Magister Public Health - MPH / Background: First line regimens give patients the best chance of long-term treatment success. It is imperative that patients stay on their original first line regimens to ensure program viability. As the ART programme matures in Namibia the proportion of patients who have had their first line regimens modified continues to increase. It is estimated that 3.1% of adults in Namibia are on second line regimens. Second line or other modified regimens are generally reserved for clinical, immunological or virological failure and toxicity related complications. These modified regimens often involve a higher pill burden, more toxicities and are often more expensive. A more detailed understanding of the factors associated with first line regimen modification could allow healthcare providers in Namibia to target these factors for intervention to reduce regimen modification and improve treatment outcomes. Methodology: This quantitative descriptive retrospective cohort study sought to describe factors associated with first line HAART regimen modification in treatment naïve adult patients who started HAART at Gobabis State Hospital between 1st January 2007 and 31st December 2010. Utilizing data from an existing electronic patient management system, quantitative methods were used to assess the prevalence, reasons and factors associated with first line HAART regimen modification. Results: The prevalence of HAART regimen modification was 14.1%. Treatment toxicity was the major reason (35%) for HAART regimen modification and this was largely due to D4T containing regimens. This was followed by treatment modification due to concurrent TB disease (27.3%), new drug availability (19%), pregnancy (6.6%) and virological failure (2%). A death rate of 9% was recorded by the end of the study period in each of the two groups, of those who had their first line HAART regimen modified and those who remained on original regimens respectively. There were statistically significant associations between regimen modification and type of regimen, care entry point, duration from HIV diagnosis to entry into HIV care, sex and functional status. Regimen modifications resulted in more AZT and TDF based regimes while 88.7% of patients had D4T taken off their HAART regimens. Conclusions: HAART regimen modification at Gobabis State hospital is lower than in other settings was largely due to treatment toxicity. The death rate is high and warrants further exploration. Regimen modifications resulted in more AZT and TDF based regimes and more patients had D4T taken off their HAART regimens. Recommendations: Patients still on D4T need close monitoring for side effects associated with this drug and should be promptly changed if this is the case. This study raises the important programmatic issue of the need for good data collection practices. HIV positive patients who are pregnant and those with concurrent TB disease need close monitoring to ensure that HAART regimens are modified appropriately.

Carcinoma of the cervix is frequently diagnosed in the department of Radiation Oncology in Charlotte Maxeke Johannesburg Academic Hospital(CMJAH). It is therefore is a condition of priority and there is scarce literature in the management of HIV positive patients. OBJECTIVES: The primary objective of the research is to determine the overall survival of 2yrs and more, as well as to determine acute and late toxicity for patients completing prescribed radiation treatment. The secondary objective was to determine the impact of highly active antiretroviral therapy on survival and toxicity. The study is limited to HIV positive women presenting with cervical cancer. DESIGN & METHOD: The study is a retrospective study of patients treated at Charlotte Maxeke Johannesburg Academic Hospital between 2008-2009. Inclusion criteria: Females between the ages of 18 and 70, Stages IB2 – Stage IIIB carcinoma of the cervix who have completed planned radiation therapy with or without chemotherapy. The sample size was 151 patients. RESULTS: The mean age was 42.7yrs. The median CD4 count was 309 and 26.2% had CD4 counts below 200.The majority of patients had either Stage IIB (55.0%) or IIIB (31.8%). The total dose to Point A was a median dose of 74Gy. The majority of patients had either Grade II (38.4%) or III (31.1%) toxicity. Significant association between these adverse events and HAART status was rated as p=0.0008. The most common late complication was cystitis (15.9%). Overall survival at 2 years was 100% for Stage I, 92.8% for Stage II and 96% for Stage III. CONCLUSION: The median age was lower than in the HIV negative patients. The acute complications for those not on HAART, were higher in comparison to patients on HAART. The overall survival at 2 yrs. was above 90% for all stages in this study / GR2018

