Summary Background In 1975–99, only 1·1% of new therapeutic products had been developed for neglected diseases. Since then, several public and private initiatives have attempted to mitigate this ...imbalance. We analysed the research and development pipeline of drugs and vaccines for neglected diseases from 2000 to 2011. Methods We searched databases of drug regulatory authorities, WHO, and clinical trial registries for entries made between Jan 1, 2000, and Dec 31, 2011. We defined neglected diseases as malaria, tuberculosis, diarrhoeal diseases, neglected tropical diseases (NTDs; WHO definition), and other diseases of poverty according to common definitions. Findings Of the 850 new therapeutic products registered in 2000–11, 37 (4%) were indicated for neglected diseases, comprising 25 products with a new indication or formulation and eight vaccines or biological products. Only four new chemical entities were approved for neglected diseases (three for malaria, one for diarrhoeal disease), accounting for 1% of the 336 new chemical entities approved during the study period. Of 148 445 clinical trials registered in Dec 31, 2011, only 2016 (1%) were for neglected diseases. Interpretation Our findings show a persistent insufficiency in drug and vaccine development for neglected diseases. Nevertheless, these and other data show a slight improvement during the past 12 years in new therapeutics development and registration. However, for many neglected diseases, new therapeutic products urgently need to be developed and delivered to improve control and potentially achieve elimination. Funding None.
Summary Background Rwanda has achieved substantial progress in scaling up of antiretroviral therapy. We aimed to assess the effect of increased access to antiretroviral therapy on life expectancy ...among HIV-positive patients in two distinct periods of lower and higher antiretroviral therapy coverage (1997–2007 and 2008–11). Methods In a retrospective observational cohort study, we collected clinical and demographic data for all HIV-positive patients enrolled in care at 110 health facilities across all five provinces of Rwanda. We included patients aged 15 years or older with a known enrolment date between 1997 and 2014. We constructed abridged life tables from age-specific mortality rates and life expectancy stratified by sex, CD4 cell count, and WHO disease stage at enrolment in care and initiation of antiretroviral therapy. Findings We included 72 061 patients in this study, contributing 213 983 person-years of follow-up. The crude mortality rate was 33·4 deaths per 1000 person-years (95% CI 32·7–34·2). Life expectancy for the overall cohort was 25·6 additional years (95% CI 25·1–26·1) at 20 years of age and 23·3 additional years (95% CI 22·9–23·7) at 35 years of age. Life expectancy at 20 years of age in the period of 1997–2007 was 20·4 additional years (95% CI 19·5–21·3); for the period of 2008–11, life expectancy had increased to 25·6 additional years (95% CI 24·8–26·4). Individuals enrolling in care with CD4 cell counts of 500 cells per μL or more, and with WHO disease stage I, had the highest life expectancies. Interpretation This study adds to the growing body of evidence showing the benefit to HIV-positive patients of early enrolment in care and initiation of antiretroviral therapy. Funding Bill & Melinda Gates Foundation.
Summary For more than two decades, CD4 cell count measurements have been central to understanding HIV disease progression, making important clinical decisions, and monitoring the response to ...antiretroviral therapy (ART). In well resourced settings, the monitoring of patients on ART has been supported by routine virological monitoring. Viral load monitoring was recommended by WHO in 2013 guidelines as the preferred way to monitor people on ART, and efforts are underway to scale up access in resource-limited settings. Recent studies suggest that in situations where viral load is available and patients are virologically suppressed, long-term CD4 monitoring adds little value and stopping CD4 monitoring will have major cost savings. CD4 cell counts will continue to play an important part in initial decisions around ART initiation and clinical management, particularly for patients presenting late to care, and for treatment monitoring where viral load monitoring is restricted. However, in settings where both CD4 cell counts and viral load testing are routinely available, countries should consider reducing the frequency of CD4 cell counts or not doing routine CD4 monitoring for patients who are stable on ART.
Summary Scaling up access to HIV viral load testing for individuals undergoing antiretroviral therapy in low-resource settings is a global health priority, as emphasised by research showing the ...benefits of suppressed viral load for the individual and the whole population. Historically, large-scale diagnostic test implementation has been slow and incomplete because of service delivery and other challenges. Building on lessons from the past, in this Personal View we propose a new framework to accelerate viral load scale-up and ensure equitable access to this essential test. The framework includes the following steps: (1) ensuring adequate financial investment in scaling up this test; (2) achieving pricing agreements and consolidating procurement to lower prices of the test; (3) strengthening functional tiered laboratory networks and systems to expand access to reliable, high-quality testing across countries; (4) strengthening national leadership, with prioritisation of laboratory services; and (5) demand creation and uptake of test results by clinicians, nurses, and patients, which will be vital in ensuring viral load tests are appropriately used to improve the quality of care. The use of dried blood spots to stabilise and ship samples from clinics to laboratories, and the use of point-of-care diagnostic tests, will also be important for ensuring access, especially in settings with reduced laboratory capacity. For countries that have just started to scale up viral load testing, lessons can be learnt from countries such as Botswana, Brazil, South Africa, and Thailand, which have already established viral load programmes. This framework might be useful for guiding the implementation of viral load with the aim of achieving the new global HIV 90-90-90 goals by 2020.
