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Background South Africa has the highest HIV prevalence and supports the largest antiretroviral therapy (ART) programme globally. With the introduction of a test and treat policy, ensuring long term optimal adherence to ART (≥95%) is essential for successful patient and public health outcomes. The aim of this study was to assess long-term ART adherence to inform best practices for chronic HIV care. Method Long-term ART adherence was retrospectively analysed over a median duration of 5 years (interquartile range [IQR]: 5.3–6.5) in patients initially enrolled in a randomised controlled trial assessing tuberculosis and HIV treatment integration and subsequently followed post-trial in an observational cohort study in Durban, South Africa. The association between baseline patient characteristics and adherence over time was estimated using generalized estimating equations (GEE). Adherence was assessed using pharmacy pill counts conducted at each study visit and compared to 6 monthly viral load measurements. A Kaplan Meier survival analysis was used to estimate time to treatment failure. The McNemar test (with exact p -values) was used to determine the effect of pill burden and concurrent ART and tuberculosis treatment on adherence. Results Of the 270 patients included in the analysis; 54.8% were female, median age was 34 years (IQR:29–40) and median time on ART was 70 months (IQR = 64–78). Mean adherence was ≥95% for each year on ART. Stable patients provided with an extended 3-month ART supply maintained adherence > 99%. At study end, 96 and 94% of patients were optimally adherent and virologically suppressed, respectively. Time since ART initiation, female gender and primary breadwinner status were significantly associated with ≥95% adherence to ART. The cumulative probability of treatment failure was 10.7% at 5 years after ART initiation. Concurrent ART and tuberculosis treatment, or switching to a second line ART regimen with higher pill burden, did not impair ART adherence. Conclusion Optimal long-term adherence with successful treatment outcomes are possible within a structured ART programme with close adherence monitoring. This adherence support approach is relevant to a resource limited setting adopting a test and treat strategy.

In this study from South Africa, earlier initiation of antiretroviral therapy in patients with newly diagnosed HIV infection and TB was associated with higher rates of the immune reconstitution inflammatory syndrome and adverse events but increased AIDS-free survival. In patients who have infection with the human immunodeficiency virus (HIV) and tuberculosis, antiretroviral therapy (ART) may be initiated at the same time as or soon after the initiation of tuberculosis treatment. However, antiretroviral agents are often deferred until after the intensive phase of tuberculosis treatment because of concern about the immune reconstitution inflammatory syndrome (IRIS), 1 , 2 a high pill burden, and overlapping side effects 3 when three antiretroviral agents are added to the standard four antituberculosis drugs. These challenges may result in interruption or discontinuation of treatment for the acquired immunodeficiency syndrome (AIDS) or tuberculosis, which can lead to drug . . .

Post-Acute Sequelae of Severe Acute Respiratory Syndrome Coronavirus – 2 (SARS-CoV-2) infection, or Long COVID, is a prevailing second pandemic with nearly 100 million affected individuals globally and counting. We propose a visual description of the complexity of Long COVID and its pathogenesis that can be used by researchers, clinicians, and public health officials to guide the global effort toward an improved understanding of Long COVID and the eventual mechanism-based provision of care to afflicted patients. The proposed visualization or framework for Long COVID should be an evidence-based, dynamic, modular, and systems-level approach to the condition. Furthermore, with further research such a framework could establish the strength of the relationships between pre-existing conditions (or risk factors), biological mechanisms, and resulting clinical phenotypes and outcomes of Long COVID. Notwithstanding the significant contribution that disparities in access to care and social determinants of health have on outcomes and disease course of long COVID, our model focuses primarily on biological mechanisms. Accordingly, the proposed visualization sets out to guide scientific, clinical, and public health efforts to better understand and abrogate the health burden imposed by long COVID.

The recognition that drug-resistant tuberculosis (DR-TB) poses a major threat to global tuberculosis (TB) control efforts has catalysed the development of new and urgently needed TB diagnostics. The full beneficial impact of the subsequent flood of new TB diagnostic tests into the market can only be realised if these diagnostic tests are readily accessible to TB programs and contribute to improved patient outcomes. Although phenotypic drug-susceptibility testing remains the gold standard, an improved understanding of the relationship between mutations and different levels of drug resistance coupled with the advantages of molecular diagnostics could result in rapid molecular diagnostic tests replacing phenotypic drug-susceptibility testing. Successful diagnostics need to diagnose all forms of drug-resistant TB prevalent in each geographic region. Given the finite number and often limited availability of effective drugs for DR-TB, the diagnostic test must be able to detect all clinically important types of resistance to available anti-TB drugs. However, less comprehensive resistance profiling may be sufficient in settings where extensively drug-resistant TB (XDR-TB) and pre-XDR are absent. Rapid molecular diagnostic tests for DR-TB detection suitable for DR-TB endemic settings should be accurate, inexpensive, suitable to be performed on an easily accessible sample, detect prevalent circulating drug-resistant strains, and provide results within a short turnaround time to enable timely treatment initiation. In this review, we appraise the wide range of molecular diagnostics for DR-TB endorsed by the World Health Organisation, discuss the challenges in the development and rollout of rapid molecular DR-TB tests in low- and middle- income countries, and highlight user perspectives and cost-effectiveness factors that influence their utility. Keywords: tuberculosis, drug resistance, molecular assays, point of care, diagnosis