This study compare immunological and virological outcomes in antiretroviral therapy naïve patients exposed to Isoniazid prevention treatment.Medical records of antiretroviral naïve patients managed in the public sector from 1st January 2006 to 31st December 2006 were analysed.Multivariate analysis of variance showed that each treatment group achieved statistically significant increases in CD4+ cell count and viral load decay at each follow-up time point. Pairwise post hoc contrast tests showed patients in NVPipt-past group and EFVipt-past group to have superior immunological and virological outcomes respectively. / Health Studies / M.A. (Public health)

This study compare immunological and virological outcomes in antiretroviral therapy naïve patients exposed to Isoniazid prevention treatment.Medical records of antiretroviral naïve patients managed in the public sector from 1st January 2006 to 31st December 2006 were analysed.Multivariate analysis of variance showed that each treatment group achieved statistically significant increases in CD4+ cell count and viral load decay at each follow-up time point. Pairwise post hoc contrast tests showed patients in NVPipt-past group and EFVipt-past group to have superior immunological and virological outcomes respectively. / Health Studies / M.A. (Public health)

A dissertation submitted to the Faculty of Science, University of the Witwatersrand, Johannesburg, in fulfilment of the requirements for the degree in Master of Science in the School of Molecular and Cell Biology August 2017 / Antiretroviral therapy (ART) drugs such as stavudine (d4T) are known to have off-target side-effects, including the inhibition of DNA polymerase gamma which replicates mitochondrial DNA (mtDNA). ART-induced depletion of mtDNA copy number may cause mitochondrial toxicities such as sensory neuropathy (SN). Genetic variation in DNA polymerase gamma or in other nuclear genes influencing mtDNA replication and mtDNA copy number may therefore contribute to susceptibility to d4T-induced SN. DNA samples from 263 HIV-positive South African adults exposed to d4T were classified as cases with SN (n = 143) and controls without SN (n = 120). A total of 28 single nucleotide polymorphism (SNPs) were chosen in nuclear genes from the mtDNA replication pathway and from a GWAS paper examining SNP association with ART-induced SN (Leger et al. 2014). Genotyping was performed using Sequenom Mass Spectrometry. MtDNA copy number was determined using a qPCR assay. Associations between SN and genetic variants, between genetic variants and mtDNA copy number, and between mtDNA copy number and SN were evaluated in univariate and multivariate models using Plink v1.07 and GraphPad v7. Age and height were significantly different in the cases with SN vs controls without SN. In univariate analyses, three SNPs and two haplotypes were significantly associated with SN, three SNPs were associated with pain intensity and three haplotypes were significantly associated with mtDNA copy number. However, there were no significant associations with SN, pain intensity or mtDNA copy number after correction for multiple SNP testing. No significant difference in mtDNA copy number in cases vs. controls was observed. In conclusion variation in nuclear-encoded mitochondrial genes examined in the current study do not play a role in ART-related mitochondrial complications such as changes in mtDNA copy number, or occurrence of SN. / MT2018

