The overall purpose of this dissertation was to examine evidence of spillover effects of HIV care and treatment service scale up in sub-Saharan Africa in the past decade. Particularly the focus was to quantify any effect HIV treatment initiation by a person living with HIV (PLHIV) may confer health benefits to the HIV negative population by increasing utilization of non-HIV services or reduce mortality risk. This dissertation had three primary aims. The first aim was to conduct a systematic review of the effect of increasing ART uptake in high HIV prevalence communities on use of non-HIV health services, including maternal, child, in/out-patient, non-HIV laboratory, and TB diagnosis and treatment services. Overall positive effects were found on the majority of health service indicators examined for non-HIV laboratory service utilization and Tuberculosis diagnosis and treatment services. We found negative associations on the majority of indicators examined for child health services. The existing evidence did not point to clear tendencies for maternal health services and outpatient and inpatient services. Restricting the sample to studies with stronger study designs for causal inference, the positive effect on non-HIV laboratory services and the negative impact on child health services held but evidence was mixed for TB diagnosis and treatment services, maternal health services and outpatient and inpatient services. The second aim of this dissertation was to conduct regression discontinuity quasi-experiments to determine whether exposure to health benefits from ART utilization by a person living with HIV (PLHIV) in a household affects uptake of TB, hypertension (HTN) and diabetes mellitus (DM) treatment by other household members with these conditions. The study was conducted in the comprehensive population cohort followed by the Africa Health Research Institute (AHRI) in Kwazulu-Natal (KZN), South Africa. We linked PLHIV engaged in HIV care to their cohabitating household members aged ≥15 years using a unique identifier for homesteads. Household ART utilization significantly increased treatment for diabetes (RR 1.90: 95% CI 1.07-3.40) but not for TB (RR 1.12: 95% CI 0.71-2.03) or hypertension (RR 1.31: 95% CI 0.97-1.77). The third aim of this dissertation was to use the same regression discontinuity design and KZN cohort data as in aim 2 to determine whether exposure to health benefits from ART utilization by PLHIV in a household reduces all-cause mortality of other household members. Overall, household ART utilization did not decrease all-cause mortality (Hazard Ratio (HR) 0.95: 95% CI 0.65-1.4), however, restricting the analysis to a narrow CD4+ cell count range around the regression discontinuity threshold showed reduced all-cause mortality by 67% (HR 0.43: 95% CI 0.22-0.85) among household members of PLHIV on ART; the reduced risk was driven largely by the significant reduction noted among female household members (HR 0.21: 95% 0.08, 0.56).

In 2007 it was reported that an estimated 33 million people worldwide were living with the Human Immunodeficiency Virus (HIV). Of this, 35% (approximately 11.5 million) live in South Africa, most of whom were infected with HIV by mother to child transmission. Due to government legislation, until 2004, South Africans had limited access to Antiretroviral (ARV) treatment at and after birth. As a consequence, treatment of HIV was, at this time, only in government facilities, initiated after the clinical presentation of immune deficiency. This study compared the memory functioning of low socio-economic seropositive adolescents that were on a managed anti-retroviral programme to that of a contrast group that were HIV negative. The groups were matched for age, gender, demographics and educational level. The relative impact of variables such as duration of ARV treatment, drug regimen, WHO stage at diagnosis and CD4+ count were all considered. Performance on a comprehensive neuropsychological battery was compared between the HIV positive group and their typically developing counterparts both in terms of memory functions as well as other cognitive processes that may have an effect on memory. The HIV positive group performed significantly below their HIV negative peers in processing speed, holistic processing, and spatial processing as well as specific visual functions such as visual constructional skills, visual recall ability, disruptions in both storage and retrieval of visuospatial information, and visual spatial working memory. No significant differences were found between the groups on tasks measuring verbal memory and verbal learning ability indicating that the neurocognitive profile of clade C HIV has a different presentation from the other clades. The findings suggest that the preferential effect HIV has on the frontostriatal circuits in the brain impacts memory processes due to the destructive impact of the virus on the myelination of these circuits. As a result of the higher degree of white matter tracts in the right hemisphere, holistic and integrative processing is impaired and visuospatial functions are affected whereas verbal processes are largely spared. The resulting neurocognitive profile is similar to that of nonverbal learning disorders and may benefit from similarly constructed interventions such as placing more emphasis on verbal learning strategies and limiting dependence on visual information for HIV positive pupils.

