In-vivo dynamics of HIV-1 evolution

Ph. D, Faculty of Science, University of Witwatersrand, 2011The evolution of drug resistance in human immunodeficiency virus (HIV) infection has been a focus of research in many fields, as it continues to pose a problem to disease prevention and HIV patient management. In addition to techniques of molecular biology, studies in mathematical modelling have contributed to the knowledge here, but many questions remain unanswered. This thesis explores the application of a number of hybrid stochastic/deterministic models of viral replication to scenarios where viral evolution may be clinically or epidemiologically important. The choice of appropriate measures of viral evolution/diversity is non-trivial, and this impacts on the choice of mathematical techniques deployed. The use of probability generating functions to describe mutations occurring during early infection scenarios suggest that very early interventions such as pre-exposure prophylaxis (PrEP) or vaccines may substantially reduce viral diversity in cases of breakthrough infection. A modified survival analysis coupled to a deterministic model of viral replication during transient and chronic treatment helps identify clinically measurable indicators of the time it takes for deleterious rare mutations to appear. Lastly, persistence of problematic mutations is studied through the use of deterministic models with stochastic averaging over initial conditions

Inferring biomarkers for Mycobacterium avium subsp. paratuberculosis infection and disease progression in cattle using experimental data

Available diagnostic assays for Mycobacterium avium subsp. paratuberculosis (MAP) have poor sensitivities and cannot detect early stages of infection, therefore, there is need to find new diagnostic markers for early infection detection and disease stages. We analyzed longitudinal IFN-γ, ELISA-antibody and fecal shedding experimental sensitivity scores for MAP infection detection and disease progression. We used both statistical methods and dynamic mathematical models to (i) evaluate the empirical assays (ii) infer and explain biological mechanisms that affect the time evolution of the biomarkers, and (iii) predict disease stages of 57 animals that were naturally infected with MAP. This analysis confirms that the fecal test is the best marker for disease progression and illustrates that Th1/Th2 (IFN-γ/ELISA antibodies) assays are important for infection detection, but cannot reliably predict persistent infections. Our results show that the theoretical simulated macrophage-based assay is a potential good diagnostic marker for MAP persistent infections and predictor of disease specific stages. We therefore recommend specifically designed experiments to test the use of a based assay in the diagnosis of MAP infections

Quantifying early COVID-19 outbreak transmission in South Africa and exploring vaccine efficacy scenarios

The emergence and fast global spread of COVID-19 has presented one of the greatest public health challenges in modern times with no proven cure or vaccine. Africa is still early in this epidemic, therefore the extent of disease severity is not yet clear. We used a mathematical model to fit to the observed cases of COVID-19 in South Africa to estimate the basic reproductive number and critical vaccination coverage to control the disease for different hypothetical vaccine efficacy scenarios. We also estimated the percentage reduction in effective contacts due to the social distancing measures implemented. Early model estimates show that COVID-19 outbreak in South Africa had a basic reproductive number of 2.95 (95% credible interval [CrI] 2.83-3.33). A vaccine with 70% efficacy had the capacity to contain COVID-19 outbreak but at very higher vaccination coverage 94.44% (95% Crl 92.44-99.92%) with a vaccine of 100% efficacy requiring 66.10% (95% Crl 64.72-69.95%) coverage. Social distancing measures put in place have so far reduced the number of social contacts by 80.31% (95% Crl 79.76-80.85%). These findings suggest that a highly efficacious vaccine would have been required to contain COVID-19 in South Africa. Therefore, the current social distancing measures to reduce contacts will remain key in controlling the infection in the absence of vaccines and other therapeutics

Interrelationship of Streptococcus pneumoniae, Haemophilus influenzae and Staphylococcus aureus colonization within and between pneumococcal-vaccine naïve mother-child dyads

