Virological failure and HIV drug resistance among adults living with HIV on second-line antiretroviral therapy in the Asia-Pacific.

OBJECTIVES: To assess second-line antiretroviral therapy (ART) virological failure and HIV drug resistance-associated mutations (RAMs), in support of third-line regimen planning in Asia. METHODS: Adults > 18 years of age on second-line ART for ≥ 6 months were eligible. Cross-sectional data on HIV viral load (VL) and genotypic resistance testing were collected or testing was conducted between July 2015 and May 2017 at 12 Asia-Pacific sites. Virological failure (VF) was defined as VL > 1000 copies/mL with a second VL > 1000 copies/mL within 3-6 months. FASTA files were submitted to Stanford University HIV Drug Resistance Database and RAMs were compared against the IAS-USA 2019 mutations list. VF risk factors were analysed using logistic regression. RESULTS: Of 1378 patients, 74% were male and 70% acquired HIV through heterosexual exposure. At second-line switch, median [interquartile range (IQR)] age was 37 (32-42) years and median (IQR) CD4 count was 103 (43.5-229.5) cells/µL; 93% received regimens with boosted protease inhibitors (PIs). Median duration on second line was 3 years. Among 101 patients (7%) with VF, CD4 count > 200 cells/µL at switch [odds ratio (OR) = 0.36, 95% confidence interval (CI): 0.17-0.77 vs. CD4 ≤ 50) and HIV exposure through male-male sex (OR = 0.32, 95% CI: 0.17-0.64 vs. heterosexual) or injecting drug use (OR = 0.24, 95% CI: 0.12-0.49) were associated with reduced VF. Of 41 (41%) patients with resistance data, 80% had at least one RAM to nonnucleoside reverse transcriptase inhibitors (NNRTIs), 63% to NRTIs, and 35% to PIs. Of those with PI RAMs, 71% had two or more. CONCLUSIONS: There were low proportions with VF and significant RAMs in our cohort, reflecting the durability of current second-line regimens.

Association of body mass index with immune recovery, virological failure and cardiovascular disease risk among people living with HIV.

OBJECTIVES: We conducted a longitudinal cohort analysis to evaluate the association of pre-treatment body mass index (BMI) with CD4 recovery, virological failure (VF) and cardiovascular risk disease (CVD) markers among people living with HIV (PLHIV). METHODS: Participants who were enrolled between January 2003 and March 2019 in a regional Asia HIV cohort with weight and height measurements prior to antiretroviral therapy (ART) initiation were included. Factors associated with mean CD4 increase were analysed using repeated-measures linear regression. Time to first VF after 6 months on ART and time to first development of CVD risk markers were analysed using Cox regression models. Sensitivity analyses were done adjusting for Asian BMI thresholds. RESULTS: Of 4993 PLHIV (66% male), 62% had pre-treatment BMI in the normal range (18.5-25.0 kg/m2 ), while 26%, 10% and 2% were underweight (< 18.5 kg/m2 ), overweight (25-30 kg/m2) and obese (> 30 kg/m2 ), respectively. Both higher baseline and time-updated BMI were associated with larger CD4 gains compared with normal BMI. After adjusting for Asian BMI thresholds, higher baseline BMIs of 23-27.5 and > 27.5 kg/m2 were associated with larger CD4 increases of 15.6 cells/µL [95% confidence interval (CI): 2.9-28.3] and 28.8 cells/µL (95% CI: 6.6-50.9), respectively, compared with normal BMI (18.5-23 kg/m2 ). PLHIV with BMIs of 25-30 and > 30 kg/m2 were 1.27 times (95% CI: 1.10-1.47) and 1.61 times (95% CI: 1.13-2.24) more likely to develop CVD risk factors. No relationship between pre-treatment BMI and VF was observed. CONCLUSIONS: High pre-treatment BMI was associated with better immune reconstitution and CVD risk factor development in an Asian PLHIV cohort.