Thesis (M.Sc.)--Memorial University of Newfoundland, 2005. / Includes bibliographical references.

<p>Many studies have reported low cure rates for multidrug-resistant tuberculosis (MDRTB) patients and MDR-TB patients co-infected with human immunodeficiency virus (HIV). However, little is&nbsp / known about the effect of HIV infection and antiretroviral therapy on the treatment outcomes of MDR-TB in South Africa. Therefore, the objectives of the study are: to find out whether HIV infection&nbsp / and interactions between ARVs and second line anti-TB drugs have an impact on the following MDR-TB treatment outcomes: cure rate and treatment failure at Brewelskloof Hospital. MDR-TB&nbsp / patients were treated for 18-24 months. The study was designed as a case-control retrospective study comparing MDR-TB treatment outcomes between HIV positive (cases) and HIV negative&nbsp / patients (controls). Patients were included in the study only if they complied with the following criteria: sensitivity to second line anti-TB drugs, MDR-TB infection, co-infection with HIV (for some&nbsp / of them), male and female patients, completion of treatment between 1 January 2006 and 31 December 2008. Any patients that presented with extreme drug-resistant tuberculosis (XDR-TB)&nbsp / were excluded from the study. Data were retrospectively collected from each patient&rsquo / s medical records. There were a total of 336 patients of which 242 (72%) were MDR-TB patients and 94&nbsp / (27.9%) MDRTB co-infected with HIV patients. Out of the 242 MDR-TB patients, 167 (69.2%) were males and 75 (30.7%) were females. Of the 94 patients with MDR-TB co-infected with HIV, 51&nbsp / (54.2%) males and 43 (45.7%) females. Patients with multidrug-resistant tuberculosis co-infected with HIV who qualify for antiretroviral therapy were treated with stavudine, lamivudine and&nbsp / efavirenz while all MDR-TB patients were given kanamycin, ethionamide, ofloxacin, cycloserine and pyrazinamide. The cure rate of MDR-TB in HIV (+) patients and in HIV (-) patients is 34.5%&nbsp / and 30 % respectively. There is no significant difference between both artes (pvalue = 0.80). The MDR-TB cure rate in HIV (+) patients taking antiretroviral drugs and in HIV (+) patients without&nbsp / antiretroviral therapy is 35% and 33% respectively. The difference between both rates is not statistically significant. The study shows that 65 (28.0%) patients completed MDR-TB treatment but&nbsp / could not be classified as cured or failure, 29 (12.5%) patients failed, 76 (32.7%) defaulted, 18 (7.7%) were transferred out and 44 (18.9%) died. As far as treatment completed and defaulted is concerned,&nbsp / there is no significant statistical difference between HIV (+) and HIV (-) The number of patients who failed the MDR-TB treatment and who were transferred out is significantly higher in the HIV (-)&nbsp / group than in the HIV (+) group. Finally the number of MDR-TB patients who died is significantly higher in the HIV (+) group). The median (range) duration of antiretroviral therapy before starting&nbsp / anti-tuberculosis drugs is 10.5 (1-60) months. According to this study results, the MDR-TB treatment cure rate at Brewelkloof hospital is similar to the cure rate at the national level. The study also&nbsp / hows that HIV infection and antiretroviral drugs do not influence any influence on MDR-TB treatment outcomes.</p>

