All-cause mortality in HIV-positive adults starting combination antiretroviral therapy: correcting for loss to follow-up

Objective: To estimate mortality in HIV-positive patients starting combination antiretroviral therapy (ART) and to discuss different approaches to calculating correction factors to account for loss to follow-up. Methods: A total of 222 096 adult HIV-positive patients who started ART 2009–2014 in clinics participating in the International epidemiology Databases to Evaluate AIDS collaboration in 43 countries in sub-Saharan Africa, Asia Pacific, Latin America, and North America were included. To allow for underascertainment of deaths due to loss to follow-up, two correction factors (one for the period 0–6 months on ART and one for later periods) or 168 correction factors (combinations of two sexes, three time periods after ART initiation, four age groups, and seven CD4þ groups) based on tracing patients lost in Kenya and data linkages in South Africa were applied. Corrected mortality rates were compared with a worst case scenario assuming all patients lost to follow-up had died. Results: Loss to follow-up differed between regions; rates were lowest in central Africa and highest in east Africa. Compared with using two correction factors (1.64 for the initial ART period and 2.19 for later), applying 168 correction factors (range 1.03–4.75) more often resulted in implausible mortality rates that exceeded the worst case scenario. Corrected mortality rates varied widely, ranging from 0.2 per 100 person-years to 54 per 100 person-years depending on region and covariates. Conclusion: Implausible rates were less common with the simpler approach based on two correction factors. The corrected mortality rates will be useful to international agencies, national programmes, and modellers

IeDEA-WHO Research-Policy Collaboration: contributing real-world evidence to HIV progress reporting and guideline development.

Partnerships between researchers and policymakers can improve uptake and integration of scientific evidence. This article describes the research-policy partnership between the International epidemiology Databases to Evaluate AIDS (IeDEA) ( www.iedea.org) and the World Health Organization (WHO), which was established in 2014. IeDEA is an international research consortium, which analyses data on almost 2 million people living with HIV under care in routine settings in 46 countries in Asia-Pacific, the Caribbean, Central and South America, North America and sub-Saharan Africa. Five multiregional analyses were identified to inform the WHO on progress towards the second and third 90s of the 90-90-90 targets in adults and children: (i) trends in CD4 cell counts at the start of antiretroviral therapy (ART); (ii) delays from enrolment in HIV care to ART initiation; (iii) the impact of ART guideline changes; (iv) retention in care, mortality and loss to follow-up; and (v) viral suppression within the first 3 years after initiating ART. Results from these analyses were contributed to the 2015 and 2016 WHO global HIV progress reports, will contribute to the 2018 report, and were published in academic journals. The partnership has been mutually beneficial: discussion of WHO policy agendas led to more policy-framed, relevant and timely IeDEA research, and the collaboration provided the WHO with timely access to the latest data from IeDEA, as it was shared prior to peer-review publication

PLoS Med

BACKGROUND: The effect of antiretroviral treatment (ART) eligibility expansions on patient outcomes, including rates of timely ART initiation among those enrolling in care, has not been assessed on a large scale. In addition, it is not known whether ART eligibility expansions may lead to "crowding out" of sicker patients. METHODS AND FINDINGS: We examined changes in timely ART initiation (within 6 months) at the original site of HIV care enrollment after ART eligibility expansions among 284,740 adult ART-naive patients at 171 International Epidemiology Databases to Evaluate AIDS (IeDEA) network sites in 22 countries where national policies expanding ART eligibility were introduced between 2007 and 2015. Half of the sites included in this analysis were from Southern Africa, one-third were from East Africa, and the remainder were from the Asia-Pacific, Central Africa, North America, and South and Central America regions. The median age of patients enrolling in care at contributing sites was 33.5 years, and the median percentage of female patients at these clinics was 62.5%. We assessed the 6-month cumulative incidence of timely ART initiation (CI-ART) before and after major expansions of ART eligibility (i.e., expansion to treat persons with CD4 </= 350 cells/muL [145 sites in 22 countries] and CD4 </= 500 cells/muL [152 sites in 15 countries]). Random effects metaregression models were used to estimate absolute changes in CI-ART at each site before and after guideline expansion. The crude pooled estimate of change in CI-ART was 4.3 percentage points (95% confidence interval [CI] 2.6 to 6.1) after ART eligibility expansion to CD4 </= 350, from a baseline median CI-ART of 53%; and 15.9 percentage points (pp) (95% CI 14.3 to 17.4) after ART eligibility expansion to CD4 </= 500, from a baseline median CI-ART of 57%. The largest increases in CI-ART were observed among those newly eligible for treatment (18.2 pp after expansion to CD4 </= 350 and 47.4 pp after expansion to CD4 </= 500), with no change or small increases among those eligible under prior guidelines (CD4 </= 350: -0.6 pp, 95% CI -2.0 to 0.7 pp; CD4 </= 500: 4.9 pp, 95% CI 3.3 to 6.5 pp). For ART eligibility expansion to CD4 </= 500, changes in CI-ART were largest among younger patients (16-24 years: 21.5 pp, 95% CI 18.9 to 24.2 pp). Key limitations include the lack of a counterfactual and difficulty accounting for secular outcome trends, due to universal exposure to guideline changes in each country. CONCLUSIONS: These findings underscore the potential of ART eligibility expansion to improve the timeliness of ART initiation globally, particularly for young adults

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to &lt;90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], &gt;300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of &lt;15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P&lt;0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P&lt;0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

The contribution of observational studies in supporting the WHO 'treat all' recommendation for HIV/AIDS.

