Antimicrobial Resistance and Molecular Typing of Neisseria gonorrhoeae Isolates From the Eastern Cape Province in South Africa.

BACKGROUND: There is a paucity of Neisseria gonorrhoeae antimicrobial resistance data from resource-constrained settings because of the lack of diagnostic testing and limited scale of surveillance programs. This study aimed to determine the antimicrobial resistance profile of N. gonorrhoeae in the rural Eastern Cape province of South Africa. METHODS: Specimens for N. gonorrhoeae culture were obtained from men with urethral discharge and women with vaginal discharge attending primary health care facilities. Direct inoculation of the agar plates was performed followed by culture and drug susceptibility testing using the Etest at the laboratory. Whole-genome sequencing of the isolates was performed to identify resistance-determining variants. RESULTS: One hundred N. gonorrhoeae isolates were obtained. Most strains were nonsusceptible to ciprofloxacin (76%), tetracycline (75%), and penicillin G (72%). The gyrA S91F mutation was present in 68 of 72 ciprofloxacin-resistant isolates (94%), with concurrent parC mutations in 47 of 68 (69%); gyrA I250M was the only mutation in 4 other resistant strains. One azithromycin-resistant isolate was identified with a minimal inhibitory concentration (MIC) of 8.0 mg/L and the 23S rDNA gene mutation C2597T. The median MIC of cefixime was 0.016 mg/L (range, 0.016-0.064 mg/L), and that of ceftriaxone was 0.016 mg/L (range, 0.016 mg/L). Whole-genome sequencing showed 58 sequence types as revealed in N. gonorrhoeae sequence typing for antimicrobial resistance and 70 sequence types in N. gonorrhoeae multiantigen sequence typing. CONCLUSIONS: This study confirmed high rates of N. gonorrhoeae antimicrobial resistance to ciprofloxacin, penicillin G, and tetracycline in our setting. The MICs of cephalosporins are reassuring for ceftriaxone use in syndromic treatment regimens, but the identification of azithromycin resistance warrants further attention.

Potential Impact and Cost-Effectiveness of Condomless-Sex-Concentrated PrEP in KwaZulu-Natal Accounting for Drug Resistance.

INTRODUCTION: Oral preexposure prophylaxis (PrEP) in the form of tenofovir-disoproxil-fumarate/emtricitabine is being implemented in selected sites in South Africa. Addressing outstanding questions on PrEP cost-effectiveness can inform further implementation. METHODS: We calibrated an individual-based model to KwaZulu-Natal to predict the impact and cost-effectiveness of PrEP, with use concentrated in periods of condomless sex, accounting for effects on drug resistance. We consider (1) PrEP availability for adolescent girls and young women aged 15-24 years and female sex workers, and (2) availability for everyone aged 15-64 years. Our primary analysis represents a level of PrEP use hypothesized to be attainable by future PrEP programs. RESULTS: In the context of PrEP use in adults aged 15-64 years, there was a predicted 33% reduction in incidence and 36% reduction in women aged 15-24 years. PrEP was cost-effective, including in a range of sensitivity analyses, although with substantially reduced (cost) effectiveness under a policy of ART initiation with efavirenz- rather than dolutegravir-based regimens due to PrEP undermining ART effectiveness by increasing HIV drug resistance. CONCLUSIONS: PrEP use concentrated during time periods of condomless sex has the potential to substantively impact HIV incidence and be cost-effective.

Sustainable HIV treatment in Africa through viral-load-informed differentiated care.

There are inefficiencies in current approaches to monitoring patients on antiretroviral therapy in sub-Saharan Africa. Patients typically attend clinics every 1 to 3 months for clinical assessment. The clinic costs are comparable with the costs of the drugs themselves and CD4 counts are measured every 6 months, but patients are rarely switched to second-line therapies. To ensure sustainability of treatment programmes, a transition to more cost-effective delivery of antiretroviral therapy is needed. In contrast to the CD4 count, measurement of the level of HIV RNA in plasma (the viral load) provides a direct measure of the current treatment effect. Viral-load-informed differentiated care is a means of tailoring care so that those with suppressed viral load visit the clinic less frequently and attention is focussed on those with unsuppressed viral load to promote adherence and timely switching to a second-line regimen. The most feasible approach to measuring viral load in many countries is to collect dried blood spot samples for testing in regional laboratories; however, there have been concerns over the sensitivity and specificity of this approach to define treatment failure and the delay in returning results to the clinic. We use modelling to synthesize evidence and evaluate the cost-effectiveness of viral-load-informed differentiated care, accounting for limitations of dried blood sample testing. We find that viral-load-informed differentiated care using dried blood sample testing is cost-effective and is a recommended strategy for patient monitoring, although further empirical evidence as the approach is rolled out would be of value. We also explore the potential benefits of point-of-care viral load tests that may become available in the future.

