Survival after long-term ART exposure: findings from an Asian patient population retained in care beyond 5 years on ART.

BACKGROUND: This study investigated survival in people living with HIV being followed-up from 5 and 10 years after antiretroviral therapy (ART) initiation in a multi-country Asian cohort. METHODS: We included patients in follow-up >5 years after ART initiation. Factors associated with mortality beyond 5 and 10 years on ART were analysed using competing risk regression with time-updated variables. RESULTS: Of 13,495 patients retained after 5 years on ART, 279 subsequently died (0.56/100 person-years). Increased mortality was associated with age >50 years (sub-hazard ratio [sHR] 2.24, 95% CI 1.58, 3.15, compared with ≤40 years), HIV exposure through injecting drug use (sHR 2.17, 95% CI 1.32, 3.56), HIV viral load ≥1,000 copies/ml: sHR 1.52, 95% CI 1.05, 2.21, compared with <400), regimen (second-line regimen: sHR 2.11, 95% CI 1.52, 2.94, and third-line regimen: sHR 2.82, 95% CI 2.00, 3.98, compared with first-line regimen), HBV coinfection (sHR 2.23, 95% CI 1.49, 3.33), fasting plasma glucose ≥126 mg/dl (sHR 1.98, 95% CI 1.22, 3.21, compared with <100 mg/dl) and estimated glomerular filtration rate <60 ml/min/1.73 m2 (sHR 2.57, 95% CI 1.56, 4.22). Decreased mortality was associated with transmission through male-to-male sexual contact (sHR 0.44, 95% CI 0.22, 0.88, compared with heterosexual transmission) and higher CD4+ T-cell count (200-349 cells/µl: sHR 0.27, 95% CI 0.20, 0.38, 350-499 cells/µl: sHR 0.10, 95% CI 0.07, 0.16 and ≥500 cells/µl: sHR 0.09, 95% CI 0.06, 0.13, compared with <200 cells/µl). Results after 10 years were similar, but most associations were weaker due to limited power. CONCLUSIONS: Next to preventing ART failure, HIV programmes should carefully monitor and treat comorbidities, including hepatitis, kidney disease and diabetes, to optimize survival after long-term ART exposure.

Global variations in mortality in adults after initiating antiretroviral treatment: an updated analysis of the International epidemiology Databases to Evaluate AIDS cohort collaboration.

BACKGROUND: UNAIDS models use data from the International epidemiology Databases to Evaluate AIDS (IeDEA) collaboration in setting assumptions about mortality rates after antiretroviral treatment (ART) initiation. This study aims to update these assumptions with new data, to quantify the extent of regional variation in ART mortality and to assess trends in ART mortality. METHODS: Adult ART patients from Africa, Asia and the Americas were included if they had a known date of ART initiation during 2001-2017 and a baseline CD4 cell count. In cohorts that relied only on passive follow-up (no patient tracing or linkage to vital registration systems), mortality outcomes were imputed in patients lost to follow-up based on a meta-analysis of tracing study data. Poisson regression models were fitted to the mortality data. RESULTS: 464 048 ART patients were included. In multivariable analysis, mortality rates were lowest in Asia and highest in Africa, with no significant differences between African regions. Adjusted mortality rates varied significantly between programmes within regions. Mortality rates in the first 12 months after ART initiation were significantly higher during 2001-2006 than during 2010-2014, although the difference was more substantial in Asia and the Americas [adjusted incidence rate ratio (aIRR) 1.43, 95% CI: 1.22-1.66] than in Africa (aIRR 1.07, 95% CI: 1.04-1.11). CONCLUSION: There is substantial variation in ART mortality between and within regions, even after controlling for differences in mortality by age, sex, baseline CD4 category and calendar period. ART mortality rates have declined substantially over time, although declines have been slower in Africa.

Cardiovascular disease incidence projections in the TREAT Asia HIV Observational Database (TAHOD).

