Modelling survival in HIV cohorts with applications to data from Zomba, Malawi

The Human Immunodeficiency Virus (HIV) pandemic still remains a major public health concern worldwide. The World Health Organization (WHO) estimates that approximately over 70% of people living with HIV in the world are in sub-Saharan region. Malawi is one of the worst affected countries in sub-Saharan Africa with prevalence reaching up to 16% in some areas. Recent study reports, largely in Africa, comparing outcomes for HIV patients with Kaposi’s sarcoma (HIV/KS) and HIV patients without KS indicate poor prognosis and poor health outcomes amongst HIV patients with KS. While efforts are being made to improve the management and care for the HIV/KS patient group, there is also need for continued efforts to better understand the survival patterns in this patients. The work presented in this thesis attempts to investigate the survival patterns in different patient subgroups in HIV cohorts in Malawi by using advanced and novel statistical techniques with an ultimate aim of informing targeted patient treatment and management practices. In this thesis, we aim to address the following four objectives; (1) to identify risk factors for mortality among HIV patients diagnosed with Kaposi’s sarcoma during routine initiation of ART, (2) to model the survival pattern among HIV patients diagnosed with KS, (3) to model local geographical variations in survival among HIV patients on ART, (4) to quantify transition dynamics in HIV and TB co-infection using multi-state modelling. For the first two objectives, we considered extended Cox models and parametric models. We also used a novel approach of accounting for high attrition in cohorts in which we used a ’gold-standard’ data to compare survival in our cohort. Sensitivity analyses indicated consistencies in our approach providing an insight into how model results change when using this comparison approach. Overall We noted an early mortality with most patients dying in the first five months after starting HIV treatment. Patients with TB and the patients who started in the early era of ART were significantly at risk of dying. The model diagnostics indicated that (i) a random effects Cox/Log-Gaussian frailty model and (ii) a flexible parametric proportional hazards model, describe the risk of mortality in the HIV/KS patients well. For the third objective, spatial survival models were considered. The study showed existence of possible residual spatial variation in survival after adjusting for age, sex, KS status, TB status and unobserved individual frailties. To further aid our understanding, we used the choropleth maps to indicate areas with substantially high probability of mortality risk at different cut-off values. These results highlight the local geographical variations in survival in HIV populations, an element more often ignored in most studies on HIV data. For the last objective, we considered the homogeneous continuous time multistate Markov models. In this study we found that patients in TB free status had a relatively higher probability of transitioning to being diagnosed with TB compared to dying while in TB free status. However, the cumulative transition hazards for the ’TB free ! death’ transitions compared to the "TB free ! TB infection" transitions were only higher during the early days of HIV treatment. This result emphasize how early periods after starting HIV treatment is crucial to ensure better prognosis. We also noted significant gender differences in the ’TB-free ! death’ transitions. It is anticipated that the findings in this thesis will help to inform treatment and management practices of HIV patients. The findings provide clear outcome pathways taken by HIV/TB patients before experiencing a terminal outcome. More importantly, the findings could help inform policies aimed at improving overall survival in HIV cohorts by establishing targeted patient management and treatment strategies and also formulating a more efficient triage system for care and treatment of particular group of patients

An Analysis of Macroeconomic Determinants of Remittances in Southern Africa

The study analyzed macroeconomic determinants of remittances in Southern Africa and used annual data for the period ranging from 2003-2016. The macroeconomic determinants used include: remittances themselves, inflation rate, GDP growth rate, nominal exchange rate, broad money and age dependency ratio. A panel study was carried out using both the fixed and random methods of which the random method was found to be most appropriate. The countries included in the study were Botswana, Lesotho, Malawi, Mozambique, South Africa, Swaziland and Zambia. It was found that of the variables used, only changes/improvements in the home countries’ economic environment and the exchange rate were statistically significant

Using the RE-AIM Framework to Evaluate Implementation of Male Involvement Strategies to Optimize the PMTCT Program in Malawi: A Mixed-Methods Study.

