Determining predictors of mortality in HIV positive people in South Africa, 2003 to 2009: a mixed methods approach incorporating unobserved variables

A thesis submitted to the School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, in fulfilment of the requirements for the degree Of Doctor of Philosophy. 02 April 2018.Background The largest proportion of HIV-infected people resides in Southern Africa. In South Africa, the government has taken the lead in the provision of free HIV treatment with a high coverage rate. Provision of free antiretroviral treatment has led to a decline in mortality rates and an increase in life expectancy. However, a significant number of people with HIV continue to die despite the availability of free treatment. A large proportion of studies have concentrated on using quantitative methods of analysis. Very few have used mixed methods that combine quantitative time-to-event frailty models and qualitative methods in assessing risk factors for mortality in HIV-infected individuals. However, use of such mixed methods approach could provide insights that may lead to an improvement in patient care and management. Aim To determine mortality risk factors in HIV-infected people through incorporating unobserved variables using a mixed methods approach in which quantitative findings are explained by the qualitative. Methods To critically review statistical methods used for assessing risk factors for mortality in HIV-infected people between the years 2002 and 2011. We conducted a literature review on the design of studies, how data were analysed and whether suitable statistical methods were utilised in assessing mortality risk factors in HIV-infected people in the period 2002-2011. Only publications written in English and listed in Pubmed/Medline were considered. In this review, papers using time-to-event techniques were regarded as appropriate. Data were split into two equal periods allowing for the comparison of the statistical methods over time. To compare the different time-to-event methods, we ran 1,000 simulations of parametric clustered data using parameters derived from an HIV study that was conducted in South Africa by the Perinatal HIV Research Unit (PHRU). Data for 5, 10 and 20 clusters of size 50 and 100 were simulated. Survival and censoring times were derived from a Weibull distribution. The minimum of survival and censoring times was taken as the study time. Using the simulated data, we compared the following time-to-event methods: Cox proportional hazards regression, shared Gamma frailty with Weibull and exponential baseline hazards (frequentist models), and the Bayesian integrated nested Laplace approximation (INLA) with Weibull baseline hazard. Parameter estimates, standard errors and their fit statistics were averaged over 1,000 simulations. Similarly, means and standard deviations from INLA were averaged (over the 1,000 simulations). Frequentist models were compared using the -2 loglikelihood fit statistics while all the four models were compared using the mean square error (MSE). Additionally, we simulated semiparametric clustered frailty models (using gamma and log-normal frailties) including INLA, h-likelihood, penalized likelihood and penalised partial likelihood estimations. Parameter estimates and their standard errors were presented graphically and compared using the MSE. To assess mortality risk factors in HIV-infected people in South Africa in different settings, factors associated with mortality in HIV-infected people were assessed by INLA survival frailty model using cohort data of HIV-infected people from South Africa. Two thirds were from Soweto (urban) and the rest from Mpumalanga (rural). Findings were evaluated by site. Mixed methods were used to evaluate risk factors for mortality by combining the best fitting model applied to retrospective data and qualitative analysis on prospective data. In order to explain the unobserved frailty modelling results, we conducted a qualitative study that enrolled 20 participants who had confirmed knowing a person that had died as a result of HIV. Participants were recruited from the Zazi VCT in PHRU and were interviewed using a semi-structured interview guide. The aim of the qualitative study was to attempt to explain the unobserved factors influencing mortality in HIV-infected individuals using perceived reasons for death given by the participants. These were later used to complement the potential reasons for death as identified in the frailty modelling (quantitative) results. Results In the critical review, 189 studies met the inclusion criteria that included prospective (69%) and retrospective (30%) studies. Of the 189 studies, 91 were published in the period 2002-2006 and 98 in 2007-2011. Cox regression analysis with frailty was used in only 7 studies (~4%); of which 6 were published between the years 2007- 2011. The simulation study showed that the shared frailty models performed better than Cox-PH. Within the shared frailty models, the Gamma frailty model with a Weibull baseline performed better than the Gamma frailty model with an exponential baseline. The MSE showed that in general, the Bayesian INLA had better results. In the semiparametric simulations, results were similar but INLA had a slightly better fit with consistently lower MSE values relative to both gamma and log-normal frailty models. The random effects estimate for INLA, whose method is slightly different, had lower MSE values consistently relative to the other methods. In the HIV cohort study, 6,690 participants were enrolled with majority being female (78%) and most participants residing in an urban area (67%). Rural participants were older (36 years; IQR: 31-44) and with a higher mortality rate (11/100 person years). Among those residing in rural areas, HAART treatment for between six and twelve months (HR: 0.2, 95% CI: 0.1-0.4) and more than 12 months (HR: 0.1, 95% CI: 0.1- 0.2) was protective relative to not being on treatment. Being on HAART treatment for greater than twelve months was protective in the urban participants (HR: 0.35, 95%CI: 0.27-0.46). Significant heterogeneity, assessed by frailty variance, was high in rural participants and lower in the urban. Since the frailty modelling results suggested that the unobserved variables had a significant effect on mortality in HIV-infected individuals, a qualitative study was conducted to explore the potential causes of death. In the qualitative study, participants perceived that mortality in HIV-infected individuals may have been influenced by engagement in risky sexual behaviour such as multiple sexual partnerships, negative attitude by healthcare workers towards HIV-infected people, believing in the healing power of religion, traditional medicine, food security and social support structure. Conclusions The study found that Cox proportional hazards regression with frailty is not commonly used in research on mortality in HIV-infected individuals as it is used in other fields of health research. Additionally, use of the more complex semiparametric frailty models was even lower in this population. From simulations, we found that frailty survival models provided a better fit in modelling mortality due to their ability to account for unobserved variables especially the Bayesian INLA. As the unobserved variables are complex to explain using only quantitative modelling techniques, qualitative analysis of perceived causes of death was explored. Unobserved variables affecting mortality were explored through qualitative analysis of perceived reasons provided by bereaved participants. This mixed methods approach optimised data by using a quantitative approach followed by a qualitative one that complemented each other. Use of optimal methods in assessing morbidity and mortality in HIV-infected patients may improve patient care and management in South Africa and other countries. Key words: HIV, Mortality, Rural, Urban, unmeasured variables, HAART, FrailtyLG201