A dissertation submitted to the Faculty of Science, University of the Witwatersrand, Johannesburg, in fulfillment of the requirements for the degree of Master of Science in Genetics. Johannesburg, South Africa 2017 / Background: Stavudine (d4T) use is associated with the development of sensory neuropathy (SN), several mechanisms may underlie d4T-induced toxicity, including: (1) Inter-patient genetic variability in the genes modulating the deoxynucleotide triphosphate (dNTP) pool sizes. (2) Variation in intracellular ARV drug concentrations due to genetic variation in drug transporters. In our study we examined the genetic variation in four stavudine transporter genes and seven genes regulating the deoxythymidine triphosphate (dTTP) synthesis and their associations with d4T-induced SN or CD4+ T cell count or mtDNA copy number. Methods: We examined a cohort of HIV-positive South African (SA) adults exposed to d4T, including 143 cases with SN and 120 controls without SN. 26 single nucleotide polymorphisms (SNPs) from the literature were chosen, prioritised on being tagSNPs with minor allele frequency >5% in Kenyan Luhya (a proxy population for the SA Black population); SNP functional effects and suitability for multiplex analysis on the genotyping platform. Genotyping was performed using Sequenom mass spectrometry. A qPCR assay was used to measure the mtDNA copy number. Association of sensory neuropathy, CD4+ T cell count and mtDNA copy number with genetic variants was evaluated using PLINK. Results: All 26 SNPs were in Hardy-Weinberg equilibrium (HWE) in both the cases and controls. SNP rs8187758 of the SLC28A1 transporter gene and a 3-SNP haplotype ABCG2 were significantly associated with CD4+ T cell count after correction for multiple testing (p = 0.043 and p=0.042 respectively), but were not significant in multivariate testing. No SNP remained significantly associated with SN or mtDNA copy number, after correction for multiple testing. Conclusion: Variation in genes encoding molecular transporters of d4T may influence CD4+ T cell counts after ART. This study presents a positive step towards achieving personalized medicine in SA. / MT 2018

Highly-active antiretroviral therapy (HAART) has improved the prognosis of HIV-infected individuals. Unfortunately it has also been associated with impaired functional capacity and development of metabolic perturbations which increases health risk. This study tested the hypothesis that a combined cardiorespiratory and resistance exercise training (CARET) intervention may result in significant health benefits in HIV-infected individuals receiving HAART. Thirty-seven HIV-infected men and women, predominantly of lower socioeconomic status (SES), were recruited and randomly assigned to: 1) a group of moderate-intensity CARET for three months or 2) a control group receiving no exercise intervention for three months. At baseline and following the intervention, physical characteristics (body weight, body mass index, waist circumference, and blood pressure), physical fitness variables (estimated VO2max and one repetition maximum for upper and lower body), metabolic variables (fasting glucose and serum lipids), immune functioning (CD4+ T Cell count, CD4/CD8 ratio, and HIV RNA viral load), and quality of life (SF-36 Health Survey) were measured. Exercise participants evidenced increases in estimated VO2max (21%, p < 0.01), upper body strength (15%, p < 0.05), and lower body strength (22%, p < 0.05), while showing reductions in waist circumference (-2%, p < 0.05), and fasting glucose (-16%, p < 0.05). While the control group showed a significant decrease in CD4+ T cell count (-16%, p < 0.05) from baseline, the exercise group maintained a more stable count following training (-3%, p = 0.39). Finally, the exercise participants showed self-reported improvements in physical (11%, p < 0.03) and mental (10%, p < 0.02) quality of life. In conclusion, our study demonstrated that a three-month supervised and moderate intensity CARET program performed three times a week, can result in significant improvements in physical characteristics, physical fitness, metabolic variables, and physical and mental quality of life. Furthermore, the same intervention resulted in more favorable immunological responses following training in HIV-infected individuals of lower SES. Key words: Highly active antiretroviral therapy, HIV, combined aerobic and resistance exercise training, cardiorespiratory fitness, muscular strength, and immune functioning.

Background: Since the beginning of 21st century, several Asian countries started implementing their national free antiretroviral therapy (ART) programs to tackle one of the most striking public health issues in Asia – HIV/AIDS. Despite the efforts being made, the treatment coverage remains as low as 44% in 2010. Previous studies have identified financial constraint is a major barrier in accessing ART and an important reason of poor ART adherence in Asia. The purpose of this literature review is to explore the extent of financial burden experienced by people living with HIV (PLHIV) where free ART policy is implemented, and to provide valuable information for policy-making in reducing financial barriers and improve uptake of ART. Methods: Literature search was performed by entering keywords in PubMed and Medline. Articles were screened and selected for in-depth review according to the inclusion and exclusion criteria. A process on data synthesis was performed on the final eligible papers. Results: Five studies from four Asian countries describing the out-of-pocket health expenditure incurred by PLHIV during the delivery of ART were included in this review. Findings: Out of all direct medical costs, the cost of drug was most important in contributing to the total costs for patients without health insurance, while the cost of transportation was more important for patients covered by health insurance. Direct medical costs increased with advancing stage of disease. Rural patients would have spent up to 1,173% of their monthly income per capita, or more than 100% of their total household expenditure even when ART was provided free-of-charge. Patients have also highlighted free ARV drugs were sometimes not available in the health facility and they had to turn to the private market. Hence, the extent of financial burden in this review might be underestimated. Conclusion: Based on the data available, we concluded that increased accessibility of free ART should be accompanied with sustained ARV drugs supply and increased financial support for PLHIV. / published_or_final_version / Community Medicine / Master / Master of Public Health

