AbstractIntroductionFailure of protease‐inhibitor (PI)‐based second‐line antiretroviral therapy (ART) with medication adherence but no protease drug resistance mutations (DRMs) is not well understood. This study investigated the involvement of gp41 and gag as alternative mechanisms, not captured by conventional resistance testing and particularly relevant in resource‐limited settings where third‐line ART is limited.MethodsWe evaluated gp41 and gag for unique amino acids in seven subtype A infected Kenyans failing second‐line therapy with no PI resistance yet detectable lopinavir (query dataset), compared to seven similar‐setting patients with PI resistance or undetectable lopinavir and 69 publically available subtype A Kenyan whole‐genomes sequences.ResultsThree gp41 (607T, 641L, 721I) and four gag (124S, 143V, 339P, 357S) amino acids were significantly more frequent in the query dataset compared to the other datasets, with significantly high co‐occurrence.ConclusionThe genotypic analysis of a unique group of HIV‐1 subtype A infected patients, identified seven amino acids that could potentially contribute to a multi‐gene mechanism of PI‐based ART failure in the absence of PI DR mutations.
BackgroundUpdated World Health Organization guidelines have amplified debate about how resource constraints should impact monitoring strategies for HIV‐infected persons on combination antiretroviral therapy (cART). We estimated the incremental benefit and cost effectiveness of alternative monitoring strategies for east Africans with known HIV infection.MethodsUsing a validated HIV computer simulation based on resource‐limited data (USAID and AMPATH) and circumstances (east Africa), we compared alternative monitoring strategies for HIV‐infected persons newly started on cART. We evaluated clinical, immunologic and virologic monitoring strategies, including combinations and conditional logic (e.g., only perform virologic testing if immunologic testing is positive). We calculated incremental cost‐effectiveness ratios (ICER) in units of cost per quality‐adjusted life year (QALY), using a societal perspective and a lifetime horizon. Costs were measured in 2008 US dollars, and costs and benefits were discounted at 3%. We compared the ICER of monitoring strategies with those of other resource‐constrained decisions, in particular earlier cART initiation (at CD4 counts of 350 cells/mm3rather than 200 cells/mm3).ResultsMonitoring strategies employing routine CD4 testing without virologic testing never maximized health benefits, regardless of budget or societal willingness to pay for additional health benefits. Monitoring strategies employing virologic testing conditional upon particular CD4 results delivered the most benefit at willingness‐to‐pay levels similar to the cost of earlier cART initiation (approximately $2600/QALY). Monitoring strategies employing routine virologic testing alone only maximized health benefits at willingness‐to‐pay levels (> $4400/QALY) that greatly exceeded the ICER of earlier cART initiation.ConclusionsCD4 testing alone never maximized health benefits regardless of resource limitations. Programmes routinely performing virologic testing but deferring cART initiation may increase health benefits by reallocating monitoring resources towards earlier cART initiation.
IntroductionTenofovir‐based first‐line antiretroviral therapy (ART) is recommended globally. To evaluate the impact of its incorporation into the World Health Organization (WHO) guidelines, we examined treatment failure and drug resistance among a cohort of patients on tenofovir‐based first‐line ART at the Academic Model Providing Access to Healthcare, a large HIV treatment programme in western Kenya.MethodsWe determined viral load (VL), drug resistance and their correlates in patients on ≥six months of tenofovir‐based first‐line ART. Based on enrolled patients' characteristics, we described these measures in those with (prior ART group) and without (tenofovir‐only group) prior non‐tenofovir‐based first‐line ART using Wilcoxon rank sum and Fisher's exact tests.ResultsAmong 333 participants (55% female; median age 41 years; median CD4 336 cells/µL), detectable (>40 copies/mL) VL was found in 18%, and VL>1000 copies/mL (WHO threshold) in 10%. Virologic failure at both thresholds was significantly higher in 217 participants in the tenofovir‐only group compared with 116 in the prior ART group using both cut‐offs (24% vs. 7% with VL>40 copies/mL; 15% vs. 1% with VL>1000 copies/mL). Failure in the tenofovir‐only group was associated with lower CD4 values and advanced WHO stage. In 35 available genotypes from 51 participants in the tenofovir‐only group with VL>40 copies/mL (69% subtype A), any resistance was found in 89% and dual‐class resistance in 83%. Tenofovir signature mutation K65R occurred in 71% (17/24) of the patients infected with subtype A. Patients with K65R had significantly lower CD4 values, higher WHO stage and more resistance mutations.ConclusionsIn this Kenyan cohort, tenofovir‐based first‐line ART resulted in good (90%) virologic suppression including high suppression (99%) after switch from non‐tenofovir‐based ART. Lower virologic suppression (85%) and high observed resistance levels (89%) in the tenofovir‐only group impact future treatment options, support recommendations for widespread VL monitoring in such resource limited settings to identify early treatment failure and suggest consideration of individualized resistance testing to design effective subsequent regimens.