Removal of user fees and system strengthening improves access to maternity care, reducing neonatal mortality in a district hospital in Lesotho.

OBJECTIVE: Lesotho has one of the highest maternal mortality rates in the world. While at primary health care (PHC) level maternity care is free, at hospital level co-payments are required from patients. We describe service utilisation and delivery outcomes before and after removal of user fees and quality of delivery care, and associated costs, at St Joseph's Hospital (SJH) in Roma, Lesotho. METHODS: We compared utilisation of delivery services, stillbirths and maternal and neonatal mortality for the periods before (1 July 2012 to 31 December 2013) and after (1 January 2014 to 30 June 2015) user fee removal through a retrospective chart review and estimated additional costs attributed to user fee removal from provider (hospital) and patient perspectives. RESULTS: Of 4715 deliveries 3855 were at SJH and 860 at PHC centres. Of women delivering at SJH 684 (18.5%) were ≤19 years and 894 (23.6%) were HIV positive. After user fee removal hospital deliveries increased by 49% - from 1547 to 2308 - and neonatal mortality decreased from 4.8 to 1.3 per 1000 live births (P = 0.033). Extrapolating costs to the entire country, 1 USD per capita per year would allow user fee removal at hospital level, the provision of free transport to/from and accommodation at hospital. CONCLUSION: Removing user fees for hospital delivery care in Lesotho is feasible and affordable, and has the potential to improve maternal and neonatal outcomes by removing financial barriers to skilled birth attendants and increasing coverage of institutional deliveries.

Delamanid for rifampicin-resistant tuberculosis: a retrospective study from South Africa.

Experience with delamanid (Dlm) is limited, particularly among HIV-positive individuals. We describe early efficacy and safety data from a programmatic setting in South Africa.This was a retrospective cohort study of patients receiving Dlm-containing treatment regimens between November 2015 and August 2017. We report 12-month interim outcomes, sputum culture conversion (SCC) by months 2 and 6, serious adverse events (SAEs) and QT intervals corrected using the Frederica formula (QTcF).Overall, 103 patients were initiated on Dlm; 79 (77%) were HIV positive. The main indication for Dlm was intolerance to second-line anti-tuberculosis (TB) drugs (n=58, 56%). There were 12 months of follow-up for 46 patients; 28 (61%) had a favourable outcome (cure, treatment completion or culture negativity). Positive cultures were found for 57 patients at Dlm initiation; 16 out of 31 (52%) had SCC within 2 months and 25 out of 31 (81%) within 6 months. There were 67 SAEs reported in 29 patients (28%). There were four instances of QTcF prolongation >500 ms in two patients (2%), leading to permanent discontinuation in one case; however, no cardiac arrhythmias occurred.This large cohort of difficult-to-treat patients receiving Dlm for rifampicin-resistant TB treatment in a programmatic setting with high HIV prevalence had favourable early treatment response and tolerated treatment well. Dlm should remain available, particularly for those who cannot be treated with conventional regimens or with limited treatment options.

Combined interventions to reduce HIV incidence in KwaZulu-Natal: a modelling study.

BACKGROUND: Combined prevention interventions, including early antiretroviral therapy initiation, may substantially reduce HIV incidence in hyperendemic settings. Our aim was to assess the potential short-term impact of combined interventions on HIV spreading in the adult population of Mbongolwane and Eshowe (KwaZulu-Natal, South Africa) using sex- and age-specific scenarios, and age-targeted interventions. METHODS: A mathematical model was used with data on adults (15-59 years) from the Mbongolwane and Eshowe HIV Impact in Population Survey to compare the effects of various interventions on the HIV incidence rate. These interventions included increase in antiretroviral therapy (ART) coverage with extended eligibility criteria, increase in voluntary medical male circumcision (VMMC), and implementation of pre-exposure prophylaxis (PrEP) among women. RESULTS: With no additional interventions to the ones in place at the time of the survey (ART at CD4 < 350 and VMMC), incidence will decrease by 24% compared to the baseline rate. The implementation of "ART at CD4<500" or "ART for all" would reduce further the incidence rate by additional 8% and 15% respectively by 4 years and 20% and 34% by 10 years. Impacts would be higher with age-targeted scenarios than without. CONCLUSIONS: In Mbongolwane and Eshowe, implementation of the new South African guidelines, recommending ART initiation regardless of CD4 count, would accelerate incidence reduction. In this setting, combining these guidelines, VMMC, and PrEP among young women could be an effective strategy in reducing the incidence to low levels.

