Recent reports of transmission of resistance has raised concern regarding the evolution of resistance in primary HIV infection (PHI) which may have potentially deleterious effects on future treatment outcomes and on community health. A number of presentations considered the impact of transmission of resistant virus on the immune system, persistence of multi-drug resistance (MDR) and the significance of secondary mutations on future resistance development.
Persistence of MDR transmission
A French multi-centre study evaluated two reports of sexual MDR transmission. MDR mutations were found even two years after infection in the absence of selective drug pressure in these two antiviral-naïve patients. Both patients in the study had been infected by their partners who had received salvage therapy for some time, and had since died. Phylogenetic analysis and clonal sequencing of complete protease and RT codons (1-230) in plasma of index and source patients were performed, confirming epidemiological linkage between source and index patients. Genotypic analysis revealed that at time of seroconversion, mutations to all three classes were present in the index patient. No WT virus was found. All mutations detected at seroconversion were present after two years in the absence of therapy and were found to be archived in the cellular reservoir. The authors note that these findings should alert us to the possibility of attenuated treatment response in patients infected with MDR virus and the public health risk conferred by future transmission of MDR viruses (Delaugerre).
Transmission and impact of secondary mutations
Whilst previous reports of resistance transmission have been associated with poor virological response to therapy, an interesting study by the US Centers for Disease Control in Atlanta examined the significance of transmission of secondary mutations at time of infection. Of the 56 individuals from their surveillance database recently diagnosed who had virus containing nucleoside analogue-associated mutations (NAMs), 16.1% had secondary secondary NAMs only. An analysis using recombinant viruses showed that four were wild type, three had D67N, four had D67N and K219Q/E and two had K219Q/E. Although all viruses showed sensitivity to NRTIs, viruses containing D67N and K219Q/E had an increased propensity to acquire K70R during selection with zidovudine (AZT) in vitro. The difference between acquisition of K70R between WT virus and resistant virus was 63 days compared to 37 days. Competition tests measuring viral fitness confirmed that D67N mutation confers a fitness advantage in the presence of AZT. The researchers conclude that viruses transmitted with these NAM profiles are not only commonly found in newly diagnosed patients, but caution against possible clinical implications for these patients, in particular future therapy containing AZT (Garcia-Lerma).
More positively, the Study Group of Seroconverters of Madrid found that transmission of drug-resistant HIV does not seem to affect CD4 cell decline in patients with three years follow up post-seroconversion in the absence of HAART. 46 treatment-naive seroconverters with 3.5 years of follow-up with genotype at time of diagnosis were assessed for virological and immunological progression.
20% had drug-resistant strains at baseline.
No differences in CD4 cell counts were observed between individuals infected with resistant or non-resistant virus either at baseline or over three years in the absence of therapy. On average, both groups reported a decline of 46 CD4 cells per year (de Mendoza).
References
Delaugerre C et al. Persistence of multidrug-resistant HIV-1 without any antiretroviral treatment 2 years after sexual transmission. Antiviral Therapy 8: S87, 2003.
Garcia-Lerma JG et al. Transmitted HIV-1 carrying D67N or K219Q evolve rapidly to zidovudine resistance in vitro and show a high replicative fitness in the presence of zidovudine. Antiviral Therapy 8: S89, 2003.
De Mendoza C et al. Impact of transmission of drug-resistant HIV viruses on viral load, CD4 counts and CD4 decline in recent seroconverters. Antiviral Therapy 8: S88, 2003.