Dissertation submitted to the Faculty of Health Sciences, University of the Witwatersrand , Johannesburg, in fulfillment of the requirements for the degree of Master of Science in Medicine, Johannesburg, 2011 / HIV-associated sensory neuropathy (HIV-SN) is a common complication of HIV infection and its treatment with dideoxynucleoside drugs such as stavudine. Pain is a symptom in about 75% of cases of HIV-SN. The aim of this study was to set up the intraepidermal nerve fibre density (IENFD) quantification technique in a South African Laboratory and then to use this technique to investigate whether the presence of pain in individuals with HIV-associated sensory neuropathy was associated with the dying back of epidermal nerve fibres at the site at which pain was experienced.

The effect of anti-retroviral therapy (ART) rollout can be measured in a number of ways including treatment coverage, behaviour change and the emergence of resistance. However, changes in population mortality are undoubtedly the most important measurable effect. Objectives: To describe trends in child and adult all-cause mortality versus HIV/AIDS related mortality before and after ART rollout; and to identify significant clusters of child and adult all-cause mortality versus HIV/AIDS related mortality in space-time, during pre and post ART rollout eras at Agincourt and Dikgale health and demographic surveillance systems (HDSSs) in South Africa. Design: Mortality data were extracted from both the Agincourt and Dikgale HDSSs for the period 1996–2010. Mortality rates by age group, year and village were calculated assuming a Poisson distribution and using precise person-years as the denominator. The Kulldorff spatial scan statistic was used to test for clusters of age group all-cause and HIV-related mortality both in space and time. Clusters were mapped using Quantum geographic information systems (GIS) software. Results: Both HIV-related and all-cause mortality decreased gradually over the years after the introduction of ART in 2007 for the two HDSS sites. Several statistically significant clusters of higher all-cause and HIV-related mortality were identified both in space and time. In the Agincourt HDSS, specific areas were consistently identified as high risk areas; namely, the east/south-east corner and upper central to west regions, pre ART. In the Dikgale HDSS, no significant clusters were identified using the spatial only analysis but one significant cluster, located towards the north of the Dikgale HDSS site, was identified using the space-time scanning, post ART. In Agincourt, no significant clusters of mortality were detected after the introduction of ART whereas in Dikgale, a significant cluster for all-cause mortality in the under-five age group was detected for the years after the introduction of ART. Conclusion: This work revealed the existence of spatio-temporal clusters of both child and adult mortality at the Agincourt and Dikgale HDSSs and that the introduction of ART had a substantial influence in reducing both HIV-related and all-cause mortality in rural South Africa. There is need though to take into account socio-demographic characteristics so as to determine fundamental risk factors influencing these spatio-temporal HIV-related and all-cause mortality patterns.

