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We describe a death associated with multidrugresistant tuberculosis and HIV infection outside Africa that can be linked to Tugela Ferry (KwaZulu-Natal, South Africa), the town most closely associated with the regional epidemic of drug-resistant tuberculosis. This case underscores the international relevance of this regional epidemic, particularly among health care workers. [ABSTRACT FROM AUTHOR]

The Alpha, Beta, and Gamma SARS-CoV-2 variants of concern (VOCs) co-circulated globally during 2020 and 2021, fueling waves of infections. They were displaced by Delta during a third wave worldwide in 2021, which, in turn, was displaced by Omicron in late 2021. In this study, we use phylogenetic and phylogeographic methods to reconstruct the dispersal patterns of VOCs worldwide. We find that source-sink dynamics varied substantially by VOC and identify countries that acted as global and regional hubs of dissemination. We demonstrate the declining role of presumed origin countries of VOCs in their global dispersal, estimating that India contributed <15% of Delta exports and South Africa <1%–2% of Omicron dispersal. We estimate that >80 countries had received introductions of Omicron within 100 days of its emergence, associated with accelerated passenger air travel and higher transmissibility. Our study highlights the rapid dispersal of highly transmissible variants, with implications for genomic surveillance along the hierarchical airline network. [Display omitted] • Global phylogenetic analysis reveals dispersal of VOCs along worldwide flight network • Omicron spread to five times more countries within 100 days of emergence than other VOCs • Delta and Omicron dispersed from secondary hubs during times of accelerating air travel • Highly connected countries were major global and regional exporters of VOCs Data analysis clarifies that dispersal of SARS-CoV-2 variants from their sites of initial detection was related to the amount of global air travel at the time of the variant's emergence and that travel volume through "hub" sites distinct from the site of emergence was a key driver of variant spread. [ABSTRACT FROM AUTHOR]

Background: Women live on average five years longer than men, and the sex difference in longevity is typically lower in populations with high mortality. South Africa—a high mortality population with a large sex disparity—is an exception, but the causes of death that contribute to this difference are not well understood. Methods: Using data from a demographic surveillance system in rural KwaZulu-Natal (2000–2014), we estimate differences between male and female adult life expectancy by HIV status. The contribution of causes of death to these life expectancy differences are computed with demographic decomposition techniques. Cause of death information comes from verbal autopsy interviews that are interpreted with the InSilicoVA tool. Results: Adult women lived an average of 10.4 years (95% confidence Interval 9.0–11.6) longer than men. Sex differences in adult life expectancy were even larger when disaggregated by HIV status: 13.1 (95% confidence interval 10.7–15.3) and 11.2 (95% confidence interval 7.5–14.8) years among known HIV negatives and positives, respectively. Elevated male mortality from pulmonary tuberculosis (TB) and external injuries were responsible for 43% and 31% of the sex difference in life expectancy among the HIV negative population, and 81% and 16% of the difference among people living with HIV. Conclusions: The sex differences in adult life expectancy in rural KwaZulu-Natal are exceptionally large, atypical for an African population, and largely driven by high male mortality from pulmonary TB and injuries. This is the case for both HIV positive and HIV negative men and women, signalling a need to improve the engagement of men with health services, irrespective of their HIV status. [ABSTRACT FROM AUTHOR]

Introduction: Anemia is common in HIV. Parvo B19 infection is a well-recognised cause of red cell aplasia. Other causes of persistent pure red cell aplasia (PRCA) include anti-retroviral drugs such as zidovudine and lamivudine. We describe a case of PRCA that strongly implicates emtricitabine as the probable cause. Patient presentation: Patient was HIV positive and on treatment with a fixed drug combination consisting of tenofovir, emtricitabine and efavirenz for 3 months when she developed severe transfusion dependent anemia. The anemia, attributed to PRCA, was persistent and transfusion dependent for about one year. Management and outcome: Replacement of emtricitabine with abacavir resulted in a prompt, complete and lasting resolution of the anaemia, suggesting an etiologic role of emtricitabine in the PRCA. Conclusion: Emtricitibine is a rare cause of pure red cell aplasia. [ABSTRACT FROM AUTHOR]