Summary Background An estimated 150 million people worldwide are infected with hepatitis C virus (HCV). HIV co-infection accelerates the progression of HCV and represents a major public health ...challenge. We aimed to determine the epidemiology of HCV and the prevalence of HIV co-infection in sub-Saharan Africa. Methods We searched Medline and Embase (Ovid) from Jan 1, 2002, to Dec 31, 2014, for studies containing data for HCV seroprevalence in different population groups in WHO-defined regions of sub-Saharan Africa. We estimated pooled regional prevalence estimates with a DerSimonian-Laird random-effects model. Data were further stratified by risk factor and HIV status. Findings We included 213 studies from 33 countries in sub-Saharan Africa, comprising 287 separate cohorts with 1 198 167 individuals. The pooled HCV seroprevalence from all cohorts was 2·98% (95% CI 2·86–3·10). The pooled HCV seroprevalence was 2·65% (95% CI 2·53–2·78) across all 185 low-risk cohorts, 3·04% (2·23–3·84) in antenatal clinic groups, 1·99% (1·86–2·12) in blood donors, but 6·9% (6·1–7·5) in other general population cohorts. The pooled seroprevalence of HCV was 11·87% (95% CI 7·05–16·70) across all high-risk groups and 9·95% (6·79–13·11) in patients with liver disease. 101 cohorts included HIV-positive samples tested for HCV (42 648 individuals), with a pooled seroprevalence of 5·73% (95% CI 4·90–6·56). Interpretation We recorded a high seroprevalence of HCV across populations of sub-Saharan Africa, including in HIV-positive adults, with evidence of regional variation in the general population. Monitoring of antenatal HCV prevalence might be a helpful indicator of population trends in HCV infection; however, larger population surveys are needed to monitor these trends. Access to prevention and treatment needs to be improved for both monoinfected and co-infected individuals. Funding None.
High adherence to antiretroviral therapy is crucial to the success of HIV treatment. We evaluated comparative effectiveness of adherence interventions with the aim of informing the WHO's global ...guidance on interventions to increase adherence.
For this systematic review and network meta-analysis, we searched for randomised controlled trials of interventions that aimed to improve adherence to antiretroviral therapy regimens in populations with HIV. We searched Cochrane Central Register of Controlled Trials, Embase, and MEDLINE for reports published up to July 16, 2015, and searched major conference abstracts from Jan 1, 2013, to July 16, 2015. We extracted data from eligible studies for study characteristics, interventions, patients' characteristics at baseline, and outcomes for the study populations of interest. We used network meta-analyses to compare adherence and viral suppression for all study settings (global network) and for studies in low-income and middle-income countries only (LMIC network).
We obtained data from 85 trials with 16 271 participants. Short message service (SMS; text message) interventions were superior to standard of care in improving adherence in both the global network (odds ratio OR 1·48, 95% credible interval CrI 1·00-2·16) and in the LMIC network (1·49, 1·04-2·09). Multiple interventions showed generally superior adherence to single interventions, indicating additive effects. For viral suppression, only cognitive behavioural therapy (1·46, 1·05-2·12) and supporter interventions (1·28, 1·01-1·71) were superior to standard of care in the global network; none of the interventions improved viral response in the LMIC network. For the global network, the time discrepancy (whether the study outcome was measured during or after intervention was withdrawn) was an effect modifier for both adherence to antiretroviral therapy (coefficient estimate -0·43, 95% CrI -0·75 to -0·11) and viral suppression (-0·48; -0·84 to -0·12), suggesting that the effects of interventions wane over time.
Several interventions can improve adherence and viral suppression; generally, their estimated effects were modest and waned over time.
WHO.
New antiretroviral therapy (ART) regimens for HIV could improve clinical outcomes for patients. To inform global guidelines, we aimed to assess the comparative effectiveness of recommended ART ...regimens for HIV in ART-naive patients.