Introduction: This study is a secondary data analysis of HIV/AIDS patients on Anti-retroviral Therapy (ART), at Themba Lethu HIV/AIDS clinic, who have had the first break in the continuity of taking their Antiretrovirals (ARVs) of more than 10 days, measured by patient missing the refill appointment for more than 10 days. The clinic started in 2004. HIV/AIDS is high in South Africa with about 400,000 AIDS patients on ARVs. For ARVs to be most effective they must be taken continuously without breaks, and for life. Without this, there is risk of ARVS drug resistance development and consequent failure of the ART program. Some patients may break this continuity and this seems to be a problem in South Africa. Where the patients develops side-effects or is not responding well to treatment, clinicians may also cause a break in the therapy. This study described the first break as when it occurred and for how long it lasted, investigated the factors associated with this break and the association of the first break and the last CD4 count. Materials and methods: 7,930 adults (≥18 years, either gender) on ART and baseline CD4 <250 cells/μl were included in the study. The study group were patients who had first break in continuity of therapy of more than 10 days. The first break was described as when it occurred after months of ART initiation and how long(days) the first break lasted. Patients on Post- Exposure Prophylaxis, single-dose Nevirapine, Prevention-of mother-To-Child- transmission therapy, and those with breaks in therapy of more than 364 days were excluded. Outcome variables was the last CD4 count. Analyses were in STATA 10, at 95% confidence interval. Median and quartile ranges were used to describe participants in the study. T-test, Fishers exact test and chi-square were used to compare groups. Regression was used to determine demographic and clinical factors associated with first break in therapy and also to determine the association of first break in therapy and the last CD4 count. Results: The median duration on ART for the patients was 764 days. 63% of patients had a break in ART. 47.5% of patients had their first break in therapy within the first 2 years of being on the ART program, with the largest proportion within the first 6 months of therapy. Most patient came with advanced disease(CD4 <100cells/μl, WHO clinical staging IV). Women were twice more than men. They tended to come earlier for therapy, took longer to improve and delayed in having the first break compared to men (254 vs. 205 days). Baseline hemoglobin and unemployment were factors associated with when the first break occurred. The median length of first break was 21 (Q1-Q3 7-43) Unemployment and baseline hemoglobin were associated with length of first break. The first break in therapy was associated with the last CD4 count. The longer the patient stayed on ART without the first break, the higher the last CD4 would be. Peripheral neuropathy had a statistically significant positive association with the last CD4 count. However, baseline CD4, Age, baseline BMI, WHO stage IV, baseline hemoglobin and unemployment had a statistically significant but negative association with the last CD4 count. The weakness of using the missing appointment system is that it does not inform clinician whether patients is really taking or not taking ARVs at home. Its strength over the self reported adherence system is that it is free of recall bias. Conclusion: Though Themba Lethu clinic has a follow-up system in place for patients missing refill appointment, up to 63% patient missed their appointment to collect medicine on time and this had a negative effect on the last CD4. There is need to strengthen existing follow-up method besides decentralising the ART services in Johannesburg.

Background In 2010, 2.2 million adolescents were living with HIV (Human Immunodeficiency Virus) worldwide. This study aimed to describe the socio-demographic and clinical characteristics of the adolescents (10-19 years old) initiating anti-retroviral treatment (ART) and to investigate characteristics that are associated with virological failure in adolescents on ART. Methods This was an analysis of adolescents initiating ART from June 2004-2010 at the Hlabisa Treatment and Care Programme in KwaZulu-Natal, South Africa. Data was collected from two datasets at Africa Centre for Health and Population Studies. Time to outcomes of death and lost to follow up (LTFU) were quantified using Kaplan-Meier estimates. The outcome was virologic response (< 70copies/ml) after at least 6 months on ART and the associations with an unsuppressed viral load were investigated using multivariable logistic regression. Results 543 adolescents, median age 15 years (IQR 12-18), initiated ART; 67.8% (368) were females. Age at treatment initiation showed a bimodal distribution, with a peak at 11 years and another at 17-19 years; 61 females aged 16-19 years initiated ART whilst pregnant. At baseline, median CD4 count was 152 cells/μl (IQR 72-251), 392 (72.2%) had prior TB and 129 (23.8%) a weight-for-age z-score ≤ -2 (i.e. were under-nourished). Numbers of adolescents starting ART increased from 53 in the years 2004-2006 to 196 in 2010. Overall mortality was 36.5 per 1000 person years (95% CI 27.2 - 48.8); LTFU 98.8 per1000 person years (95% CI 82.8-118). Adjusting for age and gender, LTFU was significantly higher in females initiating in late adolescence (15-19 years) (p<0.001) and 24 (39.3%) of those initiating ART whilst pregnant were LTFU. The first viral load after initiation was taken at a median time of 11.25 months (IQR 7.78-16.20). Of the 364 adolescents with a viral load result after at least 6 months of ART, 119 (32.7%) had an unsuppressed viral load (95% CI 27.9- 37.5). Adolescents who initiated in the year 2010 were found to have less odds of an unsuppressed viral load compared to those who initiated between 2004 and 2006 [adjusted Odds Ratio (aOR) 0.29 (95% CI 0.11-0.79)]. Those who had the first viral load test done after > 30 months of ART had higher odds of an unsuppressed viral load compared to those tested after 6-12 months of ART [ aOR 6.88 (95% CI 1.29-36.66)]. Conclusion Despite the yearly increase in adolescents initiating ART, good virological responses can be obtained through increased ART support to both individuals and health care providers. Timely viral load monitoring identifies those in need of increased adherence support on ART and may result in good virological responses. Recommendations Adolescents on ART are a vulnerable group that requires special attention to improve clinical and virological outcomes. Adolescent friendly ART clinics may be useful in providing this service and mitigate the high attrition rates of those on treatment for HIV. Public health awareness campaigns on HIV and its treatment may have a positive impact on virological response to ART and therefore campaigns targeting adolescents must be intensified. Early virological testing after 6 months on ART to monitor treatment responses helps to identify those with sub-optimal response to ART and reduce the progression to virological failure and drug resistance to anti-retroviral drugs.