Background: A high prevalence of bacterial nasopharyngeal co-infections has been reported in children, however, such data is limited in adults. We examined the interaction of Haemophilus influenzae, Staphylococcus aureus and Streptococcus pneumoniae pharyngeal colonization in mother-child dyads. Methods: Pneumococcal-vaccine naïve children and their mothers had pharyngeal swabs undertaken at 1.6, 2.5, 3.5, 4.5, 7.4, 9.5, 12.5, 16.2 and 24.2 months of child’s age. Swabs were cultured for S. pneumoniae, H. influenzae and S. aureus using standard microbiologic methods. Multivariate generalized estimating equation-models were used to explore the associations of the three bacteria within and between children and their mothers. Results: In children, the observed probability of co-colonization was higher than expected. Well-defined associations in colonization between the bacteria were observed in children but not among mothers. In children, a synergistic association was observed between S. pneumoniae and H. influenzae (Adjusted odds ratio (AOR): 1.75, 95% CI: 1.32-2.32) and a negative association between S. pneumoniae and S. aureus (AOR: 0.51, 95% CI: 0.39-0.67) or H. influenzae and S. aureus (AOR: 0.24, 95% CI: 0.16-0.34) colonization. Additionally, all three bacteria had a higher likelihood of concurrent colonization. There was a strong association in colonization by the bacteria in children and their mothers, including increased likelihood of maternal colonization if the child was colonized by S. pneumoniae (AOR: 1.84, 95% CI: 1.28-2.63) and H. influenzae (AOR: 6.34, 95% CI: 2.24-18.0). Conclusions: The effects of immunization of children with pneumococcal-conjugate-vaccine in settings such as ours needs monitoring with regard to potential changes of pharyngeal bacterial ecology which could occur in vaccinated and –unvaccinated age-groups

Indirect eff ects of childhood pneumococcal conjugate vaccination on invasive pneumococcal disease: a systematic review and meta-analysis

Background The full extent to which childhood pneumococcal conjugate vaccines (PCV) can indirectly reduce illness in unvaccinated populations is not known. We aimed to estimate the magnitude and timing of indirect eff ects of PCVs on invasive pneumococcal disease. Methods In this systematic review and meta-analysis, we searched bibliographic databases for non-randomised quasiexperimental or observational studies reporting invasive pneumococcal disease changes following PCV introduction in unvaccinated populations (studies published Sept 1, 2010, to Jan 6, 2016), updating the previous systematic review of the same topic (studies published Jan 1, 1994, to Sept 30, 2010). Two reviewers extracted summary data by consensus. We used a Bayesian mixed-eff ects model to account for between-study heterogeneity to estimate temporal indirect eff ects by pooling of invasive pneumococcal disease changes by serotype and serogroup. Findings Data were extracted from 70 studies included in the previous review and 172 additional studies, covering 27 high-income and seven middle-income countries. The predicted mean times to attaining a 90% reduction in invasive pneumococcal disease were 8·9 years (95% credible interval [CrI] 7·8–10·3) for grouped serotypes contained in the seven-valent PCV (PCV7), and 9·5 years (6·1–16·6) for the grouped six additional serotypes contained in the 13-valent PCV (PCV13) but not in PCV7. Disease due to grouped serotypes contained in the 23-valent pneumococcal polysaccharide vaccine (PPV23) decreased at similar rates per year in adults aged 19–64 years (relative risk [RR] 0·85, 95% CrI 0·75–0·95) and 65 years and older (0·87, 0·84–0·90). However, we noted no changes in either group in invasive pneumococcal disease caused by the additional 11 serotypes covered by PPV23 but not PCV13. Interpretation Population childhood PCV programmes will lead, on average, to substantial protection across the whole population within a decade. This large indirect protection should be considered when assessing vaccination of older age groups

Imputing direct and indirect vaccine effectiveness of childhood pneumococcal conjugate vaccine against invasive disease by surveying temporal changes in nasopharyngeal pneumococcal colonization