Adherence to cardiovascular therapy: a meta-analysis of prevalence and clinical consequences.

AIMS: The aim of this study was to determine the extent to which adherence to individual vascular medications, assessed by different methods, influences the absolute and relative risks (RRs) of cardiovascular disease (CVD) and all-cause mortality. METHODS AND RESULTS: We performed a systematic review and meta-analysis of prospective epidemiological studies (cohort, nested case-control, or clinical trial) identified through electronic searches using MEDLINE, Web of Science, EMBASE, and Cochrane databases, involving adult populations (≥ 18 years old) and reporting risk estimates of cardiovascular medication adherence with any CVD (defined as any fatal or non-fatal coronary heart disease, stroke or sudden cardiac death) and/or all-cause mortality (defined as mortality from any cause) outcomes. Relative risks were combined using random-effects models. Forty-four unique prospective studies comprising 1 978 919 non-overlapping participants, with 135 627 CVD events and 94 126 cases of all-cause mortality. Overall, 60% (95% CI: 52-68%) of included participants had good adherence (adherence ≥ 80%) to cardiovascular medications. The RRs (95% CI) of development of CVD in those with good vs. poor (<80%) adherence were 0.85 (0.81-0.89) and 0.81 (0.76-0.86) for statins and antihypertensive medications, respectively. Corresponding RRs of all-cause mortality were 0.55 (0.46-0.67) and 0.71 (0.64-0.78) for good adherence to statins and antihypertensive agents. These associations remained consistent across subgroups representing different study characteristics. Estimated absolute risk differences for any CVD associated with poor medication adherence were 13 cases for any vascular medication, 9 cases for statins and 13 cases for antihypertensive agents, per 100 000 individuals per year. CONCLUSION: A substantial proportion of people do not adhere adequately to cardiovascular medications, and the prevalence of suboptimal adherence is similar across all individual CVD medications. Absolute and relative risk assessments demonstrate that a considerable proportion of all CVD events (~9% in Europe) could be attributed to poor adherence to vascular medications alone, and that the level of optimal adherence confers a significant inverse association with subsequent adverse outcomes. Measures to enhance adherence to help maximize the potentials of effective cardiac therapies in the clinical setting are urgently required.

Cost effective interventions for the prevention of cardiovascular disease in low and middle income countries: a systematic review.

BACKGROUND: While there is good evidence to show that behavioural and lifestyle interventions can reduce cardiovascular disease risk factors in affluent settings, less evidence exists in lower income settings.This study systematically assesses the evidence on cost-effectiveness for preventive cardiovascular interventions in low and middle-income settings. DESIGN: Systematic review of economic evaluations on interventions for prevention of cardiovascular disease. DATA SOURCES: PubMed, Web of Knowledge, Scopus and Embase, Opensigle, the Cochrane database, Business Source Complete, the NHS Economic Evaluations Database, reference lists and email contact with experts. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: we included economic evaluations conducted in adults, reporting the effect of interventions to prevent cardiovascular disease in low and middle income countries as defined by the World Bank. The primary outcome was a change in cardiovascular disease occurrence including coronary heart disease, heart failure and stroke. DATA EXTRACTION: After selection of the studies, data were extracted by two independent investigators using a previously constructed tool and quality was evaluated using Drummond's quality assessment score. RESULTS: From 9731 search results we found 16 studies, which presented economic outcomes for interventions to prevent cardiovascular disease in low and middle income settings, with most of these reporting positive cost effectiveness results.When the same interventions were evaluated across settings, within and between papers, the likelihood of an intervention being judged cost effective was generally lower in regions with lowest gross national income. While population based interventions were in most cases more cost effective, cost effectiveness estimates for individual pharmacological interventions were overall based upon a stronger evidence base. CONCLUSIONS: While more studies of cardiovascular preventive interventions are needed in low and mid income settings, the available high-level of evidence supports a wide range of interventions for the prevention of cardiovascular disease as being cost effective across all world regions.