HIV/AIDS remains one of the most pressing challenges facing South African society. South Africa has the highest number of people living with HIV as well as the highest number of people on HIV treatment globally, yet only 37% of persons eligible for treatment have access to treatment. The advent of HAART ushered in a new era in the treatment of HIV infection. HIV infection was no longer a life threatening terminal illness, HIV/AIDS became a chronic manageable disease. The full clinical benefit of HAART can only be achieved with near perfect adherence i.e. > 95%. This means taking the medication exactly as prescribed; on time, no missed doses, every day, lifelong. No other chronic medication requires such stringent adherence rates for optimal therapeutic benefit, which may mean the choice between life and death. Achieving near perfect adherence poses a serious challenge to health service providers and persons on treatment as typical adherence rates for medication prescribed over long periods are in the 50 – 75 % range. Persons on HAART live with the additional burden of drug resistance and limited treatment options if near perfect adherence rates are not achieved. The purpose of this qualitative study was to explore the factors that influence adherence to HAART. These factors may be related to the person, the health care team and system, the treatment regimen, the social and economic environment or to the effects of HIV disease. Factors may either negatively or positively influence a person’s ability to adhere optimally to their prescribed treatment. A small sample of thirteen participants were purposefully selected for this study. Data was collected using in-depth interviews which were tape recorded and transcribed for thematic analysis. The value of this study is that it may assist health care providers, persons on treatment and the health care system to better comprehend the challenges of lifelong optimal adherence to HAART. / Thesis (M.A.)-University of KwaZulu-Natal, Durban, 2011.

There is an increasing number of patients failing second line highly active antiretroviral therapy (AZT, DDI and LPV/r) in South Africa, where HIV-1 subtype C predominates. Mutations at gag cleavage sites (CS) have been found to correlate with resistance mutations in protease (PR). Therefore, it is important to collect data on subtype C protease and gag sequences from patients as these mutations may affect the efficacy of protease inhibitor (PI) containing drug regimens. In this study, 30 subtype-C infected second-line failures were genotyped using the ViroSeqTM resistance genotyping kit and the gag region from these isolates were then characterised. These sequences were then compared to 30 HIV-1 subtype C infected first-line failures (PI-naïve) and subtype B, C and group M naïve sequences that were downloaded from the Los Alamos Sequence Database. Amino acid diversity at the CS was measured using Mega version 4.0. To investigate the effect of CS mutations on replication capacity, a mutation was introduced by site-directed mutagenesis (Stratagene’s QuikChange Site-Directed Mutagenesis kit). Of the 30 second-line failures that we genotyped, only 16 had resistance mutations in PR and 23 in gag. The most frequent major PI mutations were: I54V/L, M46I, V82A, and I84V and in gag CS were V390L/I and A431V. Interestingly the A431V mutation significantly correlated with protease mutations M46I/L, I54V and V82A. The virus carrying the A431V mutation in vitro was found to have a lower replication capacity compared to the wild type. These findings emphasize the need for further investigation of gag mutations and their contribution to the evolution of HIV resistance to PIs. / Thesis (M.Med.Sc.)-University of KwaZulu-Natal, Durban, 2010.