Two years ago at the HIV Resistance Workshop Deenan Pillay from University College London noted in his overview presentation that only 4% of the meeting abstracts addressed issues related to non-B viral subtypes – an almost inverse proportion he observed, to the world’s population affected by non-B virus. This year, Dr Pillay commended the meeting on extending this level of interest to 12%. Hopefully, future plans for surveillance and investments in research in least developed countries will teach us more about the evolution of resistance in non-B subtypes.
The slow but increasing introduction of HIV treatment in less developed countries (LDCs) has highlighted the need for data on resistance evolution in patients who have limited or no options available for switching from a failing treatment regimen. In particular, it remains imperative that we understand resistance to NNRTIs in LDC populations, given the prevalence of nevirapine (NVP) therapy including single dose NVP for the prevention of mother to child transmission (PMTCT).
Resistance following single dose nevirapine
David Katzenstein from Stanford University worked with the HPTN 023 Study Team to describe NNRTI resistance in 34 subtype C-infected women from Zimbabwe receiving single dose NVP (SDNVP) at onset of labour. The study considered resistance mutations, the rate and persistence of resistance selection and fitness of these mutations. Plasma was collected at 0, 2, 8, 20 and 32 weeks post-partum. They found from patient sequences that 76% of women harboured NNRTI-associated mutations at any given time-point in the study. At 2 weeks 75% of available samples showed a presence of Y181C (57%), K103N (25%), V106A/M (19%) and Y188C (14%). By week 8, reversion to WT was observed in 44% of samples, although the emergence of new mutations was only reported in 7% of these samples. At week 8, the most common mutations were found to be K103N (28%) and V106A and Y181C (6% each). The authors conclude that whilst Y181C predominates in early evolution, K103N is retained as the significant mutation by week 8 and that this change over time may correlate with in vivo fitness relative to WT RT found in subtype C virus (Kantor).
Algorithms need adjustment for non-B subtypes
An international collaborative study of 1993 protease sequences from treated and untreated patients with non-B HIV subtype infections in Asia, Africa, the Americas and Europe found that when comparing five algorithms for predicting phenotypic susceptibility from genotype, discordant results were most common for subtypes A and F in previously treated patients (Snoeck).
Reduced susceptibility to NNRTIs
A GlaxoSmithKline study matching 194 patient genotypes and phenotypes from two controlled clinical trials in North and South America considered prevalence of circulating recombinant forms (CRFs) and the potential genetic association with NNRTI susceptibility. 24% of this patient profile was found to be non-B subtype detected from phylogenetic analysis of the RT coding region in HIV-1.
The study revealed that 13% of patients had viruses with decreased susceptibility to efavirenz (EFV) and/or NVP. Where reduced susceptibility was observed in the absence of known NNRTI mutations, this was linked to changes at codon 135. This mutational change was more apparent in non-B subtypes - 59% compared to 41% in subtype B patients - and resulted in a decrease in susceptibility to NVP (10% reduction) but not to EFV.
These results would suggest that the negative impact of a mutation at codon 135 on reduced susceptibility to NNRTIs should be taken into consideration in the treatment of patients with NNRTI-containing regimen, particularly those patients with non-B subtype virus (Florance).
References
Florance A et al. Genotypic associations with NNRTI susceptibility in circulating recombinant forms of HIV-1 strains in North and South America. Antiviral Therapy 8: S121, 2003.
Kantor R et al. Rapid flux in NNRTI resistance mutations among subtype C HIV-1 infected women after single dose nevirapine. Antiviral Therapy 8: S85, 2003.
Snoeck J et al. Comparison of five interpretation algorithms for the prediction of protease inhibitor susceptibility in HIV-1 non-B subtypes. Antiviral Therapy 8: S111, 2003.