Pretreatment drug resistance in people initiating or re-initiating antiretroviral therapy (ART) containing non-nucleoside reverse transcriptase inhibitors (NNRTIs) might compromise HIV control in ...low-income and middle-income countries (LMICs). We aimed to assess the scale of this problem and whether it is associated with the intiation or re-initiation of ART in people who have had previous exposure to antiretroviral drugs.
This study was a systematic review and meta-regression analysis. We assessed regional prevalence of pretreatment drug resistance and risk of pretreatment drug resistance in people initiating ART who reported previous ART exposure. We systematically screened publications and unpublished datasets for pretreatment drug-resistance data in individuals in LMICs initiating or re-initiating first-line ART from LMICs. We searched for studies in PubMed and Embase and conference abstracts and presentations from the Conference on Retroviruses and Opportunistic Infections, the International AIDS Society Conference, and the International Drug Resistance Workshop for the period Jan 1, 2001, to Dec 31, 2016. To assess the prevalence of drug resistance within a specified region at any specific timepoint, we extracted study level data and pooled prevalence estimates within the region using an empty logistic regression model with a random effect at the study level. We used random effects meta-regression to relate sampling year to prevalence of pretreatment drug resistance within geographical regions.
We identified 358 datasets that contributed data to our analyses, representing 56 044 adults in 63 countries. Prevalence estimates of pretreatment NNRTI resistance in 2016 were 11·0% (7·5–15·9) in southern Africa, 10·1% (5·1–19·4) in eastern Africa, 7·2% (2·9–16·5) in western and central Africa, and 9·4% (6·6–13·2) in Latin America and the Caribbean. There were substantial increases in pretreatment NNRTI resistance per year in all regions. The yearly increases in the odds of pretreatment drug resistance were 23% (95% CI 16–29) in southern Africa, 17% (5–30) in eastern Africa, 17% (6–29) in western and central Africa, 11% (5–18) in Latin America and the Caribbean, and 11% (2–20) in Asia. Estimated increases in the absolute prevalence of pretreatment drug resistance between 2015 and 2016 ranged from 0·3% in Asia to 1·8% in southern Africa.
Pretreatment drug resistance is increasing at substantial rate in LMICs, especially in sub-Saharan Africa. In 2016, the prevalence of pretreatment NNRTI resistance was near WHO's 10% threshold for changing first-line ART in southern and eastern Africa and Latin America, underscoring the need for routine national HIV drug-resistance surveillance and review of national policies for first-line ART regimen composition.
Bill & Melinda Gates Foundation and World Health Organization.
According to the authors, only 11 low- and middle-income countries report this information, often based on small sample sizes, which may introduce bias and limit the generalizability of their ...findings. WHO’s Global Antimicrobial Resistance and Use Surveillance System (GLASS) currently recommends 11 antibiotic classes, eight bacteria (Acinetobacter spp., E. coli, K. pneumoniae, Salmonella spp., S. aureus, Streptococcus pneumoniae, Shigella spp., and N. gonorrhoeae) and blood, urine, feces, and urethral and cervical swabs as priority specimen types for routine AMR surveillance and reporting to WHO 4. To address this issue, and to accelerate the availability of representative data that can provide reliable global and national estimates of AMR over time, WHO proposes a two-pronged approach: (1) generating nationally representative data through strengthening and standardizing routine passive surveillance of AMR in clinical samples from patients with suspected infections and (2) actively conducting periodic nationally representative surveys to measure the prevalence and trends of AMR 5. ...mathematical modelling can accelerate the availability of evidence on a global scale, but its value is contingent upon the quality and representativeness of the data used and the validation of its estimates.
In 2006, WHO set forth its vision for a public health approach to delivering antiretroviral therapy. This approach has been broadly adopted in resource-poor settings and has provided the foundation ...for scaling up treatment to over 19·5 million people. There is a global commitment to end the AIDS epidemic as a public health threat by 2030 and, to support this goal, there are opportunities to adapt the public health approach to meet the ensuing challenges. These challenges include the need to improve identification of people with HIV infection through expanded approaches to testing; further simplify and improve treatment and laboratory monitoring; adapt the public health approach to concentrated epidemics; and link HIV testing, treatment, and care to HIV prevention. Implementation of these key public health principles will bring countries closer to the goals of controlling the HIV epidemic and providing universal health coverage.
