3. Electronic Theses and Dissertations (ETDs) - All submissions

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    Population dynamics in HIV-1 transmitted antiretroviral drug resistance
    (2018) Harris, Dean Mark
    It is well known that antiretroviral (ARV) drug resistant variants of HIV-1 can be sexually transmitted. Several studies have shown that in resource-rich geographical locations as many as 15-20% of individuals are newly infected with HIV-1 containing at least one drug resistant mutation. In contract, resource limited geographical locations, such as Sub-Saharan Africa, have shown prevalences in the range of 5 to 10%. Since the ART rollout in these resource-limited locations are generally not well monitored with virological genotyping, the transmission of drug resistant HIV-1 is likely to increase, with significant clinical and public health consequences. HIV-1 transmission is characterised by the transmission of a single founder virus, or narrow spectrum of founder viruses, that develop into the viral quasispecie. It is unlikely that drug resistant virus will coexist with wild type (wt) virus, in the case of non-drug resistance transmission. However, initiating in ARV treatment, drug non-adherence may select of ARV drug resistance mutations and may subsequent lead to treatment failure. Drug resistant virus may be transmitted to a new host, as drug resistant mutations do not appear to hamper transmission efficiency of the mutated virus. Several studies have shown that transmitted drug resistance mutations (TDRMs) persist either as the dominant species or as minority variants, or revert to wild type over time, in the absence of drug pressure. It is generally acknowledged that many drug resistance mutations decrease the replicative capacity of HIV-1, and thus reversion confers a potential survival advantage. Because of the emergence of wild type variants from TDRM quasispecies requires evolution and back-mutation, the rate at which individual TDRMs become undetectable may vary substantially. Contradictory findings of persistence versus reversion of TDRMs have been reported, and may be attributed to the fact that minority variants are difficult to detect by conventional population based Sanger sequencing, and patient numbers studied are small. Consequently, individuals infected with HIV-1 harbouring TDRM have a higher chance of failing their first-line therapy. Understanding the population dynamics of transmitted drug resistant HIV-1 in the absence of drug pressure is essential for clinical management and public health strategies. The individuals identified with TDRMs from the IAVI-Early Infections Cohort (Protocol C) provides a unique research opportunity to address the aforementioned issue. This study describes III the evolutionary mechanisms of ARV drug resistant HIV-1 after transmission to a new host to provide insight into persistence and/or rates of reversion to wild type. TDRMs initially identified by Price et al. (2011) in the IAVI-Early Infections Cohort (Protocol C) using population-based Sanger sequencing (the current diagnostic gold standard), were confirmed in this study by newer ultra-deep next generation sequencing (NGS) technology on the Illumina Miseq platform. Longitudinal samples were made available for individuals in which transmitted drug resistance were identified, and we also sequenced using NGS on the Illumina Miseq platform. Additional minority variants (present at <20% of the sequenced viral population) were identified by NGS. This study found a large percentage of TDRMs to persist for a significant amount of time after transmission to a new, drug naïve host, in the longitudinal samples. The level of persistence, or rate of reversion of TDRMs, appear to be subject to the type of resistance (NRTI, NNRTI or PI), level of resistance the mutation confers, as well as the combination of mutations that are cotransmitted. Findings of this study highlight the importance of drug resistance screening prior to ART initiation, as well as the importance of the drug resistance screening assay sensitivity. As rates of transmitted drug resistance are increasing in developing countries of which the IAVI-Early Infections Cohort (Protocol C) are composed of, understanding the population dynamics of transmitted drug resistant HIV-1 in the absence of drug pressure is essential for clinical management, public health strategies and informing future vaccine design.
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    ''Descriptive study of HIV drug resistance genotype testing in a public sector paediatric population in Johannesburg"
    (2015) Ngabire, Phocas
    The introduction of combined antiretroviral treatment (cART) reduced HIV related mortality more than 70% and the rate of new infection in children continue to decrease considerably. However this benefit is threatened by the emergence of drug resistant strains of HIV. Studies exploring the patterns of drug resistance in the paediatric population are crucial for policy makers and for individual patients’ management. In sub-Saharan Africa where HIV-1 subtype C is more prevalent, there is a limited number of paediatric studies exploring the drug resistance patterns. To get more insight on this problem, we explored the drug resistance mutations (DRMs) patterns in a paediatric population attending a referral public paediatric HIV clinic. Methodology The study was a cross-sectional retrospective descriptive study. Convenience sampling method was used and all paediatric patients (0-14 years) who underwent genotypic HIV drug resistance testing at Empilweni Clinic between January 1st, 2004 and February 28th, 2012 were included. Demographic and clinical data were collected from the clinical electronic database and DRM frequencies related to treatment exposure were presented. Results During our study period, 63 patient samples were sent for HIV genotyping drug resistance testing. Eleven samples did not meet the inclusion criteria. Among the 52 patient samples retained, 44 patients (84.6%) had a successful HIV amplification and all were infected with HIV-1 subtype C. Ninety one percent (n=40) of the patients had at least one DRM isolated but in only 78% (n=34) did these mutations translate into genotypic drug resistance to at least one antiretroviral drug (ARV) used in South Africa. Nucleotide reverse transcriptase inhibitors (NRTI) mutations were the most commonly identified with M184V being the most prevalent (64.4%; n=29). This was associated with thymidine analogue mutations (TAMs) in 36.3% of the patients (n=16). TAMs were identified in 25% (n=11) of the patients. K65R and Q151M were rarely identified in our cohort. V106M and K103N were the most common non-nucleotide reverse transcriptase inhibitors (NNRTI) mutations and were both identified in 21.9% (n=7) of the patients exposed to NNRTI-based regimen. V82A was the most commonly identified protease gene (PR) mutation in 29.3% (n=12) of the cases. Forty eight percent of the patients (n=21) had a dual class resistance and 11.4% (n=5) had resistance to ARVs from all the three classes. Over a quarter (27.2%, n=12) of the patients in our cohort were still sensitive to all ARVs used in South Africa. The development of drug resistance was not associated with any clinical characteristic in our cohort. Conclusion The drug resistance mutations identified in paediatric patients failing cART show a complex pattern with some failing patients still sensitive to all ARVs while others harbour complex resistance mutations. Therefore, regular counselling to optimize adherence and regular viral load monitoring for early detection of failure may be important tools for continued cART success. Given the complexity of the DRMs patterns in paediatric patients, the HIV drug resistance test is warranted to guide the choice of appropriate cART regimens.