The global burden of HIV-associated cryptococcal infection in adults in 2020: a modelling analysis.

BACKGROUND: Cryptococcal meningitis is the most common cause of meningitis in adults living with HIV in sub-Saharan Africa. The estimates of national, regional, and global burden of cryptococcal meningitis are essential to guide prevention strategies and determine needs for diagnostic tests and treatments. We present a 2020 estimate of the global burden of HIV-associated cryptococcal infection (antigenaemia), cryptococcal meningitis, and cryptococcal-associated deaths. METHODS: We defined advanced HIV disease as adults with a CD4 count of less than 200 cells/µL, as this group is at highest risk for cryptococcosis. We used UNAIDS estimates (2019-20) and population-based HIV impact assessment surveys (2016-18) to estimate the number of adults with CD4 counts of less than 200 cells/µL at risk for cryptococcosis, by country and region. Secondly, we summarised cryptococcal antigenaemia prevalence in those with a CD4 count of less than 200 cells/µL by reviewing published literature. Thereafter, we calculated the number of cryptococcal antigen (CrAg)-positive people in each country and region by multiplying the number with advanced HIV disease at risk for cryptococcal infection by the cryptococcal antigenaemia prevalence of the respective country or region. We estimated progression from cryptococcal antigenaemia to meningitis or death based on estimates from the published literature. FINDINGS: We estimated that there were 4·3 million (IQR 3·0-4·8) adults with HIV and CD4 counts of less than 200 cells/µL globally in 2020. We calculated a mean global cryptococcal antigenaemia prevalence of 4·4% (95% CI 1·6-7·4) among HIV-positive people with CD4 counts of less than 200 cells/µL, corresponding to 179 000 cases (IQR 133 000-219 000) of cryptococcal antigenaemia globally in 2020. Annually, we estimated that there are 152 000 cases (111 000-185 000) of cryptococcal meningitis, resulting in 112 000 cryptococcal-related deaths (79 000-134 000). Globally, cryptococcal disease accounts for 19% (13-24) of AIDS-related mortality. INTERPRETATION: Despite a reduction in the estimated absolute global burden of HIV-associated cryptococcal meningitis compared with 2014, likely to be due to antiretroviral therapy expansion, cryptococcal disease still accounts for 19% of AIDS-related deaths, similar to 2014 estimates. To end cryptococcal meningitis deaths by 2030, cryptococcal diagnostics, meningitis treatments, and implementation of preventive screening are urgently needed. FUNDING: None.

Outcomes of flucytosine-containing combination treatment for cryptococcal meningitis in a South African national access programme: a cross-sectional observational study.