Factors associated with not testing for HIV and consistent condom use among men in Soweto, South Africa.

BackgroundBesides access to medical male circumcision, HIV testing, access to condoms and consistent condom use are additional strategies men can use to prevent HIV acquisition. We examine male behavior toward testing and condom use.ObjectiveTo determine factors associated with never testing for HIV and consistent condom use among men who never test in Soweto.MethodsA cross-sectional survey in Soweto was conducted in 1539 men aged 18-32 years in 2007. Data were collected on socio-demographic and behavioral characteristics to determine factors associated with not testing and consistent condom use.ResultsOver two thirds (71%) of men had not had an HIV test and the majority (55%, n = 602) were young (18-23). Of those not testing, condom use was poor (44%, n = 304). Men who were 18-23 years (aOR: 2.261, CI: 1.534-3.331), with primary (aOR: 2.096, CI: 1.058-4.153) or high school (aOR: 1.622, CI: 1.078-2.439) education, had sex in the last 6 months (aOR: 1.703, CI: 1.055-2.751), and had ≥1 sexual partner (aOR: 1.749, CI: 1.196-2.557) were more likely not to test. Of those reporting condom use (n = 1036, 67%), consistent condom use was 43% (n = 451). HIV testing did not correlate with condom use.ConclusionLow rates of both condom use and HIV testing among men in a high HIV prevalence setting are worrisome and indicate an urgent need to develop innovative behavioral strategies to address this shortfall. Condom use is poor in this population whether tested or not tested for HIV, indicating no association between condom use and HIV testing

Organisational culture and the integrated chronic diseases management model implementation fidelity in South Africa: a cross-sectional study.