Early mortality after late initiation of antiretroviral therapy in the TREAT Asia HIV Observational Database (TAHOD) of the International Epidemiologic Databases to Evaluate AIDS (IeDEA) Asia-Pacific.

OBJECTIVES: Early mortality among those still initiating antiretroviral therapy (ART) with advanced stages of HIV infection in resource-limited settings remains high despite recommendations for universal HIV treatment. We investigated risk factors associated with early mortality in people living with HIV (PLHIV) starting ART at low CD4 levels in the Asia-Pacific. METHODS: PLHIV enrolled in the Therapeutics, Research, Education and AIDS Training in Asia (TREAT Asia) HIV Observational Database (TAHOD) who initiated ART with a CD4 count < 100 cells/µL between 2003 and 2018 were included in the study. Early mortality was defined as death within 1 year of ART initiation. PLHIV in follow-up for > 1 year were censored at 12 months. Competing risk regression was used to analyse risk factors with loss to follow-up as a competing risk. RESULTS: A total of 1813 PLHIV were included in the study, of whom 74% were male. With 73 (4%) deaths, the overall first-year mortality rate was 4.27 per 100 person-years (PY). Thirty-eight deaths (52%) were AIDS-related, 10 (14%) were immune reconstituted inflammatory syndrome (IRIS)-related, 13 (18%) were non-AIDS-related and 12 (16%) had an unknown cause. Risk factors included having a body mass index (BMI) < 18.5 [sub-hazard ratio (SHR) 2.91; 95% confidence interval (CI) 1.60-5.32] compared to BMI 18.5-24.9, and alanine aminotransferase (ALT) ≥ 5 times its upper limit of normal (ULN) (SHR 6.14; 95% CI 1.62-23.20) compared to ALT < 5 times its ULN. A higher CD4 count (51-100 cells/µL: SHR 0.28; 95% CI 0.14-0.55; and > 100 cells/µL: SHR 0.12; 95% CI 0.05-0.26) was associated with reduced hazard for mortality compared to CD4 count ≤ 25 cells/µL. CONCLUSIONS: Fifty-two per cent of early deaths were AIDS-related. Efforts to initiate ART at CD4 counts > 50 cell/µL are associated with improved short-term survival rates, even in those with late stages of HIV disease.

Long-term loss to follow-up in the TREAT Asia HIV Observational Database (TAHOD).

OBJECTIVES: With earlier antiretroviral therapy (ART) initiation, time spent in HIV care is expected to increase. We aimed to investigate loss to follow-up (LTFU) in Asian patients who remained in care 5 years after ART initiation. METHODS: Long-term LTFU was defined as LTFU occurring after 5 years on ART. LTFU was defined as (1) patients not seen in the previous 12 months; and (2) patients not seen in the previous 6 months. Factors associated with LTFU were analysed using competing risk regression. RESULTS: Under the 12-month definition, the LTFU rate was 2.0 per 100 person-years (PY) [95% confidence interval (CI) 1.8-2.2 among 4889 patients included in the study. LTFU was associated with age > 50 years [sub-hazard ratio (SHR) 1.64; 95% CI 1.17-2.31] compared with 31-40 years, viral load ≥ 1000 copies/mL (SHR 1.86; 95% CI 1.16-2.97) compared with viral load < 1000 copies/mL, and hepatitis C coinfection (SHR 1.48; 95% CI 1.06-2.05). LTFU was less likely to occur in females, in individuals with higher CD4 counts, in those with self-reported adherence ≥ 95%, and in those living in high-income countries. The 6-month LTFU definition produced an incidence rate of 3.2 per 100 PY (95% CI 2.9-3.4 and had similar associations but with greater risks of LTFU for ART initiation in later years (2006-2009: SHR 2.38; 95% CI 1.93-2.94; and 2010-2011: SHR 4.26; 95% CI 3.17-5.73) compared with 2003-2005. CONCLUSIONS: The long-term LTFU rate in our cohort was low, with older age being associated with LTFU. The increased risk of LTFU with later years of ART initiation in the 6-month analysis, but not the 12-month analysis, implies that there was a possible move towards longer HIV clinic scheduling in Asia.