The limited capabilities in most low-middle income countries to study the benefit of pneumococcal conjugate vaccine (PCV) against invasive pneumococcal disease (IPD), calls for alternate strategies to assess this. We used a mathematical model, to predict the direct and indirect effectiveness of PCV by analyzing serotype specific colonization prevalence and IPD incidence prior to and following childhood PCV immunization in South Africa. We analyzed IPD incidence from 2005-2012 and colonization studies undertaken in HIV-uninfected and HIV-infected child-mother dyads from 2007-2009 (pre-PCV era), in 2010 (7-valent PCV era) and 2012 (13-valent PCV era). We compared the model-predicted to observed changes in IPD incidence, stratified by HIV-status in children >3 months to 5 years and also in women aged >18-45 years. We observed reductions in vaccine-serotype colonization and IPD due to vaccine serotypes among children and women after PCV introduction. Using the changes in vaccine-serotype colonization data, the model-predicted changes in vaccine-serotype IPD incidence rates were similar to the observed changes in PCV-unvaccinated children and adults, but not among children <24 months. Surveillance of colonization prior and following PCV use can be used to impute PCVs' indirect associations in unvaccinated age groups, including in high HIV-prevalence settings

A Group Parenting Intervention for Depressed Fathers (LTP + Dads): A Feasibility Study from Pakistan

Introduction: In this study, we feasibility tested Learning Through Play Plus Dads (LTP+ Dads), a group parenting psychoeducation program adapted for depressed Pakistani fathers of children under three years of age. Methods: A total of 18 fathers with depression were recruited in Karachi, Pakistan for a pre-post feasibility study. Ten sessions of group LTP+ Dads were offered over three months. Clinical assessments were administered at baseline, 3 and 6 months and included the Edinburgh Postnatal Depression Scale, 17-item Hamilton Depression Rating Scale, Brief Disability Questionnaire, Multidimensional Scale of Perceived Social Support, Euro-Qol-5 Dimensions, Rosenberg Self-esteem Scale, Parenting Stress Index, and Knowledge, Attitude and Practices questionnaire. Results: The intervention was feasible to implement and acceptable based on a recruitment rate of 100% of eligible participants and a 100% attendance rate for 5 of the 10 sessions. Within this preliminary sample, fathers showed, on average, a reduction in depressive symptoms, an increase in most areas of fathers’ knowledge and positive attitudes about child development. Perceived social support, self-esteem and functioning scores also increased. Limitations: The small sample size and lack of control group are limitations of this study. Conclusions: In this first study of paternal depression in Pakistan, a low cost culturally adapted group intervention was found to be feasible and acceptable. Changes in depression, parenting-related and other outcomes are promising and inform a future larger trial. Keywords: Paternal depression, Cultural Adaptation, CBT, Parenting, Low and middle income countr

Residual colonization by vaccine serotypes in rural South Africa four years following initiation of pneumococcal conjugate vaccine immunization

Background: We evaluated pneumococcal colonization in children and adults between the time of 7-valent pneumococcal conjugate vaccine (PCV) introduction in the immunization program in April 2009 to two years after transitioning to 13-valent PCV in 2011. Methods: Community-based pneumococcal carriage surveillance was undertaken between May-November 2013 (Period-3; n=1884), with similar surveys in 2009 (Period-1, n=2010) and 2011 (Period-2; n=3659). Households with children below two years had a similar probability of being sampled in all surveys. Nasopharyngeal swabs were processed using standard methods and serotyped by Quellung. Results: In children >9-59 months of age, overall pneumococcal colonization prevalence declined from 81.8% in Period-1 to 65.0% in Period-3 (p<0.001). Reductions of 70% (95%CI: 60%-77%; 41.2% vs. 13.6%) in PCV7-serotypes colonization and 66% (95%CI:48%-78%; 15.3% vs. 4.4%) for the six additional PCV-serotypes in PCV13 (PCV13 add6VT) were observed. There was, however, high residual prevalence of colonization by PCV7-serotypes 19F (14.9% vs. 6.3%) and 23F (8.5% vs. 4.1%), despite reduction of 57% (95%CI:35%-80%) and 52% (95%CI:21%-83%), respectively. Among individuals >12 years of age, there was 61% (95%CI:18%-82%) reduction in PCV7-serotype colonization (3.1% vs. 1.3%; ) and 75% (95%CI: 11%-93%) decrease for PCV13-add6VT (2.1% vs. 0.6%) between Period-1 and Period-3. Conclusions: The residual prevalence of serotypes 19F and 23F in PCV-immunized and unvaccinated age-groups, four years after introducing PCV in the South African public immunization program, suggests ongoing community transmission and transient vaccine effects

