3. Electronic Theses and Dissertations (ETDs) - All submissions
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Item Population dynamics in HIV-1 transmitted antiretroviral drug resistance(2018) Harris, Dean MarkIt 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.Item Adherence to ART and retention in care among HIV-infected pregnant women starting life-long treatment in Ifakara, Tanzania.(2014) Jingo, JohnPaul KasuleAntiretroviral therapy (ART) recommendations among HIV – infected pregnant women have been revised several times by the World Health Organization (WHO). Option B+, which is the latest recommendation continues to be rolled out in several countries across the globe but mostly in sub-Saharan Africa. Retention in care and adherence to antiretroviral (ARV) drugs taken by these women remains unclear in this new program. We assessed ability to stay in care (retention) and adherence to ART among HIV – infected women starting life-long treatment during pregnancy and after, at an HIV care and treatment clinic in Ifakara Tanzania. Our study provided an opportunity to understand the trends in adherence to ART and retention in care for this population. Methods We analyzed data of HIV-infected pregnant women registered and starting ART for the first time in the Kilombero and Ulanga Antiretroviral Cohort in 2009 and 2010 with a follow up period of up to two years to 2011 and 2012 respectively. Adherence was by patient self-report (PSR) and was sufficient (good) if the woman took all the prescribed pills of the issued batch or insufficient (poor) if she missed two or more pills. Women that missed two or more consecutive scheduled visits to the clinic were not retained while those that honored their scheduled visits were retained in care. Two sample t test and Wilcoxon rank sum test were used to test predictor outcome associations for continuous variables while Pearson’s and Fisher’s exact tests were used for categorical ones. Hazard ratios of each predictor variable were calculated using Cox regression. Student No: 737395 Page v Results A total of 1,282 HIV – infected women were registered in KIULARCO between 2009 and 2010. Fifty (50) were pregnant and started life-long ART upon registration in this period. Of these, 25 (50%) were registered in 2009 and the other 25 (50%) in 2010. Slightly more than half, 52.2% had CD4 cell counts above 350cells/mm3. Almost half, 49% of the women were registered in their final (third) pregnancy trimester. About 82% were in WHO stage one and 60% of all the 50 women were initiated on AZT/3TC/EFV regimen. Only 5.7% had secondary education while the rest had primary or no education at all. Of the women that reported their partners HIV state, 54.5% had partners that had never tested for HIV. Adherence for all participants was reported as sufficient (good) for the entire period the women were in care. No one had insufficient (poor) adherence. Retention in care was higher during pregnancy than after delivery. Generally, loss to follow up was 40%. About 30% were lost during pregnancy and the majority, 70% lost after they had delivered their babies. There was no evidence to prove that any of the factors studied independently predicted non retention. The most likely time to non retention was six months after delivery. Conclusions Our study, despite small sample size, shows that among women diagnosed HIV – infected and starting life-long ART during pregnancy (Option B+), adherence to ART is sufficient and retention in care similar during and after pregnancy. Counseling on the importance of staying in care especially around the first few months after delivery should be emphasized at ANC.