Smoking and projected cardiovascular risk in an HIV-positive Asian regional cohort.

OBJECTIVES: The aim of the study was to assess the prevalence and characteristics associated with current smoking in an Asian HIV-positive cohort, to calculate the predictive risks of cardiovascular disease (CVD), coronary heart disease (CHD) and myocardial infarction (MI), and to identify the impact that simulated interventions may have. METHODS: Logistic regression analysis was used to distinguish associated current smoking characteristics. Five-year predictive risks of CVD, CHD and MI and the impact of simulated interventions were calculated utilizing the Data Collection on Adverse Effects of Anti-HIV Drugs Study (D:A:D) algorithm. RESULTS: Smoking status data were collected from 4274 participants and 1496 of these had sufficient data for simulated intervention calculations. Current smoking prevalence in these two groups was similar (23.2% vs. 19.9%, respectively). Characteristics associated with current smoking included age > 50 years compared with 30-39 years [odds ratio (OR) 0.65; 95% confidence interval (CI) 0.51-0.83], HIV exposure through injecting drug use compared with heterosexual exposure (OR 3.03; 95% CI 2.25-4.07), and receiving antiretroviral therapy (ART) at study sites in Singapore, South Korea, Malaysia, Japan and Vietnam in comparison to Thailand (all OR > 2). Women were less likely to smoke than men (OR 0.11; 95% CI 0.08-0.14). In simulated interventions, smoking cessation demonstrated the greatest impact in reducing CVD and CHD risk and closely approximated the impact of switching from abacavir to an alternate antiretroviral in the reduction of 5-year MI risk. CONCLUSIONS: Multiple interventions could reduce CVD, CHD and MI risk in Asian HIV-positive patients, with smoking cessation potentially being the most influential.

Prognostic significance of the interval between the initiation of antiretroviral therapy and the initiation of anti-tuberculosis treatment in HIV/tuberculosis-coinfected patients: results from the TREAT Asia HIV Observational Database.

OBJECTIVES: We evaluated the effect of the time interval between the initiation of antiretroviral therapy (ART) and the initiation of tuberculosis (TB) treatment on clinical outcomes in HIV/TB-coinfected patients in an Asian regional cohort. METHODS: Adult HIV/TB-coinfected patients in an observational HIV-infected cohort database who had a known date of ART initiation and a history of TB treatment were eligible for study inclusion. The time interval between the initiation of ART and the initiation of TB treatment was categorized as follows: TB diagnosed while on ART, ART initiated ≤ 90 days after initiation of TB treatment ('early ART'), ART initiated > 90 days after initiation of TB treatment ('delayed ART'), and ART not started. Outcomes were assessed using survival analyses. RESULTS: A total of 768 HIV/TB-coinfected patients were included in this study. The median CD4 T-cell count at TB diagnosis was 100 [interquartile range (IQR) 40-208] cells/µL. Treatment outcomes were not significantly different between the groups with early ART and delayed ART initiation. Kaplan-Meier analysis indicated that mortality was highest for those diagnosed with TB while on ART (3.77 deaths per 100 person-years), and the prognoses of other groups were not different (in deaths per 100 person-years: 2.12 for early ART, 1.46 for delayed ART, and 2.94 for ART not started). In a multivariate model, the interval between ART initiation and TB therapy initiation did not significantly impact all-cause mortality. CONCLUSIONS: A negative impact of delayed ART in patients coinfected with TB was not observed in this observational cohort of moderately to severely immunosuppressed patients. The broader impact of earlier ART initiation in actual clinical practice should be monitored more closely.