Non-nucleoside reverse transcriptase inhibitor (NNRTI) is one of the key components of antiretroviral drug regimen against human immunodeficiency virus type-1 (HIV-1) replication. However, the low genetic barriers to drug-resistance or cross-resistance, side effects, as well as the unaffordable cost of NNRTIs compromise their clinical usage. Therefore, to develop novel NNRTIs with potent antiviral activity against HIV-1 becomes a major concern in the treatment and prevention of HIV/AIDS. (+)-Calanolide A, which is a natural product initially extracted from the tropical rainforest tree Calophyllum lanigerum, was identified as an attractive NNRTI against HIV-1 despite virus strains containing drug-resistant K103N/Y181C mutations. In this study, a chemical library was constructed based on the three chiral carbon centers of (+)-Calanolide A. After screening the activity against HIVNL4-3 wild-type and several NNRTI-resistant pseudoviruses, a small molecule 10-chloromethyl-11- demethyl-12-oxo-calanolide A (F18) was identified as novel NNRTI with promising anti-HIV efficacy. Further studies were performed to investigate the antiviral breadth, drug resistance profile and underlying mechanism of the action of F18. F18 consistently displayed a potent activity against primary HIV-1 isolates including various subtypes of M group, CRF01_AE, and laboratory-adapted drug-resistant viruses in PBMC based assay. Moreover, F18 displayed distinct profiles against 17 NNRTI-resistant pseudoviruses, with an excellent potency especially against one of the most prevalent strains with the Y181C mutation (EC50=1.0nM) in cell line based assay, which was in stark contrast from the extensively used NNRTIs nevirapine and efavirenz. F18-resistant viruses were induced by in vitro serial passages, and mutation L100I was appeared to be the dominant contributor to F18-resistance, further suggesting a binding motif different from nevirapine and efavirenz. The efficacy of F18 was non-antagonistic when used in combination with other antiretrovirals against both wild-type and drug-resistant viruses in infected PBMCs. Interestingly, F18 displayed a highly synergistic antiviral effect with nevirapine against nevirapine-resistant virus (Y181C). Furthermore, in silico docking analysis suggested that F18 may bind to the HIV-1 reverse transcriptase in a way different to other NNRTIs. For the potential as an anti-HIV-1 microbicide, F18 also showed the stable and rapid release, as well as the sustained antiviral activity against HIV-1 wild-type virus in a formulation temperature-sensitive acidic gel. In summary, this study presents F18 as a new potential drug for clinical use and also underlies new mechanism-based design for future NNRTI. / published_or_final_version / Microbiology / Doctoral / Doctor of Philosophy

Introduction: While the antiretroviral (ARV) coverage has been scaled- up in the last 3 years in South Africa, there is limited data on the operating costs and financial sustainabihty of an anti- retroviral programme. Study Aim: To conduct a cost analysis of the stepdown ARV programme at the Kwadukuza Municipality Clinic (KMC) in the Ilembe district from a healthcare providers' perspective for the period 1st April 2005 to 31st March2006. Study Objectives: To determine the total costs and cost per patient per visit for outpatients attending the ARV, Wellness and VCT clinics respectively at KMC. Study Methods: Study location: This study was conducted at the Kwadukuza Municipality Clinic located in the Ilembe district in Kwazulu- Natal, South Africa. Study population: The population that is included in this study for the purposes of costing comprised: all the patients who received ARVs for the period under study; all the patients who attended the Wellness and VCT clinics and all the staff attached to the ARV programme at the KMC clinic Study design: This is a retrospective and cross- sectional study with both a descriptive and analytical component. Results: Seventy- one percent of the patients on ARVs were female with 50% of the patients being between 31 and 40 years of age. The total operating costs of running the ARV programme was R2 439 940- 90. The total cost accrued to the ARV clinic was R 1 698 003- 60. The Wellness clinic had a total cost of R 460 279- 68 and the VCT clinic accounted for the least total operating cost of R 281 657-77. The cost per patient visit was R440- 13 for the ARV clinic; R133- 05 for the VCT clinic and an amount of R61- 71 for the Wellness clinic. Conclusion This study provides the basis for determining the three cardinal cost components of the ARV programme, namely human resources, the cost of ARVs and the costs of viral load testing for the purposes of future planning and sustainability. The cost- effectiveness of ARV drugs can be improved if the healthcare providers negotiate a lower price for these drugs. The high cost due to monitoring tests can be lowered by decreasing the frequency of these tests but this may allow ARV drug resistance to be undetected. / Thesis (M.Med.)-University of KwaZulu-Natal, Durban, 2008.

