Impact of haptoglobin gene variation on HIV resistance and the rate of disease progression in the South African black population

Student Number : 0318625T - MSc dissertation - School of Molecular and Cell Biology - Faculty of ScienceGenetic variation in haptoglobin, a plasma protein, has been reported to be associated with susceptibility to and the rate of HIV/AIDS progression. The purpose of this study was to investigate the influence of haptoglobin polymorphism on HIV/AIDS in black South Africans. Polymorphism in the coding region of the haptoglobin gene was detected by direct DNA and allele-specific amplification. Polymorphism in the coding region of the gene was detected by amplification of DNA and by polyacrylamide gel electrophoresis of plasma protein. A statistically significant association was observed between allele -61C and resistance to HIV infection. The Hp0 phenotype, in which no haptoglobin protein is detected, was associated with HIV status and some promoter genotypes. Since in our study population there were a few samples with usable clinical data , further investigations need to be done to confirm the association of the -61C allele and the Hp0 phenotype with the risk of HIV infection

Decentralised Strategic Planning and Capacity Development as Drivers of Leadership Performance in Schools

The purpose of this article is to determine the association between decentralised strategic planning and capacity development as driving forces of leadership for improved performance in public high schools in Mpumalanga Province, South Africa. This study used pragmatism as a research paradigm and followed a parallel convergent mixed methods research approach. The sample comprised 170 respondents consisting of 130 school governing body (SGB) members and 40 Department of Education (DoE) officials. Quantitative data were collected from SGB members through a survey while qualitative data were collected from participants using focus group discussions (FGDs) and individual interviews. The qualitative data were analysed using thematic analysis while SPSS software was used to analyse quantitative data. In testing the hypothesis, it was proven that decentralised strategic planning capacity in SGBs was associated with the effectiveness of strategic planning in Mpumalanga’s high schools. The study revealed that the variables, capacity development and decentralised strategic planning, are well associated, and influence leadership for improved performance in high schools. The study also found that school leaders who can develop capacity are able to promote better performance in their schools. Meanwhile, the qualitative results concurrently supported the results of the quantitative study as the influence of capacity development on decentralised school planning proved to have improved school performance and effective decentralised school leadership

Mutational Correlates of Virological Failure in Individuals Receiving a WHO-Recommended Tenofovir-Containing First-Line Regimen: An International Collaboration.

Tenofovir disoproxil fumarate (TDF) genotypic resistance defined by K65R/N and/or K70E/Q/G occurs in 20% to 60% of individuals with virological failure (VF) on a WHO-recommended TDF-containing first-line regimen. However, the full spectrum of reverse transcriptase (RT) mutations selected in individuals with VF on such a regimen is not known. To identify TDF regimen-associated mutations (TRAMs), we compared the proportion of each RT mutation in 2873 individuals with VF on a WHO-recommended first-line TDF-containing regimen to its proportion in a cohort of 50,803 antiretroviral-naïve individuals. To identify TRAMs specifically associated with TDF-selection pressure, we compared the proportion of each TRAM to its proportion in a cohort of 5805 individuals with VF on a first-line thymidine analog-containing regimen. We identified 83 TRAMs including 33 NRTI-associated, 40 NNRTI-associated, and 10 uncommon mutations of uncertain provenance. Of the 33 NRTI-associated TRAMs, 12 - A62V, K65R/N, S68G/N/D, K70E/Q/T, L74I, V75L, and Y115F - were more common among individuals receiving a first-line TDF-containing compared to a first-line thymidine analog-containing regimen. These 12 TDF-selected TRAMs will be important for monitoring TDF-associated transmitted drug-resistance and for determining the extent of reduced TDF susceptibility in individuals with VF on a TDF-containing regimen

High prevalence of the K65R mutation in HIV-1 subtype C infected patients failing tenofovir-based first-line regimens in South Africa.