BACKGROUND: Although flucytosine is a key component of WHO-recommended induction treatment for HIV-associated cryptococcal meningitis, this antifungal agent is not widely available in low-income and middle-income countries due to limited production and cost. In 2018, a national flucytosine access programme was initiated in South Africa. We aimed to determine the effectiveness of flucytosine-containing induction regimens in routine care to motivate for the urgent registration of flucytosine and its inclusion in treatment guidelines. METHODS: In this cross-sectional study, we compared outcomes of adults aged 18 years and older with incident laboratory-confirmed cryptococcal meningitis treated with or without flucytosine-containing regimens at 19 sentinel hospitals in South Africa. A case of cryptococcosis was defined as illness in an adult with: (1) positive cerebrospinal fluid (CSF) India ink microscopy; (2) a positive CSF cryptococcal antigen test; or (3) culture of Cryptococcus neoformans or Cryptococcus gattii from CSF or any other specimen. We excluded patients without a case report form, those with an unknown or negative HIV serology result, those with a recurrent episode, and those who did not receive antifungal treatment in hospital. We assessed cumulative in-hospital mortality at 14 days and 30 days and calculated the overall crude in-hospital case-fatality ratio. We used random-effects logistic regression to examine the association between treatment group and in-hospital mortality. FINDINGS: From July 1, 2018, to March 31, 2020, 10 668 individuals were diagnosed with laboratory-confirmed cryptococcal meningitis, 7787 cases diagnosed at non-enhanced surveillance sites and 567 cases from eight enhanced surveillance sites with no access to flucytosine were excluded. Of 2314 adults with a first episode of cryptococcosis diagnosed at 19 facilities with access to flucytosine, 1996 had a case report form and of these, 1539 received induction antifungal treatment and were confirmed HIV-seropositive first-episode cases. Of 1539 patients who received antifungal therapy, 596 (38·7%) individuals received a flucytosine-containing regimen and 943 (61·3%) received another regimen. The median age was 36 years (IQR 32-43) and 906 (58·9%) participants were male and 633 (41·1%) were female. The crude in-hospital case-fatality ratio was 23·9% (95% CI 20·0-27·0; 143 of 596) in those treated with flucytosine-containing regimens and 37·2% (95% CI 34·0-40·0; 351 of 943) in those treated with other regimens. Patients admitted to non-academic hospitals (adjusted odds ratio [aOR] 1·95 [95% CI 1·53-2·48]; p<0·0001) and those who were antiretroviral treatment-experienced (aOR 1·30 [1·02-1·67]; p=0·033) were more likely to receive flucytosine. After adjusting for relevant confounders, flucytosine treatment was associated with a 53% reduction in mortality (aOR 0·47 [95% CI 0·35-0·64]; p<0·0001). Among survivors, the median length of hospital admission in the flucytosine group was 11 days (IQR 8-15) versus 17 days (13-21) in the comparison group (p=0·0010). INTERPRETATION: In-hospital mortality among patients treated with a flucytosine-containing regimen was comparable to reduced mortality reported in patients receiving a flucytosine-containing regimen in a recent multicentre African clinical trial. Flucytosine-based treatment can be delivered in routine care in a middle-income country with a substantial survival benefit. FUNDING: National Institute for Communicable Diseases, a Division of the National Health Laboratory Service. TRANSLATION: For the Zulu translation of the abstract see Supplementary Materials section.

Induction-phase treatment costs for cryptococcal meningitis in high HIV-burden African countries: New opportunities with lower costs.

Introduction: Access to and the cost of induction treatment for cryptococcal meningitis (CM) is rapidly changing. The newly-announced price for flucytosine ($0.75 per 500 mg pill) and possibly lower prices for liposomal amphotericin B (AmB-L) create opportunities to reduce CM treatment costs compared to the current standard treatment in low- and middle-income countries. Methods: We developed an Excel-based cost model to estimate health system treatment costs for CM over a two-week induction phase for multiple treatment combinations, newly feasible with improved access to flucytosine and AmB-L. CM treatment costs include medications, laboratory tests and other hospital-based costs (bed-day costs and healthcare worker time). We report results from applying the model using country-specific information for South Africa, Uganda, Nigeria, and Botswana. Results: A 14-day induction-phase of seven days of inpatient AmB-D with flucytosine, followed by seven days of high-dose fluconazole as an outpatient, will cost health systems less than a 14-day hospital stay with AmB-D and fluconazole. If daily AmB-L replaces AmB-D for those with baseline renal dysfunction, with a cost of $50 or less per 50 mg vial, incremental costs would still be less than the AmB-D with fluconazole regimen. Simple oral combinations (e.g., seven days of flucytosine with fluconazole as an inpatient) are practical when AmB-D is not available, and treatment costs would remain less than the current standard treatment. Conclusions: Improved access to and lower prices for flucytosine and AmB-L create opportunities for improving CM treatment regimens. An induction regimen of flucytosine and AmB-D for seven days is less costly than standard care in the settings studied here. As this regimen has also been shown to be more effective than current standard care, countries should prioritize scaling up flucytosine access. The cost of AmB-L based regimens is highly dependent on the price of AmB-L, which currently remains unclear.

Establishing targets for advanced HIV disease: A call to action.