In the last seven to eight years, Antiretroviral Treatment (ART) has received an increasing amount of attention internationally. It has come to be viewed as an important way of preventing new HIV infections and prolonging HIV-positive peoples' lives. In late 2003 the increased attention, amongst other factors, led the South African government to publish a comprehensive health care plan stating that all citizens in South Africa who need ART should receive it by year 2009. Patients' adherence and their sexual behavior are crucial to the success of ART. This thesis focuses on what factors influence patients' sexual behavior after commencing ART. It will especially look at ART patients' perception of their own infectiousness, as studies have suggested that lower viral loads caused by ART will increase their sexual risk behaviour. The research was conducted on patients attending Ithembalabantu Clinic in KwaZulu-Natal, South Africa. Qualitative and quantitative data were used in the study. The quantitative data involved 271 face-to-face interviews based on a survey. The qualitative data involved conducting 20 semistructured interviews. The results indicated that consistent condom use was high among the sample population (72%), and only two females and seven males having multiple partners (7%). However, due to ART just recently having been introduced in South Africa, the average time spent on ART was 14 months. The findings reveal that a partner's attitude to HIV/AIDS and the levels of communication and openness in a relationship influenced consistent use of condoms. The use of condoms was significantly related to knowledge of partners' status. A high level of sexual assertiveness amongst the females in the sample might have made it easier for them to negotiate condom use. The stage at which members of the sample population entered the relationship was also a predictor of condom use. People who were unemployed and over 35 years in age were less likely to use condoms consistently. The study also examined the respondents' perception of their own infectiousness. The results indicate that respondents and participants felt that it was just as, or even more dangerous, to have sexual intercourse without a condom when they are on ART. Few of the participants in the study understood the concept of viral load. They used the same explanation for both viral load and CD4 count. / Thesis (M.A.)-University of KwaZulu-Natal, 2006.

<p>Many studies have reported low cure rates for multidrug-resistant tuberculosis (MDRTB) patients and MDR-TB patients co-infected with human immunodeficiency virus (HIV). However, little is&nbsp / known about the effect of HIV infection and antiretroviral therapy on the treatment outcomes of MDR-TB in South Africa. Therefore, the objectives of the study are: to find out whether HIV infection&nbsp / and interactions between ARVs and second line anti-TB drugs have an impact on the following MDR-TB treatment outcomes: cure rate and treatment failure at Brewelskloof Hospital. MDR-TB&nbsp / patients were treated for 18-24 months. The study was designed as a case-control retrospective study comparing MDR-TB treatment outcomes between HIV positive (cases) and HIV negative&nbsp / patients (controls). Patients were included in the study only if they complied with the following criteria: sensitivity to second line anti-TB drugs, MDR-TB infection, co-infection with HIV (for some&nbsp / of them), male and female patients, completion of treatment between 1 January 2006 and 31 December 2008. Any patients that presented with extreme drug-resistant tuberculosis (XDR-TB)&nbsp / were excluded from the study. Data were retrospectively collected from each patient&rsquo / s medical records. There were a total of 336 patients of which 242 (72%) were MDR-TB patients and 94&nbsp / (27.9%) MDRTB co-infected with HIV patients. Out of the 242 MDR-TB patients, 167 (69.2%) were males and 75 (30.7%) were females. Of the 94 patients with MDR-TB co-infected with HIV, 51&nbsp / (54.2%) males and 43 (45.7%) females. Patients with multidrug-resistant tuberculosis co-infected with HIV who qualify for antiretroviral therapy were treated with stavudine, lamivudine and&nbsp / efavirenz while all MDR-TB patients were given kanamycin, ethionamide, ofloxacin, cycloserine and pyrazinamide. The cure rate of MDR-TB in HIV (+) patients and in HIV (-) patients is 34.5%&nbsp / and 30 % respectively. There is no significant difference between both artes (pvalue = 0.80). The MDR-TB cure rate in HIV (+) patients taking antiretroviral drugs and in HIV (+) patients without&nbsp / antiretroviral therapy is 35% and 33% respectively. The difference between both rates is not statistically significant. The study shows that 65 (28.0%) patients completed MDR-TB treatment but&nbsp / could not be classified as cured or failure, 29 (12.5%) patients failed, 76 (32.7%) defaulted, 18 (7.7%) were transferred out and 44 (18.9%) died. As far as treatment completed and defaulted is concerned,&nbsp / there is no significant statistical difference between HIV (+) and HIV (-) The number of patients who failed the MDR-TB treatment and who were transferred out is significantly higher in the HIV (-)&nbsp / group than in the HIV (+) group. Finally the number of MDR-TB patients who died is significantly higher in the HIV (+) group). The median (range) duration of antiretroviral therapy before starting&nbsp / anti-tuberculosis drugs is 10.5 (1-60) months. According to this study results, the MDR-TB treatment cure rate at Brewelkloof hospital is similar to the cure rate at the national level. The study also&nbsp / hows that HIV infection and antiretroviral drugs do not influence any influence on MDR-TB treatment outcomes.</p>

