BACKGROUND:Recent attention has focused on the question of how quickly antiretroviral therapy (ART) should be started once HIV diagnosis is confirmed. We assessed whether rapid ART initiation ...improves patient outcomes.
METHODS:We searched five databases from inception up to August 2017. Rapid ART initiation was defined as initiation within 14 days of HIV diagnosis. Data were pooled using random effects meta-analysis.
RESULTS:Across the randomized trials, ART start on the same day increased viral suppression at 12 months three trialsrelative risk (RR) 1.17, 95% confidence interval (CI) 1.07–1.27, retention in care at 12 months (RR 1.11, 95% CI 0.99–1.26), and the likelihood of starting ART within 90 days (four trialsRR 1.35, 95% CI 1.13–1.62) and 12 months after eligibility was established (three trialsRR 1.17, 95% CI 1.07–1.27). There was a nonsignificant trend toward reduced mortality (three trialsRR 0.53, 95% CI 0.24–1.08), as well as reduced loss to follow-up at 12 months (2 trialsRR 0.66, 95% CI 0.42–1.04). In the observational studies, offering accelerated ART initiation resulted in a greater likelihood of having started ART within 3 months (two studiesRR 1.53, 95% CI 1.11–2.10). There was a trend toward an increased risk of being lost to follow-up at 6 months (three studiesRR 1.85, 95% CI 0.96–3.55).
CONCLUSION:Accelerated ART initiation can lead to improved clinical outcomes and is likely to be of particular benefit in those settings where extensive patient preparation prior to starting ART results in long delays. These findings informed a WHO recommendation supporting accelerated ART initiation, including same day ART start.
Although lifelong combination antiretroviral therapy (ART) is recommended for all individuals with HIV, few data exist for pregnancy outcomes associated with ART initiation before conception. We ...assessed adverse pregnancy outcomes associated with ART initiated before conception compared with that of ART started after conception.
We did a systematic review of studies from low-income, middle-income, and high-income countries by searching the Cochrane Central Register of Controlled Trials, Embase, LILACS, MEDLINE, Toxline, Web of Knowledge, and WHO Global Index Medicus and trials in progress (International Clinical Trials Registry Platform) for randomised trials, quasi-randomised trials, and prospective cohort studies done between Jan 1, 1980, and June 1, 2016, in which timing of ART initiation in pregnant women living with HIV was reported. We used the risk ratio (RR) and corresponding 95% CIs as the primary measure to assess the association between the selected outcomes and ART initiation before conception versus after conception. We used a random-effects model to pool risk ratios.
We included 11 studies with 19 189 mother–infant pairs. Women who started ART before conception were significantly more likely to deliver preterm (pooled RR 1·20, 95% CI 1·01−1·44) or very preterm (1·53, 1·22−1·92), or to have low-birthweight infants (1·30, 1·04−1·62) than were those who began ART after conception. Few data exist for neonatal mortality. The risk of very low birthweight, small for gestational age, severe small for gestational age, stillbirth, and congenital anomalies did not differ significantly between women who were taking ART before conception and those who began ART after conception.
The benefits of ART for maternal health and prevention of perinatal transmission outweigh risks, but data for the extent and severity of these risks are scarce and of low quality. As use of ART before conception rapidly increases globally, monitoring for potential adverse pregnancy outcomes will be crucial.
WHO.
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.
The use of individual patient data (IPD) in network meta-analyses (NMA) is rapidly growing. This study aimed to determine, through simulations, the impact of select factors on the validity and ...precision of NMA estimates when combining IPD and aggregate data (AgD) relative to using AgD only.
Three analysis strategies were compared via simulations: 1) AgD NMA without adjustments (AgD-NMA); 2) AgD NMA with meta-regression (AgD-NMA-MR); and 3) IPD-AgD NMA with meta-regression (IPD-NMA). We compared 108 parameter permutations: number of network nodes (3, 5 or 10); proportion of treatment comparisons informed by IPD (low, medium or high); equal size trials (2-armed with 200 patients per arm) or larger IPD trials (500 patients per arm); sparse or well-populated networks; and type of effect-modification (none, constant across treatment comparisons, or exchangeable). Data were generated over 200 simulations for each combination of parameters, each using linear regression with Normal distributions. To assess model performance and estimate validity, the mean squared error (MSE) and bias of treatment-effect and covariate estimates were collected. Standard errors (SE) and percentiles were used to compare estimate precision.
