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A case of necrotising migratory erythema (NME), which is one of the distinctive paraneoplastic skin manifestations associated with the glucagonoma syndrome, is described and discussed. In 80% of all patients with glucagonoma, NME is the first clinical sign. The glucagonoma syndrome is a constellation of clinical features: NME, weight loss, anaemia, diabetes, diarrhoea, thromboembolism and neuropsychiatric symptoms. The global incidence of glucagonoma is one in 20 million people per year. The male to female ratio is 0.8:1 with the mean age of diagnosis being 52.2 years. The median time in relation to the initial onset of symptoms and the correct diagnosis is 3.5 years. The 10-year survival rate in patients with metastatic disease is 51.6% and without metastatic disease 64.3%. SPECT scan has a sensitivity range of 67-100% for detecting neuroendocrine tumours. Differential diagnoses of other skin conditions that mimic NME are: bullous pemphigoid, vasculitis, acrodermatitis enteropathica, chronic mucocutaneous candidiasis, seborrhoeic dermatitis, contact dermatitis, pellagra, inflammatory bowel disease, liver cirrhosis, coeliac disease, chemical burns, eczema, herpes etc. A satisfactory response to somatostatin as medical therapy in a case-study patient with metastatic disease is reported.

Differences among hosts, resulting from genetic variation in the immune system or heterogeneity in drug treatment, can impact within-host pathogen evolution. Genetic association studies can potentially identify such interactions. However, extensive and correlated genetic population structure in hosts and pathogens presents a substantial risk of confounding analyses. Moreover, the multiple testing burden of interaction scanning can potentially limit power. We present a Bayesian approach for detecting host influences on pathogen evolution that exploits vast existing data sets of pathogen diversity to improve power and control for stratification. The approach models key processes, including recombination and selection, and identifies regions of the pathogen genome affected by host factors. Our simulations and empirical analysis of drug-induced selection on the HIV-1 genome show that the method recovers known associations and has superior precision-recall characteristics compared to other approaches. We build a high-resolution map of HLA-induced selection in the HIV-1 genome, identifying novel epitope-allele combinations. Various host factors may impact within-host pathogen evolution. Here, the authors develop a Bayesian approach for identifying host-pathogen interactions using large data sets of pathogen diversity, and apply it to investigate HLA-induced selection in the HIV-1 genome.

Robust evidence of the effectiveness of task shifting of antiretroviral therapy (ART) from doctors to other health workers is scarce. We aimed to assess the effects on mortality, viral suppression, and other health outcomes and quality indicators of the Streamlining Tasks and Roles to Expand Treatment and Care for HIV (STRETCH) programme, which provides educational outreach training of nurses to initiate and represcribe ART, and to decentralise care. We undertook a pragmatic, parallel, cluster-randomised trial in South Africa between Jan 28, 2008, and June 30, 2010. We randomly assigned 31 primary-care ART clinics to implement the STRETCH programme (intervention group) or to continue with standard care (control group). The ratio of randomisation depended on how many clinics were in each of nine strata. Two cohorts were enrolled: eligible patients in cohort 1 were adults (aged ≥16 years) with CD4 counts of 350 cells per μL or less who were not receiving ART; those in cohort 2 were adults who had already received ART for at least 6 months and were being treated at enrolment. The primary outcome in cohort 1 was time to death (superiority analysis). The primary outcome in cohort 2 was the proportion with undetectable viral loads (<400 copies per mL) 12 months after enrolment (equivalence analysis, prespecified difference <6%). Patients and clinicians could not be masked to group assignment. The interim analysis was blind, but data analysts were not masked after the database was locked for final analysis. Analyses were done by intention to treat. This trial is registered, number ISRCTN46836853. 5390 patients in cohort 1 and 3029 in cohort 2 were in the intervention group, and 3862 in cohort 1 and 3202 in cohort 2 were in the control group. Median follow-up was 16·3 months (IQR 12·2–18·0) in cohort 1 and 18·0 months (18·0–18·0) in cohort 2. In cohort 1, 997 (20%) of 4943 patients analysed in the intervention group and 747 (19%) of 3862 in the control group with known vital status at the end of the trial had died. Time to death did not differ (hazard ratio [HR] 0·94, 95% CI 0·76–1·15). In a preplanned subgroup analysis of patients with baseline CD4 counts of 201–350 cells per μL, mortality was slightly lower in the intervention group than in the control group (0·73, 0·54–1.00; p=0·052), but it did not differ between groups in patients with baseline CD4 of 200 cells per μL or less (0·94, 0·76–1·15; p=0·577). In cohort 2, viral load suppression 12 months after enrolment was equivalent in intervention (2156 [71%] of 3029 patients) and control groups (2230 [70%] of 3202; risk difference 1·1%, 95% CI −2·4 to 4·6). Expansion of primary-care nurses' roles to include ART initiation and represcription can be done safely, and improve health outcomes and quality of care, but might not reduce time to ART or mortality. UK Medical Research Council, Development Cooperation Ireland, and Canadian International Development Agency.