Background: Antiretroviral therapy (ART) suppresses HIV viral load in all body compartments and so limits the risk of HIV transmission. It has been suggested that ART not only contributes to preventing transmission at individual but potentially also at population level. This trial aims to evaluate the effect of ART initiated immediately after identification/diagnosis of HIV-infected individuals, regardless of CD4 count, on HIV incidence in the surrounding population. The primary outcome of the overall trial will be HIV incidence over two years. Secondary outcomes will include i) socio-behavioural outcomes (acceptability of repeat HIV counselling and testing, treatment acceptance and linkage to care, sexual partnerships and quality of life); ii) clinical outcomes (mortality and morbidity, retention into care, adherence to ART, virologic failure and acquired HIV drug resistance), iii) cost-effectiveness of the intervention. The first phase will specifically focus on the trial's secondary outcomes.Methods/design: A cluster-randomised trial in 34 (2 × 17) clusters within a rural area of northern KwaZulu-Natal (South Africa), covering a total population of 34,000 inhabitants aged 16 years and above, of whom an estimated 27,200 would be HIV-uninfected at start of the trial. The first phase of the trial will include ten (2 × 5) clusters. Consecutive rounds of home-based HIV testing will be carried out. HIV-infected participants will be followed in dedicated trial clinics: in intervention clusters, they will be offered immediate ART initiation regardless of CD4 count and clinical stage; in control clusters they will be offered ART according to national treatment eligibility guidelines (CD4 <350 cells/μL, World Health Organisation stage 3 or 4 disease or multidrug-resistant/extensively drug-resistant tuberculosis). Following proof of acceptability and feasibility from the first phase, the trial will be rolled out to further clusters.Discussion: We aim to provide proof-of-principle evidence regarding the effectiveness of Treatment-as-Prevention in reducing HIV incidence at the population level. Data collected from the participants at home and in the clinics will inform understanding of socio-behavioural, economic and clinical impacts of the intervention as well as feasibility and generalizability.Trial Registration: Clinicaltrials.gov: NCT01509508; South African Trial Register: DOH-27-0512-3974. [ABSTRACT FROM AUTHOR]

Background: Antiretroviral therapy (ART) roll-out is fraught with challenges, many with serious repercussions. We explored and described patient behaviour-related challenges from the perspective of health care providers from non-governmental organisations involved in ART programmes in KwaZulu-Natal, South Africa. Methods: A descriptive case study design using qualitative approach was applied during this study. Data was collected from nine key informants from the three biggest NGOs involved in ART roll-out using in-depth semistructured interviews. Transcribing and coding for emergent themes was done by two independent reviewers. Ethical approval for the study was granted by the UNISA research ethics committee of The Faculty of Health Sciences. Written consent was obtained from directors of the three NGOs involved and individual audio taped informed consent was obtained from all study participants prior to data collection. Results: Findings revealed six broad areas of patient behaviour challenges. These were patient behaviour related to socio-economic situation of patient (skipping of medication due to lack of food, or due to lack of transport fees), belief systems (traditional and religious), stigma (non- disclosure), sexual practices (non-acceptability of condoms, teenage pregnancies), escapism (drug and alcohol abuse) and opportunism (skipping medication in order to access disability grant, teenage pregnancies in order to access child grant). Conclusion: New programmes need to address patient behaviour as a complex phenomenon requiring a multipronged approach that also addresses social norms and institutions. In the face of continued ART scale up, this is further evidence for the need for multi-sectoral collaboration to ensure successful and sustainable ART roll-out. [ABSTRACT FROM AUTHOR]