Overall, IPD-NMA performed best in terms of validity and precision. The median MSE was lower in the IPD-NMA in 88 of 108 scenarios (similar results otherwise). On average, the IPD-NMA median MSE was 0.54 times the median using AgD-NMA-MR. Similarly, the SEs of the IPD-NMA treatment-effect estimates were 1/5 the size of AgD-NMA-MR SEs. The magnitude of superior validity and precision of using IPD-NMA varied across scenarios and was associated with the amount of IPD. Using IPD in small or sparse networks consistently led to improved validity and precision; however, in large/dense networks IPD tended to have negligible impact if too few IPD were included. Similar results also apply to the meta-regression coefficient estimates.
Our simulation study suggests that the use of IPD in NMA will considerably improve the validity and precision of estimates of treatment effect and regression coefficients in the most NMA IPD data-scenarios. However, IPD may not add meaningful validity and precision to NMAs of large and dense treatment networks when negligible IPD are used.
This systematic review aimed to compare body weight gain associated outcomes over time between dolutegravir (DTG)-based antiretroviral (ART) regimens to other ART regimens, to compare tenofovir ...alafenamide (TAF)-based regimens, and to evaluate the associated prognostic factors.
Systematic searches of MEDLINE, Embase, and CENTRAL for RCTs and observational studies comparing ART regimens were conducted on 13 September 2021. Outcomes of interest included: change in body weight, body mass index (BMI), waist circumference; and risk of hyperglycaemia and diabetes. Network meta-analyses were conducted at 12, 24, 48, 96 and 144 weeks using two networks differentiated by 3rd agents and backbone agents.
The review identified 113 publications reporting on 73 studies. DTG-based regimens led to statistically higher weight gains than efavirenz-based regimens at all time points (mean difference: 1·99 kg at 96 weeks; 95% credible interval: 0·85–3·09) and was higher over time than low-dose efavirenz-, elvitegravir-, and rilpivirine-based regimens. They were comparable to raltegravir-, bictegravir- and atazanavir-based regimens. For backbones, TAF led to higher weight gain relative to tenofovir disoproxil fumarate (TDF), abacavir, and zidovudine. Prognostic factor analysis showed both low CD4 cell count and high HIV RNA viral load at baseline were consistently associated with higher weight gain, while sex was an effect modifier to African origins.
DTG-based regimens lead to larger average weight gains than some other ART regimens and TAF leads to larger average weight gains than all other backbone antiretrovirals. Further research is needed to better understand long-term outcomes and their relationship to other metabolic outcomes.
The WHO Global HIV, Hepatitis and Sexually Transmitted Infections Programmes.
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.
Patients with follicular lymphoma (FL) can have high response rates to early lines of treatment. However, among FL patients relapsed/refractory (r/r) after ≥2 prior lines of therapy (LOT), remission ...tends to be shorter and there is limited treatment guidance. This study sought to evaluate the clinical outcomes for r/r FL after ≥2 prior LOT identified through systematic literature review.
Eligible studies included comparative or non-comparative interventional or observational studies of systemic therapies among adults with FL r/r after ≥2 prior LOT published prior to 31st May 2021. Prior LOT must have included an anti-CD20 monoclonal antibody and an alkylating agent, in combination or separately. Overall response rate (ORR) and complete response (CR) were estimated using inverse-variance weighting with Freeman-Tukey double-arcsine transformations. Kaplan-Meier (KM) curves for progression-free survival (PFS) and overall survival (OS) estimated by reconstructing digitized curves using the Guyot algorithm, and survival analyses were conducted, stratified by ≥2 prior LOT and ≥ 3 prior LOT groups (as defined in the source material). Restricting the analyses to the observational cohorts was investigated as a sensitivity analysis.