These guidelines are intended as an update to those published in the Southern African Journal of HIV Medicine in 2014 and the update on when to initiate antiretroviral therapy in 2015. Since the release of the previous guidelines, the scale-up of antiretroviral therapy (ART) in southern Africa has continued. New antiretroviral drugs have become available with improved efficacy, safety and robustness. The guidelines are intended for countries in the southern African region, which vary between lower and middle income.

The Southern African HIV Clinicians Society would like to update all HIV-treating clinicians with regard to the use of dolutegravir in women of childbearing potential (WOCP). In preliminary data from the Tsepamo study in Botswana, it was found that 0.94% (95% confidence interval [CI]: 0.37 – 2.4) of babies (4/426) born to women who were taking dolutegravir periconception had neural tube defects (NTDs), compared with 0.1% of babies (14/11 173) of women taking other antiretroviral drugs (ARVs) in the periconception period.1 No NTDs were observed in pregnancies where dolutegravir was initiated later in pregnancy. Further data from the Tsepamo study were presented at AIDS 2018: the updated number of NTDs with periconception dolutegravir exposure in the Tsepamo cohort is 4/596, 0.67% (95% CI: 0.26 to 1.7). The next formal analysis will occur after 31 March 2019 and will include women exposed to dolutegravir from conception before the recent change in guidance. Tsepamo plans to expand the number of study sites, increasing the coverage from 45% to 72% of births in Botswana with a projected denominator of over 1200 by March 2019.

HIV infection is associated with a complex pattern of Mycobacterium tuberculosis–specific T-cell impairment. In South African participants, we report an HIV-associated depletion of tuberculosis-specific Th1 and Th17 CD4+ T cells compounded by loss of corresponding CD8+ T-cell function. Abstract Background Human immunodeficiency virus (HIV)–infected individuals have a higher risk of developing active tuberculosis (TB) than HIV-uninfected individuals, but the mechanisms underpinning this are unclear. We hypothesized that depletion of specific components of Mycobacterium tuberculosis (Mtb)–specific CD4+ and CD8+ T-cell responses contributed to this increased risk. Methods Mtb-specific T-cell responses in 147 HIV-infected and 44 HIV-uninfected control subjects in a TB-endemic setting in Bloemfontein, South Africa, were evaluated. Using a whole-blood flow cytometry assay, we measured expression of interferon gamma, tumor necrosis factor alpha, interleukin 2, and interleukin 17 in CD4+ and CD8+ T cells in response to Mtb antigens (PPD, ESAT-6/CFP-10 [EC], and DosR regulon-encoded α-crystallin [Rv2031c]). Results Fewer HIV-infected individuals had detectable CD4+ and CD8+ T-cell responses to PPD and Rv2031c than HIV-uninfected subjects. Mtb-specific T cells showed distinct patterns of cytokine expression comprising both Th1 (CD4 and CD8) and Th17 (CD4) cytokines, the latter at highest frequency for Rv2031c. Th17 antigen-specific responses to all antigens tested were specifically impaired in HIV-infected individuals. Conclusions HIV-associated impairment of CD4+ and CD8+Mtb-specific T-cell responses is antigen specific, particularly impacting responses to PPD and Rv2031c. Preferential depletion of Th17 cytokine-expressing CD4+ T cells suggests this T-cell subset may be key to TB susceptibility in HIV-infected individuals.