Background The global predominance of tuberculosis in men has received significant attention. However, epidemiological studies now demonstrate that there is an increased representation of young women with tuberculosis, especially in high HIV burden settings where young women bear a disproportionate burden of HIV. The role of the HIV epidemic, as well as changes in behavioural, biological, and structural risk factors are explored as potential explanations for the increasing burden of tuberculosis in young women. Discussion As young women are particularly vulnerable to HIV infection in sub-Saharan Africa, it is unsurprising that the TB epidemic in this setting has become increasingly feminised. This age-sex trend of TB in South Africa is similar to WHO estimates for other countries with a high HIV prevalence where there are more female than male cases notified up to the age of 25 years. The high prevalence of anaemia of chronic disease in young women with HIV is an additional potential reason for their increased TB risk. The widespread use of injectable medroxyprogesterone acetate contraception, which has been shown to possess selective glucocorticoid effect and oestrogen suppression, in young women may be an important emerging biological risk factor for tuberculosis in young women. Behavioural factors such as alcohol use and tobacco smoking patterns are further factors which may be responsible for the narrowing of the sex gap in TB epidemiology. In comparison to the significantly higher alcohol consumption rates in men globally, there is a narrowing gap in alcohol consumption between the sexes in South Africa with alarming rates of alcohol abuse in young women. There is a similar narrowing of the tobacco smoking gap between the sexes in South Africa, with increasing smoking prevalence in young women. Conclusion With nearly 70% of all TB patients being co-infected with HIV in our setting, it is not surprising that the age and sex distribution of TB is increasingly resembling the distribution of HIV in this region of dual hyperendemicity. New TB service design must begin to reflect the presence of young women as a significant group burdened by the disease.

Hypertension is a leading risk factor for cardiovascular disease among people living with human immunodeficiency virus (PLWH). This study determined incidence and prevalence of hypertension among PLWH receiving antiretroviral therapy (ART). We prospectively followed-up 642 HIV and tuberculosis (TB) co-infected study participants from 2005-2013. We defined hypertension as two consecutive elevated systolic and/or diastolic blood pressure measurements above 139/89 mmHg or current use of antihypertensive therapy. Of 507 participants analyzed, 53% were women. Median [interquartile range (IQR)] age, body mass index (BMI), and CD4 count was 34 (28.0-40.0) years, 22.7 (20.5-25.4) kg/m2, and 145 (69.0-252.0) cells/mm3, respectively. Incidence [95% confidence interval (CI)] of both systolic and diastolic hypertension overall, in men, and in women over 40 years was 1.9 (1.4-2.6), 5.9 (3.6-9.6), and 5.0 (2.7-9.3) per 100 person-years (PY), respectively. Risk of developing hypertension was higher in men [(adjusted hazard ratio (aHR) 12.04, 95% CI: 4.35-33.32)] and women over 40 years (aHR 8.19, 95% CI 2.96-22.64), and in men below 40 years (aHR 2.79, 95% CI 0.95-8.23). Higher incidence rates of hypertension among older men and women accessing ART highlight opportunities to expand current integrated HIV-TB care models, to include cardiovascular disease risk screening and care to prevent premature death.

Xpert MTB/XDR (Xpert-XDR) testing can significantly shorten time to initiating appropriate drug-resistant tuberculosis (DR-TB) treatment, but its introduction may impact laboratory workflow, especially in laboratories not currently performing drug susceptibility testing. This study evaluated the feasibility and acceptability of implementing the Xpert-XDR for rapid triage and selection of all-oral regimens for DR-TB. This was a multi-country, multi-site qualitative study conducted between July and November 2023, as part of the larger TriAD (Triage test for All oral DR TB drugs) study implemented in South Africa, Ethiopia, and Nigeria. We conducted semi-structured in-depth interviews with clinicians, nurses and laboratory staff at each study site until thematic saturation was achieved. Additionally, we interviewed policy makers (n = 9) and people with TB (PWTB) (n = 11), to provide additional insight on the implementation of this new diagnostic assay. Healthcare workers (n = 61) found the new workflow feasible and acceptable. It was the increased speed in which PWTB would receive a correct diagnosis and appropriate treatment that provided the biggest benefit to moving to Xpert-XDR for healthcare workers and PWTB. Laboratory staff mentioned that Xpert-XDR had expedited and simplified the laboratory workflows. Role-appropriate and ongoing training is a key factor in effective implementation as described by policy makers and healthcare workers alike. Barriers impacting the ability to perform Xpert-XDR included unstable power supply, internet, and temperature control. Additionally, the Xpert MTB/Rif Ultra test has higher sensitivity for the detection of TB than the Xpert-XDR test, leading to discordant test results. This study showed that implementation of Xpert-XDR in health facilities is both feasible and acceptable by all types of healthcare workers. Some barriers with Xpert-XDR are not exclusive to this particular diagnostic tool but are important to address when policy makers are deciding which tools to implement.

