Despite the improved survival of human immunodeficiency virus (HIV) infected individuals with the introduction of highly active anti-retroviral therapy (HAART) in the South African public sector in 2004, new challenges have been brought to the fore. These include drug-related toxicities, particular those of stavudine, which remains in common use within developing countries.
A prospective analysis of 9040 HIV-1-infected adults initiated on HAART from 2004 to 2007 at the Themba Lethu Clinic, Helen Joseph Hospital in Johannesburg, confirmed the ability to roll out a successful HAART programme in a resource limited environment with a high retention rate of 70%. Nearly 30% of patients switched to non-stavudine based regimens due to side effects - predominantly peripheral neuropathy, symptomatic hyperlactataemia and lipoatrophy.
In an attempt to look for safer options, a prospective randomized controlled trial comparing standard and low dose stavudine with tenofovir was undertaken in 2009. Sixty patients were randomized 1:1:1 to either standard (30-40 mg), low (20-30 mg) dose stavudine or tenofovir (300 mg) each combined with lamivudine and efavirenz. Adipocyte mitochondrial DNA (mtDNA) levels, gene expression, anthropometry, markers of inflammation, lipid and glucose metabolism were assessed at various time intervals.
Results demonstrate early mitochondrial depletion among black South African patients receiving low and standard doses of stavudine, with preservation of gene expression levels, except for NRF1 and MTCYB, when compared to patients on tenofovir. Mitochondrial toxicities occurred in both the stavudine arms. Immunological and virological outcomes were similar for all three arms. Both drugs caused lipid changes, but tenofovir had a more favourable effect on anthropometry and adipokines. Both stavudine regimens increased fasting insulin and C-peptide levels, with the higher stavudine dose also causing increased fasting glucose and HOMA levels.
This study demonstrates an early association between mitochondrial depletion and stavudine
therapy in the black South African population and shows that tenofovir has a minimal effect on mitochondrial numbers. Only two of eight adipocyte genes were significantly affected by stavudine therapy when compared with tenofovir, but this was only seen with the standard dose. This study highlights the occurrence of significant metabolic abnormalities with both drugs. Therefore, awareness of the potential increased cardiovascular risk should be of concern with tenofovir and stavudine, although toxicity is lower in the low dose compared to the standard dose stavudine regimen with no attenuation of anti-retroviral effectivity.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:wits/oai:wiredspace.wits.ac.za:10539/14582 |
| Date | 24 April 2014 |
| Creators | Menezes, Colin Nigel |
| Source Sets | South African National ETD Portal |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Format | application/pdf |
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