OBJECTIVE: To assess whether organisational culture influences the fidelity of implementation of the Integrated Chronic Disease Management (ICDM) model at primary healthcare (PHC) clinics. DESIGN: A cross-sectional study. SETTING: The ICDM model was introduced in South African clinics to strengthen delivery of care and improve clinical outcomes for patients with chronic conditions, but the determinants of its implementation have not been assessed. PARTICIPANTS: The abbreviated Denison organisational culture (DOC) survey tool was administered to 90 staff members to assess three cultural traits: involvement, consistency and adaptability of six PHC clinics in Dr. Kenneth Kaunda and West Rand (WR) health districts. PRIMARY AND SECONDARY OUTCOME MEASURES: Each cultural trait has three indices with five items, giving a total of 45 items. The items were scored on a Likert scale ranging from one (strongly disagree) to five (strongly agree), and mean scores were calculated for each item, cultural traits and indices. Descriptive statistics were used to describe participants and clinics, and Pearson correlation coefficient to asses association between fidelity and culture. RESULTS: Participants' mean age was 38.8 (SD=10.35) years, and 54.4% (49/90) were nurses. The overall mean score for the DOC was 3.63 (SD=0.58). The involvement (team orientation, empowerment and capability development) cultural trait had the highest (3.71; SD=0.72) mean score, followed by adaptability (external focus) (3.62; SD=0.56) and consistency (3.56; SD=0.63). There were no statistically significant differences in cultural scores between PHC clinics. However, culture scores for all three traits were significantly higher in WR (involvement 3.39 vs 3.84, p=0.011; adaptability 3.40 vs 3.73, p=0.007; consistency 3.34 vs 3.68, p=0.034). CONCLUSION: Leadership intervention is required to purposefully enhance adaptability and consistency cultural traits of clinics to enhance the ICDM model's principles of coordinated, integrated, patient-centred care

Evaluation of the impact of reliance on the regulatory performance in the South African Health Products Regulatory Authority: implications for African regulatory authorities

© 2023 The Author(s). This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY), https://creativecommons.org/licenses/by/4.0/Introduction: The World Health Organization (WHO) advocates the use of reliance practices to enable national regulatory authorities (NRAs) to improve patients’ access to medicines. This study considered whether reliance review translates into swifter medicine authorization. Methods: Abridged review outcomes were examined for New Chemical Entity (NCE) and generic applications to the South African Health Products Regulatory Authority (SAHPRA) in Chemistry, Manufacturing and Controls (CMC) and clinical/bioequivalence (BE), as well as overall NCE authorization times. Results: SAHPRA NCE CMC review time was 91 days (abridged) vs. 179 days (full), applicant response time was 34 vs. 105 days, respectively, and there was a >2-fold time reduction for abridged vs. full CMC review (125 vs. 284 days). There was a 99-day decrease in clinical approval time through an abridged review (230 vs. 329 days) and a decrease in marketing authorization time for NCE abridged assessment (446 vs. 619 days). SAHPRA review time for generic applications was 97 days (abridged) vs. 191 days (full); applicant response time was 26 days (abridged) vs. 81 days (full) and there was a >2-fold time reduction for CMC and BE abridged vs. full review (122 vs. 272 days). Conclusion: These results clearly support World Health Organization recommendations for the use of reliance-based regulatory review to expedite the worldwide availability of safe, effective and needed medications.Peer reviewe

Meaning of Family Reported Outcome Measure (FROM-16) severity score bands: a cross-sectional online study in the UK

© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. http://creativecommons.org/licenses/by-nc/4.0/Objective: To assign clinical meanings to the Family Reported Outcome Measure (FROM-16) scores through the development of score bands using the anchor-based approach. Design and setting: A cross-sectional online study recruited participants through UK-based patient support groups, research support platforms (HealthWise Wales, Autism Research Centre-Cambridge University database, Join Dementia Research) and through social service departments in Wales. Participants: Family members/partners (aged ≥18 years) of patients with different health conditions. Intervention: Family members/partners of patients completed the FROM-16 questionnaire and a Global Question (GQ). Main outcome measure: Various FROM-16 band sets were devised as a result of mapping of mean, median and mode of the GQ scores to FROM-16 total score, and receiver operating characteristic-area under the curve cut-off values. The band set with the best agreement with GQ based on weighted kappa was selected. Results: A total of 4413 family members/partners (male=1533, 34.7%; female=2858, 64.8%; Prefer not to say=16, 0.4%; other=6, 0.14%) of people with a health condition (male=1994, 45.2%; female=2400, 54.4%; Prefer not to say=12, 0.3%; other=7, 0.16%) completed the online survey: mean FROM-16 score=15.02 (range 0–32, SD=8.08), mean GQ score=2.32 (range 0–4, SD=1.08). The proposed FROM-16 score bandings are: 0–1=no effect on the quality of life of family member; 2–8=small effect on family member; 9–16=moderate effect on family member; 17–25=very large effect on family member; 26–32=extremely large effect on family member (weighted kappa=0.60). Conclusion: The FROM-16 score descriptor bands provide new information to clinicians about interpreting scores and score changes, allowing better-informed treatment decisions for patients and their families. The score banding of FROM-16, along with a short administration time, demonstrates its potential to support holistic clinical practice.Peer reviewe

Uptake of genital mucosal sampling in HVTN 097, a phase 1b HIV vaccine trial in South Africa

Because sexual transmission of HIV occurs across mucosal membranes, understanding the immune responses of the genital mucosa to vaccines may contribute knowledge to finding an effective candidate HIV vaccine. We describe the uptake of rectal secretion, cervical secretion and seminal mucosal secretion sampling amongst volunteers in a Phase 1b HIV vaccine trial. Age at screening, gender, study site and the designation of the person conducting the informed consent procedure were collected for volunteers who screened for the HVTN 097 study. A total of 211 volunteers (54% female) were screened at three sites in South Africa: Soweto (n = 70, 33%), Cape Town (n = 68, 32%) and Klerksdorp (n = 73, 35%). Overall uptake of optional mucosal sampling amongst trial volunteers was 71% (n = 149). Compared to Cape Town, volunteers from Soweto and Klerksdorp were less likely to consent to sampling (Soweto OR 0.08 CI: 0.03-0.25 p<0.001 and Klerksdorp OR 0.13 CI: 0.04-0.41 p = 0.001). In contrast, volunteers over 25 years of age were 2.39 times more likely to consent than younger volunteers (CI: 1.13-5.08, p = 0.02). Further studies are required to better understand the cultural, demographic and sociobehavioral factors which influence willingness to participate in mucosal sampling in HIV prevention studies. Trial Registration ClinicalTrials.gov: NCT0210935

Predictors of HVTN 503 MRK-AD5 HIV-1 gag/pol/nef vaccine Induced immune responses

BACKGROUND: Phambili, the Merck (MRK)-Adenovirus Type 5 (Ad5) HIV-1 gag/pol/nef subtype B vaccine study, conducted in South Africa, suspended enrollment and vaccination when companion study, Step, was found non-efficacious. Although the vaccine did not prevent HIV-1 infection or lower viral-load setpoint, immune responses recognized clades B and C HIV-1 subtypes. We investigated predictors of the vaccine-induced antigen-specific immune responses. METHODS: Vaccine-induced immunogenicity was ascertained by interferon-γ ELISpot assays on the first 186 enrolled participants receiving two vaccinations. Analyses, stratified by study arm/sex, were performed on baseline demographics [sex, age, Body Mass Index (BMI), site, Adenovirus Type-5 (Ad5) titer, Herpes Simplex Virus Type-2 (HSV2) status, heavy drinking]. Multivariate logistic regression determined predictors. RESULTS: Of the 186 participants, 53.7% (n = 100) were female, median BMI was 22.5 [IQR: 20.4-27.0], 85.5% (n = 159) were Ad5 seropositive, and 18.8% (n = 35) drank heavily. All vaccine recipients responded to both clade B (n = 87; 47%) and/or C (n = 74; 40%), p = 0.17. In multivariate analysis, female sex [Adjusted Odds Ratio (AOR): 6.478; p = 0.0159], overweight/obese BMI (AOR: 0.186; p = 0.0452), and heavy drinking (AOR: 0.270; p = 0.048) significantly predicted immune response to clade C for any antigens. A marginally significant predictor of clade C-pol antigen was female sex (AOR: 3.182; p = 0.0500). CONCLUSIONS: Sex, BMI, and heavy drinking affected vaccine-induced HIV-1 specific immune responses to clade C antigens. The role of female sex and overweight/obese BMI boosting and suppressing vaccine-induced HIV-1 specific immune responses, respectively, requires elucidation, including any effect on HIV vaccine efficacy, especially in the era of colliding epidemics (HIV and obesity)