BACKGROUND: We aimed to project the 10-year future incidence of cardiovascular disease (CVD) and model several intervention scenarios based on a multi-site Asian HIV-positive cohort. METHODS: Analyses were based on patients recruited to the TREAT Asia HIV Observational Database (TAHOD), consisting of 21 sites in 12 countries. Patients on triple antiretroviral therapy (ART) were included if they were alive, without previous CVD, and had data on CVD risk factors. Annual new CVD events for 2019-2028 were estimated with the D:A:D equation, accounting for age- and sex-adjusted mortality. Modelled intervention scenarios were treatment of high total cholesterol, low high-density lipoprotein cholesterol (HDL) or high blood pressure, abacavir or lopinavir substitution, and smoking cessation. RESULTS: Of 3,703 included patients, 69% were male, median age was 46 (IQR 40-53) years and median time since ART initiation was 9.8 years (IQR 7.5-14.1). Cohort incidence rates of CVD were projected to increase from 730 per 100,000 person-years (pys) in 2019 to 1,432 per 100,000 pys in 2028. In the modelled intervention scenarios, most events can be avoided by smoking cessation, abacavir substitution, lopinavir substitution, decreasing total cholesterol, treating high blood pressure and increasing HDL. CONCLUSIONS: Our projections suggest a doubling of CVD incidence rates in Asian HIV-positive adults in our cohort. An increase in CVD can be expected in any ageing population, however, according to our models, this can be close to averted by interventions. Thus, there is an urgent need for risk screening and integration of HIV and CVD programmes to reduce the future CVD burden.

Diabetes mellitus burden among people living with HIV from the Asia-Pacific region.

INTRODUCTION: Comorbidities including diabetes mellitus (DM) among people living with HIV (PLHIV) are of increasing clinical concerns in combination antiretroviral therapy (cART) era. We aimed to determine the incidence and risk factors of new-onset DM among PLHIV in Asian settings. METHODS: PLHIV from a regional observational cohort without DM prior to antiretroviral therapy (ART) initiation were included in the analysis. DM was defined as having a fasting blood glucose ≥126 mg/dL, glycated haemoglobin ≥6.5%, a two-hour plasma glucose ≥200 mg/dL, or a random plasma glucose ≥200 mg/dL. A Cox regression model, stratified by site, was used to identify risk factors associated with DM. RESULTS AND DISCUSSION: Of the 1927 participants included, 127 were diagnosed with DM after ART initiation. Median follow-up time from ART initiation to DM diagnosis was 5.9 years (interquartile range (IQR): 2.8 to 8.9 years). The crude incidence rate of DM was 1.08 per 100 person-years (100 PYS), 95% confidence interval (CI) (0.9 to 1.3). In the multivariate analysis, later years of follow-up (2011 to 2013: HR = 2.34, 95% CI 1.14 to 4.79, p = 0.02; and 2014 to 2017: HR = 7.20, 95% CI 3.27 to 15.87, p < 0.001) compared to <2010, older age (41 to 50 years: HR = 2.46, 95% CI 1.39 to 4.36, p  = 0.002; and >50 years: HR = 4.19, 95% CI 2.12 to 8.28, p < 0.001) compared to <30 years, body mass index (BMI) >30 kg/m2 (HR = 4.3, 95% CI 1.53 to 12.09, p = 0.006) compared to BMI <18.5 kg/m2 , and high blood pressure (HR = 2.05, 95% CI 1.16 to 3.63, p = 0.013) compared to those without high blood pressure, were associated with developing DM. The hazard was reduced for females (HR = 0.47, 95% CI 0.28 to 0.80, p = 0.006). CONCLUSIONS: Type 2 DM in HIV-infected Asians was associated with later years of follow-up, high blood pressure, obesity and older age. This highlights the importance of monitoring and routine screening for non-communicable diseases including DM as PLHIV age.

Trends in CD4 cell count response to first-line antiretroviral treatment in HIV-positive patients from Asia, 2003-2013: TREAT Asia HIV Observational Database Low Intensity Transfer.