Background: Increased mortality among men on antiretroviral therapy (ART) has been documented but remains poorly understood. We examined the magnitude of and risk factors for gender differences in mortality on ART. Methods and Findings: Analyses included 46,201 ART-naï ve adults starting ART between January 2002 and December 2009 in eight ART programmes across South Africa (SA). Patients were followed from initiation of ART to outcome or analysis closure. The primary outcome was mortality; secondary outcomes were loss to follow-up (LTF), virologic suppression, and CD4+ cell count responses. Survival analyses were used to examine the hazard of death on ART by gender. Sensitivity analyses were limited to patients who were virologically suppressed and patients whose CD4+ cell count reached .200 cells/ml. We compared gender differences in mortality among HIV+ patients on ART with mortality in an age-standardised HIV-negative population. Among 46,201 adults (65% female, median age 35 years), during 77,578 person-years of follow-up, men had lower median CD4+ cell counts than women (85 versus 110 cells/μl, p<0.001), were more likely to be classified WHO stage III/IV (86 versus 77%, p<0.001), and had higher mortality in crude (8.5 versus 5.7 deaths/100 person-years, p<0.001) and adjusted analyses (adjusted hazard ratio [AHR] 1.31, 95% CI 1.22-1.41). After 36 months on ART, men were more likely than women to be truly LTF (AHR 1.20, 95% CI 1.12-1.28) but not to die after LTF (AHR 1.04, 95% CI 0.86-1.25). Findings were consistent across all eight programmes. Virologic suppression was similar by gender; women had slightly better immunologic responses than men. Notably, the observed gender differences in mortality on ART were smaller than gender differences in age-standardised death rates in the HIV-negative South African population. Over time, non-HIV mortality appeared to account for an increasing proportion of observed mortality. The analysis was limited by missing data on baseline HIV disease characteristics, and we did not observe directly mortality in HIV-negative populations where the participating cohorts were located. Conclusions: HIV-infected men have higher mortality on ART than women in South African programmes, but these differences are only partly explained by more advanced HIV disease at the time of ART initiation, differential LTF and subsequent mortality, and differences in responses to treatment. The observed differences in mortality on ART may be best explained by background differences in mortality between men and women in the South African population unrelated to the HIV/AIDS epidemic. [ABSTRACT FROM AUTHOR]

Unlabelled: Background: Although access to life-saving treatment for patients infected with HIV in South Africa has improved substantially since 2004, treating all eligible patients (universal access) remains elusive. As the prices of antiretroviral drugs have dropped over the past years, availability of human resources may now be the most important barrier to achieving universal access to HIV treatment in Africa. We quantify the number of HIV health workers (HHWs) required to be added to the current HIV workforce to achieve universal access to HIV treatment in South Africa, under different eligibility criteria.Methods: We performed a time and motion study in three HIV clinics in a rural, primary care-based HIV treatment program in KwaZulu-Natal, South Africa, to estimate the average time per patient visit for doctors, nurses, and counselors. We estimated the additional number of HHWs needed to achieve universal access to HIV treatment within one year.Results: For universal access to HIV treatment for all patients with a CD4 cell count of ≤350 cells/μl, an additional 2,200 nurses, 3,800 counselors, and 300 doctors would be required, at additional annual salary cost of 929 million South African rand (ZAR), equivalent to US$ 141 million. For universal treatment ('treatment as prevention'), an additional 6,000 nurses, 11,000 counselors, and 800 doctors would be required, at an additional annual salary cost of ZAR 2.6 billion (US$ 400 million).Conclusions: Universal access to HIV treatment for patients with a CD4 cell count of ≤350 cells/μl in South Africa may be affordable, but the number of HHWs available for HIV treatment will need to be substantially increased. Treatment as prevention strategies will require considerable additional financial and human resources commitments. [ABSTRACT FROM AUTHOR]

Background: Cryptococcal meningitis (CM) remains a leading cause of death for HIV-infected individuals in sub-Saharan Africa. Improved treatment strategies are needed if individuals are to benefit from the increasing availability of antiretroviral therapy. We investigated the factors associated with mortality in routine care in KwaZulu-Natal, South Africa. Methodology/Principal Findings: A prospective year long, single-center, consecutive case series of individuals diagnosed with cryptococcal meningitis 190 patients were diagnosed with culture positive cryptococcal meningitis, of whom 186 were included in the study. 52/186 (28.0%) patients died within 14 days of diagnosis and 60/186 (32.3%) had died by day 28. In multivariable cox regression analysis, focal neurology (aHR 11 95%C.I. 3.08-39.3, P<0.001), diastolic blood pressure <60 mmHg (aHR 2.37 95%C.I. 1.11-5.04, P = 0.025), concurrent treatment for tuberculosis (aHR 2.11 95%C.I. 1.02-4.35, P = 0.044) and use of fluconazole monotherapy (aHR 3.69 95% C.I. 1.74-7.85, P<0.001) were associated with increased mortality at 14 and 28 days. Conclusions: Even in a setting where amphotericin B is available, mortality from cryptococcal meningitis in this setting is high, particularly in the immediate period after diagnosis. This highlights the still unmet need not only for earlier diagnosis of HIV and timely access to treatment of opportunistic infections, but for better treatment strategies of cryptococcal meningitis. [ABSTRACT FROM AUTHOR]