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    Genotypic and phenotypic heterogeneity of Mycobacterium tuberculosis recovered from patients with pulmonary disease involving drug-resistant tuberculosis
    (2012) Axcell, Amanda
    Genetic heterogeneity of Mycobacterium tuberculosis demonstrating mixed infections or affecting single strains has been previously described. A single sputum culture from five patients with drug-resistant tuberculosis treated at Sizwe Hospital was analysed in-depth for genotypic and phenotypic heterogeneity. IS6110-based restriction fragment length polymorphism (RFLP) was performed on 20 colonies from each sputum for detection of mixed infections and clonal heterogeneity. No mixed infections were found, but IS6110-RFLP-linked clonal heterogeneity was observed in one patient. Drug susceptibility testing (DST) and sequencing of nine drug-resistance-associated genes performed on a total of 99 colonies from the five patients failed to show genotypic hetero-resistance. On DST, however, discordant rifampicin resistance findings were encountered in one patient. Minimal inhibitory concentrations performed on these colonies were close to the rifampicin critical concentration used for resistance determination, suggesting failure of the BACTEC MGIT 960 assay to reliably determine rifampicin susceptibility in strains with borderline resistance.
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    Factors associated with antiretroviral resistance in human immunodeficiency virus patients on antiretroviral therapy in South Africa
    (2013) Gareta, Dickman Pangaume
    Introduction: Access to highly active antiretroviral therapy has dramatically increased worldwide since 2004. However, the emergence of HIV drug resistance presents huge obstacle in ART scale up as it contributes to treatment failure and poses a greater risk of disease progression and loss of treatment options. The study therefore investigated the risk factors and the association of HIV drug resistance, virological failure and CD4 cell count changes in patients on ART at Aurum Institute for Health Research in South Africa. Methods: A cohort of HIV infected patients who developed virological failure of their first HAART regimen was assessed. A genotypic resistance testing was performed using stored plasma on a subset of patients at first detection of virological failure. Data were collected prospectively on all registered patients using standardised forms. Clinical data was obtained from laboratory and pharmacy electronic records. Logistic regression and Cox proportional hazard models were used to assess factors associated with HIV drug resistance and virological failure respectively. Linear mixed-effects regression models were used to assess the changes in the CD4 cell count among patients who developed HIVDR. Results: Between January 2003 and December 2010, a total of 146 ART-treated patients who experienced virological failure were assessed. Of these, 108 (74%) developed HIVDR, of whom 80 (74%) were males; the median CD4 cell count at ART initiation was 121 cells/mm3 (interquartile range, 61-210). The most frequent NNRTI mutations patterns found were mutations leading to resistance to NNRTI agents with 33% having NNRTI resistance. The second most common resistance v pattern was resistance to lamivudine conferred by the M184V mutation (30%). The multivariable analysis showed that higher CD4 cell count at HIVDR detection was significantly associated with the reduced odds of developing HIV drug resistant mutation after adjusting for gender and age(adjusted OR=0.37, 95% CI 0.15–0.94). Similarly, there was significant association between age at ART initiation (adjusted HR=0.71, 95% CI 0.52–0.97) and CD4 cell count during follow-up (adjusted HR= 0.54 95% CI 0.36–0.81) with virological failure in those patients who developed HIVDR. The CD4 cell count slope on average increased by 10 cells per mL per year for the patients without any resistance (average annual change 9.89 cells per mL, 95% CI -6.90-26.69) and decreased by 10 cells per mL per year for patients who had any resistance (average annual change -9.61 cells per mL, 95% CI -19.41- 0.17). Conclusion and recommendation: HIV drug resistant virus was found in 74% of the South African patients who were accessing HIV care at Aurum Heath Institute and developed virological failure of first HAART regimen. Higher CD4 count at detection of HIVDR was significantly associated with lower risk of developing HIV drug resistant virus. Lower CD4 count and male gender were significantly associated with the development of virological failure. Patients with virological failure had significantly great CD4 count declines when any mutation and thymidine analog mutation (TAM) mutation were present. There is a great need therefore for multifaceted approach to target interventions that aim to increase patients CD4 cell counts. Patients should be either screened, possibly with HIVDR testing, prior to reinitiation of a first-line regimen
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