Antiretroviral treatment (ART) guidelines have changed over the past decade, recommending earlier initiation and more tolerable regimens. The study objective was to examine the CD4 response to ART, depending on the year of ART initiation, in HIV-positive patients in the Asia-Pacific. We included HIV-positive adult patients who initiated ART between 2003 and 2013 in our regional cohort from eight urban referral centres in seven countries within Asia. We used mixed-effects linear regression models to evaluate differences in CD4 response by year of ART initiation during 36 months of follow-up, adjusted a priori for other covariates. Overall, 16,962 patients were included. Patients initiating in 2006-9 and 2010-13 had an estimated mean CD4 cell count increase of 8 and 15 cells/µl, respectively, at any given time during the 36-month follow-up, compared to those in 2003-5. The median CD4 cell count at ART initiation also increased from 96 cells/µl in 2003-5 to 173 cells/µl in 2010-13. Our results suggest that the CD4 response to ART is modestly higher for those initiating ART in more recent years. Moreover, fewer patients are presenting with lower absolute CD4 cell counts over time. This is likely to reduce their risk of opportunistic infections and future non-AIDS defining cancers.

Loss to Follow-up Trends in HIV-Positive Patients Receiving Antiretroviral Treatment in Asia From 2003 to 2013.

INTRODUCTION: Over time, there has been a substantial improvement in antiretroviral treatment (ART) programs, including expansion of services and increased patient engagement. We describe time trends in, and factors associated with, loss to follow-up (LTFU) in HIV-positive patients receiving ART in Asia. METHODS: Analysis included HIV-positive adults initiating ART in 2003-2013 at 7 ART programs in Asia. Patients LTFU had not attended the clinic for ≥180 days, had not died, or transferred to another clinic. Patients were censored at recent clinic visit, follow-up to January 2014. We used cumulative incidence to compare LTFU and mortality between years of ART initiation. Factors associated with LTFU were evaluated using a competing risks regression model, adjusted for clinical site. RESULTS: A total of 8305 patients were included. There were 743 patients LTFU and 352 deaths over 26,217 person-years (pys), a crude LTFU, and mortality rate of 2.83 (2.64-3.05) per 100 pys and 1.34 (1.21-1.49) per 100 pys, respectively. At 24 months, the cumulative LTFU incidence increased from 4.3% (2.9%-6.1%) in 2003-05 to 8.1% (7.1%-9.2%) in 2006-09 and then decreased to 6.7% (5.9%-7.5%) in 2010-13. Concurrently, the cumulative mortality incidence decreased from 6.2% (4.5%-8.2%) in 2003-05 to 3.3% (2.8%-3.9%) in 2010-13. The risk of LTFU reduced in 2010-13 compared with 2006-09 (adjusted subhazard ratio = 0.73, 0.69-0.99). CONCLUSIONS: LTFU rates in HIV-positive patients receiving ART in our clinical sites have varied by the year of ART initiation, with rates declining in recent years whereas mortality rates have remained stable. Further increases in site-level resources are likely to contribute to additional reductions in LTFU for patients initiating in subsequent years.

Association of worse prognosis with an aberrant diurnal cortisol rhythm in patients with advanced lung cancer.

