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  International HIV and Hepatitis Drug Resistance Workshop
June 8-12, 2010,
Dubrovnik Croatia
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Infection With 3TC/FTC Mutant Virus Favors Lower Pretreatment Viral Load
  International HIV and Hepatitis Drug Resistance Workshop, June 8-12, 2010, Dubrovnik, Croatia
Mark Mascolini
Antiretroviral-naive people infected with virus carrying the M184V/I mutations evoked by lamivudine (3TC) or emtricitabine (FTC) had pretreatment viral lowers significantly lower than people not infected with resistance mutations, according to results of an 8000-person study in Britain [1]. The findings suggest that the impaired replication capacity of M184V/I virus translates into a lower viral load in the absence of treatment. But the investigators suggested the effect may be too small to have any clinical or public health impact.
David Dunn and colleagues with the UK HIV Drug Resistance Database and the UK CHIC Study planned this analysis because resistant virus created by site-directed mutagenesis has a lower replication capacity ("fitness") than nonmutant (wild-type) virus, and because about 10% of newly infected people in high-income countries get infected with resistant virus. Those people may be expected to have a lower viral load because of the reduced fitness of their viral population, but studies on this question have proved inconclusive.
This analysis focused on people who had resistance genotyping before starting antiretrovirals and then had a viral load assay and CD4 count within 6 months of the resistance test and before therapy. The investigators defined transmitted drug resistance according to the 2007 World Health Organization surveillance list.
Among the 7994 people included, 12% got genotyped in 1997-1999, 36% in 2000-2004, and 52% in 2005-2007. Nearly two thirds (62%) were gay men, while 16% were heterosexual women, and 10% heterosexual men. While 62% were white, 22% were black and 16% of other races. Subtype B predominated (68%), followed by C (13%), A (4%), CRF_AG (4%), and others (11%). The group CD4 count averaged 361 and the viral load about 40,000 copies.
Dunn and colleagues counted 709 people (9%) with a transmitted drug resistance mutation, including nucleoside mutations only in 4%, nonnucleoside mutations only in 2%, protease inhibitor mutations only in 1%, and mutations conferring resistance to two or more antiretroviral classes in the rest. Initial viral loads did not differ by class of transmitted mutants.
Sixty-one people had the M184V/I mutations , 53 of them with other mutations. Of all the mutations detected, only M184V/I correlated with a pretreatment viral load lower than the load among all people with a transmitted mutation. People with virus carrying M184V/I had a first viral load 0.33 log lower than the rest of the group (95% confidence interval -0.54 to -0.11). Viral load in people with M184V/I was 53% lower than the group load of people not infected with mutant virus (P = 0.002). None of the mutations analyzed correlated with a viral load significantly higher than the rest of the mutant virus group or significantly higher than in people without mutant virus.
Dunn noted that most people in this study group had chronic HIV infection when tested, so additional people may have been infected with mutant virus that reverted to wild-type before testing. As a result, the study did not assess the initial impact of transmitted mutant virus on viral load.
The investigators mentioned previous speculation that transmitted resistance mutations may lower the risk of HIV transmission by blunting viral loads in untreated people. Dunn and coworkers believe their data "suggest that any such population-level effect is likely to be small" for two reasons: They found that only M184V/I had an effect on first-measured viral load, and the overall prevalence of M184V/I in this large group of chronically infected people was only 0.8%.
1. Harrison L, Castro H, Cane P, et al. The effect of transmitted HIV-1 drug resistance on pre-therapy viral load. International HIV and Hepatitis Drug Resistance Workshop. June 8-12, 2010. Dubrovnik, Croatia. Abstract 41.