published_or_final_version / Pharmacology and Pharmacy / Doctoral / Doctor of Philosophy

A systematic review and meta-analysis was conducted to evaluate the efficacy of different infant antiretroviral (ARV) prophylaxis regimens for prevention of mother to child transmission (MTCT) of human immunodeficiency virus (HIV) infection in breastfeeding infants who were born to HIV positive mothers but were HIV uninfected at birth. The systematic review of the literature published during January 2000 to April 2012 resulted in ten randomized and controlled clinical studies which met the study inclusion criteria. Two datasets were identified from the ten selected clinical trials. One dataset contains six studies evaluating short-course ARV prophylaxis regimens, and the second dataset contains four studies evaluating short-course versus extended ARV prophylaxis regimens. The odds ratio was used as the effect size to measure the efficacy between two comparative infant ARV prophylaxis regimens. Meta-analyses were conducted to assess the overall (pooled) treatment effect of the two comparative infant ARV prophylaxis regimens of the two datasets. The pooled ARV treatment effect was calculated as a weighted average of the effect estimated in the individual studies. If no heterogeneity was identified, a fixed-effect meta-analysis by the Mantel-Haenszel method was used. The random-effects method was used when there was heterogeneity in the meta-analysis. The inverse-variance method was used in the random-effects method of meta-analysis. Heterogeneity in the meta-analysis was accessed by the Chi-squared (χ2) test and I2 test. The combined sample size of all ten clinical trials was a total of 10,316 breastfeeding infants, and the overall postnatal HIV transmission rate regardless of ARV regimens and the timing of HIV infection status was approximately 8.7%. The overall HIV transmission rates of the short-course ARV prophylaxis regimen groups were 10.3% at 4-8 weeks and 9.0% at 6-9 months, respectively. The overall late postnatal HIV transmission rate (at 6-9 months after birth) was 5.5% in the extended ARV prophylaxis regimen group. The first dataset contains six randomized and controlled studies to evaluate the efficacy outcome (defined as the unadjusted HIV infection status at 4-8 weeks after birth) of two short-course infant ARV prophylaxis regimens, the nevirapine (NVP) regimen and the zidovudine (ZDV) with or without combination of lamivudine (3TC) or NVP regimen. Due to the existence of substantial heterogeneity, a random-effects method was used to test for the overall treatment effect. The results show that there was no significant difference between the two short-course infant ARV prophylaxis regimens (odds ratio:1.07; 95% CI: 0.69-1.66; Z=0.31, p=0.76). The results of the meta-analysis of five comparative short-course versus extended infant ARV prophylaxis regimens from four randomized and controlled clinical trials, demonstrate a favorable efficacy outcome (defined as the unadjusted HIV infection status at 6-9 months after birth), of the extended ARV regimens. There was no heterogeneity found in this dataset. There was a highly significant difference in the overall effect between the two ARV prophylaxis regimens by a fixed-effect model (odds ratio: 1.72; 95% CI:1.45-2.04; Z=0.68, p<0.00001). In summary, there was no significant difference in the overall treatment effect in reducing the early postnatal MTCT of HIV infection by infant short-course regimens of ARV prophylaxis, which include NVP, ZDV and their combination regimens. In comparison with the short-course ARV regimens, the extended ARV prophylaxis further reduced the risk of the late postnatal MTCT of HIV infection in breastfeeding infants. / published_or_final_version / Public Health / Master / Master of Public Health

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The manifestation of HIV-1 infection is different in children and adults. Most of the children who acquire HIV perinatally progress to disease within the first two years of life, while adults can remain asymptomatic for up to ten years. However, a small minority group of children can control the virus for years in the absence of antiretroviral therapy. We characterized CD8+ T cell responses critical for the containment of HIV infection in a cohort of infants HIV infected from birth using IFN- γ ELISPOT, multicolour flow cytometry and viral sequencing of the Gag protein. We investigated whether the age at the time of infection, specificity and functionality of the generated responses, genetic make up and the maternal immune responses to HIV, influenced disease progression in the child. We found that the majority of in-utero infected infants mounted CD8+ T cell responses from the first days of life. In contrast to chronically infected children or adults, the specificity of the initial response in acutely infected infants was directed towards Env and Rev proteins and CD4+ T cell responses were minimal during the first 6 months of life. Slow progression to disease was associated with possession of one of the protective HLA-B alleles by either the mother or the child (P=0.007) and targeting of Gag epitopes presented by the protective HLA-B alleles. Mothers who expressed protective alleles but whose children did not possess these alleles, transmitted less fit viruses that benefited their children. Furthermore, slow progressor children had more polyfunctional CD8+ T cell responses in early infection when compared to rapid progressors (P=0.05). The ability of infants to induce CD8+ T cell responses early in life is encouraging for vaccine interventions. The differences in the specificity of the initial responses between adults and children, insufficient priming of these responses as a result of minimal CD4+ T cell help during infancy and possession of non-protective HLA alleles shared between mother and child, may explain the rapid disease progression generally noted in most infants. However, slow progression to disease in the minority group of children may be attributed to functional capacity of the CD8+ T cells generated by the child, mediation by protective HLA alleles, acquisition of low fitness viruses from the mother or de novo attenuation of the virus by the child’s own immune responses. / Thesis (Ph.D.)-University of KwaZulu-Natal, Durban, 2011.