Global tuberculosis (TB) eradication is undermined by increasing prevalence of emerging resistance to available drugs, fuelling ongoing demand for more complex diagnostic and treatment strategies. Early detection of TB drug resistance coupled with therapeutic decision making guided by rapid characterisation of pre-treatment and treatment emergent resistance remains the most effective strategy for averting Drug-Resistant TB (DR-TB) transmission, reducing DR-TB associated mortality, and improving patient outcomes. Solid- and liquid-based mycobacterial culture methods remain the gold standard for Mycobacterium tuberculosis (MTB) detection and drug susceptibility testing (DST). Unfortunately, delays to result return, and associated technical challenges from requirements for specialised resource and capacity, have limited DST use and availability in many high TB burden resource-limited countries. There is increasing availability of a variety of rapid nucleic acid-based diagnostic assays with adequate sensitivity and specificity to detect gene mutations associated with resistance to one or more drugs. While a few of these assays produce comprehensive calls for resistance to several first- and second-line drugs, there is still no endorsed genotypic drug susceptibility test assay for bedaquiline, pretomanid, and delamanid. The global implementation of regimens comprising these novel drugs in the absence of rapid phenotypic drug resistance profiling has generated a new set of diagnostic challenges and heralded a return to culture-based phenotypic DST. In this review, we describe the available tools for rapid diagnosis of drug-resistant tuberculosis and discuss the associated opportunities and challenges.

Background Little is known about the clinical presentation and outcomes amongst older HIV infected populations accessing ART in sub-Saharan Africa. We compared mortality amongst HIV infected patients accessing ART that were <  50 years to those ≥50 years in Kwa-Zulu Natal, South Africa. Methods We undertook a retrospective review of medical records of patients that accessed HIV services at the CAPRISA AIDS Treatment program (CAT) between June 2004 to December 2012 ( N  = 4003). HIV infected patients, 14 years or older were enrolled. All-cause mortality and treatment response to ART in those < 50 years to those ≥50 years were compared. A Kaplan-Meier curve and log-rank test were used to compare the cumulative probability of death between the two age groups with the primary endpoint being mortality. Statistical analysis was done using SAS (version 9.4.; SAS Institute Inc., Cary, NC, USA). Results Of 4003 individuals, 262 (6.5%) were ≥ 50 years (older group). The median age in those ≥50 years and <  50 year was 54.5 and 32.0 years, respectively. The younger group was mainly female (64.7%). There was no difference in mortality rate, between the older (6.9/100 person-years (py), 95% confidence interval (CI): 4.7–9.6) and younger group (5.3/100 py, 95% CI: 4.7–5.8) at 60 months ( p  = 0.137). In the multivariable model older patients had a significantly higher risk of death compared to younger patients. (hazard ratio (HR) 1.60, 95% CI: 1.08–2.39, p  = 0.019).The rate of CD4+ cell count increase was higher in those < 50 years (β = 0.34, 95% CI: 0.19–0.50, p  < 0.001) with no difference in viral suppression. The older group showed significantly higher prevalence of diabetes (6.3%) and hypertension (21.5%), p  < 0.001. Conclusion ART initiation in older HIV infected patients was associated with a higher mortality compared to those younger than 50 years. ART immunological response was less robust in older individuals. The increase in hypertension and diabetes among older patients suggests the need to restructure and integrate primary and specialized health care services into ART services.

Background High early morbidity and mortality following antiretroviral therapy (ART) initiation has been a distinguishing feature of ART programmes in resource limited settings (RLS) compared to high-income countries. This study assessed how well body mass index (BMI: kg/m 2 ) correlated with survival among HIV infected patients with and without TB co-infection. Methods We retrospectively evaluated clinical data from 1000 HIV infected patients, among whom 389 were also co-infected with TB, between January 2008 and December 2010, in KwaZulu-Natal, South Africa. Results Among 948 patients eligible for analysis, 15.7% (149/948) were underweight (< 18.50), 55.9% (530/948) had normal BMI (≥18.50–24.90), 18.7% (177/948) were overweight (25.00–29.00) and 9.7% (92/948) were obese (≥30.00). Irrespective of TB status, underweight patients, had significantly higher risk of death compared to those with normal BMI at baseline (aHR = 2.9; 95% CI : 1.5–5.7; P  = 0.002). Conclusions Irrespective of TB co-infection, low BMI correlated with mortality in HIV infected patients. Trial registration UKZN Biomedical Research Ethics Committee Reference number E 248/05, 23 September 2005.