Infection with a drug-resistant strain of HIV slightly accelerates CD4 T-cell decreases in the first year after seroconversion, but causes no difference in CD4 cell counts thereafter, according to a research letter published in the July 2nd edition of AIDS.
The transmission of drug-resistant HIV is well documented, but the effect of resistance on the course of disease in antiretroviral-naive patients has not previously been assessed. “Our finding of little eventual difference in CD4 cell levels between those with and without transmitted drug resistance… suggests that any loss of fitness as a result of resistance may not impact on disease progression in the absence of therapy,” the authors conclude.
The investigators, from London and Brighton, used data from the UK Register of HIV Seroconverters, a national reference of patients whose time of seroconversion can be reliably estimated. They analysed CD4 cell counts from a subset of 124 patients who had had a genotypic resistance test close to seroconversion.
Twenty-one (17%) of these patients had been infected with drug-resistant virus, the majority of whom had one (eleven patients, 52%) or more (four patients, 19%) mutations associated with nucleoside analogue resistance. There were few demographic differences between the patients with and without drug-resistant virus, with most being gay men (86% versus 88%) and with a median age of 32.8 years (34.7 versus 32.4).
The authors used a mathematical model to estimate the patients’ CD4 cell counts at seroconversion, and the rate of CD4 T-cell decline, adjusting for age at seroconversion, sex, route of exposure, and presentation during primary infection.
There were non-significant trends for patients with drug-resistant virus to have higher CD4 cell counts at seroconversion (658 versus 554 cells/mm3, p = 0.39), and to have faster CD4 T-cell declines in the first year after seroconversion (166 versus 47 cells/mm3 for an individual with an initial CD4 cell count of 500 cells/mm3, p = 0.08). “Although not statistically significant, [this] is consistent with previous data showing increased CD4 cell counts in patients infected with transmitted drug resistance,” the authors comment. “This suggests a difference in the initial pathogenic mechanisms induced by resistant compared with wild-type virus after infection.”
After the first year, the rate of cell decline was similar in both groups (56 cells/mm3 each year, p = 0.64). “Our data suggested that after the first year, the CD4 cell profiles of those with and without transmitted drug resistance tended to converge.”
The reasons for the trend towards more rapid CD4 T-cell loss with resistant virus are unclear. The authors admit that “it remains difficult to explain the possible faster CD4 cell decline… on the basis of viral genome determinants.” They claim that reversion of the drug-resistant virus to a fitter wild-type version only occurs rarely, which “casts doubt on the clinical relevance of reduced replicative capacity associated with transmitted drug resistance.”
An alternative possibility is that the initial burst of replication of the drug-resistant virus is sub-optimal, accounting for the higher initial CD4 cell count after seroconversion, but that this is followed by higher viral loads and greater declines in CD4 cell counts.
The authors plan to examine these possibilities by assessing viral load changes over time in patients with and without drug-resistant virus. Their future studies will also encompass an assessment of the impact of individual mutations on disease progression.
Further information on this website
Transmission of drug-resistant HIV
Resistance - factsheet
Resistance - patient information booklet
Study finds that 8% of newly diagnosed HIV patients in US have drug resistance - news story
Genotype testing before treatment may identify patients susceptible to protease inhibitor resistance - news story
Reference
Bhaskaran K et al. Do patients who are infected with drug-resistant HIV have a different CD4 cell decline after seroconversion? An exploratory analysis in the UK Register of HIV Seroconverters. AIDS 18: 1471-1473, 2004.