Summary Background The emergence and spread of high levels of HIV-1 drug resistance in resource-limited settings where combination antiretroviral treatment has been scaled up could compromise the ...effectiveness of national HIV treatment programmes. We aimed to estimate changes in the prevalence of HIV-1 drug resistance in treatment-naive individuals with HIV since initiation of rollout in resource-limited settings. Methods We did a systematic search for studies and conference abstracts published between January, 2001, and July, 2011, and included additional data from the WHO HIV drug resistance surveillance programme. We assessed the prevalence of drug-resistance mutations in untreated individuals with respect to time since rollout in a series of random-effects meta-regression models. Findings Study-level data were available for 26 102 patients from sub-Saharan Africa, Asia, and Latin America. We recorded no difference between chronic and recent infection on the prevalence of one or more drug-resistance mutations for any region. East Africa had the highest estimated rate of increase at 29% per year (95% CI 15 to 45; p=0·0001) since rollout, with an estimated prevalence of HIV-1 drug resistance at 8 years after rollout of 7·4% (4·3 to 12·7). We recorded an annual increase of 14% (0% to 29%; p=0·054) in southern Africa and a non-significant increase of 3% (–0·9 to 16; p=0·618) in west and central Africa. There was no change in resistance over time in Latin America, and because of much country-level heterogeneity the meta-regression analysis was not appropriate for Asia. With respect to class of antiretroviral, there were substantial increases in resistance to non-nucleoside reverse transcriptase inhibitors (NNRTI) in east Africa (36% per year 21 to 52; p<0·0001) and southern Africa (23% per year 7 to 42; p=0·0049). No increase was noted for the other drug classes in any region. Interpretation Our findings suggest a significant increase in prevalence of drug resistance over time since antiretroviral rollout in regions of sub-Saharan Africa; this rise is driven by NNRTI resistance in studies from east and southern Africa. The findings are of concern and draw attention to the need for enhanced surveillance and drug-resistance prevention efforts by national HIV treatment programmes. Nevertheless, estimated levels, although increasing, are not unexpected in view of the large expansion of antiretroviral treatment coverage seen in low-income and middle-income countries—no changes in antiretroviral treatment guidelines are warranted at the moment. Funding Bill & Melinda Gates Foundation and the European Community's Seventh Framework Programme
To establish estimates of viral suppression in low- and middle-income countries (LMICs) in patients who received antiretroviral therapy (ART) for human immunodeficiency virus (HIV) infection.
Data on ...viral suppression after 12 months of ART in LMICs were collected from articles published in 2003 to 2011 and from abstracts of conferences held between 2009 and 2011. Pooled proportions for on-treatment and intention-to-treat populations were used as summary estimates. Random-effects models were used for heterogeneous groups of studies (I (2) > 75%).
Overall, 49 studies covering 48 cohorts and 30 016 individuals met the inclusion criteria. With thresholds for suppression between 300 and 500 copies of viral ribonucleic acid (RNA) per ml of plasma, 84.3% (95% confidence interval, CI: 80.4-87.9) of the pooled on-treatment population and 70.5% (95% CI: 65.2-75.6) of the intention-to-treat population showed suppression. Use of different viral RNA thresholds changed the proportions showing suppression: to 84% and 76% of the on-treatment population with thresholds set above 300 and at or below 200 RNA copies per ml, respectively, and to 78%, 71% and 63% of the intention-to-treat population at thresholds set at 1000, 300 to 500, and 200 or fewer copies per ml, respectively.
The pooled estimates of viral suppression recorded after 12 months of ART in LMICs provide benchmarks that other ART programmes can use to set realistic goals and perform predictive modelling. Evidence from this review suggests that the current international target - i.e. viral suppression in > 70% of the intention-to-treat population, with a threshold of 1000 copies per ml - should be revised upwards.