Submitted in partial fulfilment of the requirements for the degree of Master of Public Health, in the field of Maternal and Child Health, to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, September 2014 / Introduction: Nevirapine (NVP) is used in combination antiretroviral treatment especially for pregnant HIV infected women. NVP has been shown to be inferior and more toxic than other similar drugs, but continues to be used in developing countries due to cost. Aim: This study aimed to determine the prevalence of NVP toxicity and associated factors among 478 pregnant women from three public health facilities in inner city Johannesburg. Materials and methods: We employed a cross-sectional retrospective record review study design to analyse the records of 478 pregnant women in the above mentioned public health facilities. Variables including demographic (age, weight, gestational age) and clinical (CD4 cell count, WHO HIV clinical stage, prior ART experience) characteristics were extracted and the association between these characteristics and the development of toxicity post NVP exposure was explored. Results: The study found that approximately nine out of ten women (89.5%) were ART naïve at the time of NVP initiation. When compared with ART naïve women, ART experienced women had a slightly higher mean CD4 cell count, however, for both groups of women, mean CD4 cell count was less than 250 cells/mm3. Overall, 85.1% of women had a CD4 cell count less than 250 cells/mm3. More than half (55.3%) of the women were in the third trimester of pregnancy and the majority (82%) classified as WHO HIV clinical stage one. At least one adverse event was reported in 63 (13.2%) women. Mild skin rash was the most prevalent adverse event, occurring in 9.6% of women. Hepatotoxicity occurred in 5.3% of women and severe skin rash occurred in 1.5% of women. Almost 85% of adverse events occurred in women with CD4 cell counts <250 cells/mm3. WHO HIV clinical stage II and IV were significantly associated with the overall development of toxicity (ρ <0.01). Conclusions: Whilst the overall prevalence of mild and severe skin rash in this sample was less than that demonstrated in earlier studies, a higher overall prevalence of hepatotoxicity was found. When compared with ART naïve women, ART experienced women were found to have a higher prevalence of mild skin rash. Hepatotoxicity and severe skin rash only occurred in ART naïve women. In this sample, CD4 cell count ≥250 cells/mm3 was not associated with the development of NVP adverse events. Recommendations: Our findings support the continued use of NVP as part of combination ART regimens in women of African descent. In contrast with previously published data, our study showed a significant association between WHO HIV clinical stage and NVP toxicity, our study also included relatively few women with higher CD4 cell counts. Further research including predominantly healthy HIV infected pregnant African women as well as women with higher CD4 cell counts is required in order to fully explore the association between these variables and the development of NVP post-exposure toxicity.

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.