Reverse transcription of human immunodeficiency virus type-1 (HIV-1) is primed by cellular tRNALys3, which is selectively packaged into viral particles where it is bound at its 3' terminus to a complementary sequence of viral RNA termed the primer binding site (PBS). In addition to the PBS, other regions within the viral genome also interact with tRNALys3. Initiation of HIV-1 reverse transcription requires specific recognition of the viral genome, tRNA primer, and reverse transcriptase (RT). In this work, we study the important role played by the initiation complex in the initiation of HIV-1 reverse transcription. An "A-rich loop" located upstream of the PBS has been shown to interact with the anticodon loop of tRNALys3 and deletion of this A-rich loop caused diminished viral replication fitness. We have now studied the mechanisms involved in the altered replication capacities of the deletion-containing viruses in the context of both wild type HIV-1 and viruses also containing the M184V substitution in RT. We found that the M184V mutation in RT compromises the ability of deletion-containing viruses to restore wild-type replication. Further biochemical study indicates that both the M184V mutation in RT and deletion of sequences upstream of PBS caused diminished viral replication fitness by compromising the efficiency of reverse transcription initiation. / Since the initiation of DNA synthesis was shown to be a highly specific process, it represents a potential target for the development of novel antiviral agents. We developed strategies for inhibition of the HIV-1 replication via interference with the tRNALys3/viral RNA complex. To target primer tRNALys3, we employed oligodeoxyribonucleotides (ODNs) that are complementary to different parts of the tRNA primer. To target viral RNA, we devised a tRNALys3-like molecule, termed tRNA Lys*, that contained sequence alterations that direct initiation from a region distant from the natural PBS, designated PBS*. PBS* is involved in the formation of the natural tRNA/PBS complex and binding of tRNALys* was shown to interfere specifically with the initiation of reverse transcription. Inhibition of the synthesis of (-) strand strong-stop DNA was achieved successfully with both strategies by interfering with the formation of the initiation complex.

The HIV and Aids pandemic not only has an impact on women but also on men. Young people in their early and late adolescent years, between the ages 12 and 24 years of age, find themselves in a period of exploration and experimentation that can enhance high-risk sexual behaviour. In research done in South Africa it was estimated that half of all young men and woman are sexually active by the age of 16. Unfortunately, we in South Africa live in an era where HIV and AIDS do not allow such behaviours and this situation makes male youths one of the most vulnerable groups in our society to be infected by the HI-virus. This study focused on male youths on ARV therapy (ART). The antiretroviral therapy requires maximum adherence from the people living with HIV and AIDS. Adherence to antiretroviral therapy poses a great challenge to the youth, especially if they are unemployed and have families who depend on them for financial as well as emotional support. The aim of this study was to evaluate the impact of a social group work empowerment programme on male youths undergoing ARV therapy. To achieve the aim of this study the following objectives were set: • To investigate the needs of male youths on ARV therapy in a rural area. This objective was achieved by obtaining a theoretical perspective from the literature as well as undertaking empirical research by means of the interviewing process. According to these findings male youths on ARV therapy have many needs, such as the need for more information on ARV therapy, the role of the Departments of Health and Social Development, the role of social workers, and how to disclose their HIV status to people other than their family members. •To determine the role of social group work in empowering male youths who are on antiretroviral therapy to cope with the illness and ARV therapy by means of a literature study. It was important for the researcher to do a literature study on social group work to enhance her knowledge and skills, because this is a method of social work that she not often implemented in practice. • To develop and implement a social group work programme for male youths on ARV therapy. The social group work empowerment programme for male youth on ARV therapy was implemented over nine group work sessions and tested on 10 respondents who were part of the needs assessment and were willing to be part of the group work programme in the rural area of the Motheo District. The programme consisted of nine group sessions with different topics discussed in each session for the empowerment of the target group. According to the group members, they acquired adequate skills to enable them to act properly in solving their problems. The programme impacted a lot on how they felt about themselves and the circumstances around them. • To evaluate the effectiveness of the social group work empowerment programme on male youths on ARV therapy. This objective was achieved in the sense that the general satisfaction of the young men had increased according to the Generalized Contentment Scale (GCS) of Perspective Training College. The measuring scale was utilized before the first session started, at the end of the fifth session (in the middle measurement phase), and at the end of the last session. The findings from the research indicated that significant personal growth had taken place among the male youth on ARV therapy in a rural area. Scientifically proven research emerged from this study and proved that a well-designed social group work empowerment programme can enhance the social functioning and general contentment of the male youths on ARV therapy. / Thesis (PhD (Social Work))--North-West University, Potchefstroom Campus, 2013

