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Immunologic monitoring is part of the standard care for patients on antiretroviral treatment. Yet, little is known about the routine implementation of immunologic monitoring in Ethiopia. This study assessed the pattern of immunologic monitoring, immunologic response, level of immunologic treatment failure and factors related to it among patients on antiretroviral therapy in selected hospitals in southern Ethiopia. A retrospective longitudinal analytic study was conducted using documents of patients started on antiretroviral therapy. A total of 1,321 documents of patients reviewed revealed timely immunologic monitoring were inadequate. Despite overall adequate immunologic response, the prevalence of immunologic failure was 11.5% (n=147). Having WHO Stage III/IV of the disease and a higher CD4 (cluster differentiation 4) cell count at baseline were identified as risks for immunologic failure. These findings highlight the magnitude of the problem of immunologic failure. Prioritizing monitoring for high risk patients may help in effective utilisation of meager resources / Health Studies / M.A. (Public Health)

Immunologic monitoring is part of the standard care for patients on antiretroviral treatment. Yet, little is known about the routine implementation of immunologic monitoring in Ethiopia. This study assessed the pattern of immunologic monitoring, immunologic response, level of immunologic treatment failure and factors related to it among patients on antiretroviral therapy in selected hospitals in southern Ethiopia. A retrospective longitudinal analytic study was conducted using documents of patients started on antiretroviral therapy. A total of 1,321 documents of patients reviewed revealed timely immunologic monitoring were inadequate. Despite overall adequate immunologic response, the prevalence of immunologic failure was 11.5% (n=147). Having WHO Stage III/IV of the disease and a higher CD4 (cluster differentiation 4) cell count at baseline were identified as risks for immunologic failure. These findings highlight the magnitude of the problem of immunologic failure. Prioritizing monitoring for high risk patients may help in effective utilisation of meager resources / Health Studies / M. A. (Public Health)

Submitted in fulfillment of the requirements for the Degree of Master of Technology: Biomedical Technology, Durban University of Technology, 2012. / Antiretroviral therapy (ART) was introduced because it has shown to reverse the Acquired Immunodeficiency syndrome (AIDS), by reducing the HIV replication, allowing the regeneration of the patient’s immune system. ART is given to patients for the rest of their lives as part of HIV clinical care, but the use of ART has shown evidence of metabolic side effects which range from manageable to life threatening complications. Aims and objectives of the study The aim of the study was to investigate whether patients on ART developed metabolic side effects such as pancreatitis, dyslipidaemia and hepatotoxicity. These metabolic side effects were determined by laboratory testing of blood levels of specific biomarkers at stipulated intervals. Any significant change in the blood levels of these specific biomarkers was identified. Methodology : The study included 92 patients who were already selected for the ART programme which is in accordance to the South African National Antiretroviral Therapy Guidelines of 2003 Laboratory blood analysis was conducted. The repeated measures analysis of variance (ANOVA) was used to compare changes in biomarkers over time. The severity of each side effect was assessed by grading each biomarker laboratory result through the use of an established toxicity grading table. Results : It was found that the biomarker blood levels were not significantly altered within 12 months of ART, however, there was a gradual increase of most biomarker values, indicating that abnormalities may be detected after a longer period of treatment. Conclusion : Within 12 months of treatment, life-threatening toxicities were not detected. It may be speculated that if ART is monitored correctly, life-threatening toxicities may be avoided in many patients.