Involvement of male partners has been shown to be key for the prevention of mother-to-child HIV transmission (PMTCT). Despite the recorded success, uptake and implementation of strategies to involve men in PMTCT continues to be low in Malawi. In this study, we used the Reach Effectiveness Adoption Implementation and Maintenance (RE-AIM) implementation science framework to explore the implementation of male involvement (MI) strategies in Lilongwe, Malawi. We used a cross-sectional mixed-methods complementary-concurrent design from September to October 2020 in two health facilities. Qualitatively, we used a phenomenological approach and conducted seven focus group discussions (FGDs), three with women and four with men. We further conducted four key informant interviews (KIIs) among health care workers. Quantitatively, we conducted a cross-sectional study comprising 138 men presenting at an antenatal clinic (ANC). We used univariate analysis in Stata for the quantitative data, whereas a manual thematic analysis was applied to the qualitative data. Implementation and adoption of the strategies was high among health providers and there were indications of maintenance of the strategies. Provider's attitude, coordinated service provision, integrated training and service provision, information provision, and baby's HIV outcomes were driving factors in implementing the MI strategies. These factors have contributed to the sustained implementation of the strategies over time. In contrast, financial and time constraints, inadequate human resources, and male-friendly spaces impede the implementation of MI strategies. Improving MI will require a systems approach considering health system and individual-level factors for both providers and consumers

Leveraging routine viral load testing to integrate diabetes screening among patients on antiretroviral therapy in Malawi

Background People living with HIV are at an increased risk of diabetes mellitus due to HIV infection and exposure to antiretroviral therapy (ART). Despite this, integrated diabetes screening has not been implemented commonly in African HIV clinics. Our objective was to explore the feasibility of integrating diabetes screening into existing routine HIV viral load (VL) monitoring and to determine a group of HIV patients that benefit from a targeted screening for diabetes. Methods A mixed methods study was conducted from January to July 2018 among patients on ART aged≥18 y and healthcare workers at an urban HIV clinic in Zomba Central Hospital, Malawi. Patients who were due for routine VL monitoring underwent a finger-prick for simultaneous point-of-care glucose measurement and dried blood spot sampling for a VL test. Diabetes was diagnosed according to WHO criteria. We collected demographic and medical history information using an interviewer-administered questionnaire and electronic medical records. We conducted focus group discussions among healthcare workers about their experience and perceptions regarding the integrated diabetes screening program. Results Of patients undergoing routine VL monitoring, 1316 of 1385 (95%) had simultaneous screening for diabetes during the study period. The median age was 44 y (IQR: 38–53); 61% were female; 28% overweight or obese; and median ART duration was 83 mo (IQR: 48–115). At baseline, median CD4 count was 199 cells/mm3 (IQR: 102–277) and 50% were in WHO clinical stages I or II; 45% were previously exposed to stavudine and 88% were virologically suppressed (<1000 copies/mL). Diabetes prevalence was 31/1316 (2.4%). Diabetes diagnosis was associated with age ≥40 y (adjusted OR [aOR] 7.44; 95% CI: 1.74 to 31.80), being overweight and/or obese (aOR 2.46; 95% CI: 1.13 to 5.38) and being on a protease inhibitor-based ART regimen (aOR 5.78; 95% CI: 2.30 to 14.50). Healthcare workers appreciated integrated diabetes screening but also reported challenges including increased waiting time, additional workload and inadequate communication of results to patients. Conclusions Integrating diabetes screening with routine VL monitoring (every 2 y) seems feasible and was valued by healthcare workers. The additional cost of adding diabetes screening into VL clinics requires further study and could benefit from a targeted approach prioritizing patients aged ≥40 y, being overweight/obese and on protease inhibitor-based regimens

Using routinely collected blood donation data for expanded HIV and syphilis surveillance in Blantyre District, Malawi