A flatter diurnal rhythm of cortisol has been reported to be associated with early mortality in patients with metastatic breast cancer. The clinical stage of disease at the time of diagnosis and the patient's performance status (PS) are known to be important prognostic factors for lung cancer (LC) survival. The authors examined the relationship between diurnal cortisol rhythms and these prognostic factors in patients with advanced LC. Cortisol concentrations were measured in saliva samples collected from 52 patients (37 males/15 females) with advanced LC and from 56 healthy subjects (32 males/24 females) to characterize the diurnal cortisol rhythm, specifically the cortisol awakening response (CAR) and diurnal cortisol decline (DCD). Variations of CAR and DCD in the patients were analyzed according to their clinical disease stage and PS score, and the differences in CAR and DCD between patients and healthy controls were compared. The patient group showed significantly reduced diurnal cortisol secretory activity and rhythmicity, compared with healthy controls. When the patients were subgrouped according to their clinical disease stage, patients with stage 4 disease showed significantly reduced CAR and flatter DCD compared with the healthy controls. However, the CAR and DCD in patients with stage 3a and 3b disease were comparable to those of healthy controls. Neither the CAR nor the DCD showed stepwise changes as the disease stage worsened. When patients were subgrouped according to their Eastern Cooperative Oncology Group (ECOG) PS score, there was stepwise reduction in the CAR and flattening of the DCD as the PS score increased. Both an abolished CAR and a flattened DCD were common in patients with ECOG PS scores of 3 and 4. These results indicate that alteration of the diurnal cortisol rhythm in patients with advanced LC is more closely associated with their PS score than with their clinical disease stage. Gradual alteration of the CAR and DCD, indicative of loss of 24-h cortisol rhythm, in concert with increase in PS score implies that endogenous circadian rhythms may also be disintegrating as the PS score worsens in these patients.

Failure to prescribe pneumocystis prophylaxis is associated with increased mortality, even in the cART era: results from the Treat Asia HIV observational database.

BACKGROUND: Pneumocystis jiroveci pneumonia (PCP) prophylaxis is recommended for patients with CD4 counts of less than 200 cells/mm3. This study examines the proportion of patients in the TREAT Asia HIV Observational Database (TAHOD) receiving PCP prophylaxis, and its effect on PCP and mortality. METHODS: TAHOD patients with prospective follow up had data extracted for prophylaxis using co-trimoxazole, dapsone or pentamidine. The proportion of patients on prophylaxis was calculated for each calendar year since 2003 among patients with CD4 counts of less than 200 cells/mm3. The effect of prophylaxis on PCP and survival were assessed using random-effect Poisson regression models. RESULTS: There were a total of 4050 patients on prospective follow up, and 90% of them were receiving combination antiretroviral therapy. Of those with CD4 counts of less than 200 cells/mm3, 58% to 72% in any given year received PCP prophylaxis, predominantly co-trimoxazole. During follow up, 62 patients developed PCP (0.5 per 100 person-years) and 169 died from all causes (1.36/100 person-years). After stratifying by site and adjusting for age, CD4 count, CDC stage and antiretroviral treatment, those without prophylaxis had no higher risk of PCP, but had a significantly higher risk of death (incident rate ratio 10.8, p<0.001). PCP prophylaxis had greatest absolute benefit in patients with CD4 counts of less than 50 cells/mm3, lowering mortality rates from 33.5 to 6.3 per 100 person-years. CONCLUSIONS: Approximately two-thirds of TAHOD patients with CD4 counts of less than 200 cells/mm3 received PCP prophylaxis. Patients without prophylaxis had significantly higher mortality, even in the era of combination ART. Although PCP may be under-diagnosed, these data suggest that prophylaxis is associated with important survival benefits.

Short-term clinical disease progression in HIV-infected patients receiving combination antiretroviral therapy: results from the TREAT Asia HIV observational database.

OBJECTIVE: The aim of our study was to develop, on the basis of simple clinical data, predictive short-term risk equations for AIDS or death in Asian patients infected with human immunodeficiency virus (HIV) who were included in the TREAT Asia HIV Observational Database. METHODS: Inclusion criteria were highly active antiretroviral therapy initiation and completion of required laboratory tests. Predictors of short-term AIDS or death were assessed using Poisson regression. Three different models were developed: a clinical model, a CD4 cell count model, and a CD4 cell count and HIV RNA level model. We separated patients into low-risk, high-risk, and very high-risk groups according to the key risk factors identified. RESULTS: In the clinical model, patients with severe anemia or a body mass index (BMI; calculated as the weight in kilograms divided by the square of the height in meters)