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 We systematically screened publications and unpublished datasets for pretreatment drug-resistance data in individuals in LMICs initiating or re-initiating first-line ART from LMICs.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.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
•High global demand for SARS-CoV-2 testing to identify COVID-19 cases.•qRT-PCR recommended diagnostic test but constraints such as cost prevent its use.•Simple, low cost, and easy-to-use rapid ...antigen diagnostic tests urgently required.•STANDARD Q COVID-19 Ag test exhibits less than optimal performance.•Test may be used when molecular testing access is poor but qRT-PCR still required.
There is a high demand for SARS-CoV-2 testing to identify COVID-19 cases. Real-time quantitative PCR (qRT-PCR) is the recommended diagnostic test but a number of constraints prevent its widespread implementation, including cost. The aim of this study was to evaluate a low cost and easy to use rapid antigen test for diagnosing COVID-19 at the point of care.
Nasopharyngeal swabs from suspected COVID-19 cases and low-risk volunteers were tested with the STANDARD Q COVID-19 Ag Test and the results were compared with the qRT-PCR results.
In total, 262 samples were collected, including 90 qRT-PCR positives. The majority of samples were from males (89%) with a mean age of 34 years and only 13 (14%) of the positives were mildly symptomatic. The sensitivity and specificity of the antigen test were 70.0% (95% confidence interval (CI): 60–79) and 92% (95% CI: 87–96), respectively, and the diagnostic accuracy was 84% (95% CI: 79–88). The antigen test was more likely to be positive for samples with qRT-PCR Ct values ≤29, with a sensitivity of 92%.
The STANDARD Q COVID-19 Ag Test performed less than optimally in this evaluation. However, the test may still have an important role to play early in infection when timely access to molecular testing is not available but the results should be confirmed by qRT-PCR.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
With the scale-up of antiretroviral therapy (ART) there is a need to monitor programme performance to maximize ART efficacy and to prevent emergence of HIV drug resistance (HIVDR). In keeping with ...the elements of the World Health Organisation (WHO) guidance we carried out a nationally representative assessment of early warning indicators (EWI) at 304 randomly selected ART service outlets in Uganda.
Retrospective patient data was extracted for the six EWIs for HIVDR including; on-time antiretroviral (ARV) drug pick-up, patient retention on ART at 12 months, ART dispensing practices, ARV drug stock-outs, viral load suppression (VLS) and viral load (VL) testing completion. Point prevalence for each clinic and national aggregate prevalence with 95% confidence intervals (CI) for all clinics were estimated and facility performances were computed and association between EWIs and programmatic factors assessed using Fisher's Exact Test.
Facilities meeting the EWI targets: on-time pill pick-up was 9.5%, more facilities in the north met this target (p = 0.040). Retention on ART at 12 months was 24.1%, facilities in Kampala region (p<0.001) and Specialized ART clinics (p = 0.01) performed better in this indicator. Pharmacy stock-outs was 33.6%, with more facilities in Kampala (p<0.001), specialized ART clinics (p<0.001) and private-for-profit (p<0.001) meeting this target. Dispensing practices was met by 100% of the facilities. VLS was met by 49.2% and 50.8% of facilities met VL completion target with facilities in central region performing better (p<0.001). National prevalence for the EWIs was: on-time pill pick-up 63.3% (CI: 58.9-67.8); retention on ART at 12 months 69.9% (CI: 63.8-76.0); dispensing practices 100.0%; VLS 85.2% (CI: 81.8-88.5) and VL completion, 60.7% (CI: 56.9-64.6).
Dispensing practices in all facilities were in line with the national guidelines however, there still remains a challenge to long-term ART programmatic success in monitoring patient response to treatment, and maintaining patients on ART without interruptions arising due to poor patient adherence and as a consequence of ARV supply interruption. It is therefore of high importance that the national ART program ensures intensified follow-up for patients, ensuring uninterrupted supply of ARV drugs and increasing VL monitoring at treatment centres, in order to improve patient outcomes and avert preventable HIVDR.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
●This study identified the best performing rapid diagnostic kits for the detection of COVID-19 antibodies.●A characterized reference panel of specimens was used to evaluate the serological kits.●For ...IgM/IgG, Autobio, MultiG, and Standard Q had sensitivity and specificity ≥98%.●For IgG, Boson, MultiG, Standard Q, and VivaDiag had sensitivity and specificity ≥98%.●Serological testing will help better understand the epidemiology of the virus.
Serological testing is needed to better understand the epidemiology of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. Rapid diagnostic tests (RDTs) have been developed to detect specific antibodies, IgM and IgG, to the virus. The performance of 25 of these RDTs was evaluated.
A serological reference panel of 50 positive and 100 negative plasma specimens was developed from SARS-CoV-2 PCR and antibody positive patients and pre-pandemic SARS-CoV-2-negative specimens collected in 2016. Test performance of the 25 RDTs was evaluated against this panel.