Background. The 90-90-90 goal to achieve viral suppression in 90% of all human immunodeficiency virus (HIV)-infected people on antiretroviral treatment (ART) is especially challenging in children. ...Global estimates of viral suppression among children in low- and middle-income countries (LMICs) are lacking. Methods. We searched for randomized controlled trials and observational studies and analyzed viral suppression rates among children started on ART during 3 time periods: early (2000-2005), intermediate (2006-2009), and current (2010 and later), using random effects meta-analysis. Results. Seventy-two studies, reporting on 51 347 children (aged <18 years), were included. After 12 months on first-line ART, viral suppression was achieved by 64.7% (95% confidence interval CI, 57.5-71.8) in the early, 74.2% (95% CI, 70.2-78.2) in the intermediate, and 72.7% (95% 62.6-82.8) in the current time period. Rates were similar after 6 and 24 months of ART. Using an intention-to-treat analysis, 42.7% (95% CI, 33.7-51.7) in the early, 45.7% (95% CI, 33.2-58.3) in the intermediate, and 62.5% (95% CI, 53.3-72.6) in the current period were suppressed. Long-term follow-up data were scarce. Conclusions. Viral suppression rates among children on ART in LMICs were low and considerably poorer than those previously found in adults in LMICs and children in high-income countries. Little progress has been made in improving viral suppression rates over the past years. Without increased efforts to improve pediatric HIV treatment, the 90-90-90 goal for children in LMIC will not be reached.
IntroductionTo accelerate the response to the public health threat by antimicrobial resistance (AMR), the WHO is developing a Global Research Agenda for AMR in the human health sector that aims to ...provide a global and transparent assessment of priority knowledge gaps related to critical bacteria—including Mycobacterium tuberculosis—and fungi that inform control and response strategies to tackle AMR by 2030. A literature scoping review represents the first phase in a stepwise process, and we hereby outline the protocol to review current knowledge gaps and research questions on AMR in the human health sector.Methods and analysisThis literature scoping review will follow the Arksey and O’Malley (2005) methodology and will include: (1) a hand search to identify relevant WHO guidelines and documents suggested by the WHO Steering Group for the AMR Global Research Agenda; (2) a grey literature search through a stakeholder mapping process and google searches of organisational websites; (3) a systematic search of relevant systematic reviews through bibliographic databases (PubMed, Embase and Web of Science); (4) screening of the reference lists of included studies. We will include relevant publications from the last 10 years (January 2012 to December 2021). Two researchers separately will review the yielded citations to determine eligibility based on predefined criteria. Relevant research questions with attributes will be extracted using a tool developed through an iterative process by the research team. Each identified research question will be classified and aggregated according to a conceptual framework (ie, ‘knowledge matrix’), composed of three themes (ie, Prevention, Diagnosis and Care & Treatment) and four cross-cutting domains (ie, Descriptive, Discovery, Development, Delivery). We will present numerical and thematic summaries of the knowledge matrix. A qualitative content analysis is out of the scope of this protocol.Ethics and disseminationThe scoping review process will only involve identification, selection and analysis of documents available for use in the public domain, and will not include any personal information on individuals, therefore ethical approval is not required. The findings will be disseminated through a peer-reviewed publication and stakeholder meetings.
•This review aggregated knowledge gaps in human health across 14 antimicrobial resistance (AMR) areas.•It covered the World Health Organization's (WHO) priority bacteria, Mycobacterium tuberculosis, ...Candida, and Aspergillus spp.•The 2340 identified knowledge gaps were consolidated into 177 research questions.•In total, 78 research questions had specific relevance for low- and middle-income countries.•These findings inform the novel WHO Global AMR Research Agenda for human health.
To identify and summarize existing global knowledge gaps on antimicrobial resistance (AMR) in human health, focusing on the World Health Organization (WHO) bacterial priority pathogens, Mycobacterium tuberculosis, and selected fungi.
