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Roos Barth

Thursday 27 May 2010

Treating HIV in rural South Africa, Successes and Challenges

Promotor: Prof.dr I.M. Hoepelman
Defence: 27 May 2010
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Summary
The aim of this thesis was to evaluate the virological efficacy of the antiretroviral treatment (ART) programme of Ndlovu Medical Centre (NMC). NMC is a rurally located clinic in Elandsdoorn, South Africa. NMC has provided free testing, monitoring and treatment of HIV-infected individuals since 2003. Treating HIV in a rural African setting is associated with many challenges. Some of these challenges are addressed in this thesis.

To put our data in a broader perspective, we first review all available, virological data of Sub-Saharan African ART programmes. On-treatment, short-term outcomes of these programmes are promising and similar to those initially observed in western settings. However, high early attrition (composed of all-cause mortality and patients being lost to follow up) is frequently observed and virological failure was observed in fifteen percent of patients within a few years after treatment start. Less than one percent of patients included in the African cohorts harbour a subtype-B virus. This is in stark contrast to western countries, where most HIV-infected individuals are infected with subtype-B virus. Available genotypic resistance data of individuals experiencing virological failure showed a frequent occurrence of the lamivudine-associated M184V mutation and (multiple) non-nucleoside-reverse-transcriptase-inhibitors (NNRTIs) mutations. The commonly used second-line regimen in African ART programmes includes a boosted protease inhibitor (PI) in combination with a nucleoside-reverse-transcriptase-inhibitors (NRTI) backbone. This seems like a reasonable option in light of the observed resistance profiles, but second-line efficacy data are limited at present.

In the following chapters we analyze the outcome data of NMC’s HIV-treatment programme. Short-term results were excellent; patients remaining in care gained weight, had a significant increase in their CD4+ T-cell counts and most reached virological suppression. In patients who did experience treatment failure, genotypic analysis was done. All patients were HIV-1 subtype-C infected. Interestingly, apart from the lamivudine-associated M184V mutation, an accumulation of major NNRTI-associated mutations was observed. In contrast, thymidine analogue-associated mutations (TAMs), conferring resistance to most NRTIs and frequently observed in the western world, were not found. Moreover, it appeared that transmission of resistance may have contributed to the accumulation of NNRTI-mutations, as several patients harboured drug-associated mutations prior to starting ARVs.

Long-term data showed that adults generally continue to show a good, virological response. An “all or nothing” phenomenon was observed; high early attrition, but complete virological suppression (HIV-RNA <50 copies/mL) in the majority of patients remaining in care. The picture was somewhat different where children were concerned; nearly forty percent of children experienced virological failure on first-line ART within a year after initial virological suppression. Genotypic resistance data were available for children experiencing virological failure. All children harboured subtype-C viruses and lamivudine- and NNRTI-associated mutations were most prevalent. However, TAMs were also detected in several children, minimizing future NRTI-treatment options.
Both for adults as for children we found immunological parameters to be poor predictors of virological failure. We therefore feel that efforts should be made to make HIV-RNA testing more widely available.

Subsequently, some issues regarding important opportunistic infections are addressed. We reviewed the potential of a new diagnostic test for tuberculosis in a setting where both HIV and TB are highly endemic. Furthermore, we looked at the prevalence-rates of hepatitis B (HBV) and C (HCV) amongst HIV-infected individuals in Sub-Saharan Africa as a whole, as well as amongst patients at NMC.

To conclude, we describe successes achieved in global HIV-care, and the challenges that remain for the future.

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