IntroductionAntiretroviral resistance leads to treatment failure and resistance transmission. Resistance data in western Kenya are limited. Collection of non‐plasma analytes may provide additional resistance information.MethodsWe assessed HIV diversity using the REGA tool, transmitted resistance by the WHO mutation list and acquired resistance upon first‐line failure by the IAS–USA mutation list, at the Academic Model Providing Access to Healthcare (AMPATH), a major treatment programme in western Kenya. Plasma and four non‐plasma analytes, dried blood‐spots (DBS), dried plasma‐spots (DPS), ViveSTTM‐plasma (STP) and ViveST‐blood (STB), were compared to identify diversity and evaluate sequence concordance.ResultsAmong 122 patients, 62 were treatment‐naïve and 60 treatment‐experienced; 61% were female, median age 35 years, median CD4 182 cells/µL, median viral‐load 4.6 log10 copies/mL. One hundred and ninety‐six sequences were available for 107/122 (88%) patients, 58/62 (94%) treatment‐naïve and 49/60 (82%) treated; 100/122 (82%) plasma, 37/78 (47%) attempted DBS, 16/45 (36%) attempted DPS, 14/44 (32%) attempted STP from fresh plasma and 23/34 (68%) from frozen plasma, and 5/42 (12%) attempted STB. Plasma and DBS genotyping success increased at higher VL and shorter shipment‐to‐genotyping time. Main subtypes were A (62%), D (15%) and C (6%). Transmitted resistance was found in 1.8% of plasma sequences, and 7% combining analytes. Plasma resistance mutations were identified in 91% of treated patients, 76% NRTI, 91% NNRTI; 76% dual‐class; 60% with intermediate‐high predicted resistance to future treatment options; with novel mutation co‐occurrence patterns. Nearly 88% of plasma mutations were identified in DBS, 89% in DPS and 94% in STP. Of 23 discordant mutations, 92% in plasma and 60% in non‐plasma analytes were mixtures. Mean whole‐sequence discordance from frozen plasma reference was 1.1% for plasma‐DBS, 1.2% plasma‐DPS, 2.0% plasma‐STP and 2.3% plasma‐STB. Of 23 plasma‐STP discordances, one mutation was identified in plasma and 22 in STP (p<0.05). Discordance was inversely significantly related to VL for DBS.ConclusionsIn a large treatment programme in western Kenya, we report high HIV‐1 subtype diversity; low plasma transmitted resistance, increasing when multiple analytes were combined; and high‐acquired resistance with unique mutation patterns. Resistance surveillance may be augmented by using non‐plasma analytes for lower‐cost genotyping in resource‐limited settings.