The World Health Organization (WHO) has published a guideline for the management of individuals with advanced HIV disease (AHD) to reduce HIV-related deaths. The guideline consists of a package of recommendations including interventions to prevent, diagnose and treat common opportunistic infections, including tuberculosis (TB), cryptococcosis and severe bacterial infections, along with rapid initiation of antiretroviral treatment and enhanced adherence support. Currently no clear targets exist for these key interventions. Emerging programmatic data from Uganda, Tanzania and Nigeria suggest that an estimated 80% of eligible people continue to miss the recommended cryptococcal or TB testing, highlighting the remaining challenges to the effective implementation of WHO-recommended AHD packages of care in real-world resource-limited settings. The absence of mortality indicators for the leading causes of HIV-related deaths, because of the lack of mechanisms to ascertain cause of death, has had a negative impact on establishing interventions to reduce mortality. We suggest that setting 95-95-95 targets for CD4 testing, cryptococcal antigen and TB testing, and treatment that are aligned to the WHO AHD package of care would be a step in the right direction to achieving the greater goal of the WHO End TB strategy and the proposed new strategy to end cryptococcal meningitis deaths. However, these targets will only be achieved if there is healthcare worker training, expanded access to bedside point-of-care diagnostics for hospitalised patients and those in outpatient care who meet the criteria for AHD, and health systems strengthening to minimise delays in initiating the WHO-recommended therapies for TB and cryptococcal disease.

National cardiovascular prevention should be based on absolute disease risks, not levels of risk factors.

BACKGROUND: It has been shown that the prevention of multicausal diseases such as heart attack (at an individual level) should be guided by absolute risks rather than by the level of risk factors. Here, we show that an analogous argument should form the basis of population-level prevention. METHODS: Estimates of age- and sex-specific means and standard deviations for systolic blood pressures and blood cholesterol concentrations and for deaths assigned to all vascular causes in 2002 were obtained from the World Health Organization for 25 current member states of the European Union, for the ages 30-69 years. Predicted effects of 5 mmHg reductions in mean systolic blood pressures and 0.5 mmol l(-1) reductions in mean total blood cholesterol concentrations on deaths and years of life lost (YLL) per 100,000 person-years from vascular diseases were modelled using proportional risk coefficients from meta-analyses of cohort studies and randomized controlled trials. RESULTS: Potential absolute benefits were strongly positively associated with current levels of absolute mortality risk: in the case of systolic blood pressure, predicted vascular deaths averted in the highest risk populations (Romania, Bulgaria) were over five times higher than in the lowest risk populations (Spain, France). Potential benefits were only weakly related to existing levels of the risk factor of interest. CONCLUSIONS: High-risk populations should give the highest priority to achieving favourable shifts in all modifiable risk factors. Irrespective of the level of any particular risk factor, the rewards will be greatest in these populations.

Time to embrace access programmes for medicines: lessons from the South African flucytosine access programme.

BACKGROUND: Cryptococcal meningitis (CM) is estimated to cause 181 000 deaths annually, with the majority occurring in Sub-Saharan Africa. Flucytosine is recommended by the World Health Organization as part of the treatment for CM. Widespread use of flucytosine could reduce mortality in hospital by as much as 40% compared to the standard of care, yet due to market failure, quality-assured flucytosine remains unregistered and largely inaccessible throughout Africa. METHODS: The recently established South African flucytosine clinical access programme is an attempt to address the market failure that led to a lack of public sector access to flucytosine for CM, by making the medicine freely available to tertiary hospitals in South Africa. RESULTS: Between November 2018 and September 2019, 327 CM patients received flucytosine through this programme, with efforts to support sustainable national scale-up presently ongoing. We describe why this programme was needed, its catalytic potential, what is still required to ensure widespread access to flucytosine, and observations from this experience that may have wider relevance. CONCLUSIONS: The South African flucytosine access programme illustrates how access programmes may be one part of the solution to addressing the vicious cycle of perceived low demand, limiting manufacturer interest in specific product markets.

The Continuing Value of CD4 Cell Count Monitoring for Differential HIV Care and Surveillance.

The move toward universal provision of antiretroviral therapy and the expansion of HIV viral load monitoring call into question the ongoing value of CD4 cell count testing and monitoring. We highlight the role CD4 monitoring continues to have in guiding clinical decisions and measuring and evaluating the epidemiology of HIV. To end the HIV/AIDS epidemic, we require strategic information, which includes CD4 cell counts, to make informed clinical decisions and effectively monitor key surveillance indicators.

Simplifying switch to second-line antiretroviral therapy in sub Saharan Africa: predicted effect of using a single viral load to define efavirenz-based first-line failure.

