HIV-positive patients infected with a drug-resistant strain of the virus may not show a reversion to the wild-type strain for up to seven years after infection, according to two studies presented in the August 20th edition of AIDS. This suggests that the future treatment options available to people infected with drug-resistant HIV may be limited.
Drug resistance can be acquired in one of two ways. ‘Primary’ resistance occurs after infection with a drug-resistant strain of HIV, and accounts for between ten and 20% of new infections in the UK, Western Europe and North America. In contrast, ‘secondary’ or ‘acquired’ resistance is brought about when mutations occur in the virus that allow it to replicate in the presence of the antiretroviral drugs in the blood.
While patients with secondary resistance usually display a rapid reversion to wild-type virus if they stop taking their antiretroviral drugs, these two studies demonstrate that patients infected with resistant virus do not revert to wild-type virus in the months and years following seroconversion, in the absence of antiretroviral drug treatment.
“This persistence differs from the rapid outgrowth of wild-type viruses in established infections upon treatment interruption,” comment the first study’s authors. “Archival wild-type viruses may not exist in multiple drug resistant infections transmitted during primary HIV infection.”
In the first study (Brenner), investigators from Quebec, Canada, evaluated the changes in HIV genotype in 31 newly infected HIV-positive patients from the Quebec Primary Infection Study. Fifteen of these patients had acquired wild-type virus, ten had acquired virus resistant to one drug class, and six had multiple drug resistance.
After following the patients for between eighteen months and seven years, the authors observed that all but one of the patients showed no changes in the pattern of resistance-associated mutations in the HIV reverse transcriptase or protease genes. This suggests that “a single dominant HIV-1 species persists … in circulating blood and peripheral blood mononuclear cells,” regardless of the route of infection (sex between men or intravenous drug use) or whether the patients had been infected with wild-type or resistant virus.
Importantly, the investigators were able to analyse the virus from the partners of two of the patients infected with multiple drug resistance. In both patients' partners, treatment interruption led to a rapid reversion of the multi-drug resistant virus to wild-type HIV, in contrast to the absence of reversion to wild-type strains in the people they had infected.
The authors also demonstrated that the one patient who showed dramatic changes in resistance mutations did so following infection with a second strain of multiple drug-resistant virus from another partner. This superinfection was accompanied by a dramatic increase in viral load and acquisition of a new pattern of mutations similar to that of the partner from whom he contracted the new viral strain.
The investigators note that superinfection is rare, possibly due to the immune responses which can protect against re-infection. They speculate that "the impaired viral fitness of the initial multiple drug resistant infection may be a factor in permitting superinfection" in this case.
In the second article (Barbour), the group of investigators from San Francisco come to similar conclusions regarding the persistence of drug-resistant HIV in patients with primary resistance. They followed 22 patients recently infected with HIV, six of whom had resistance to at least one class of drug, for a median of 12 months.
All six patients maintained phenotypic and genotypic drug resistance for the period of observation. Although two of the patients lost one mutation (to AZT [zidovudine] and to 3TC [lamivudine]) after 15 months of infection, both continued to demonstrate phenotypic resistance to the nucleoside analogue class as a whole and there were no changes in genotypic or phenotypic resistance to protease inhibitors or non-nucleoside reverse transcriptase inhibitors.
“In contrast to secondary resistant infections that are rapidly overgrown when therapy is stopped, primary drug resistance persists over time,” they conclude. “Primary drug resistance will persist and remain detectable via genotypic and phenotypic tests for a year or longer after acquisition of infection.”
“Resistance testing performed early in infection will allow the clinician and patient to consider regimens most likely to lead to optimal virologic suppression once treatment is elected.”
References
Brenner B et al. Persistence of multidrug-resistant HIV-1 in primary infection leading to superinfection. AIDS 18: 1653-1660, 2004.
Barbour JD et al. Persistence of primary drug resistance among recently HIV-1 infected adults. AIDS 18: 1683-1689, 2004.