AbstractIntroductionCOVID‐19 stretched healthcare systems to their limits, particularly in settings with a pre‐existing high burden of infectious diseases, including HIV and tuberculosis (TB). We studied the impact of COVID‐19 on TB services at antiretroviral therapy (ART) clinics in low‐ and middle‐income countries.MethodsWe surveyed ART clinics providing TB services in the International Epidemiology Databases to Evaluate AIDS (IeDEA) consortium in Africa and the Asia‐Pacific until July 2021 (TB diagnoses until the end of 2021). We collected site‐level data using standardized questionnaires.ResultsOf 46 participating ART clinics, 32 (70%) were in Africa and 14 (30%) in the Asia‐Pacific; 52% provided tertiary care. Most clinics (85%) reported disrupted routine HIV care services during the pandemic, both in Africa (84%) and the Asia‐Pacific (86%). The most frequently reported impacts were on staff (52%) and resource shortages (37%; protective clothing, face masks and disinfectants). Restrictions in TB health services were observed in 12 clinics (26%), mainly reduced access to TB diagnosis and postponed follow‐up visits (6/12, 50% each), and restrictions in TB laboratory services (22%). Restrictions of TB services were addressed by dispensing TB drugs for longer periods than usual (7/12, 58%), providing telehealth services (3/12, 25%) and with changes in directly observed therapy (DOT) (e.g. virtual DOT, 3/12). The number of TB diagnoses at participating clinics decreased by 21% in 2020 compared to 2019; the decline was more pronounced in tertiary than primary/secondary clinics (24% vs. 12%) and in sites from the Asia‐Pacific compared to Africa (46% vs. 14%). In 2021, TB diagnoses continued to decline in Africa (–8%) but not in the Asia‐Pacific (+62%) compared to 2020. During the pandemic, new infection control measures were introduced or intensified at the clinics, including wearing face masks, hand sanitation and patient triage.ConclusionsThe COVID‐19 pandemic led to staff shortages, reduced access to TB care and delays in follow‐up visits for people with TB across IeDEA sites in Africa and the Asia‐Pacific. Increased efforts are needed to restore and secure ongoing access to essential TB services in these contexts.
AbstractIntroductionIdentification of persons living with human immunodeficiency virus (HIV)‐associated tuberculosis (TB) at increased risk for unfavourable TB outcomes would inform efforts to improve such outcomes. We sought to identify factors associated with a decreased risk of unfavourable TB treatment outcomes among people living with HIV‐infection (PLHIV) in low‐ and middle‐income countries (LMIC), with a specific focus on directly observed therapy (DOT) compared with self‐administered therapy (SAT) during the continuation phase of anti‐TB therapy.MethodsWe conducted a retrospective cohort study among adults diagnosed with HIV‐associated TB in Africa, Asia and the Americas from 2012 to 2013; data were collected from 2012 to 2016. Unfavourable TB treatment outcomes (death during TB treatment, and TB treatment failure or recurrence) were defined according to World Health Organization criteria. Receipt of DOT was obtained at the site level and defined as ≥5 days of DOT per week. The person administering DOT and treatment location varied by site. Lack of receipt of DOT was defined as SAT. Multivariable logistic regression estimated the adjusted odds of unfavourable TB treatment outcomes.ResultsAmong 1862 adults with HIV‐associated TB included, 252 (13.5%) had unfavourable TB outcomes (226 deaths, 26 recurrences/failures). Overall, 1825 (98%) received DOT in the intensive phase and 1617 (87%) received DOT in the continuation phase. DOT in the continuation phase was not significantly associated with unfavourable TB outcomes (aOR 1.43, 95% CI 0.86 to 2.38) compared to SAT. Body mass index (BMI) change during anti‐TB treatment (per 2 units increase, aOR 0.74, 95% CI 0.68 to 0.82) and CD4+ count at TB diagnosis (200 vs. 50 cells/µL, aOR 0.54, 95% CI 0.39 to 0.73) were both independently associated with decreased odds of unfavourable TB treatment outcomes.ConclusionsIn this large, international cohort of people living with HIV‐associated TB in LMIC who received intensive phase DOT, DOT during the continuation phase of anti‐TB therapy was not associated with a decreased odds of unfavourable TB treatment outcomes compared to SAT. Randomized trials evaluating the effect of continuation‐phase DOT on TB outcomes among PLHIV are needed.