BACKGROUND:Tenofovir (TDF) has replaced stavudine (d4T) as the preferred nucleoside reverse transcriptase inhibitor (NRTI) in first-line regimens in South Africa, but limited information is available on the resistance patterns that develop after the introduction of TDF. This study investigated the antiretroviral drug resistance patterns in South African HIV-1 subtype C-infected patients failing stavudine- (d4T) and tenofovir- (TDF) based first-line regimens and assess the suitability of TDF as the preferred first-line nucleotide reverse transcriptase inhibitor (NRTI). METHODS:Resistance patterns of HIV-1 from 160 adult patients virologically failing TDF- (n = 80) and d4T- (n = 80) based first-line regimens were retrospectively analyzed. The pol gene was sequenced using an in-house protocol and mutations were analysed using the IAS-USA 2014 Drug Resistance Mutation list. RESULTS:Compared to d4T-exposed patients (n = 7), patients failing on a TDF-containing regimen (n = 43) were almost 5 times more likely to present with a K65R mutation (aRR 4.86 95% CI 2.29 - 10.34). Y115F was absent in the d4T group, and detected in 13.8% (n = 11) of TDF-exposed patients, p = 0.0007. Virus from 9 of the 11 patients (82.0%) who developed the Y115F mutation also developed K65R. Intermediate or high-level resistance to most NRTIs was common in the TDF-treatment group, but these patients twice more likely to remain susceptible to AZT as compared to those exposed to d4T (aRR 2.09 95% CI 1.13 - 3.90). CONCLUSION:The frequency of the TDF induced K65R mutation was higher in our setting compared to non-subtype C dominated countries. However, despite the higher frequency of cross-resistance to NRTIs, most patients remained susceptible to AZT, which is reflected in the South African treatment guidelines that recommend AZT as an essential component of second-line regimens

Prevalence of resistance to nucleoside/tide inhibitors (NRTI) and non- nucleoside Reverse Transcriptase Inhibitors (NNRTI).

<p>Prevalence of susceptible (S, dotted bars), intermediate (I, striped bars) or high-level resistance (R, solid bars) to NRTIs and NNRTIs after exposure to a tenofovir (TDF) containing regimen (n = 80, black) or stavudine (d4T) containing regimen (n = 80, white). The numbers represent percentages. 3TC: lamivudine; FTC: emtricitabine; ABC: abacavir; AZT: zidovudine; d4T: stavudine; ddI: didanosine; TDF: tenofovir; EFV: efavirenz; ETR: etravirine; NVP: nevirapine; RPV: rilpivirine.</p

Prevalence of nucleoside reverse transcriptase inhibitor mutations and thymidine analogue mutations (TAMs) in tenofovir (TDF; black) and stavudine (d4T, white) treatment groups.

<p>The mutations that were not detected in either treatment groups are not included in the graph. The numbers represent percentages. P1: TAM pathway 1, P2: TAM pathway 2, P1+2: combination of TAM pathway 1 and 2.</p

Crude and adjusted relative risk calculations for mutation prevalence and drug resistance call between different groups.

<p>Log-binomial regression analysis was used and the model was adjusted with CD4, VL and time on treatment where possible. Adjusted relative risk was only calculated for N: Number of patients; RR: relative risk; CI: confidence interval; VL: RNA Viral Load; ART: antiretroviral treatment; 3TC: lamivudine; FTC: emtricitabine; ABC: abacavir; AZT: zidovudine; d4T: stavudine; ddI: didanosine; TDF: tenofovir; EFV: efavirenz; ETR: etravirine; NVP: nevirapine; RPV: rilpivirine; S: susceptible; IR: intermediate resistance; HR: high-level resistance; ND: not done</p><p>Crude and adjusted relative risk calculations for mutation prevalence and drug resistance call between different groups.</p

Patient demographics and clinical characteristics of South African patients failing stavudine (d4T)- or tenofovir (TDF)-based 1^st-line regimens.

<p>N: Number of patients, VL: RNA Viral Load, ART: Antiretroviral treatment, 3TC: Lamivudine, NVP: Nevirapine, EFV: Efavirenz.</p><p>Patient demographics and clinical characteristics of South African patients failing stavudine (d4T)- or tenofovir (TDF)-based 1^st-line regimens.</p

Prevalence of non-nucleoside reverse transcriptase inhibitor mutations after exposure to nevirapine (NVP) containing regimen (n = 68, black) and efavirenz (EFV) containing regimen (n = 92, white).

<p>The mutations that were not detected in either treatment groups are not included. The numbers represent percentages.</p