BACKGROUND: Many individuals failing first-line antiretroviral therapy (ART) in sub-Saharan Africa never initiate second-line ART or do so after significant delay. For people on ART with a viral load more than 1000 copies/ml, the WHO recommends a second viral load measurement 3 months after the first viral load and enhanced adherence support. Switch to a second-line regimen is contingent upon a persistently elevated viral load more than 1000 copies/ml. Delayed second-line switch places patients at increased risk for opportunistic infections and mortality. METHODS: To assess the potential benefits of a simplified second-line ART switch strategy, we use an individual-based model of HIV transmission, progression and the effect of ART which incorporates consideration of adherence and drug resistance, to compare predicted outcomes of two policies, defining first-line regimen failure for patients on efavirenz-based ART as either two consecutive viral load values more than 1000 copies/ml, with the second after an enhanced adherence intervention (implemented as per current WHO guidelines) or a single viral load value more than 1000 copies/ml. We simulated a range of setting-scenarios reflecting the breadth of the sub-Saharan African HIV epidemic, taking into account potential delays in defining failure and switch to second-line ART. FINDINGS: The use of a single viral load more than 1000 copies/ml to define ART failure would lead to a higher proportion of persons with nonnucleoside reverse-transcriptase inhibitor resistance switched to second-line ART [65 vs. 48%; difference 17% (90% range 14-20%)], resulting in a median 18% reduction in the rate of AIDS-related death over setting scenarios (90% range 6-30%; from a median of 3.1 to 2.5 per 100 person-years) over 3 years. The simplified strategy also is predicted to reduce the rate of AIDS conditions by a median of 31% (90% range 8-49%) among people on first-line ART with a viral load more than 1000 copies/ml in the past 6 months. For a country of 10 million adults (and a median of 880 000 people with HIV), we estimate that this approach would lead to a median of 1322 (90% range 67-3513) AIDS deaths averted per year over 3 years. For South Africa this would represent around 10 215 deaths averted annually. INTERPRETATION: As a step towards reducing unnecessary mortality associated with delayed second-line ART switch, defining failure of first-line efavirenz-based regimens as a single viral load more than 1000 copies/ml should be considered.

The epidemiology of rape and sexual violence in the platinum mining district of Rustenburg, South Africa: Prevalence, and factors associated with sexual violence.

BACKGROUND: Estimates for the prevalence of rape and other forms of sexual violence (SV) vary in South Africa. This survey aimed to provide clarity by quantifying the prevalence of SV (forced sex or sexual acts) by 1) sexual partners, and 2) non-partners, and to describe factors associated with these outcomes among women (18-49 years) living in Rustenburg Municipality. MATERIALS AND METHODS: We conducted a cluster-randomized household survey (November-December 2015). Women were asked about their experiences of SV, associated attitudes and behaviours, and access to services. Logistic regression was used to determine factors associated with partner and non-partner SV. RESULTS: Of eligible households, 83·1% (1700/2044) participated. Of 966 women invited, 836 participated (86·5%). Average age of participants was 31.6 years (95%CI: 30·9, 32·4) with 45% having completed at least secondary school, and 60% unemployed or looking for work. Lifetime prevalence of SV was 24.9% (95%CI: 21·7-28·5), reaching 9.0% (95% CI: 6·6-12·1) by age 15. Almost one third told no one of their SV experiences. Factors related to financial dependence were associated with SV by a partner. History of termination of pregnancy increased the likelihood of SV by a non-partner as an adult. Women who experienced SV in childhood or as an adult were more likely to experience SV from a different type of perpetrator than those who did not. CONCLUSIONS: We found a high prevalence of SV, including during childhood, in this setting, with limited access to care. This and the high morbidity attributed to SV calls for increased service provision.

Investigating the addition of oral HIV self-tests among populations with high testing coverage - Do they add value? Lessons from a study in Khayelitsha, South Africa.