BackgroundEast Africa has experienced a rapid expansion in access to antiretroviral therapy (ART) for HIV‐infected patients. Regionally representative socio‐demographic, laboratory and clinical characteristics of patients accessing ART over time and across sites have not been well described.MethodsWe conducted a cross‐sectional analysis of characteristics of HIV‐infected adults initiating ART between 2002 and 2009 in Kenya, Uganda and Tanzania and in the International Epidemiologic Databases to Evaluate AIDS Consortium. Characteristics associated with advanced disease (defined as either a CD4 cell count level of less than 50 cells/mm3 or a WHO Stage 4 condition) at the time of ART initiation and use of stavudine (D4T) or nevirapine (NVP) were identified using a log‐link Poisson model with robust standard errors.ResultsAmong 48, 658 patients (69% from Kenya, 22% from Uganda and 9% from Tanzania) accessing ART at 30 clinic sites, the median age at the time of ART initiation was 37 years (IQR: 31‐43) and 65% were women. Pre‐therapy CD4 counts rose from 87 cells/mm3 (IQR: 26‐161) in 2002‐03 to 154 cells/mm3 (IQR: 71‐233) in 2008‐09 (p < 0.001). Accessing ART at advanced disease peaked at 35% in 2005‐06 and fell to 27% in 2008‐09. D4T use in the initial regimen fell from a peak of 88% in 2004‐05 to 59% in 2008‐09, and a greater extent of decline was observed in Uganda than in Kenya and Tanzania. Self‐pay for ART peaked at 18% in 2003, but fell to less than 1% by 2005. In multivariable analyses, accessing ART at advanced immunosuppression was associated with male sex, women without a history of treatment for prevention of mother to child transmission (both as compared with women with such a history) and younger age after adjusting for year of ART initiation and country of residence. Receipt of D4T in the initial regimen was associated with female sex, earlier year of ART initiation, higher WHO stage, and lower CD4 levels at ART initiation and the absence of co‐prevalent tuberculosis.ConclusionsPublic health ART services in east Africa have improved over time, but the fraction of patients accessing ART with advanced immunosuppression is still high, men consistently access ART with more advanced disease, and D4T continues to be common in most settings. Strategies to facilitate access to ART, overcome barriers among men and reduce D4T use are needed.
BACKGROUND: Drug resistance is a challenge for the global control of tuberculosis. We examined mortality in tuberculosis patients from high-burden countries, according to concordance or discordance of results from drug susceptibility testing (DST) done locally and in a reference laboratory. METHODS: We collected Mycobacterium tuberculosis isolates from adult patients in Côte d'Ivoire, Democratic Republic of the Congo, Kenya, Nigeria, South Africa, Peru, and Thailand, stratified by HIV status and tuberculosis drug resistance. Molecular or phenotypic drug susceptibility testing (DST) was done locally and at the Swiss tuberculosis reference laboratory. We examined mortality during treatment according to DST results and treatment adequacy in logistic regression models adjusting for sex, age, sputum microscopy and HIV status. FINDINGS: 634 tuberculosis patients were included; median age was 33.2 years, 239 (37.7%) were female, 272 (42.9%) HIV-positive and 69 (10.9%) patients died. Based on the reference laboratory DST, 394 (62.2%) strains were pan-susceptible, 45 (7.1%) mono-resistant, 163 (25.7%) multidrug-resistant (MDR-TB), and 30 (4.7%) had pre-extensive or extensive drug resistance (pre-XDR/XDR-TB). Results of reference and local laboratories were discordant in 121 (19.1%) cases. Overall, sensitivity and specificity to detect any resistance were 90.8% and 84.3%, respectively. Mortality ranged from 6.0% (20/336) in patients with pan-susceptible tuberculosis treated according to WHO guidelines to 57.1% (8/14) in patients with resistant strains who were under treated. In logistic regression, compared to concordant DST results, the adjusted odds ratio of death was 7.33 (95% CI 2.70–19.95) for patients with discordant results potentially leading to under treatment. INTERPRETATION: Inaccurate DST by comparison to a reference standard led to under treatment of drug resistant tuberculosis and increased mortality. Rapid molecular DST of first- and second-line drugs at diagnosis is required to improve outcomes in patients ...