We conducted a scoping review of gray and peer-reviewed literature, published in English from January 2012 through December 2021, that reported on the prevention, diagnosis, treatment, and care of drug-resistant infections. We extracted relevant knowledge gaps and, through an iterative process, consolidated those into thematic research questions.
Of 8409 publications screened, 1156 were included, including 225 (19.5%) from low- and middle-income countries. A total of 2340 knowledge gaps were extracted, in the following areas: antimicrobial research and development, AMR burden and drivers, resistant tuberculosis, antimicrobial stewardship, diagnostics, infection prevention and control, antimicrobial consumption and use data, immunization, sexually transmitted infections, AMR awareness and education, policies and regulations, fungi, water sanitation and hygiene, and foodborne diseases. The knowledge gaps were consolidated into 177 research questions, including 78 (44.1%) specifically relevant to low- and middle-income countries and 65 (36.7%) targeting vulnerable populations.
This scoping review presents the most comprehensive compilation of AMR-related knowledge gaps to date, informing a priority-setting exercise to develop the WHO Global AMR Research Agenda for the human health sector.
To describe the monthly distribution of COVID-19 hospitalisations, deaths and case-fatality rates (CFR) in Lombardy (Italy) throughout 2020.
We analysed de-identified hospitalisation data comprising ...all COVID-19-related admissions from 1 February 2020 to 31 December 2020. The overall survival (OS) from time of first hospitalisation was estimated using the Kaplan-Meier method. We estimated monthly CFRs and performed Cox regression models to measure the effects of potential predictors on OS.
Hospitalisation and death peaks occurred in March and November 2020. Patients aged ≥70 years had an up to 180 times higher risk of dying compared to younger patients 70-80: HR 58.10 (39.14-86.22); 80-90: 106.68 (71.01-160.27); ≥90: 180.96 (118.80-275.64). Risk of death was higher in patients with one or more comorbidities 1: HR 1.27 (95% CI 1.20-1.35); 2: 1.44 (1.33-1.55); ≥3: 1.73 (1.58-1.90) and in those with specific conditions (hypertension, diabetes).
Our data sheds light on the Italian pandemic scenario, uncovering mechanisms and gaps at regional health system level and, on a larger scale, adding to the body of knowledge needed to inform effective health service planning, delivery, and preparedness in times of crisis.
The increasing prevalence of acquired and transmitted HIV-1 drug resistance is an obstacle to successful antiretroviral therapy (ART) in the low- and middle-income countries (LMICs) hardest hit by ...the HIV-1 pandemic. Genotypic drug resistance testing could facilitate the choice of initial ART in areas with rising transmitted drug resistance (TDR) and enable care-providers to determine which individuals with virological failure (VF) on a first- or second-line ART regimen require a change in treatment. An inexpensive near point-of-care (POC) genotypic resistance test would be useful in settings where the resources, capacity, and infrastructure to perform standard genotypic drug resistance testing are limited. Such a test would be particularly useful in conjunction with the POC HIV-1 viral load tests that are currently being introduced in LMICs. A POC genotypic resistance test is likely to involve the use of allele-specific point mutation assays for detecting drug-resistance mutations (DRMs). This study proposes that two major nucleoside reverse transcriptase inhibitor (NRTI)-associated DRMs (M184V and K65R) and four major NNRTI-associated DRMs (K103N, Y181C, G190A, and V106M) would be the most useful for POC genotypic resistance testing in LMIC settings. One or more of these six DRMs was present in 61.2% of analyzed virus sequences from ART-naïve individuals with intermediate or high-level TDR and 98.8% of analyzed virus sequences from individuals on a first-line NRTI/NNRTI-containing regimen with intermediate or high-level acquired drug resistance. The detection of one or more of these DRMs in an ART-naïve individual or in a individual with VF on a first-line NRTI/NNRTI-containing regimen may be considered an indication for a protease inhibitor (PI)-containing regimen or closer virological monitoring based on cost-effectiveness or country policy.
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