The potential and challenges of district rural development planning in South Africa : the case Gert Sibande District Municipality, Mpumalanga Province

Abstract: Rural and former homeland areas, mostly within a semi-urban context, are predominantly characterised by parallel statutory and customary legislative regimes which are both fully recognised under the current constitutional dispensation of the Republic of South Africa. The existence of this dichotomy in rural South Africa pre-dates the 1996 Constitutional dispensation and is therefore the legacy of the apartheid era, which saw the passing of various laws such as the Bantu Homelands Constitution Act, 1971 (Act 21 of 1971) which was also later renamed the Self-Governing Territories Constitution Act, 1971 (Act 21 of 1971). The basis of the passing of these laws emanated from subsequent laws such as the Bantu Authorities Act, 1951 (Act 68 of 1951) and the Promotion of Bantu Self-Government Act, 1959 (Act 46 of 1959) which also resulted in the establishment of tribal/traditional, territorial and regional authorities which relied on customary and indigenous understanding to the management of land. The statutory regulation of planning and land use management was later introduced in the self-governing and homeland areas with the promulgation of Proclamations R293 of 1962 and R188 of 1969 which were enacted as Land Use and Planning Regulations in terms of the Black Administration Act, 1927 (Act 38 of 1927). This signalled the beginning of a legacy of parallel land use and land development application procedures found in the semi-urban contexts of Post-Apartheid South Africa...M.Eng. (Sustainable Urban Planning and Development

CD8+ T cell breadth and ex vivo virus inhibition capacity distinguish between viremic controllers with and without protective HLA class I alleles.

CAPRISA, 2016.Abstract available in PDF file

Project Masihambisane: a cluster randomised controlled trial with peer mentors to improve outcomes for pregnant mothers living with HIV

Abstract Background Pregnant women living with HIV (WLH) face daily challenges maintaining their own and their babies' health and mental health. Standard Prevention of Maternal to Child Transmission (PMTCT) programs are not designed to address these challenges. Methods/Design As part of a cluster randomized controlled trial, WLH are invited to attend four antenatal and four postnatal small group sessions led by a peer WLH (a Peer Mentor). The WLH and their babies are assessed during pregnancy and at one week, six months, and twelve months post-birth. Mobile phones are used to collect routine information, complete questionnaires and remain in contact with participants over time. Pregnant WLH (N = 1200) are randomly assigned by clinic (N = 8 clinics) to an intervention program, called Masihambisane (n = 4 clinics, n = 600 WLH) or a standard care PMTCT control condition (n = 4 clinics; n = 600 WLH). Discussion Data collection with cellular phones are innovative and effective in low-resource settings. Standard PMTCT programs are not designed to address the daily challenges faced by WLH; Peer Mentors may be useful in supporting WLH to cope with these challenges. Trial registration ClinicalTrials.gov registration # NCT0097269

Dolutegravir twice-daily dosing in children with HIV-associated tuberculosis: a pharmacokinetic and safety study within the open-label, multicentre, randomised, non-inferiority ODYSSEY trial

Background: Children with HIV-associated tuberculosis (TB) have few antiretroviral therapy (ART) options. We aimed to evaluate the safety and pharmacokinetics of dolutegravir twice-daily dosing in children receiving rifampicin for HIV-associated TB. Methods: We nested a two-period, fixed-order pharmacokinetic substudy within the open-label, multicentre, randomised, controlled, non-inferiority ODYSSEY trial at research centres in South Africa, Uganda, and Zimbabwe. Children (aged 4 weeks to <18 years) with HIV-associated TB who were receiving rifampicin and twice-daily dolutegravir were eligible for inclusion. We did a 12-h pharmacokinetic profile on rifampicin and twice-daily dolutegravir and a 24-h profile on once-daily dolutegravir. Geometric mean ratios for trough plasma concentration (Ctrough), area under the plasma concentration time curve from 0 h to 24 h after dosing (AUC0–24 h), and maximum plasma concentration (Cmax) were used to compare dolutegravir concentrations between substudy days. We assessed rifampicin Cmax on the first substudy day. All children within ODYSSEY with HIV-associated TB who received rifampicin and twice-daily dolutegravir were included in the safety analysis. We described adverse events reported from starting twice-daily dolutegravir to 30 days after returning to once-daily dolutegravir. This trial is registered with ClinicalTrials.gov (NCT02259127), EudraCT (2014–002632-14), and the ISRCTN registry (ISRCTN91737921). Findings: Between Sept 20, 2016, and June 28, 2021, 37 children with HIV-associated TB (median age 11·9 years [range 0·4–17·6], 19 [51%] were female and 18 [49%] were male, 36 [97%] in Africa and one [3%] in Thailand) received rifampicin with twice-daily dolutegravir and were included in the safety analysis. 20 (54%) of 37 children enrolled in the pharmacokinetic substudy, 14 of whom contributed at least one evaluable pharmacokinetic curve for dolutegravir, including 12 who had within-participant comparisons. Geometric mean ratios for rifampicin and twice-daily dolutegravir versus once-daily dolutegravir were 1·51 (90% CI 1·08–2·11) for Ctrough, 1·23 (0·99–1·53) for AUC0–24 h, and 0·94 (0·76–1·16) for Cmax. Individual dolutegravir Ctrough concentrations were higher than the 90% effective concentration (ie, 0·32 mg/L) in all children receiving rifampicin and twice-daily dolutegravir. Of 18 children with evaluable rifampicin concentrations, 15 (83%) had a Cmax of less than the optimal target concentration of 8 mg/L. Rifampicin geometric mean Cmax was 5·1 mg/L (coefficient of variation 71%). During a median follow-up of 31 weeks (IQR 30–40), 15 grade 3 or higher adverse events occurred among 11 (30%) of 37 children, ten serious adverse events occurred among eight (22%) children, including two deaths (one tuberculosis-related death, one death due to traumatic injury); no adverse events, including deaths, were considered related to dolutegravir. Interpretation: Twice-daily dolutegravir was shown to be safe and sufficient to overcome the rifampicin enzyme-inducing effect in children, and could provide a practical ART option for children with HIV-associated TB