There is a need for effective therapy for COVID-19 pneumonia. Convalescent plasma has antiviral activity and early observational studies suggested benefit in reducing COVID-19 severity. We investigated the safety and efficacy of convalescent plasma in hospitalized patients with COVID-19 in a population with a high HIV prevalence and where few therapeutic options were available. We performed a double-blinded, multicenter, randomized controlled trial in one private and three public sector hospitals in South Africa. Adult participants with COVID-19 pneumonia requiring non-invasive oxygen were randomized 1:1 to receive a single transfusion of 200 mL of either convalescent plasma or 0.9% saline solution. The primary outcome measure was hospital discharge and/or improvement of ≥ 2 points on the World Health Organisation Blueprint Ordinal Scale for Clinical Improvement by day 28 of enrolment. The trial was stopped early for futility by the Data and Safety Monitoring Board. 103 participants, including 21 HIV positive individuals, were randomized at the time of premature trial termination: 52 in the convalescent plasma and 51 in the placebo group. The primary outcome occurred in 31 participants in the convalescent plasma group and and 32 participants in the placebo group (relative risk 1.03 (95% CI 0.77 to 1.38). Two grade 1 transfusion-related adverse events occurred. Participants who improved clinically received convalescent plasma with a higher median anti-SARS-CoV-2 neutralizing antibody titre compared with those who did not (298 versus 205 AU/mL). Our study contributes additional evidence for recommendations against the use of convalescent plasma for COVID-19 pneumonia. Safety and feasibility in this population supports future investigation for other indications.

Southern African HIV Clinicians Society adult antiretroviral therapy (ART) guidelines currently recommend ritonavir-boosted atazanavir (ATV/r) 300/100 mg as preferred boosted protease inhibitor (PI/r) for second-line ART. It was noted in the guidelines that once a suitable tablet for DRV/r 800/100 mg dosing became available, DRV/r 800/100 mg would be a feasible option in second-line ART, with fewer side effects than the DRV/r 600/100 mg twice-daily dosing.

Cytolytic CD4+ T cells play a prominent role in chronic viral infection. CD4+ CTLs clones specific for HIV-1 Nef and Gag are capable of killing HIV-1 infected CD4+ T cells and macrophages. Additionally, HIV-specific cytolytic CD4+ T cell responses in acute HIV infection are predictive of disease progression. CD57 expression on CD4s identifies cytolytic cells. These cells were dramatically increased in chronic HIV infection. CD57 expression correlated with cytolytic granules, granzyme B and perforin expression. They express lower CCR5 compared to CD57- cells, have less HIV total DNA, and were a minor component of the HIV reservoir. A small percentage of CD57+ CD4+ CTLs from EC were HIV-specific, could upregulate IFNγ with Gag peptide stimulation, express cytolytic granule markers and maintain Tbet Eomes+ transcription factor phenotype. This was not observed in viraemic controllers. The maintenance of HIV-specific CD4 cytolytic function in Elite controllers together with CD8 CTLs may be important for the control of HIV viraemia and of potential relevance to cure strategies.

HIV-1 drug resistance to older thymidine analogue nucleoside reverse transcriptase inhibitor drugs has been identified in sub-Saharan Africa in patients with virological failure of first-line combination antiretroviral therapy (ART) containing the modern nucleoside reverse transcriptase inhibitor tenofovir. We aimed to investigate the prevalence and correlates of thymidine analogue mutations (TAM) in patients with virological failure of first-line tenofovir-containing ART. We retrospectively analysed patients from 20 studies within the TenoRes collaboration who had locally defined viral failure on first-line therapy with tenofovir plus a cytosine analogue (lamivudine or emtricitabine) plus a non-nucleoside reverse transcriptase inhibitor (NNRTI; nevirapine or efavirenz) in sub-Saharan Africa. Baseline visits in these studies occurred between 2005 and 2013. To assess between-study and within-study associations, we used meta-regression and meta-analyses to compare patients with and without TAMs for the presence of resistance to tenofovir, cytosine analogue, or NNRTIs. Of 712 individuals with failure of first-line tenofovir-containing regimens, 115 (16%) had at least one TAM. In crude comparisons, patients with TAMs had lower CD4 counts at treatment initiation than did patients without TAMs (60·5 cells per μL [IQR 21·0–128·0] in patients with TAMS vs 95·0 cells per μL [37·0–177·0] in patients without TAMs; p=0·007) and were more likely to have tenofovir resistance (93 [81%] of 115 patients with TAMs vs 352 [59%] of 597 patients without TAMs; p<0·0001), NNRTI resistance (107 [93%] vs 462 [77%]; p<0·0001), and cytosine analogue resistance (100 [87%] vs 378 [63%]; p=0·0002). We detected associations between TAMs and drug resistance mutations both between and within studies; the correlation between the study-level proportion of patients with tenofovir resistance and TAMs was 0·64 (p<0·0001), and the odds ratio for tenofovir resistance comparing patients with and without TAMs was 1·29 (1·13–1·47; p<0·0001) TAMs are common in patients who have failure of first-line tenofovir-containing regimens in sub-Saharan Africa, and are associated with multidrug resistant HIV-1. Effective viral load monitoring and point-of-care resistance tests could help to mitigate the emergence and spread of such strains. The Wellcome Trust.