The analysis-set included 20 studies published between 2014 and 2021. Studies were primarily US and/or European based, with the few exceptions using treatments approved in US/Europe. The estimated ORR was 58.47% (95% confidence interval CI: 51.13-65.62) and proportion of patients with CR was 19.63% (95% CI: 15.02-24.68). The median OS among those ≥2 prior LOT was 56.57 months (95% CI: 47.8-68.78) and median PFS was 9.78 months (95% CI: 9.01-10.63). The 24-month OS decreased from 66.50% in the ≥2 prior LOT group to 59.51% in the ≥3 prior LOT group, with a similar trend in PFS at 24-month (28.42% vs 24.13%).
This study found that few r/r FL patients with ≥2 prior LOT achieve CR, and despite some benefit, approximately 1/3 of treated patients die within 24 months. The shorter median PFS with increasing prior LOT suggest treatment durability is suboptimal in later LOT. These findings indicate that patients are underserved by treatments currently available in the US and Europe.
The SCHOLAR-5 study examines treatment patterns and outcomes of real-world follicular lymphoma (FL) patients on 3rd line of treatment (LoT) or higher, for whom existing data are limited. SCHOLAR-5 is ...a retrospective cohort study using data from adults (≥ 18 years) with grade 1-3a FL, initiating ≥3rd LoT after June 2014 at major lymphoma centers in the US and Europe. Objective response rate (ORR), complete response (CR), progression-free survival (PFS) and overall survival (OS) were analyzed by LoT. Time-to-event outcomes were assessed using Kaplan-Meier methods. Of 128 patients, 87 initiated 3rd LoT, 63 initiated 4th LoT, and 47 initiated 5th LoT. At 1st eligible LoT, 31% progressed within 24-months of 1st LoT anti-CD20 combination therapy, 28% had prior autologous stem cell transplantation, and 31% were refractory to the previous LoT. The most common regimen in each LoT was chemoimmunotherapy; however, experimental drugs were increasingly used at later LoT. In the US, anti-CD20 monotherapy was more common at ≥3rd LoT compared to Europe, where stem cell transplants were more common. ORR at 3rd LoT was 68% (CR 44%), but decreased after each LoT to 37% (CR 22%) in ≥5 LoT. Median OS and PFS at 3rd LoT were 68 and 11 months, respectively, and reduced to 43 and 4 months at ≥5 LoT. Treatments were heterogenous at each LoT in both the US and Europe. Few FL patients achieved CR in later LoT, and duration of response and survival diminished with each subsequent line.
To inform World Health Organization (WHO) global guidelines, we updated and expanded the evidence base to assess the comparative efficacy, tolerability, and safety of first-line antiretroviral ...therapy (ART) regimens.
We searched Embase, Medline and CENTRAL on 28 February 2020 to update the systematic literature review of clinical trials comparing recommended first-line ART that informed previous WHO guidelines. Outcomes included viral suppression, change in CD4 cell counts, mortality, serious and overall adverse events (AEs), discontinuation, discontinuations due to AEs (DAEs); and new outcomes: drug-resistance, neuropsychiatric AEs, early viral suppression, weight gain and birth outcomes. Comparative effects were assessed through network meta-analyses and certainty in the evidence was assessed using the GRADE framework.
We identified 156 publications pertaining to 68 trials for the primary population. Relative to efavirenz, dolutegravir had improved odds of viral suppression across all time points (odds ratio OR: 1·94; 95% credible interval CrI: 1·48–2·56 at 96 weeks); was protective of drug-resistance (OR: 0·13; 95%CrI: 0·04–0·48); and led to fewer discontinuations (OR: 0·58; 95%CrI: 0·48–0·70). Evidence supported dolutegravir use among TB-HIV co-infected persons and pregnant women. Adverse birth outcomes were observed in 33.2% of dolutegravir-managed pregnancies and 35.0% of efavirenz-managed pregnancies. Low-dose efavirenz had comparable efficacy and safety to standard-dose efavirenz, but led to fewer DAEs (OR: 0·70; 95%CrI: 0·50–0·92).
The evidence supports choosing dolutegravir in combination with lamivudine/emtricitabine and tenofovir disoproxil fumarate as the preferred first-line regimen and low-dose efavirenz-based regimens as an alternative. Dolutegravir can be considered to be effective, safe and tolerable.
WHO.
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