INTRODUCTION: HIV self-testing (HIVST) offers a useful addition to HIV testing services and enables individuals to test privately. Despite recommendations to the contrary, repeat HIV testing is frequent among people already on anti-retroviral treatment (ART) and there are concerns that oral self-testing might lead to false negative results. A study was conducted in Khayelitsha, South Africa, to assess feasibility and uptake of HIVST and linkage-to-care following HIVST. METHODS: Participants were recruited at two health facilities from 1 March 2016 to 31 March 2017. People under 18 years, or with self-reported previously-diagnosed HIV infection, were excluded. Participants received an OraQuick Rapid HIV-1/2 Antibody kit, and reported their HIVST results by pre-paid text message (SMS) or by returning to the facility. Those not reporting within 7 days were contacted by phone. Electronic and paper-based clinical and laboratory records were retrospectively examined for all participants to identify known HIV outcomes, after matching for name, date of birth, and sex. These findings were compared with self-reported HIVST results where available. RESULTS: Of 639 participants, 401 (62.8%) self-reported a negative HIVST result, 27 (4.2%) a positive result, and 211 (33.0%) did not report. The record search identified that of the 401 participants self-reporting a negative HIVST result, 19 (4.7%) were already known to be HIV positive; of the 27 self-reporting positive, 12 (44%) were known HIV positive. Overall, records showed 57/639 (8.9%) were HIV positive of whom 39/57 (68.4%) had previously-diagnosed infection and 18/57 (31.6%) newly-diagnosed infection. Of the 428 participants who self-reported a result, 366 (85.5%) reported by SMS. CONCLUSIONS: HIVST can improve HIV testing uptake and linkage to care. SMS is acceptable for reporting HIVST results but negative self-reports by participants may be unreliable. Use of HIVST by individuals on ART is frequent despite recommendations to the contrary and its implications need further consideration.

Stock-outs of antiretroviral and tuberculosis medicines in South Africa: A national cross-sectional survey.

BACKGROUND: HIV and TB programs have rapidly scaled-up over the past decade in Sub-Saharan Africa and uninterrupted supplies of those medicines are critical to their success. However, estimates of stock-outs are largely unknown. This survey aimed to estimate the extent of stock-outs of antiretroviral and TB medicines in public health facilities across South Africa, which has the world's largest antiretroviral treatment (ART) program and a rising multidrug-resistant TB epidemic. METHODS: We conducted a cross-sectional telephonic survey (October-December 2015) of public health facilities. Facilities were asked about the prevalence of stock-outs on the day of the survey and in the preceding three months, their duration and impact. RESULTS: Nationwide, of 3547 eligible health facilities, 79% (2804) could be reached telephonically. 88% (2463) participated and 4% (93) were excluded as they did not provide ART or TB treatment. Of the 2370 included facilities, 20% (485) reported a stock-out of at least 1 ARV and/or TB-related medicine on the day of contact and 36% (864) during the three months prior to contact, ranging from 74% (163/220) of health facilities in Mpumalanga to 12% (32/261) in the Western Cape province. These 864 facilities reported 1475 individual stock-outs, with one to fourteen different medicines out of stock per facility. Information on impact was provided in 98% (1449/1475) of stock-outs: 25% (366) resulted in a high impact outcome, where patients left the facility without medicine or were provided with an incomplete regimen. Of the 757 stock-outs that were resolved 70% (527) lasted longer than one month. INTERPRETATION: There was a high prevalence of stock-outs nationwide. Large interprovincial differences in stock-out occurrence, duration, and impact suggest differences in provincial ability to prevent, mitigate and cope within the same framework. End-user monitoring of the supply chain by patients and civil society has the potential to increase transparency and complement public sector monitoring systems.

Leave no one behind: response to new evidence and guidelines for the management of cryptococcal meningitis in low-income and middle-income countries.

In 2018, WHO issued guidelines for the diagnosis, prevention, and management of HIV-related cryptococcal disease. Two strategies are recommended to reduce the high mortality associated with HIV-related cryptococcal meningitis in low-income and middle-income countries (LMICs): optimised combination therapies for confirmed meningitis cases and cryptococcal antigen screening programmes for ambulatory people living with HIV who access care. WHO's preferred therapy for the treatment of HIV-related cryptococcal meningitis in LMICs is 1 week of amphotericin B plus flucytosine, and the alternative therapy is 2 weeks of fluconazole plus flucytosine. In the ACTA trial, 1-week (short course) amphotericin B plus flucytosine resulted in a 10-week mortality of 24% (95% CI -16 to 32) and 2 weeks of fluconazole and flucytosine resulted in a 10-week mortality of 35% (95% CI -29 to 41). However, with widely used fluconazole monotherapy, mortality because of HIV-related cryptococcal meningitis is approximately 70% in many African LMIC settings. Therefore, the potential to transform the management of HIV-related cryptococcal meningitis in resource-limited settings is substantial. Sustainable access to essential medicines, including flucytosine and amphotericin B, in LMICs is paramount and the focus of this Personal View.