A research report submitted to, the Faculty of Health Sciences, University of Witwatersrand, in partial fulfilment of the requirements for the degree of Master of Science in Population based field epidemiology March, 2013 / Introduction: Access to highly active antiretroviral therapy has dramatically increased worldwide since 2004. However, the emergence of HIV drug resistance presents huge obstacle in ART scale up as it contributes to treatment failure and poses a greater risk of disease progression and loss of treatment options. The study therefore investigated the risk factors and the association of HIV drug resistance, virological failure and CD4 cell count changes in patients on ART at Aurum Institute for Health Research in South Africa. Methods: A cohort of HIV infected patients who developed virological failure of their first HAART regimen was assessed. A genotypic resistance testing was performed using stored plasma on a subset of patients at first detection of virological failure. Data were collected prospectively on all registered patients using standardised forms. Clinical data was obtained from laboratory and pharmacy electronic records. Logistic regression and Cox proportional hazard models were used to assess factors associated with HIV drug resistance and virological failure respectively. Linear mixed-effects regression models were used to assess the changes in the CD4 cell count among patients who developed HIVDR. Results: Between January 2003 and December 2010, a total of 146 ART-treated patients who experienced virological failure were assessed. Of these, 108 (74%) developed HIVDR, of whom 80 (74%) were males; the median CD4 cell count at ART initiation was 121 cells/mm3 (interquartile range, 61-210). The most frequent NNRTI mutations patterns found were mutations leading to resistance to NNRTI agents with 33% having NNRTI resistance. The second most common resistance v pattern was resistance to lamivudine conferred by the M184V mutation (30%). The multivariable analysis showed that higher CD4 cell count at HIVDR detection was significantly associated with the reduced odds of developing HIV drug resistant mutation after adjusting for gender and age(adjusted OR=0.37, 95% CI 0.15–0.94). Similarly, there was significant association between age at ART initiation (adjusted HR=0.71, 95% CI 0.52–0.97) and CD4 cell count during follow-up (adjusted HR= 0.54 95% CI 0.36–0.81) with virological failure in those patients who developed HIVDR. The CD4 cell count slope on average increased by 10 cells per mL per year for the patients without any resistance (average annual change 9.89 cells per mL, 95% CI -6.90-26.69) and decreased by 10 cells per mL per year for patients who had any resistance (average annual change -9.61 cells per mL, 95% CI -19.41- 0.17). Conclusion and recommendation: HIV drug resistant virus was found in 74% of the South African patients who were accessing HIV care at Aurum Heath Institute and developed virological failure of first HAART regimen. Higher CD4 count at detection of HIVDR was significantly associated with lower risk of developing HIV drug resistant virus. Lower CD4 count and male gender were significantly associated with the development of virological failure. Patients with virological failure had significantly great CD4 count declines when any mutation and thymidine analog mutation (TAM) mutation were present. There is a great need therefore for multifaceted approach to target interventions that aim to increase patients CD4 cell counts. Patients should be either screened, possibly with HIVDR testing, prior to reinitiation of a first-line regimen

Research Report submitted in fulfillment of the requirements for the degree of Master in Public Health (MPH) at the University of the Witwatersrand. April 2015 / Introduction: Antiretroviral therapy (ART) is a lifesaving clinical intervention for people living with HIV (PLHIV). An important barrier to accessing therapy is the shortage of the health workforce particularly doctors. In order to mitigate the shortage, a nurse driven ART delivery approach known as Nurse Initiated and Managed Antiretroviral Therapy (NIMART) has been implemented in the public sector in South Africa and in other countries. NIMART enables professional nurses to initiate HIV positive persons on ART and manage their care at primary health care clinics. This study sought to explore and describe perceptions of operational managers, facility managers and professional nurses on the facilitators and barriers to the implementation of NIMART in the City of Joburg (CoJ) clinics. Methodology: This was an exploratory descriptive qualitative study which used in-depth interviews with a variety of respondents in order to gain insights into their perceptions of the implementation of NIMART in the CoJ clinics. In total, 26 respondents, comprising of operational managers, facility managers and professional nurses participated in the study. Thematic content analysis was used to analyse data drawing from the Donabedian structure-process-outcome framework. Results: The respondents identified the adequacy of NIMART training and mentoring; the availability and use of NIMART guidelines and the integration of NIMART into Primary Health Care (PHC) services as structural facilitative factors for NIMART implementation. The shortage of the health workforce, shortage of antiretrovirals (ARVs), poor referral feedback, food insecurity and the mobility of patients were identified as key structural and process barriers to the implementation of NIMART. Respondents perceived the improvement in quality of life of NIMART patients and the clinics’ ability to retain patients in care as indicative of the success of iii NIMART implementation. Finally, respondent’s suggestions for improving NIMART implementation in CoJ clinics focussed on improving shortage of the health workforce, improving the availability of ARV drugs and providing opportunities for continuing education for professional nurses. Discussion, conclusion and recommendations: In order to mitigate the barriers identified in this study, recommendations were that the City of Joburg should utilize lower level health care cadres such as nursing assistants and lay counsellors to reduce the professional nurses’ workload and thus improve access to treatment. In addition, the City of Joburg should revise the antiretroviral drug allocations to clinics and revise delivery schedules to ensure that clinics do not run out of ARV drugs. The referral feedback process should be strengthened through the referring clinic and the referral hospital jointly developing referral protocols that should be used by both institutions. Finally, the City of Joburg should consider conducting consultative discussions with professional nurses prior to introduction of new programmes and provide opportunities for regular updates for operational managers, facility managers and professional nurses. Future research could look at the role of PHC qualification in the implementation of NIMART.