The Human immunodeficiency virus (HIV) pandemic has resulted in a heavy global disease burden, and clinically causes Acquired Immuno-Deficiency Syndrome (AIDS). The development of highly active antiretroviral therapy (HAART) has achieved remarkable control of the rapidly evolving HIV. However, HIV remains neither curable nor preventable by vaccine, and in the developing regions worst affected by HIV, HAART remains inaccessible to most patients. Furthermore, the change in both immunology and viral evolution during chronic HIV infection and its relation to AIDS pathogenesis remains unknown. Following the failure of recent HIV vaccines, it is believed that a better understanding of host-pathogen interaction is vital to advance therapeutic (vaccine and drug) design. In this thesis, I have performed an investigation of viral adaptation in response to different selection forces during advanced HIV infection and AIDS. The thesis first examined a case study that reveals the potential role of B cell-mediated neutralising antibody (NAb) in chronic HIV infection through the unexpected effect of B cell depletion agent, anti-CD20 (Rituximab). Here, longitudinal results have shown that viral load (VL), env gene diversity, and NAb sensitive strains increased during B cell and NAb depletion as a result of Rituximab administration, and reversed as B cells recovered. The study provides preliminary evidence to support the idea that NAb may be effective at suppressing HIV. The rest of the thesis focused on the cross-sectional cohort at Bloemfontein, South Africa (n=1491), a resource-limited region affected by the pandemic. Here, we used methods that include molecular and pretherapy drug resistance epidemiology, mathematical modelling, phylogenetically adjusted bioinformatics analysis and in vitro viral replication capacity (VRC) assay to study materials including cohort demography, plasma samples, CD4 cell count, VL, viral genetic sequences and host human leukocyte antigen (HLA) tissue types. Our analysis was further augmented by the additional data kindly contributed by our neighbouring Durban cohort collaborators (n=775), which also includes an IFN! ELISPOT assay that measures cytotoxic T lymphocyte (CTL) responses. Using the HIV pol sequencing data and phylogenetic analysis we confirmed that the local molecular epidemiology is similar to the circulating strains documented in the regional database. However, the pretherapy drug resistance mutation screening results have revealed an unexpected high incidence of drug-induced viral mutants in the AIDS patients with CD4 counts <100 cells/μl. According to mathematical modelling, this finding is attributable to additional sources of antiretroviral therapy exposure, which warrants public health caution. The investigation then focused on studying the changes in HLA class I mediated CTL selection and viral evolution as CD4 counts are reduced in AIDS. Interestingly we have noted evidence that suggest weakening CTL immune selection against gag during AIDS is associated with increased viral fitness (measured by VRC) and reversion of previous immune-escape mutations which conferred high fitness costs. In conclusion, this thesis compared different sources of host and drug mediated HIV selection and its implication for viral evolution. The identification of more bottleneck sites conferring high fitness costs to the selection of escape mutants is expected to be helpful in the design of future therapeutics (via vaccine, drug, immune therapy, or public health strategy). As we have learnt from the principle of combinational ARV, it would be desirable for a vaccine to select HIV at multiple sites of high escape-mutation fitness cost, hence offering protective effect.

Thesis (MPH.) --University of Limpopo, 2018 / Background: The prevalence of HIV in South Africa has increased largely due to the combined effect of new infections, and a successfully expanded antiretroviral treatment programme, which has increased survival among people living with HIV. As the up-scaling of patients on ART has been increased, the aim of the current study was to investigate the variations of the clinical outcomes between patients initiated with CD4 < 350 and of those above 350 after the implementation of the new eligibility criteria for ARV therapy. Methods The current study used quantitative approach to retrospectively review a total of 488 records of adult patient who were registered in health facilities which were purposefully sampled from Sekhukhune District of Limpopo Province. SPSS version 23.0 was used to analyse data. Results Approximately 60% of the patients initiated on ART were having CD4 count <350 and male patients were more at 74% as compared to females at 54.7%. Patients who started ART with a baseline CD4 >350 had a high rate of lost to follow up within 3 months after start of ART at 15% than those with a baseline CD4 <350 at 10.2. More patients were lost to follow-up shortly after starting treatment at 3 months at an average of 13.8% in both CD4 counts. Majority of patients retained in care were those who started ART treatment with a baseline CD4<350 at 87.4%. Viral load completion rate at 12 months was higher than that of 6 months, at 86.8 and 80.5 respectively. Patients with a baseline CD4 >350 suppressed more than those who started ART with a baseline CD4 <350 at both 6 and 12 months at >90% suppression rate. Lastly, most of the patients died within 3 months of ART treatment and had a baseline CD4 < 350 than at 2.4% those with a baseline CD4 >350 at 0.6%. Conclusions The implementation of the new eligibility criteria of ART initiation improves the clinical outcome of patients on ART. There are still patients that are missed to be monitored viral load bloods which play a key role in determining the clinical outcomes of patients. Clinicians and nurses should adhere to the recommended time frames for monitoring of ART patients to improve clinical outcomes. Keywords: HIV/AIDS, antiretroviral therapy, clinical outcome, ART initiation; Eligibility Criteria;

Measles remains a major global public health problem. Attainment of high population immunity to measles through vaccination is necessary to control this disease. Children infected with HIV infection often experience secondary measles vaccine failure by 2 years of age, making them susceptible to measles. It is not clear whether HIV-infected children on Highly Active Antiretroviral Treatment (HAART), older than 2 years, have a higher risk of measles than HIV-uninfected children. This retrospective cohort study, guided by the proximate determinants framework, was conducted to compare the risk of measles between HIV-infected children on HAART (exposed) and HIV-uninfected peers (unexposed). The age group with the highest measles susceptibility in the exposed children, which could inform timing for revaccination, was investigated. The role of age at initiation of HAART, low CD4+ count, and undernutrition as predictors of the risk of measles in the exposed children was examined. Univariate, bivariate, and binomial logistic regression analytical procedures were used in data analysis. Results showed no significant difference in the risk of measles between exposed and unexposed children. The age groups 5 to 9 years and 2 to 4 years were the first and second most affected by measles among the exposed children. Undernutrition (stunting) was a significant predictor of measles in exposed children (odds ratio of 4.14, p = 0.02), while age at initiation of HAART and CD4+ count prior to measles exposure were not. The study findings provide evidence to inform vaccination policy and nutrition care for HIV-infected children on HAART in Uganda, so as to reduce their risk of measles illness and mortality, thus contributing to positive social change for the children and the country.

