversion for as long as three years post-infection. Eleventh Conference on Retroviruses and Opportunistic Infections, San Francisco, abstract 684, 2004.
Little S et al. Persistence of transmitted drug-resistant virus among subjects with primary HIV infection deferring antiretroviral therapy. Eleventh Conference on Retroviruses and Opportunistic Infections, San Francisco, abstract 36LB, 2004.
Pillay D et al. The effect of transmitted drug resistance on virological response to HAART regimens adjusted for genotypic resistance at baseline. Eleventh Conference on Retroviruses and Opportunistic Infections, San Francisco, abstract 685, 2004.