Thesis (MPH) -- University of Limpopo, 2012. / No Summary

Thesis (MPH.) -- University of Limpopo, 2015 / Purpose / Aim: To find out determinants affecting adherence to antiretroviral therapy in patients receiving free treatment from the wellness clinic at Bela Bela District Hospital in Limpopo province of South Africa. Objectives: To identify the determinants which affect the adherence to ART treatment among patients living with HIV and AIDS and to determine which of these determinants are significant predictors of adherence among HIV and AIDS patients. Methodology: a descriptive retrospective, quantitative research. Sampling: A population of 800 patients existing in the recording book was retrieved from the patients’ records at the wellness clinic. Out of 800 a sample of 260 was derived using a simple size calculator tool. Analysis: data were analysed by SPSS Windows Version 21.0. Descriptive statistics means and frequencies were calculated. Chi-Square tests were done in order to test the association between variables (such as age groups, gender, weight groups, regimens and WHO stages). Logistic regression was run to assess the effect of different determinants on the adherence to ART (e.g. viral load affected the adherence contrary to age, gender and others). Results: Female (65%) was more compliant to their male counterpart (35%). Most of the patients (47.3%) in the study belonged to the age group 21 to 35 years and only (2.7%) in the age group less or equal to 20 years. Most patients were categorised into WHO stage I (31.2%). Only 9.2% of the patients were categorised into WHO Stage IV. Most of the patients in group 2 (41.3%) had a weight between 40kgs and 54kgs and group 1 (4.2%) with patients whose weight was less than 40kgs. One of the patients has no record on weight. The majority of patients (44.2%) had CD4 count, less or equal to 100. Only 2.7% had CD4 count 300 and more. After 6 months of treatment, 37% of patients had CD4 count from 300 and above; 9.7% of the patients had CD4 countless than 200. For 136 (52.3%) of the patients in the sample the information on CD4 count at 6 xi months was missing. The majority of patients (72.7%) in the sample had low viral load and only (27.3%) of the patients had high viral load. Majority of patients (48.5%) were on New 1a Regimen instead of Regimen 1a (30.8%) because of the side effects the latter has on them. Some patients (11.2%) were on Regimen 1b, followed by patients (8.1%) on Regimen New 1b. The remaining patients were on Regimen 1c, Reg 2 and Truvada (1.6%). Findings: The majority of patients were young females; in the age-group of 21-35 years. This is reproductive age with many challenges: earlier exposed to infection, more vulnerable than males, stigmatisation, rape, fear of isolation. Majority of patients were in the WHO stage 1 and 2. The WHO stage does not depend on the level of CD4 count. It is important to consider the weight of the patient before to initiate the treatment. More than the half patients had a CD4 count required to start with ART. After 6 months they were more adherent. Most of them were on regimen Reg (New 1a) because of less side effects. The findings showed also different types of associations with some variables were significant determinants such as CD4 count had significant associations with gender, viral load, regimen, WHO staging, the p-value was lesser than 0.05. Conclusion: The results showed that viral load was the only determinant affecting adherence in the current study. The number of males in this study population was lower than females from the age group of less than 20 and age group of 21 to 35, and females than males in age group 36 to 50 and 51 or more. The lower infectivity of males is linked to the state of denial and not testing for HIV. The lower number in females can be due to their positive trends to the ART in their old age. The reasons for the low number need to be investigated. Awareness campaigns should be intentioned towards males. There should be publicity about the equality of both male and female genders.