Thesis (MPH.) -- University of Limpopo, 2021 / Background: The provision and success of Antiretroviral therapy (ART) depend on monitoring and evaluation of treatment programmes which should be assessed during regular patient follow-ups. The treatment of HIV infection can only be effective if patients are retained in care and programme monitoring is adequately undertaken to understand the effectiveness of the emerging treatment. The outcome of patients lost to follow-up (LTFU) has received relatively little attention and it is predicted that these patients may have stopped taking antiretroviral drugs, resulting in high morbidity and mortality. The provision of ART was introduced into South African public health facilities in 2003 and therefore, attention has shifted from the immediate need to get patients into care, to the long-term challenges of keeping patients in care and on treatment. The objective of the current study was to determine the trends at which HIV-positive patients become LTFU on the ART programme at Shiluvana Local Area’s six clinics in the Greater Tzaneen Sub-District, Limpopo Province, South Africa. Methods: A retrospective cohort study approach was used and data was collected from the database of patients who were LTFU from 2012 – 2017 in the electronic data management system of the District Health Information System. Data was collected from 1161 patients. Data analysis was done using SPSS version 25, in which categorical data was presented using frequencies and percentages and comparisons between groups was done using Chi-square test for categorical data, and Student’s t-test for continuous data. A p-value of <0.05 was considered statistically significant. Univariate regression analysis was done to determine the contributory factors to LTFU for a period of more than 3 months. Results: The mean age of the study population was 36.5 years old ranging from 16 years to 87 years old and the age distribution of people who were LTFU for ART showed a significant association (p = 0.001). The study participants’ distribution by gender revealed that majority were females at 71.4%. The study findings also revealed there was a statistically significance difference in health status of the study population and majority of the LTFU were in the younger age group. The CD4 count of LTFU patients showed a statistically significance difference and majority of the LTFU in patients with a CD4 count of less than 200 were in younger age group also. The TB/HIV co-infection in the study population showed a statistically significance difference and majority of LTFU in the study did not have TB/HIV co-infection. The WHO clinical HIV staging in the study population did not show a statistically significance difference. Marital status, TB/HIV co-infection and WHO clinical staging were found to be a strong predictor of LTFU of more than 3 months. Conclusion: The study findings bring with them a number of recommendations such as there is a need to have a standardised tracking method of patients who migrate to other health facilities for their ART treatment. This will provide more accurate information regarding LTFU levels and reduce the misclassification of patients. The age group which is affected by LTFU in all variables was in the 20 – 34 years’ age group. This is of great concern, as this is the age group who are economically active and should contribute to the future economy of the country. It is therefore recommended that a greater focus should be placed in this age group, with policies and programmes that bring them into ART and retain them there. Lastly, educational campaigns, in a form of pamphlets and posters to emphasize adherence to ART and the importance of remaining on ART within designated health facilities. In conclusion, patients should be retained in care for as long as possible to prevent the prevalence of the ARV resistant virus that can impact negatively on the ART programme. Keywords: Antiretroviral treatment. Human immunodeficiency virus, Loss to follow-up, socio-demographic.