Neuropsychiatric manifestations and sleep disturbances with dolutegravir-based antiretroviral therapy versus standard of care in children and adolescents: a secondary analysis of the ODYSSEY trial

BACKGROUND: Cohort studies in adults with HIV showed that dolutegravir was associated with neuropsychiatric adverse events and sleep problems, yet data are scarce in children and adolescents. We aimed to evaluate neuropsychiatric manifestations in children and adolescents treated with dolutegravir-based treatment versus alternative antiretroviral therapy. METHODS: This is a secondary analysis of ODYSSEY, an open-label, multicentre, randomised, non-inferiority trial, in which adolescents and children initiating first-line or second-line antiretroviral therapy were randomly assigned 1:1 to dolutegravir-based treatment or standard-of-care treatment. We assessed neuropsychiatric adverse events (reported by clinicians) and responses to the mood and sleep questionnaires (reported by the participant or their carer) in both groups. We compared the proportions of patients with neuropsychiatric adverse events (neurological, psychiatric, and total), time to first neuropsychiatric adverse event, and participant-reported responses to questionnaires capturing issues with mood, suicidal thoughts, and sleep problems. FINDINGS: Between Sept 20, 2016, and June 22, 2018, 707 participants were enrolled, of whom 345 (49%) were female and 362 (51%) were male, and 623 (88%) were Black-African. Of 707 participants, 350 (50%) were randomly assigned to dolutegravir-based antiretroviral therapy and 357 (50%) to non-dolutegravir-based standard-of-care. 311 (44%) of 707 participants started first-line antiretroviral therapy (ODYSSEY-A; 145 [92%] of 157 participants had efavirenz-based therapy in the standard-of-care group), and 396 (56%) of 707 started second-line therapy (ODYSSEY-B; 195 [98%] of 200 had protease inhibitor-based therapy in the standard-of-care group). During follow-up (median 142 weeks, IQR 124–159), 23 participants had 31 neuropsychiatric adverse events (15 in the dolutegravir group and eight in the standard-of-care group; difference in proportion of participants with ≥1 event p=0·13). 11 participants had one or more neurological events (six and five; p=0·74) and 14 participants had one or more psychiatric events (ten and four; p=0·097). Among 14 participants with psychiatric events, eight participants in the dolutegravir group and four in standard-of-care group had suicidal ideation or behaviour. More participants in the dolutegravir group than the standard-of-care group reported symptoms of self-harm (eight vs one; p=0·025), life not worth living (17 vs five; p=0·0091), or suicidal thoughts (13 vs none; p=0·0006) at one or more follow-up visits. Most reports were transient. There were no differences by treatment group in low mood or feeling sad, problems concentrating, feeling worried or feeling angry or aggressive, sleep problems, or sleep quality. INTERPRETATION: The numbers of neuropsychiatric adverse events and reported neuropsychiatric symptoms were low. However, numerically more participants had psychiatric events and reported suicidality ideation in the dolutegravir group than the standard-of-care group. These differences should be interpreted with caution in an open-label trial. Clinicians and policy makers should consider including suicidality screening of children or adolescents receiving dolutegravir

Project Masihambisane : a cluster randomised controlled trial with peer mentors to improve outcomes for pregnant mothers living with HIV