Voluntary medical male circumcision (VMMC) for prevention of heterosexual transmission of HIV and risk compensation in adult males in Soweto: Findings from a programmatic setting.

BACKGROUND: Clinical trials have clearly shown a reduction in HIV acquisition through voluntary medical male circumcision (VMMC). However, data assessing risk compensation under programmatic conditions is limited. METHODS: This was a prospective cohort of HIV seronegative males aged 18-40 years receiving VMMC between November 2012 and July 2014. HIV serostatus was determined pre and post VMMC. Risk compensation was defined as a decrease in condom use at last sex act and/or an increase in concurrent sexual relationships, both measured twelve months post-circumcision. RESULTS: A total of 233 males were enrolled and underwent voluntary medical male circumcision (VMMC) for prevention against HIV. There was no evidence of risk compensation post-circumcision as defined in this study. Significant increases in proportion of participants in the 18-24 years age group who knew the HIV status of their sexual partner (39% to 56%, p = 0.0019), self-reported condom use at last sex act (21% to 34%, p = 0.0106) and those reporting vaginal sexual intercourse in the past 12 months (67% to 79%, p-value = <0.0001) were found. In both 18-24 and 25-40 years age groups, there was a significant increase in perception of being at risk of contracting HIV (70% to 84%, p-value = <0.0001). CONCLUSION: No significant risk compensation was observed in this study on comparing pre-and post-circumcision behaviour. An increase in proportion of participants in the 18-24 years age group who had vaginal intercourse in the first 12 months post-circumcision as a possibility of risk compensation was minimal and negated by an increase in proportion of those reporting using a condom at the last sex act, increase in knowledge of partner's HIV status and lack of increase in alcohol post-circumcision

Thymic output and CD4 T-cell reconstitution in HIV-infected children on early and interrupted antiretroviral treatment: evidence from the CHER trial.

Objectives: Early treatment of HIV-infected children and adults is important for optimal immune reconstitution. Infants’ immune systems are more plastic and dynamic than older children’s or adults’, and deserve particular attention. This study aimed to understand the response of the HIV-infected infant immune system to early antiretroviral therapy (ART) and planned ART interruption and re-start. Design: We used linear and nonlinear regression and mixed-effects models to describe children’s CD4 trajectories and to identify predictors of CD4 count during early and interrupted ART. Methods: Data from HIV-infected children enrolled CHER trial, starting ART aged between 6 and 12 weeks, was used to explore the effect of ART on immune reconstitution. Results: Early treatment arrested the decline in CD4 count but did not fully restore it to the levels observed in HIV-uninfected children. Treatment interruption at 40 or 96 weeks resulted in a rapid decline in CD4 T-cells, which on retreatment returned to levels observed before interruption. Naïve CD4 T-cell count was an important determinant of overall CD4 levels. A strong correlation was observed between thymic output and the stable CD4 count both before and after treatment interruption. Conclusions: Early identification and treatment of HIV-infected infants is important to stabilize CD4 counts at the highest levels possible. Once stabilized, children’s CD4 counts appear resilient, with good potential for recovery following treatment interruption. The naïve T-cell pool and thymic production of naive cells are key determinants of children’s CD4 levels