Thesis (Ph. D. (Statistics)) -- University of Limpopo, 2019 / Refer to document / NRF-TDG

Aim 1. Accelerated antiretroviral therapy (ART) initiation, including starting ART on the day of HIV diagnosis, has emerged to be one of the approaches to improve ART uptake by shortening or removing some preparatory steps before ART initiation. By doing so, accelerated ART initiation is thought to remove some structural barriers associated with ART initiation process. However, several concerns still need to be addressed, such as whether the expedited process would lead to adverse treatment outcomes after ART initiation. Searched strategy was developed using both MeSH and free text terms relevant to accelerated ART initiation (same-day, immediate, rapid). Exclusion criteria were studies that did not focus on HIV, did not involve HIV treatment, included individuals with HIV aged lower than 12, and contained non-human subjects. Additionally, we excluded articles that were case-reports, qualitative studies, systematic reviews, commentary, points of view, and conference presentations. Four electronic databases (PubMed, Embase, Web of Science, MEDLINE) were used to identify relevant studies published in English between January 2015 and December 2023. Outcomes were retention, viral suppression, pre-ART screening procedures, preferred baseline antiretroviral regimens, additional baseline medications, and adverse events after ART initiation. Two independent researchers were involved in the study selection process. Of 5,455 studies retrieved, 25 studies were included in the review (Cohen’s kappa: 0.88). Six studies reported findings from randomized controlled trials conducted in Lesotho (n=2), Haiti (n=1), South Africa (n=3), and Kenya (n=1), with one study conducted in both South Africa and Keya; 19 studies were observational cohort study from Ethiopia (n=4), West Africa (n=1), Italy (n=2), the United States (n=3), South Africa (n=3), Kenya (n=1), Rwanda (n=1), Sub-Saharan African region (n=1), the United Kingdom (n=1), Turkey (n=1), and China (n=1). The majority of the studies were conducted in urban areas (n=19). Of the 25 included studies, 19 had same-day ART initiation as the intervention or the exposure (three studies measured the time to ART initiation from the day of care engagement, and 16 studies measured it from the day of HIV diagnosis). There was heterogeneity in the pre-ART screening procedures, from relying on symptomatic screening and history assessment to using non-molecular rapid tests to help identify individuals with increased risk of clinical contraindications. Despite this, individuals with symptoms consistent with WHO stage 4 neurological diseases were not eligible for ART. Efavirenz-based ARV was the most regimen reported. The majority of PWH preferred to start ART within 7 days of HIV diagnosis or care engagement (range: 56.5%-86%). Our review suggested mixed results on retention in care and viral suppression after ART initiation, although many studies indicated potential benefits. Despite this, no study reported an association between clinical adverse events, including deaths, and accelerated ART initiation. Our review suggested that accelerated ART initiation can potentially increase ART uptake while not negatively impacting treatment outcomes in some settings. New tools in HIV treatment, such as safer drug regimens and injectable ART, may help improve PWH’s experience and reduce the burden associated with pill burden and frequent clinic visits. Aim 2. Accelerated antiretroviral therapy (ART) initiation has been proposed to address some structural barriers associated with the ART initiation process and improve ART uptake. Despite this, there has yet to be a consensus on how this approach should be implemented, especially concerning the clinical readiness screening procedures. While emerging literature has reported the clinical safety of accelerated ART, limited data are reported from Thailand. Given the heterogeneity of clinical profiles of people with HIV (PWH) in different regions, past studies may not be generalizable to Thailand. Additionally, as different screening procedures affect the time to ART initiation, we need to learn how these procedures impact treatment outcomes. Data were obtained from PWH from 10 ART facilities in six provinces (Chiang Rai, Chiang Mai, Chonburi, Ubon Ratchathani, Songkhla, and Bangkok) in Thailand between July 2017 and July 2019 and followed up until January 2021. All PWH registered in HIV care were included in the analysis, regardless of baseline clinical status. ART facilities were categorized into three models according to the hospital policy on pre-ART laboratory screening procedures: Model A did not consider any lab results at the initiation, Model B considered only CD4 count, and Model C considered other non-CD4 baseline laboratory results. Log-Poisson regression was used to assess the impact of hospital policies on adverse outcomes (deaths, ART discontinuation, loss to follow-up) at months three, six, 12, 18, and 24 after care engagement. Logistic regression was used to examine the impact of hospital policies on viral non-suppression (VNS, HIV-1 RNA>50 copies/mL) at months six, 12, and 18 after ART initiation. Multilevel mixed model was used to account for potential clustering within each hospital policy. Of 10,926 PWH in the dataset, 9,695 (88.7%) were included in this study. Among these, 68% (6,571/9,695), 13% (1,236/9,695), and 19% (1,888/9,695) were in Models A, B, and C, respectively. Both Models A and B had 2 ART facilities each, while Model C had 6 ART facilities. 