Deferred modification of antiretroviral regimen following documented treatment failure in Asia: results from the TREAT Asia HIV Observational Database (TAHOD).

OBJECTIVE: The aim of the study was to examine the rates and predictors of treatment modification following combination antiretroviral therapy (cART) failure in Asian patients with HIV enrolled in the TREAT Asia HIV Observational Database (TAHOD). METHODS: Treatment failure (immunological, virological and clinical) was defined by World Health Organization criteria. Countries were categorized as high or low income by World Bank criteria. RESULTS: Among 2446 patients who initiated cART, 447 were documented to have developed treatment failure over 5697 person-years (7.8 per 100 person-years). A total of 253 patients changed at least one drug after failure (51.6 per 100 person-years). There was no difference between patients from high- and low-income countries [adjusted hazard ratio (HR) 1.02; P=0.891]. Advanced disease stage [Centers for Disease Control and Prevention (CDC) category C vs. A; adjusted HR 1.38, P=0.040], a lower CD4 count (>or=51 cells/microL vs. or=400 HIV-1 RNA copies/mL vs. <400 copies/mL; adjusted HR 2.69, P<0.001) were associated with a higher rate of treatment modification after failure. Compared with patients from low-income countries, patients from high-income countries were more likely to change two or more drugs (67%vs. 49%; P=0.009) and to change to a protease-inhibitor-containing regimen (48%vs. 16%; P<0.001). CONCLUSIONS: In a cohort of Asian patients with HIV infection, nearly half remained on the failing regimen in the first year following documented treatment failure. This deferred modification is likely to have negative implications for accumulation of drug resistance and response to second-line treatment. There is a need to scale up the availability of second-line regimens and virological monitoring in this region.

Measures of site resourcing predict virologic suppression, immunologic response and HIV disease progression following highly active antiretroviral therapy (HAART) in the TREAT Asia HIV Observational Database (TAHOD).

OBJECTIVES: Surrogate markers of HIV disease progression are HIV RNA in plasma viral load (VL) and CD4 cell count (immune function). Despite improved international access to antiretrovirals, surrogate marker diagnostics are not routinely available in resource-limited settings. Therefore, the objective was to assess effects of economic and diagnostic resourcing on patient treatment outcomes. METHODS: Analyses were based on 2333 patients initiating highly active antiretroviral therapy (HAART) from 2000 onwards. Sites were categorized by World Bank country income criteria (high/low) and annual frequency of VL (> or = 3, 1-2 or <1) or CD4 (> or = 3 or <3) testing. Endpoints were time to AIDS/death and change in CD4 cell count and VL suppression (<400 HIV-1 RNA copies/mL) at 12 months. Demographics, Centers for Disease Control and Prevention (CDC) classification, baseline VL/CD4 cell counts, hepatitis B/C coinfections and HAART regimen were covariates. Time to AIDS/death was analysed by proportional hazards models. CD4 and VL endpoints were analysed using linear and logistic regression, respectively. RESULTS: Increased disease progression was associated with site-reported VL testing less than once per year [hazard ratio (HR)=1.4; P=0.032], severely symptomatic HIV infection (HR=1.4; P=0.003) and hepatitis C virus coinfection (HR=1.8; P=0.011). A total of 1120 patients (48.2%) had change in CD4 cell count data. Smaller increases were associated with older age (P<0.001) and 'Other' HIV source exposures, including injecting drug use and blood products (P=0.043). A total of 785 patients (33.7%) contributed to the VL suppression analyses. Patients from sites with VL testing less than once per year [odds ratio (OR)=0.30; P<0.001] and reporting 'Other' HIV exposures experienced reduced suppression (OR=0.28; P<0.001). CONCLUSION: Low measures of site resourcing were associated with less favourable patient outcomes, including a 35% increase in disease progression in patients from sites with VL testing less than once per year.

Atherosclerotic cardiovascular disease screening and management protocols among adult HIV clinics in Asia.