The independent emergence late in 2020 of the B.1.1.7, B.1.351, and P.1 lineages of SARS-CoV-2 prompted renewed concerns about the evolutionary capacity of this virus to overcome public health interventions and rising population immunity. Here, by examining patterns of synonymous and non-synonymous mutations that have accumulated in SARS-CoV-2 genomes since the pandemic began, we find that the emergence of these three "501Y lineages" coincided with a major global shift in the selective forces acting on various SARS-CoV-2 genes. Following their emergence, the adaptive evolution of 501Y lineage viruses has involved repeated selectively favored convergent mutations at 35 genome sites, mutations we refer to as the 501Y meta-signature. The ongoing convergence of viruses in many other lineages on this meta-signature suggests that it includes multiple mutation combinations capable of promoting the persistence of diverse SARS-CoV-2 lineages in the face of mounting host immune recognition. [Display omitted] • Detected a major global shift in the SARS-CoV-2 selective landscape in late 2020 • Identified ongoing convergent evolution between the alpha, beta, and gamma lineages • Defined the mutational meta-signature upon which these lineages are converging An analysis of synonymous and non-synonymous mutations in SARS-CoV-2 genomes since the inception of the COVID-19 pandemic provides insights into the emergence of a convergent mutational signature in the 501Y lineage (alpha, beta, and gamma variants) that is also likely present in other lineages that impacts host immune recognition. [ABSTRACT FROM AUTHOR]

The COVID-19 pandemic has spread very fast around the world. A few days after the first detected case in South Africa, an infection started in a large hospital outbreak in Durban, KwaZulu-Natal (KZN). Phylogenetic analysis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genomes can be used to trace the path of transmission within a hospital. It can also identify the source of the outbreak and provide lessons to improve infection prevention and control strategies. This manuscript outlines the obstacles encountered in order to genotype SARS-CoV-2 in near-real time during an urgent outbreak investigation. This included problems with the length of the original genotyping protocol, unavailability of reagents, and sample degradation and storage. Despite this, three different library preparation methods for Illumina sequencing were set up, and the hands-on library preparation time was decreased from twelve to three hours, which enabled the outbreak investigation to be completed in just a few weeks. Furthermore, the new protocols increased the success rate of sequencing whole viral genomes. A simple bioinformatics workflow for the assembly of high-quality genomes in near-real time was also fine-tuned. In order to allow other laboratories to learn from our experience, all of the library preparation and bioinformatics protocols are publicly available at protocols.io and distributed to other laboratories of the Network for Genomics Surveillance in South Africa (NGS-SA) consortium. [ABSTRACT FROM AUTHOR]

Summary: Objective: To investigate the diagnostic value of abdominal ultrasound in HIV-positive inpatients in a rural African setting. Methods: This was a prospective case series over 3 months of adult HIV-positive patients with symptoms suggestive of abdominal tuberculosis (TB). Diagnostic ultrasound was performed for all patients: sonographic criteria included abdominal lymph node enlargement (>1.5cm) and focal splenic lesions; ascites was a supportive finding. Further diagnostic studies, e.g., aspiration or biopsy were not routinely performed. TB treatment was initiated on the basis of clinical and sonographic features. The patients were contacted after 4 months to evaluate the clinical outcome. Results: One hundred and eighty adult HIV-positive patients were screened; 30 (16.7%) showed sonographic signs of abdominal TB. The median CD4 count was 78 cells/mm3. Presenting symptoms were weight loss (86.7%), abdominal pain (76.7%), and diarrhea (60%). Abdominal lymph node enlargement was the diagnostic finding in almost all cases (96.7%); hypoechoic lesions of the spleen were seen in 50% and ascites in 73.3%. Follow-up information was available for 25 patients: 24% had died and the remaining 76% reported symptomatic improvement and weight gain. Conclusions: Characteristic sonographic features of abdominal TB are common in HIV-infected inpatients in a rural African setting. Ultrasound should be introduced into clinical algorithms for the diagnosis of extrapulmonary TB. [ABSTRACT FROM AUTHOR]