Developing a framework for public involvement in mathematical and economic modelling : bringing new dynamism to vaccination policy recommendations

Objectives The Mathematical and Economic Modelling for Vaccination and Immunisation Evaluation (MEMVIE) programme aimed to explore, capture and support the potential contribution of the public to mathematical and economic modelling, in order to identify the values that underpin public involvement (PI) in modelling and co-produce a framework that identifies the nature and type of PI in modelling and supports its implementation. Methods We established a PI Reference Group, who worked collaboratively with the academic contributors to create a deliberative knowledge space, which valued different forms of knowledge, expertise and evidence. Together, we explored the key steps of mathematical and economic methods in 21 meetings during 2015–2020. These deliberations generated rich discussion, through which we identified potential points of public contribution and the values that underpin PI in modelling. We iteratively developed a framework to guide future practice of PI in modelling. Results We present the MEMVIE Public Involvement Framework in two forms: a short form to summarise key elements, and a long form framework to provide a detailed description of each potential type of public contribution at each stage of the modelling process. At a macro level, the public can contribute to reviewing context, reviewing relevance, assessing data and justifying model choice, troubleshooting, and interpreting and reviewing outcomes and decision making. The underpinning values that drive involvement include the public contributing to the validity of the model, potentially enhancing its relevance, utility and transparency through diverse inputs, and enhancing the credibility, consistency and continuous development through scrutiny, in addition to contextualising the model within a wider societal view. Discussion and Conclusion PI in modelling is in its infancy. The MEMVIE Framework is the first attempt to identify potential points of collaborative public contribution to modelling, but it requires further evaluation and refinement that we are undertaking in a subsequent study

Cryptococcal Meningitis Screening and Community-based Early Adherence Support in People With Advanced Human Immunodeficiency Virus Infection Starting Antiretroviral Therapy in Tanzania and Zambia: A Cost-effectiveness Analysis.

BACKGROUND: A randomized trial demonstrated that among people living with late-stage human immunodeficiency virus (HIV) infection initiating antiretroviral therapy, screening serum for cryptococcal antigen (CrAg) combined with adherence support reduced all-cause mortality by 28%, compared with standard clinic-based care. Here, we present the cost-effectiveness. METHODS: HIV-infected adults with CD4 count <200 cells/μL were randomized to either CrAg screening plus 4 weekly home visits to provide adherence support or to standard clinic-based care in Dar es Salaam and Lusaka. The primary economic outcome was health service care cost per life-year saved as the incremental cost-effectiveness ratio (ICER), based on 2017 US dollars. We used nonparametric bootstrapping to assess uncertainties and univariate deterministic sensitivity analysis to examine the impact of individual parameters on the ICER. RESULTS: Among the intervention and standard arms, 1001 and 998 participants, respectively, were enrolled. The annual mean cost per participant in the intervention arm was US$339 (95$331-$347), resulting in an incremental cost of the intervention of US$77 (95% CI, $66-$88). The incremental cost was similar when analysis was restricted to persons with CD4 count <100 cells/μL. The ICER for the intervention vs standard care, per life-year saved, was US$70 (95$43-$211) for all participants with CD4 count up to 200 cells/μL and US$91 (95% CI, $49-$443) among those with CD4 counts <100 cells /μL. Cost-effectveness was most sensitive to mortality estimates. CONCLUSIONS: Screening for cryptococcal antigen combined with a short period of adherence support, is cost-effective in resource-limited settings