Please cite as follows:Rotheram-Borus, M-J. et al. 2011. Project Masihambisane : a cluster randomised controlled trial with peer mentors to improve outcomes for pregnant mothers living with HIV. Trials, 12(1):2, doi:10.1186/1745-6215-12-2.The original publication is available at http://www.trialsjournal.com/content/12/1/2Background: Pregnant women living with HIV (WLH) face daily challenges maintaining their own and their babies' health and mental health. Standard Prevention of Maternal to Child Transmission (PMTCT) programs are not designed to address these challenges. Methods/Design: As part of a cluster randomized controlled trial, WLH are invited to attend four antenatal and four postnatal small group sessions led by a peer WLH (a Peer Mentor). The WLH and their babies are assessed during pregnancy and at one week, six months, and twelve months post-birth. Mobile phones are used to collect routine information, complete questionnaires and remain in contact with participants over time. Pregnant WLH (N = 1200) are randomly assigned by clinic (N = 8 clinics) to an intervention program, called Masihambisane (n = 4 clinics, n = 600 WLH) or a standard care PMTCT control condition (n = 4 clinics; n = 600 WLH). Discussion: Data collection with cellular phones are innovative and effective in low-resource settings. Standard PMTCT programs are not designed to address the daily challenges faced by WLH; Peer Mentors may be useful in supporting WLH to cope with these challenges. Trial registration: ClinicalTrials.gov registration # NCT00972699Publishers' Versio

High Frequency of Transmitted HIV-1 Gag HLA Class I-Driven Immune Escape Variants but Minimal Immune Selection over the First Year of Clade C Infection

In chronic HIV infection, CD8+ T cell responses to Gag are associated with lower viral loads, but longitudinal studies of HLA-restricted CD8+ T cell-driven selection pressure in Gag from the time of acute infection are limited. In this study we examined Gag sequence evolution over the first year of infection in 22 patients identified prior to seroconversion. A total of 310 and 337 full-length Gag sequences from the earliest available samples (median = 14 days after infection [Fiebig stage I/II]) and at one-year post infection respectively were generated. Six of 22 (27%) individuals were infected with multiple variants. There was a trend towards early intra-patient viral sequence diversity correlating with viral load set point (p = 0.07, r = 0.39). At 14 days post infection, 59.7% of Gag CTL epitopes contained non-consensus polymorphisms and over half of these (35.3%) comprised of previously described CTL escape variants. Consensus and variant CTL epitope proportions were equally distributed irrespective of the selecting host HLA allele and most epitopes remained unchanged over 12 months post infection. These data suggest that intrapatient diversity during acute infection is an indicator of disease outcome. In this setting, there is a high rate of transmitted CTL escape variants and limited immune selection in Gag during the first year of infection. These data have relevance for vaccine strategies designed to elicit effective CD8+ T cell immune responses

Percentage distribution of consensus and variant Gag sequence patterns in individuals over one year of HIV-1 infection.

<p>(A) Percentage of consensus, variant and known CTL variants within host specific epitopes from HLA class I alleles at one year post infection. Distribution of consensus, variant and percentage of variants as CTL variants within host-specific HLA restricted Gag epitopes in individuals possessing the selecting HLA-A (B), HLA-B (C) and HLA-C (D) allele and those individuals who do not possess the selecting HLA allele over one year of infection. (E) Overall distribution of adapted and non-adapted HLA-associated escape mutations within individuals that select and do not select for Gag polymorphisms by one year post infection. Distribution of adapted (F) and non-adapted (G) mutations expressing HLA-A, HLA-B and HLA-C alleles that select and do not select for Gag polymorphisms one year post infection.</p

Summary of reversion of HLA associated mutations following transmission in the presence or absence of the selecting HLA type.

<p><i>a</i>"None" indicates no known HLA-association of mutation</p><p><i>b</i>(+): presence of HLA-association, (−): absence of previously identified HLA association</p><p>Bold restricting HLA indicates the HLA which is positively associted with the non-adapted mutation at one-year post infection</p><p>Summary of reversion of HLA associated mutations following transmission in the presence or absence of the selecting HLA type.</p

Neighbour joining trees and Highlighter plots of longitudinal HIV-1 gag diversity from recently infected individuals.

<p>(A) Neighbour-joining phylogenetic tree of longitudinal (from 14 days to 1 year post infection) <i>gag</i> sequences from 22 recently infected HIV-1 participants and consensus subtype C reference sequence from the HIV database (<a href="http://www.hiv.lanl.gov" target="_blank">www.hiv.lanl.gov</a>). Gag sequences from the earliest time point are shown in red circles and in blue circles at 1 year post infection. (*) denotes samples sequenced later than 14 days post infection (AS3–0513, AS2–1037, AS2–0802, AS2–0945 and AS1–0876 were sequenced at 28, 34, 35, 46 and 101 days post-infection respectively). (B) Participant AS3_0513 with a highly homogeneous <i>gag</i> sequence population at screening (∼28 days post infection) displaying limited structure on a tree (left) and little or no nucleotide changes from the intrapatient consensus at 28 days post infection. (C) Participant AS3_0767 infected with four closely related <i>gag</i> populations based on the clustering of sequences. Heterogeneous, multiple variant <i>gag</i> sequences population at 14 days post infection visually represented by a phylogenetic tree (left) with extensive branching topology and Highlighter plots (right) with diverse pattern of nucleotide base mutations compared to consensus. Nucleotide polymorphisms are indicated by a colored tic mark (thymine in red, adenine in green, cytosine in blue and guanine in orange) and deletions are shown by gray tics in the Highlighter plots. (★) denotes the consensus sequence obtained from the earliest time point sequences.</p