In 2015, the World Health Organization (WHO) recommended that all people living with HIV (PLWH) should start antiretroviral therapy (ART) irrespective of clinical or immune status. This recommendation followed almost 20 years of research into the clinical and population-level benefits and risks of starting ART early compared with deferring treatment. This article summarises the ways in which observational data support the work of WHO, including the support provided by the International epidemiology Databases to Evaluate AIDS (IeDEA), taking the example of 'treat all'

Trends in CD4 and viral load testing 2005 to 2018: multi-cohort study of people living with HIV in Southern Africa.

INTRODUCTION The World Health Organization (WHO) recommends a CD4 cell count before starting antiretroviral therapy (ART) to detect advanced HIV disease, and routine viral load (VL) testing following ART initiation to detect treatment failure. Donor support for CD4 testing has declined to prioritize access to VL monitoring. We examined trends in CD4 and VL testing among adults (≥15 years of age) starting ART in Southern Africa. METHODS We analysed data from 14 HIV treatment programmes in Lesotho, Malawi, Mozambique, South Africa, Zambia and Zimbabwe in 2005 to 2018. We examined the frequency of CD4 and VL testing, the percentage of adults with CD4 or VL tests, and among those having a test, the percentage starting ART with advanced HIV disease (CD4 count 1000 HIV-RNA copies/mL) after ART initiation. We used mixed effect logistic regression to assess time trends adjusted for age and sex. RESULTS Among 502,456 adults, the percentage with CD4 testing at ART initiation decreased from a high of 78.1% in 2008 to a low of 38.0% in 2017; the probability declined by 14% each year (odds ratio (OR) 0.86; 95% CI 0.86 to 0.86). Frequency of CD4 testing also declined. The percentage starting ART with advanced HIV disease declined from 83.3% in 2005 to 23.5% in 2018; each year the probability declined by 20% (OR 0.80; 95% CI 0.80 to 0.81). VL testing after starting ART varied; 61.0% of adults in South Africa and 10.7% in Malawi were tested, but fewer than 2% were tested in the other four countries. The probability of VL testing after ART start increased only modestly each year (OR 1.06; 95% CI 1.05 to 1.06). The percentage with unsuppressed VL was 8.6%. There was no evidence of a decrease in unsuppressed VL over time (OR 1.00; 95% CI 0.99 to 1.01). CONCLUSIONS CD4 cell counting declined over time, including testing at the start of ART, despite the fact that many patients still initiated ART with advanced HIV disease. Without CD4 testing and expanded VL testing many patients with advanced HIV disease and treatment failure may go undetected, threatening the effectiveness of ART in sub-Saharan Africa

All-cause mortality in HIV-positive adults starting combination antiretroviral therapy: correcting for loss to follow-up.

OBJECTIVE To estimate mortality in HIV-positive patients starting combination antiretroviral therapy (ART) and to discuss different approaches to calculating correction factors to account for loss to follow-up. METHODS A total of 222 096 adult HIV-positive patients who started ART 2009-2014 in clinics participating in the International epidemiology Databases to Evaluate AIDS collaboration in 43 countries in sub-Saharan Africa, Asia Pacific, Latin America, and North America were included. To allow for underascertainment of deaths due to loss to follow-up, two correction factors (one for the period 0-6 months on ART and one for later periods) or 168 correction factors (combinations of two sexes, three time periods after ART initiation, four age groups, and seven CD4 groups) based on tracing patients lost in Kenya and data linkages in South Africa were applied. Corrected mortality rates were compared with a worst case scenario assuming all patients lost to follow-up had died. RESULTS Loss to follow-up differed between regions; rates were lowest in central Africa and highest in east Africa. Compared with using two correction factors (1.64 for the initial ART period and 2.19 for later), applying 168 correction factors (range 1.03-4.75) more often resulted in implausible mortality rates that exceeded the worst case scenario. Corrected mortality rates varied widely, ranging from 0.2 per 100 person-years to 54 per 100 person-years depending on region and covariates. CONCLUSION Implausible rates were less common with the simpler approach based on two correction factors. The corrected mortality rates will be useful to international agencies, national programmes, and modellers

Effects of national adoption of Treat-All guidelines on pre-ART CD4 testing and viral load monitoring after ART initiation: A regression discontinuity analysis