54.2% (5,257/9,695) self-reported to be men who have sex with men, and the overall baseline median CD4 (IQR) was 168 (129-404) cells/mm3. Compared to Model A, the average risk ratio (95%CI) of adverse events at months three, six, 12, 18, and 24 for Model B was 1.14(1.08-1.20), 1.40(1.31-1.49), 1.19(1.10-1.27), 1.11(1.02-1.21), and 1.32(1.21-1.44), respectively, while it was 1.21(1.16-1.27), 1.76(1.67-1.85), 1.59(1.50-1.67), 1.81(1.71-1.90), and 1.98(1.88-2.10) for Model C, respectively. Of 9,695 PWH, 6,785 (70%) had a confirmed date of ART initiation; 37% (2,513/6,785), 34% (2,332/6,785), and 13% (851/6,785) PWH had information on viral load status at months six, 12, and 24 after ART initiation, respectively. Among these samples, compared to Model A, the average odds ratio (95%CI) of VNS for Model B at months six, 12, and 18 was 0.79(0.59-1.06), 1.06(0.71-1.55), and 1.47(0.49-3.58), respectively, while it was 1.01(0.77-1.32), 0.68(0.40-1.09), and 0.93(0.31-2.22) for Model C, respectively. ART facilities that considered CD4 or any other non-CD4 baseline laboratory results before starting ART had, on average, a higher likelihood of adverse outcomes after the initial care engagement visit and viral non-suppression after ART initiation than ART facilities that did not consider any baseline laboratory result. Aim 3. Clinical screening and psychosocial readiness assessments prior to antiretroviral therapy (ART) initiation are imperative to ensure clinical safety and ART adherence among people with HIV (PWH). However, multiple preparation steps and long wait times associated with ART initiation can contribute to HIV care disengagement and low ART uptake. To address some of the barriers associated with lengthy assessment process, accelerated ART initiation, an approach to start ART on or near the day of HIV diagnosis, has been proposed. Despite this, concerns with the expedited preparation process remain, especially with the PWH’s readiness to have optimal HIV care adherence. This study examined the impact of time to ART initiation on adverse outcomes after care engagement and viral non-suppression (VNS) after ART initiation among PWH in Thailand. Data were obtained from PWH from 10 ART facilities in 6 provinces (Chiang Rai, Chiang Mai, Chonburi, Ubon Ratchathani, Songkhla, and Bangkok) in Thailand between July 2017 and July 2019 and followed up until January 2021. PWH who tested negative for cryptococcal antigen test at baseline and had a confirmed date of ART initiation were included in the analysis and were categorized into three groups based on the time interval between care engagement (defined as the day that PWH first registered at an ART facility) and ART initiation: (1) same day (ART initiation upon the day of care engagement or same day), (2) 1-7 days, and (3) more than 7 days. Log-Poisson regression was used to assess the impact of time to ART initiation on adverse outcomes (deaths, ART discontinuation, and loss to follow-up) at months three, six, 12, 18, and 14 after care engagement. Logistic regression was used to examine the impact of time to ART initiation on VNS (HIV-1 RNA>50 copies/mL) after ART initiation at months six, 12, and 18 after ART initiation. Age, population, hospital policy on pre-ART screening procedures, and baseline CD4 were adjusted in the final models. Of 10,926 PWH in the dataset, 5,528 (50.6%) had complete information on the date of care engagement, negative results for the cryptococcal antigen test, and the date of ART initiation. Among these, 44.23% (2,445/5,528), 38.69% (2,139/5,528), and 17.08% (944/5,528) started ART on the day of, 1-7 days from, and more than 7 days from HIV care engagement visit, respectively. The median age (IQR) was 29 (24-36) and 61% (3,387/5,528) identified themselves as men who have sex with men. The baseline median CD4 (IQR) was 283 (162-412) cells/mm3. Compared to PWH who started ART on the day of HIV care engagement visit, the average risk ratio (RR) of adverse outcomes for those who started ART between 1-7 days at months three, six, 12, 18, and 24 was 0.73(0.60-0.89), 0.66(0.55-0.79), 0.74(0.63-0.86), 0.83(0.71-0.98), and 0.84(0.70-1.01), respectively, while it was 2.27(1.91-2.71), 2.16(1.85-2.52), 1.70(1.46-1.98), 1.93(1.65-2.25), and 2.83(2.44-3.30) for those who started ART more than 7 days, respectively. In the adjusted models, the associations from both groups became statistically non-significant, except for the more than 7 days at month 24 (adjusted RR:1.08; 95%CI:1.04-1.12). Of 5,528 PWH, 29% (1,616/55,28), 36% (1,967/5,528), and 14% (795/5,528) had information on viral load status at months six, 12, and 18 after ART initiation, respectively. Among these individuals, time to ART initiation was determined to have no impact on VNS in both crude and adjusted models. Accelerated ART initiation has the potential to improve ART uptake while maintaining optimal adherence to HIV care. However, HIV programs should recognize and respond to the diversity of needs among PWH to minimize adverse outcomes following ART initiation.