OBJECTIVES: Integration of HIV and non-communicable disease services improves the quality and efficiency of care in low- and middle-income countries (LMICs). We aimed to describe current practices for the screening and management of atherosclerotic cardiovascular disease (ASCVD) among adult HIV clinics in Asia. METHODS: Sixteen LMIC sites included in the International Epidemiology Databases to Evaluate AIDS - Asia-Pacific network were surveyed. RESULTS: Sites were mostly (81%) based in urban public referral hospitals. Half had protocols to assess tobacco and alcohol use. Protocols for assessing physical inactivity and obesity were in place at 31% and 38% of sites, respectively. Most sites provided educational material on ASCVD risk factors (between 56% and 75% depending on risk factors). A total of 94% reported performing routine screening for hypertension, 100% for hyperlipidaemia and 88% for diabetes. Routine ASCVD risk assessment was reported by 94% of sites. Protocols for the management of hypertension, hyperlipidaemia, diabetes, high ASCVD risk and chronic ischaemic stroke were in place at 50%, 69%, 56%, 19% and 38% of sites, respectively. Blood pressure monitoring was free for patients at 69% of sites; however, most required patients to pay some or all the costs for other ASCVD-related procedures. Medications available in the clinic or within the same facility included angiotensin-converting enzyme inhibitors (81%), statins (94%) and sulphonylureas (94%). CONCLUSION: The consistent availability of clinical screening, diagnostic testing and procedures and the availability of ASCVD medications in the Asian LMIC clinics surveyed are strengths that should be leveraged to improve the implementation of cardiovascular care protocols.

Socio-economic status and risk of tuberculosis: a case-control study of HIV-infected patients in Asia.

SETTING: Tuberculosis (TB) is the most common human immunodeficiency virus (HIV) related opportunistic infection and cause of acquired immune-deficiency syndrome related death. TB often affects those from a low socio-economic background. OBJECTIVE: To assess the socio-economic determinants of TB in HIV-infected patients in Asia. DESIGN: This was a matched case-control study. HIV-positive, TB-positive cases were matched to HIV-positive, TB-negative controls according to age, sex and CD4 cell count. A socio-economic questionnaire comprising 23 questions, including education level, employment, housing and substance use, was distributed. Socio-economic risk factors for TB were analysed using conditional logistic regression analysis. RESULTS: A total of 340 patients (170 matched pairs) were recruited, with 262 (77.1%) matched for all three criteria. Pulmonary TB was the predominant type (n = 115, 67.6%). The main risk factor for TB was not having a university level education (OR 4.45, 95%CI 1.50-13.17, P = 0.007). Burning wood or coal regularly inside the house and living in the same place of origin were weakly associated with TB diagnosis. CONCLUSIONS: These data suggest that lower socio-economic status is associated with an increased risk of TB in Asia. Integrating clinical and socio-economic factors into HIV treatment may help in the prevention of opportunistic infections and disease progression.

AIDS-defining illness diagnosed within 90 days after starting highly active antiretroviral therapy among patients from the TREAT Asia HIV Observational Database.

Using data from TREAT Asia HIV Observational Database (TAHOD), this paper aims to assess the rate of, and factors associated with the diagnosis of new AIDS-defining illness (ADI) within 90 days after antiretroviral treatment. Patients starting three or more antiretroviral combinations and having subsequent follow-up were included. New ADI cases were checked for evidence of immune reconstitution syndrome (IRS). Among the 1185 patients included, 75 (6.3%) were diagnosed with a new ADI within 90 days, giving a rate of 26.8/100 person-years, compared with a further 3.6% cumulative incidence of new ADI between 90 days to one year (4.2/100 person-years). Of the 75 patients, 21 were judged as definitive or presumptive IRS, giving a rate of 7.3/100 person-years. Patients with new ADI generally had lower CD4 counts before treatment started (median, 43 cells/microL). Lower CD4 count, lower body mass index and starting treatment in the same year as the first HIV-positive test done were associated with developing a new ADI. The higher rate of new ADI within 90 days may be partly explained by IRS occurring shortly after treatment. Although it is difficult to identify IRS from observational data, it appears that in TAHOD setting IRS was relatively uncommon.