BACKGROUND: WHO recommends all blood donations be screened for transfusion transmissible infections. However, these data are not incorporated into national surveillance systems in Malawi. We set out to use routinely collected data from blood donors in Blantyre district, Malawi, an area of high HIV and syphilis prevalence, to explore current HIV and syphilis prevalence and identify recent sero-conversions among repeat donors. METHODS: We conducted a retrospective cohort analysis of blood donation data collected by the Malawi Blood Transfusion Service (MBTS) between October 1st 2015 and May 31st 2021. All blood donations were routinely screened for WHO-prioritized transfusion-transmissible infections, including HIV and syphilis. We characterized donor demographics as well as screening outcomes, including identifying sero-conversions among repeat donors who previously tested negative. Logistic regression was used to model the impact of individual level covariates on the probability of sero-conversion. RESULTS: A total of 93,199 donations from 5,054 donors were recorded, with 7 donors (0.1%) donating a maximum of 24 times. The majority of donors were male (4,294; 85%) and students (3264; 64.6%) at the time of their first donation. Of those screened for HIV and syphilis, 126 (2.5%, 126/5,049) and 245 (4.9%, 245/5,043) tested positive respectively.Among repeat donors who previously tested negative, 87 HIV sero-conversions and 195 syphilis sero-conversions were identified over the study period, indicating an HIV incidence rate of 6.86 per 1,000 person-years and a syphilis incidence rate of 15.37 per 1,000 person-years. Donors who were female or aged 16-19 at the time of first donation had a higher risk of HIV or syphilis sero-conversion. CONCLUSIONS: Routinely collected data from national blood donation services may be used to enhance existing population-level disease surveillance systems, particularly in high prevalence areas. While blood donors are generally considered a low-risk population for HIV and syphilis, we were able to identify and characterise blood donor populations at increased risk of sero-conversion over the study period. This information will provide insight into priority prevention areas in Blantyre district and help to inform targeted interventions for improved prevention, testing and treatment

Are venue-based strategies the ticket to the last mile in HIV prevention in Malawi

Background: In 2016, Blantyre District had the highest adult HIV prevalence in Malawi (17% overall; 22% in women) and the lowest viral suppression rate (60%). In response, the MOH expanded prevention and treatment strategies. We hypothesized that social venues patronized by people with high sexual partnerships rates could identify sub-groups currently missed. Methods: We conducted cross-sectional bio-behavioral surveys of representative samples of individuals seeking care in government clinics (n=2313) and social venue patrons (n=1802) Jan-Mar 2022. Clinics were randomly selected from government clinics providing HIV testing. Venues were randomly sampled from urban and rural strata with oversampling of rural venues. Sampling weights were based on 2-stage sampling probabilities. We followed national testing protocols for rapid tests, recency testing and viral load measurements. Acute infections were identified by pooling dried blood spots from persons with an HIV- rapid test. Results: Compared to the clinic population, the venue population was more likely to: be male (68% vs 28%); aged >25 years (61% vs 51%); unmarried (62% vs 40%); drink alcohol daily (43% vs 8%); have more sexual partners in the last year (mean 16 vs 2); report a new sex partner in the past 4 weeks (42% vs 14%); and report transactional sex (52% vs 12%). HIV prevalence (Table 1) was higher among the venue population (19% vs 9%); the proportion HIV+ suppressed was similar (78%). Among women recruited at venues, prevalence increased by age: 0% among age 15-17 to 41% among age 18-21. At venues, factors associated with HIV infection include female sex (39% vs 10%); having a new partner in the past 4 weeks (28% vs 13%) and transactional sex (25% vs 13%). Acute and recent infections were uncommon. Clinic participants who reported visiting venues were less likely to have a suppressed viral load than other PLHIV clinic participants (53% vs 81%). Among both populations, reporting a genital sore in the past 4 weeks was associated with non-suppression (40% vs 20% in clinic; 48% vs 20% in venues). Conclusions: Lower HIV prevalence and greater viral suppression suggests that Blantyre’s HIV epidemic is slowing. Strategies to further reduce transmission should include outreach to venues with higher prevalence of unsuppressed infection and to young women at venues. Testing for acute or recent infection yielded few cases and thus did not provide sufficient value to warrant the cost

Task shifting routine inpatient pediatric HIV testing improves program outcomes in urban Malawi: a retrospective observational study.