For this systematic review and network meta-analysis, we searched for randomised clinical trials published up to July 5, 2015, comparing recommended antiretroviral regimens in treatment-naive adults and adolescents (aged 12 years or older) with HIV. We extracted data on trial and patient characteristics, and the following primary outcomes: viral suppression, mortality, AIDS defining illnesses, discontinuations, discontinuations due to adverse events, and serious adverse events. We synthesised data using network meta-analyses in a Bayesian framework and included older treatments, such as indinavir, to serve as connecting nodes. We defined network nodes in terms of specific antivirals rather than specific ART regimens. We categorised backbone regimens and adjusted for them through group-specific meta-regression. We used the GRADE framework to interpret the strength of inference.
We identified 5865 citations through database searches and other sources, of which, 126 articles related to 71 unique trials were included in the network analysis, including 34 032 patients randomly assigned to 161 treatment groups. For viral suppression at 48 weeks, compared with efavirenz, the odds ratio (OR) for viral suppression was 1·87 (95% credible interval CrI 1·34-2·64) with dolutegravir and 1·40 (1·02-1·96) with raltegravir; with respect to viral suppression, low-dose efavirenz was similar to all other treatments. Both low-dose efavirenz and integrase strand transfer inhibitors tended to be protective of discontinuations due to adverse events relative to normal-dose efavirenz. The most protective effect relative to efavirenz in network meta-analyses was that of dolutegravir (OR 0·26, 95% CrI 0·14-0·47), followed by low-dose efavirenz (0·39, 0·16-0·92). Owing to insufficient data, we could make no conclusions about serious adverse events. Low event rates also limited the quality of evidence with regard to mortality and AIDS defining illnesses.
The efficacy and safety of ART has substantially improved with the introduction of newer drug classes of antiretrovirals that are now available to patients and HIV care providers. Their improved tolerance could be part of a larger solution to improve retention, which is a challenge, particularly in low-income and middle-income country settings.
The World Health Organization.
Summary Cryptococcal meningitis is the leading cause of adult meningitis in sub-Saharan Africa, and contributes up to 20% of AIDS-related mortality in low-income and middle-income countries every ...year. Antifungal treatment for cryptococcal meningitis relies on three old, off-patent antifungal drugs: amphotericin B deoxycholate, flucytosine, and fluconazole. Widely accepted treatment guidelines recommend amphotericin B and flucytosine as first-line induction treatment for cryptococcal meningitis. However, flucytosine is unavailable in Africa and most of Asia, and safe amphotericin B administration requires patient hospitalisation and careful laboratory monitoring to identify and treat common side-effects. Therefore, fluconazole monotherapy is widely used in low-income and middle-income countries for induction therapy, but treatment is associated with significantly increased rates of mortality. We review the antifungal drugs used to treat cryptococcal meningitis with respect to clinical effectiveness and access issues specific to low-income and middle-income countries. Each drug poses unique access challenges: amphotericin B through cost, toxic effects, and insufficiently coordinated distribution; flucytosine through cost and scarcity of registration; and fluconazole through challenges in maintenance of local stocks—eg, sustainability of donations or insufficient generic supplies. We advocate ten steps that need to be taken to improve access to safe and effective antifungal therapy for cryptococcal meningitis.
Summary Background Most couples affected by HIV/AIDS in sub-Saharan Africa live in discordant relationships. Men are thought to be the index case in most relationships, and most social marketing and ...awareness campaigns are focused on men. We investigated serodiscordance in stable relationships to establish the gender balance of index-case infections. Methods We did a systematic review, random-effects meta-analysis, and meta-regression of published and unpublished studies enrolling discordant couples and assessed the proportion of men and women that were index cases. We repeated the analysis with data from demographic and health surveys (DHS) from the 14 countries that have documented the HIV status of couples. Our primary outcome was the total number of HIV discordant couples, including the proportion of HIV-positive women. Findings We included data from 27 cohorts of 13 061 couples and DHS data from 14 countries of 1145 couples. The proportion of HIV-positive women in stable heterosexual serodiscordant relationships was 47% (95% CI 43–52), which shows that women are as likely as men to be the index partner in a discordant couple. DHS data (46%, 41–51) and our sensitivity analysis (47%, 43–52) showed similar findings. Meta-regression showed that urban versus rural residence (odds ratio 0·31, 95% CI 0·22–0·39), latitude (β coefficient 0·02, 0·023–0·034), gender equality (β coefficient −0·42, −0·56 to −0·27), HIV prevalence (β coefficient −0·037, −0·04 to −0·030), and older age (β coefficient 0·20, 0·08–0·32) were associated with the proportion of female index cases. Interpretation Our study shows the need to focus on both sexes in HIV prevention strategies, such as promotion of condom use and mitigation of risk behaviours. Funding None.
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