Predictors of clinical progression in HIV-1-infected adults initiating combination antiretroviral therapy with advanced disease in the Asia-Pacific region: results from the TREAT Asia HIV observational database.

The majority of HIV-infected patients in developing countries commences combination antiretroviral therapy (cART) with advanced disease. We examined predictors of disease progression in patients initiating cART with CD4 count ≤200 cells/mm(3) in the TREAT Asia HIV Observational Database. The main outcome measure was progression to either an AIDS-defining illness or death occurring 6 months after initiation of cART. We used survival analysis methods. A total of 1255 patients contributed 2696 person years of follow-up; 73 were diagnosed with AIDS and 9 died. The rate of progression to the combined end point was 3.0 per 100 person years. The factors significantly associated with a higher risk of disease progression were Indian ethnicity, infection through intravenous drug use, lower CD4 count, and hemoglobin ≤130 g/dL at 6 months. In conclusion, measurements of CD4 count and hemoglobin at month 6 may be useful for early identification of disease progression in resource-limited settings.

Prior antiretroviral therapy experience protects against zidovudine-related anaemia.

OBJECTIVE: We investigated the use of antiretroviral therapy regimens containing zidovudine or stavudine, using data from the TREAT Asia HIV Observational Database (TAHOD), a multicentre, prospective, observational study of an HIV-infected cohort in the Asia-Pacific Region. METHODS: A proportional hazards regression analysis of factors associated with the time to discontinuation of initial regimens containing zidovudine or stavudine and a logistic regression analysis to identify factors associated with a diagnosis of anaemia within 6 months of commencement of zidovudine in initial or subsequent regimens were performed. RESULTS: Patients who started zidovudine were more likely to stop within the first 9 months of treatment than those who started on stavudine; the reverse was true after 9 months. Anaemia (haemoglobin

Experience with the use of a first-line regimen of stavudine, lamivudine and nevirapine in patients in the TREAT Asia HIV Observational Database.

BACKGROUND: The antiretroviral treatment (ART) combination of stavudine, lamivudine and nevirapine (d4T/3TC/NVP) is the most frequently used initial regimen in many Asian countries. There are few data on the outcome of this treatment in clinic cohorts in this region. METHODS: We selected patients from the TREAT Asia HIV Observational Database (TAHOD) who started their first ART regimen with d4T/3TC/NVP. Treatment change was defined as cessation of therapy or the addition or change of one or more drugs. Clinical failure was defined as diagnosis with an AIDS-defining illness, or death while on d4T/3TC/NVP treatment. RESULTS: The rate of treatment change among TAHOD patients starting d4T/3TC/NVP as their first antiretroviral treatment was 22.3 per 100 person-years, with lower baseline haemoglobin (i.e. anaemia) associated with slower rate of treatment change. The rate of clinical failure while on d4T/3TC/NVP treatment was 7.3 per 100 person-years, with baseline CD4 cell count significantly associated with clinical failure. After d4T/3TC/NVP was stopped, nearly 40% of patients did not restart any treatment and, of those who changed to other treatment, the majority changed to zidovudine (ZDV)/3TC/NVP and less than 3% of patients changed to a protease inhibitor (PI)-containing regimen. The rates of disease progression on the second-line regimen were similar to those on the first-line regimen. CONCLUSION: These real-life data provide an insight into clinical practice in Asia and the Pacific region. d4T/3TC/NVP is maintained longer than other first-line regimens and change is mainly as a result of adverse effects rather than clinical failure. There is a need to develop affordable second-line antiretroviral treatment options for patients with HIV infection in developing countries.