This study evaluated two models of routine HIV testing of hospitalized children in a high HIV-prevalence resource-constrained African setting. Both models incorporated "task shifting," or the allocation of tasks to the least-costly, capable health worker.Two models were piloted for three months each within the pediatric department of a referral hospital in Lilongwe, Malawi between January 1 and June 30, 2008. Model 1 utilized lay counselors for HIV testing instead of nurses and clinicians. Model 2 further shifted program flow and advocacy responsibilities from counselors to volunteer parents of HIV-infected children, called "patient escorts." A retrospective review of data from 6318 hospitalized children offered HIV testing between January-December 2008 was conducted. The pilot quarters of Model 1 and Model 2 were compared, with Model 2 selected to continue after the pilot period. There was a 2-fold increase in patients offered HIV testing with Model 2 compared with Model 1 (43.1% vs 19.9%, p<0.001). Furthermore, patients in Model 2 were younger (17.3 vs 26.7 months, p<0.001) and tested sooner after admission (1.77 vs 2.44 days, p<0.001). There were no differences in test acceptance or enrollment rates into HIV care, and the program trends continued 6 months after the pilot period. Overall, 10244 HIV antibody tests (4779 maternal; 5465 child) and 453 DNA-PCR tests were completed, with 97.8% accepting testing. 19.6% of all mothers (n = 1112) and 8.5% of all children (n = 525) were HIV-infected. Furthermore, 6.5% of children were HIV-exposed (n = 405). Cumulatively, 72.9% (n = 678) of eligible children were evaluated in the hospital by a HIV-trained clinician, and 68.3% (n = 387) successfully enrolled into outpatient HIV care.The strategy presented here, task shifting from lay counselors alone to lay counselors and patient escorts, greatly improved program outcomes while only marginally increasing operational costs. The wider implementation of this strategy could accelerate pediatric HIV care access in high-prevalence settings

Differences in survival among adults with HIV-associated Kaposi's sarcoma during routine HIV treatment initiation in Zomba district, Malawi:a retrospective cohort analysis

Background: The HIV epidemic is a major public health concern throughout Africa. Malawi is one of the worst affected countries in sub-Saharan Africa with a 2014 national HIV prevalence currently estimated at 10% (9.3-10.8%) by UNAIDS. Study reports, largely in the African setting comparing outcomes in HIV patients with and without Kaposi's sarcoma (KS) indicate poor prognosis and poor health outcomes amongst HIV+KS patients. Understanding the mortality risk in this patient group could help improve patient management and care. Methods: Using data for the 559 adult HIV+KS patients who started ART between 2004 and September 2011 at Zomba clinic in Malawi, we estimated relative hazard ratios for all-cause mortality by controlling for age, sex, TB status, occupation, date of starting treatment and distance to the HIV+KS clinic. Results: Patients with tuberculosis (95% CI: 1.05-4.65) and patients who started ART before 2008 (95% CI: 0.34-0.81) were at significantly greater risk of dying. A random-effects Cox model with Log-Gaussian frailties adequately described the variation in the hazard for mortality. Conclusion: The year of starting ART and TB status significantly affected survival among HIV+KS patients. A sub-population analysis of this kind can inform an efficient triage system for managing vulnerable patients

Mixed method joint display to illustrate how quantitative and qualitative data were integrated.

Abbreviations: C, Complementarity; D, Divergence; E, Expansion; NHS, National Health Service; QQD, Quantitizing Qualitative Data. Three themes: 1. Lived experiences, 2. Health seeking and decision making 3. Experiences of hospital.</p

Supplementary data.

Table A Attendance figures compared to study data. Table B Responses to questionnaire compared between the two groups. Table C Quantitizing of the qualitative responses. Table D Quantitizing of qualitative responses around sources of information. (DOCX)</p