PhD (Molecular Medicine and Haematology), Faculty of Health Sciences, University of the Witwatersrand / Background: The availability of highly active antiretroviral (ARV) treatment in the South
African government sector has reduced the morbidity and mortality associated with HIV-1
infection. However, ARV drug resistance and toxicity are major obstacles to achieving and
maintaining virus suppression, but there is no provision for ARV drug resistance testing in
the public sector. To date, most studies of ARV drug resistance in HIV-1 reverse
transcriptase (RT) and protease (PR), are based on sequence data from HIV-1 subtype B,
whereas subtype C is the predominant circulating subtype in South Africa. Moreover, host
genetic polymorphisms associated with ARV drug toxicity have not been investigated in
South African populations. This study evaluated viral and host genetic factors associated
with ARV treatment outcome in 812 ARV drug-naive South African AIDS participants
enrolled on the CIPRA-SA study from Johannesburg and Cape Town.
Methodology: An affordable in-house genotyping protocol (subtype C specific) was
established and validated to monitor the emergence of ARV drug resistance. This assay
was used to genotype all CIPRA-SA participants failing the first- and second-line ARV
drug regimens. Allellic discrimination assays to identify the G1344A, A6986G, G516T and
C3435T SNPs in CYP3A4, 3A5, 2B6 and MDR-1, respectively, associated with ARV
metabolism and absorption were performed.
Results: The in-house ARV drug resistance assay successfully genotyped 95% of patient
samples, including non-C subtypes from 8 African sites. Treatment failure was
experienced in 371 participants, mainly due to toxicity (n=134) or virological failure
(n=83). Overall, CIPRA-SA participants with a lower CD4+ T-cell count at study onset
were more likely to experience viral failure. Genotyping using the in-house assay revealed
that 6 participants had ARV drug resistance mutations at study entry. Treatment failure of
58 participants was a result of ARV drug resistance mutations, whereas 19 had no known
ARV drug resistance mutations. The most frequent mutations were M184V (67%) and
K103N (50%). K65R was present (3%) and one participant harboured TAMs. Longitudinal
genotypic analysis showed that NNRTI mutations accumulated at a rate of one per three
months left on failing therapy. No PR mutations were detected amongst participants
experiencing second-line failure. The four SNPs analysed occured in similar frequencies
between a background and the CIPRA-SA cohort. Furthermore, no statistically significant
association could be found between these four SNPs and viral failure and/or toxicity.
Conclusion: Overall, HIV-1 subtype C-infected individuals receiving ARV therapy
develop many of the known subtype B drug resistance mutations. However, the ARV drug
resistance patterns in the closely monitored CIPRA-SA cohort were less complex
compared to published data from the region, confirming that more frequent viral load
monitoring, genotyping, and a virological failure cut-off value of 1000 RNA copies/ml
ensure a better prognosis, and preserve future ARV treatment options.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:wits/oai:wiredspace.wits.ac.za:10539/8745 |
| Date | 20 September 2010 |
| Creators | Wallis, Carole Lorraine |
| Source Sets | South African National ETD Portal |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Format | application/pdf |
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