BACKGROUND: The World Health Organization's Treat-All guidance recommends CD4 testing prior to antiretroviral treatment (ART) initiation, and routine viral load (VL) monitoring (over CD4 monitoring) for patients on ART. METHODS: We used regression discontinuity analyses to estimate changes in CD4 testing and VL monitoring among 547,837 ART-naïve patients enrolling in HIV care during 2006-2018 at 225 clinics in 26 countries where Treat-All policies were adopted. We examined CD4 testing within 12 months before and VL monitoring 6 months after ART initiation among adults (≥20 years), adolescents (10-19 years) and children (0-9 years) in low/lower-middle income countries (L/LMICs) and high/upper-middle income countries (H/UMICs). RESULTS: Treat-All adoption led to an immediate decrease in pre-ART CD4 testing among adults in L/LMICs, from 57.0% to 48.1% (-8.9 percentage points [pp]; 95% CI: -11.0, -6.8), and a small increase in in H/UMICs, from 90.1 to 91.7% (+1.6pp; 95% CI: 0.2, 3.0), with no changes among adolescents or children; decreases in pre-ART CD4 testing accelerated after Treat-All adoption in L/LMICs. In L/LMICs, VL monitoring after ART initiation was low among all patients just before Treat-All; while there was no immediate change at Treat-All adoption, VL monitoring trends significantly increased afterwards. In H/UMICs, VL monitoring increased among adults immediately after Treat-All adoption, from 58.2% to 61.1% (+2.9pp; 95% CI: 0.5, 5.4), with no significant changes among adolescents/children. CONCLUSIONS: While on-ART VL monitoring has improved in L/LMICs, Treat-All adoption has accelerated and disparately worsened suboptimal pre-ART CD4 monitoring, which may compromise care outcomes for individuals with advanced HIV

Regression discontinuity analysis demonstrated varied effect of Treat-All on CD4 testing among Southern African countries.

OBJECTIVE To determine whether Treat-All policy impacted laboratory testing practices of antiretroviral therapy (ART) programs in Southern Africa. STUDY DESIGN AND SETTING We used HIV cohort data from Lesotho, Malawi, Mozambique, South Africa, Zambia and Zimbabwe in a regression discontinuity design to estimate changes in pre-ART CD4 testing and viral load monitoring following national Treat-all adoption that occurred during 2016-2017. This study included more than 230,000 ART-naïve people living with HIV (PLHIV) aged five years or older who started ART within two years of national Treat-All adoption. RESULTS We found pre-ART CD4 testing decreased following adoption of Treat-All recommendations in Malawi (-21.4 percentage points (pp), 95% CI: -26.8, -16.0) and in Mozambique (-8.8pp, 95% CI: -14.9, -2.8), but increased in Zambia (+2.7pp, 95% CI: +0.4, +5.1). Treat-All policy had no effect on viral load monitoring, except among females in South Africa (+7.1pp, 95% CI: +1.1, +13.0). CONCLUSION Treat-All policy expanded ART eligibility, but led to reductions in pre-ART CD4 testing in some countries that may weaken advanced HIV disease management. Continued and expanded support of CD4 and viral load laboratory capacity is needed to further improve treatment successes and allow for uniform evaluation of ART implementation across Southern Africa

HIV Viral Load Suppression in Adults and Children Receiving Antiretroviral Therapy-Results From the IeDEA Collaboration.

BACKGROUND Having 90% of patients on antiretroviral therapy (ART) and achieving an undetectable viral load (VL) is 1 of the 90:90:90 by 2020 targets. In this global analysis, we investigated the proportions of adult and paediatric patients with VL suppression in the first 3 years after ART initiation. METHODS Patients from the IeDEA cohorts who initiated ART between 2010 and 2014 were included. Proportions with VL suppression (<1000 copies/mL) were estimated using (1) strict intention to treat (ITT)-loss to follow-up (LTFU) and dead patients counted as having detectable VL; and (2) modified ITT-LTFU and dead patients were excluded. Logistic regression was used to identify predictors of viral suppression at 1 year after ART initiation using modified ITT. RESULTS A total of 35,561 adults from 38 sites/16 countries and 2601 children from 18 sites/6 countries were included. When comparing strict with modified ITT methods, the proportion achieving VL suppression at 3 years from ART initiation changed from 45.1% to 90.2% in adults, and 60.6% to 80.4% in children. In adults, older age, higher CD4 count pre-ART, and homosexual/bisexual HIV exposure were associated with VL suppression. In children, older age and higher CD4 percentage pre-ART showed significant associations with VL suppression. CONCLUSIONS Large increases in the proportion of VL suppression in adults were observed when we excluded those who were LTFU or had died. The increases were less pronounced in children. Greater emphasis should be made to minimize LTFU and maximize patient retention in HIV-infected patients of all age groups