A total of 10 RDTs had a sensitivity ≥98%, while 13 RDTs had a specificity ≥98% to anti-SARS-CoV-2 IgG antibodies. Four RDTs (Boson, MultiG, Standard Q, and VivaDiag) had both sensitivity and specificity ≥98% to anti-SARS-CoV-2 IgG antibodies. Only three RDTs had a sensitivity ≥98%, while 10 RDTs had a specificity ≥98% to anti-SARS-CoV-2 IgM antibodies. Three RDTs (Autobio, MultiG, and Standard Q) had sensitivity and specificity ≥98% to combined IgG/IgM. The RDTs that performed well also had perfect or almost perfect inter-reader agreement.
This evaluation identified three RDTs with a sensitivity and specificity to IgM/IgG antibodies of ≥98% with the potential for widespread antibody testing in Uganda.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
With the scale-up of antiretroviral therapy (ART), monitoring programme performance is needed to maximize ART efficacy and limit HIV drug resistance (HIVDR).
We implemented a WHO HIVDR prospective ...survey protocol at three treatment centers between 2012 and 2013. Data were abstracted from patient records at ART start (T1) and after 12 months (T2). Genotyping was performed in the HIV pol region at the two time points.
Of the 425 patients enrolled, at T2, 20 (4.7%) had died, 66 (15.5%) were lost to follow-up, 313 (73.6%) were still on first-line, 8 (1.9%) had switched to second-line, 17 (4.0%) had transferred out and 1 (0.2%) had stopped treatment. At T2, 272 out of 321 on first and second line (84.7%) suppressed below 1000 copies/ml and the HIV DR prevention rate was 70.1%, just within the WHO threshold of ≥ 70%. The proportion of participants with potential HIVDR was 20.9%, which is higher than the 18.8% based on pooled analyses from African studies. Of the 35 patients with mutations at T2, 80% had M184V/I, 65.7% Y181C, and 48.6% (54.8% excluding those not on Tenofovir) had K65R mutations. 22.9% had Thymidine Analogue Mutations (TAMs). Factors significantly associated with HIVDR prevention at T2 were: baseline viral load (VL) <100,000 copies/ml Adjusted odds ratio (AOR) 3.13, 95% confidence interval (CI): 1.36-7.19 and facility. Independent baseline predictors for HIVDR mutations at T2 were: CD4 count < 250 cells/μl (AOR 2.80, 95% CI: 1.08-7.29) and viral load ≥ 100,000 copies/ml (AOR 2.48, 95% CI: 1.00-6.14).
Strengthening defaulter tracing, intensified follow-up for patients with low CD4 counts and/or high VL at ART initiation together with early treatment initiation above 250 CD4 cells/ul and adequate patient counselling would improve ART efficacy and HIVDR prevention. The high rate of K65R and TAMs could compromise second line regimens including NRTIs.
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The World Health Organization recommends that countries conduct two phase evaluations of HIV rapid tests (RTs) in order to come up with the best algorithms. In this report, we present the first ever ...such evaluation in Uganda, involving both blood and oral based RTs. The role of weak positive (WP) bands on the accuracy of the individual RT and on the algorithms was also investigated.
In total 11 blood based and 3 oral transudate kits were evaluated. All together 2746 participants from seven sites, covering the four different regions of Uganda participated. Two enzyme immunoassays (EIAs) run in parallel were used as the gold standard. The performance and cost of the different algorithms was calculated, with a pre-determined price cut-off of either cheaper or within 20% price of the current algorithm of Determine + Statpak + Unigold. In the second phase, the three best algorithms selected in phase I were used at the point of care for purposes of quality control using finger stick whole blood.
We identified three algorithms; Determine + SD Bioline + Statpak; Determine + Statpak + SD Bioline, both with the same sensitivity and specificity of 99.2% and 99.1% respectively and Determine + Statpak + Insti, with sensitivity and specificity of 99.1% and 99% respectively as having performed better and met the cost requirements. There were 15 other algorithms that performed better than the current one but rated more than the 20% price. None of the 3 oral mucosal transudate kits were suitable for inclusion in an algorithm because of their low sensitivities. Band intensity affected the performance of individual RTs but not the final algorithms.
We have come up with three algorithms we recommend for public or Government procurement based on accuracy and cost. In case one algorithm is preferred, we recommend to replace Unigold, the current tie breaker with SD Bioline. We further recommend that all the 18 algorithms that have shown better performance than the current one are made available to the private sector where cost may not be a limiting factor.
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Some HIV infected individuals remain asymptomatic for protracted periods of time in the absence of antiretroviral therapy (ART). Virological control, CD4 T cell loss and HIV-specific responses are ...some of the key interrelated determinants of HIV-1 disease progression. In this study, possible interactions between viral load, CD4 T cell slopes, host genetics and HIV-specific IFN-gamma responses were evaluated in chronically HIV-1-infected adults.