Longitudinal data tend to be correlated and hence posing a challenge in the analysis since the correlation has to be accounted for to obtain valid inference. We study various statistical methods for such correlated longitudinal binary responses. These models can be grouped into five model families, namely, marginal, subject-specific, transition, joint and semi-parametric models. Each one of the models has its own strengths and weaknesses. Application of these models is carried out by analyzing data on patient’s adherence status to highly active antiretroviral therapy (HAART). One other complicating issue with the HAART adherence data is missingness. Although some of the models are flexible in handling missing data, they make certain assumptions about missing data mechanisms, the most restrictive being missing completely at random (MCAR). The test for MCAR revealed that dropout did not depend on the previous outcome. A logistic regression model was used to identify predictors for the patients’ first month’s adherence status. A marginal model was then fitted using generalized estimating equations (GEE) to identify predictors of long-term HAART adherence. This provided marginal population-based estimates, which are important for public health perspective. We further explored the subject’s specific effects that are unique to a particular individual by fitting a generalized linear mixed model (GLMM). The GLMM was also used to assess the association structure of the data. To assess whether the current optimal adherence status of a patient depended on the previous adherence measurements (history) in addition to the explanatory variables, a transition model was fitted. Moreover, a joint modeling approach was used to investigate the joint effect of the predictor variables on both HAART adherence status of patients and duration between successive visits. Assessing the association between the two outcomes was also of interest. Furthermore, longitudinal trajectories of observed data may be very complex especially when dealing with practical applications and as such, parametric statistical models may not be flexible enough to capture the main features of the longitudinal profiles, and so a semiparametric approach was adopted. Specifically, generalized additive mixed models were used to model the effect of time as well as interactions associated with time non-parametrically. / Thesis (Ph.D.)-University of KwaZulu-Natal, Pietermaritzburg, 2010.

Highly active antiretroviral therapy (HAART) is currently the only treatment that effectively reduces the morbidity and mortality of individuals infected with Human Immunodeficiency Virus-1 (HIV-1). Standard HAART regimens typically comprise 2 nucleoside reverse transcriptase inhibitors and either one non-nucleoside reverse transcriptase inhibitor or a protease inhibitor. These drugs bind to and inhibit the HIV-1 Reverse Transcriptase and Protease enzymes respectively, thereby suppressing viral replication. The nucleoside reverse transcriptase inhibitors promote mitochondrial (mt) dysfunction by strongly inhibiting mt polymerase gamma (Pol-y) and subsequently, mtDNA replication. In contrast, the non-nucleoside reverse transcriptase inhibitors, efavirenz (EFV) and nevirapine (NVP) do not inhibit Pol-y although EFV has been shown to induce mt depolarisation ( mlow) in vitro at supra-therapeutic concentrations. However, the capacity of non-nucleoside reverse transcriptase inhibitor drugs to induce mt toxicity in vivo previously remained undetermined. The objective of this study was to determine the influence of EFV and NVP on peripheral lymphocyte mt transmembrane potential (Avj/m) and apoptosis in HIV-1-infected patients treated with these non-nucleoside reverse transcriptase inhibitors. Thirty-two HIV-1-infected patients on HAART between 4 and 24 months (12 on EFV, 20 on NVP) and 16 HAART-naive HIV-1-infected patients were enrolled into this study. All participants were black South African patients. Spontaneous peripheral lymphocyte apoptosis and mlow were measured ex vivo by flow cytometry for all patients. CD4 T-helper apoptosis for the EFV and NVP cohorts was 19.38% ± 2.62% and 23.35% ± 1.51% (mean ± SEM), respectively, whereas total lymphocyte mlow was 27.25% ± 5.05% and 17.04% ± 2.98%, respectively. Both parameters for each cohort were significantly lower (P < 0.05) than that of the HAART-naive patients. The NVP cohort exhibited both a significant time dependent increase in peripheral lymphocyte ö¿mlow (P = 0.038) and correlation between Thelper apoptosis and low (P = 0.0005). These trends were not observed in the EFV cohort. This study provides evidence that both EFV and NVP induce peripheral lymphocyte ö¿ m low in HIV-1-infected patients on non-nucleoside reverse transcriptase inhibitor-based HAART, which in the case of NVP is sufficient to induce the apoptosis cascade. / Thesis (M.Med.Sci.)--University of KwaZulu-Natal, 2008.