The HIV and Aids pandemic not only has an impact on women but also on men. Young people in their early and late adolescent years, between the ages 12 and 24 years of age, find themselves in a period of exploration and experimentation that can enhance high-risk sexual behaviour. In research done in South Africa it was estimated that half of all young men and woman are sexually active by the age of 16. Unfortunately, we in South Africa live in an era where HIV and AIDS do not allow such behaviours and this situation makes male youths one of the most vulnerable groups in our society to be infected by the HI-virus. This study focused on male youths on ARV therapy (ART). The antiretroviral therapy requires maximum adherence from the people living with HIV and AIDS. Adherence to antiretroviral therapy poses a great challenge to the youth, especially if they are unemployed and have families who depend on them for financial as well as emotional support. The aim of this study was to evaluate the impact of a social group work empowerment programme on male youths undergoing ARV therapy. To achieve the aim of this study the following objectives were set: • To investigate the needs of male youths on ARV therapy in a rural area. This objective was achieved by obtaining a theoretical perspective from the literature as well as undertaking empirical research by means of the interviewing process. According to these findings male youths on ARV therapy have many needs, such as the need for more information on ARV therapy, the role of the Departments of Health and Social Development, the role of social workers, and how to disclose their HIV status to people other than their family members. •To determine the role of social group work in empowering male youths who are on antiretroviral therapy to cope with the illness and ARV therapy by means of a literature study. It was important for the researcher to do a literature study on social group work to enhance her knowledge and skills, because this is a method of social work that she not often implemented in practice. • To develop and implement a social group work programme for male youths on ARV therapy. The social group work empowerment programme for male youth on ARV therapy was implemented over nine group work sessions and tested on 10 respondents who were part of the needs assessment and were willing to be part of the group work programme in the rural area of the Motheo District. The programme consisted of nine group sessions with different topics discussed in each session for the empowerment of the target group. According to the group members, they acquired adequate skills to enable them to act properly in solving their problems. The programme impacted a lot on how they felt about themselves and the circumstances around them. • To evaluate the effectiveness of the social group work empowerment programme on male youths on ARV therapy. This objective was achieved in the sense that the general satisfaction of the young men had increased according to the Generalized Contentment Scale (GCS) of Perspective Training College. The measuring scale was utilized before the first session started, at the end of the fifth session (in the middle measurement phase), and at the end of the last session. The findings from the research indicated that significant personal growth had taken place among the male youth on ARV therapy in a rural area. Scientifically proven research emerged from this study and proved that a well-designed social group work empowerment programme can enhance the social functioning and general contentment of the male youths on ARV therapy. / Thesis (PhD (Social Work))--North-West University, Potchefstroom Campus, 2013

HIV-associated lipodystrophy (HIVLD) syndrome is a condition comprising abnormalities in distribution of body fat and metabolism of lipids and glucose that arises in HIV-infected patients on long-term antiretroviral therapy. This thesis describes clinical research into aspects of the natural history and treatment of HIVLD, as well as molecular research into its pathogenesis centred on subcutaneous adipose tissue. Results demonstrate HIVLD to be a treatment-induced syndrome characterised by initial gains in body fat followed by selective, progressive loss of limb fat. Exposure to thymidineanalogue nucleoside reverse transcriptase inhibitors (tNRTI) induces lipoatrophy through mitochondrial dysfunction of which inhibition of mitochondrial RNA expression, rather than mitochondrial DNA depletion, is an early feature. Mitochondrial dysfunction is associated with decreases in expression of peroxisome proliferatoractivated receptor gamma (PPAR??), an adipocyte transcription factor, which helps explain how tNRTI exposure leads to the loss of adipocyte function. Once established, lipoatrophy is characterised by mitochondrial DNA depletion, although this depletion occurs throughout the mitochondrial genome, suggesting an underlying cause other than inhibition of DNA polymerase gamma. HIVLD is a difficult syndrome to treat. Lipoatrophy is resistant to treatment with rosiglitazone, an agonist of PPAR??, which is ineffective in the setting of ongoing tNRTI therapy and mitochondrial dysfunction. Dyslipidaemia is also difficult to treat as use of pravastatin in the setting of ongoing exposure to protease inhibitors results in only modest declines in fasting cholesterol concentrations. Gains in central fat, such as that seen in patients with buffalo hump, are associated with insulin resistance and diabetes, but only occur in a relatively small percentage of treated patients, suggesting a role for genetic factors in its development. Use of strategies such as avoidance of tNRTI in firstline ART, genetic screening to identify those at risk of toxicities and targeted selection of interventions in subgroups of affected patients, may help prevent this syndrome occurring and better treat those patients in which it has already occurred.

Thesis (MSc)--University of Stellenbosch, 2007. / Bibliography. Also available via the Inernet.

Thesis (M.A.)--Georgia State University, 2008. / Title from file title page. Cassandra White, committee chair; Kathryn A. Kozaitis, Susan McCombie, committee members. Electronic text (95 p.) : digital, PDF file. Description based on contents viewed Sept. 29, 2008. Includes bibliographical references (p. 90-94).