AbstractIntroductionLiver disease is a leading cause of morbidity and mortality among persons living with HIV (PLHIV). While chronic viral hepatitis has been extensively studied in low‐ and middle‐income countries (LMICs), there is limited information about the burden of metabolic disorders on liver disease in PLHIV.MethodsWe conducted a cross‐sectional analysis of baseline data collected between October 2020 and July 2022 from the IeDEA‐Sentinel Research Network, a prospective cohort enrolling PLHIV ≥40 years on antiretroviral treatment (ART) for ≥6 months from eight clinics in Asia, Americas, and central, East, southern and West Africa. Clinical assessments, laboratory testing on fasting blood samples and liver stiffness measurement (LSM)/controlled attenuation parameter (CAP) by vibration‐controlled transient elastography were performed. Multivariable logistic regression models assessed factors associated with liver fibrosis (LSM ≥7.1 kPa) and steatosis (CAP ≥248 dB/m). Population attributable fraction (PAF) of each variable associated with significant liver fibrosis was estimated using Levin's formula.ResultsOverall, 2120 PLHIV (56% female, median age 50 [interquartile range: 45−56] years) were included. The prevalence of obesity was 19%, 12% had type 2 diabetes mellitus (T2DM), 29% had hypertension and 53% had dyslipidaemia. The overall prevalence of liver fibrosis and steatosis was 7.6% (95% confidence interval [CI] 6.1−8.4) and 28.4% (95% CI 26.5−30.7), respectively, with regional variability. Male sex at birth (odds ratio [OR] 1.62, CI 1.10−2.40), overweight/obesity (OR = 2.50, 95% CI 1.69−3.75), T2DM (OR 2.26, 95% CI 1.46−3.47) and prolonged exposure to didanosine (OR 3.13, 95% CI 1.46−6.49) were associated with liver fibrosis. Overweight/obesity and T2DM accounted for 42% and 11% of the PAF for liver fibrosis, while HBsAg and anti‐HCV accounted for 3% and 1%, respectively. Factors associated with steatosis included overweight/obesity (OR 4.25, 95% CI 3.29−5.51), T2DM (OR 2.06, 95% CI 1.47−2.88), prolonged exposure to stavudine (OR 1.69, 95% CI 1.27−2.26) and dyslipidaemia (OR 1.68, 95% CI 1.31−2.16).ConclusionsMetabolic disorders were significant risk factors for liver disease among PLHIV in LMICs. Early recognition of metabolic disorders risk factors might be helpful to guide clinical and lifestyle interventions. Further prospective studies are needed to determine the causative natures of these findings.
AbstractIntroductionDolutegravir is being scaled up globally as part of antiretroviral therapy (ART), but for people with HIV and tuberculosis co‐infection, its use is complicated by a drug–drug interaction with rifampicin requiring an additional daily dose of dolutegravir. This represents a disadvantage over efavirenz, which does not have a major drug–drug interaction with rifampicin. We sought to describe HIV clinic practices for prescribing concomitant dolutegravir and rifampicin, and characterize virologic outcomes among patients with tuberculosis co‐infection receiving dolutegravir or efavirenz.MethodsWithin the four sub‐Saharan Africa regions of the International epidemiology Databases to Evaluate AIDS consortium, we conducted a site survey (2021) and a cohort study (2015–2021). The cohort study used routine clinical data and included patients newly initiating or already receiving dolutegravir or efavirenz at the time of tuberculosis diagnosis. Patients were followed from tuberculosis diagnosis until viral suppression (<1000 copies/ml), a competing event (switching ART regimen; loss to program/death) or administrative censoring at 12 months.ResultsIn the survey, 86 of 90 (96%) HIV clinics in 18 countries reported prescribing dolutegravir to patients who were receiving rifampicin as part of tuberculosis treatment, with 77 (90%) reporting that they use twice‐daily dosing of dolutegravir, of which 74 (96%) reported having 50 mg tablets available to accommodate twice‐daily dosing. The cohort study included 3563 patients in 11 countries, with 67% newly or recently initiating ART. Among patients receiving dolutegravir (n = 465), the cumulative incidence of viral suppression was 58.9% (95% confidence interval [CI]: 54.3–63.3%), switching ART regimen was 4.1% (95% CI: 2.6–6.2%) and loss to program/death was 23.4% (95% CI: 19.7–27.4%). Patients receiving dolutegravir had improved viral suppression compared with patients receiving efavirenz who had a tuberculosis diagnosis before site dolutegravir availability (adjusted subdistribution hazard ratio [aSHR]: 1.47, 95% CI: 1.28–1.68) and after site dolutegravir availability (aSHR 1.28, 95% CI: 1.08–1.51).ConclusionsAt a programmatic level, dolutegravir was being widely prescribed in sub‐Saharan Africa for people with HIV and tuberculosis co‐infection with a dose adjustment for the drug–drug interaction with rifampicin. Despite this more complex regimen, our cohort study revealed that dolutegravir did not negatively impact viral suppression.