Multilevel regression modeling was used to stratify clade A or D HIV-infected individuals into disease progression groups based on CD4 T cell slopes. ELISpot assays were used to quantify the frequency and magnitude of HIV-induced IFN-gamma responses in 7 defined rapid progressors (RPs) and 14 defined slow progressors (SPs) at a single time point. HLA typing was performed using reference strand conformational analysis (RSCA). Although neither the breadth nor the magnitude of the proteome-wide HIV-specific IFN-gamma response correlated with viral load, slow disease progression was associated with over-representation of host immunogenetic protective HLA B* alleles (10 of 14 SPs compared to 0 of 7; p = 0.004, Fisher's Exact) especially B*57 and B*5801, multiclade Gag T-cell targeting (71%, 10 of 14 SPs compared to 14%, 1 of 7 RPs); p = 0.029, Fisher's Exact test and evident virological control (3.65 compared to 5.46 log10 copies/mL in SPs and RPs respectively); p<0.001, unpaired student's t-test
These data are consistent with others that associated protection from HIV disease with inherent host HLA B allele-mediated ability to induce broader Gag T-cell targeting coupled with apparent virological control. These immunogenetic features of Gag-specific immune response which could influence disease progression may provide useful insight in future HIV vaccine design.
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The CHAVI002 study was designed to characterize immune responses, particularly HIV-specific T-cell responses, amongst 2 cohorts of HIV-exposed seronegative (HESN) individuals. The absence of a clear ...definition of HESNs has impaired comparison of research within and between such cohorts. This report describes two distinct HESN cohorts and attempts to quantify HIV exposure using a 'HIV risk index' (RI) model.
HIV serodiscordant couples (UK; 24, Uganda; 72) and HIV unexposed seronegative (HUSN) controls (UK; 14, Uganda; 26 couples, 3 individuals) completed sexual behavior questionnaires every 3 months over a 9 month period. The two cohorts were heterogeneous, with most HESNs in the UK men who have sex with men (MSM), while all HESNs in Uganda were in heterosexual relationships. Concordance of responses between partners was determined. Each participant's sexual behavior score (SBS) was estimated based on the number and type of unprotected sex acts carried out in defined time periods. Independent HIV acquisition risk factors (partner plasma viral load, STIs, male circumcision, pregnancy) were integrated with the SBS, generating a RI for each HESN.
96 HIV serodiscordant couples completed 929 SBQs. SBSs remained relatively stable amongst the UK cohort, whilst decreasing from Visit 1 to 2 in the Ugandan cohort. Compared to the Ugandan cohort, SBSs and RIs in the UK cohort were lower at visit 1, and generally higher at later visits. Differences between the cohorts, with lower rates of ART use in Uganda and higher risk per-act sex in the UK, had major impacts on the SBSs and RIs of each cohort. There was one HIV transmission event in the UK cohort.
Employment of a risk quantification model facilitated quantification and comparison of HIV acquisition risk across two disparate HIV serodiscordant couple cohorts.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Summary Background Antiretroviral therapy (ART) is crucial for controlling HIV-1 infection through wide-scale treatment as prevention and pre-exposure prophylaxis (PrEP). Potent tenofovir disoproxil ...fumarate-containing regimens are increasingly used to treat and prevent HIV, although few data exist for frequency and risk factors of acquired drug resistance in regions hardest hit by the HIV pandemic. We aimed to do a global assessment of drug resistance after virological failure with first-line tenofovir-containing ART. Methods The TenoRes collaboration comprises adult HIV treatment cohorts and clinical trials of HIV drug resistance testing in Europe, Latin and North America, sub-Saharan Africa, and Asia. We extracted and harmonised data for patients undergoing genotypic resistance testing after virological failure with a first-line regimen containing tenofovir plus a cytosine analogue (lamivudine or emtricitabine) plus a non-nucleotide reverse-transcriptase inhibitor (NNRTI; efavirenz or nevirapine). We used an individual participant-level meta-analysis and multiple logistic regression to identify covariates associated with drug resistance. Our primary outcome was tenofovir resistance, defined as presence of K65R/N or K70E/G/Q mutations in the reverse transcriptase ( RT ) gene. Findings We included 1926 patients from 36 countries with treatment failure between 1998 and 2015. Prevalence of tenofovir resistance was highest in sub-Saharan Africa (370/654 57%). Pre-ART CD4 cell count was the covariate most strongly associated with the development of tenofovir resistance (odds ratio OR 1·50, 95% CI 1·27–1·77 for CD4 cell count <100 cells per μL). Use of lamivudine versus emtricitabine increased the risk of tenofovir resistance across regions (OR 1·48, 95% CI 1·20–1·82). Of 700 individuals with tenofovir resistance, 578 (83%) had cytosine analogue resistance (M184V/I mutation), 543 (78%) had major NNRTI resistance, and 457 (65%) had both. The mean plasma viral load at virological failure was similar in individuals with and without tenofovir resistance (145 700 copies per mL SE 12 480 versus 133 900 copies per mL SE 16 650; p=0·626). Interpretation We recorded drug resistance in a high proportion of patients after virological failure on a tenofovir-containing first-line regimen across low-income and middle-income regions. Effective surveillance for transmission of drug resistance is crucial. Funding The Wellcome Trust.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
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