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 (≥3, 1–2 or <1) or CD4 (≥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.     

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 (≥51 cells/μL vs . ≤50 cells/μL; adjusted HR 0.61, P =0.022) and a higher HIV viral load (≥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.     

Hepatitis B and C virus coinfection in The TREAT Asia HIV Observational Database

BACKGROUND AND AIM: Most studies of hepatitis B virus (HBV) and hepatitis C virus (HCV) coinfection with HIV have been conducted among Western patient populations. This study aims to assess rates of HBV and HCV coinfection, and their impact on response to antiretroviral therapy and mortality, using data from The TREAT Asia HIV Observational Database (TAHOD), a multi-center cohort of patients with HIV in the Asia-Pacific region. METHODS: Patients who had been tested either HBV surface antigen (HBsAg) or HCV antibody were included. Patients who ever tested positive for HBV or HCV were regarded as coinfected for the duration of the study. RESULTS: Results of hepatitis tests were available for 55% (HBV) and 49% (HCV) of 2979 TAHOD patients, with prevalence of HBV and HCV coinfection both at approximately 10%. Mean CD4 change at 180 days after antiretroviral treatment initiation was 118.8 cells/muL and patients with either HBV or HCV had a lower but non-significant CD4 increase compared with patients with HIV only. Median time to reach undetectable viral load (<400 copies/mL) was 148 days and was not independently associated with HBV or HCV. In univariate analysis, patients with HCV had increased mortality (unadjusted hazard ratio, HR 2.80, P = 0.007). However, neither HBV (adjusted HR 0.80, 95% confidence interval CI 0.24-2.64, P = 0.710) nor HCV (adjusted HR 1.06, 95% CI 0.40-2.79, P = 0.905) was associated with increased mortality after adjustment for other covariates. Both HBV and HCV remained independently associated with elevated alanine aminotransferase (ALT) in the multivariate model (HBV, adjusted HR 1.94, 95% CI 1.04-3.62, P = 0.037; HCV, adjusted HR 2.74, 95% CI 1.47-5.12, P = 0.002). CONCLUSION: The impact of hepatitis coinfection on immunological and virological responses to antiretroviral therapy and HIV disease progression among this Asian cohort are similar to that seen in Western countries. The longer-term impact of hepatitis coinfection on both HIV disease and liver disease morbidity and mortality needs to be monitored.     

Predicting short-term disease progression among HIV-infected patients in Asia and the Pacific region: preliminary results from the TREAT Asia HIV Observational Database (TAHOD)

OBJECTIVES: HIV disease progression has been well documented in Western populations. This study aimed to estimate the short-term risk of AIDS and death from the TREAT Asia HIV Observational Database (TAHOD), a prospective, multicentre cohort study in Asia and the Pacific region. METHODS: Prospective data were analysed to estimate short-term disease progression. Endpoints were defined as the time from study entry to diagnosis with AIDS or death. Antiretroviral treatment was fitted as a time-dependent variable. Predictors of disease progression were assessed using Cox proportional hazards models, and prognostic models were developed using Weibull models. RESULTS: A total of 1260 patients with prospective follow-up data contributed 477 person-years of follow-up, during which 18 patients died and 34 were diagnosed with AIDS, a combined rate of 10.1 per 100 person-years. Compared with patients receiving antiretroviral treatment, patients not on treatment had a higher rate of disease progression (17.6 vs. 8.1 per 100 person-years, respectively). Baseline CD4 count was the strongest predictor of disease progression. Prognostic models, using either a baseline CD4 count as the sole marker or markers including baseline haemoglobin, AIDS-related symptoms and previous or current antiretroviral treatment, were successful at identifying patients at high risk of short-term disease progression. CONCLUSIONS: Similar to the situation in Western countries, baseline CD4 count was the strongest predictor of short-term disease progression. Prognostic models based on readily available clinical data and haemoglobin level should be useful in estimating short-term clinical risk in HIV-infected patients in Asia and the Pacific region.     

Antiretroviral treatment change among HIV, hepatitis B virus and hepatitis C virus co-infected patients in the Australian HIV Observational Database

OBJECTIVES: To assess the impact of highly active antiretroviral therapy (HAART) on rates of change of antiretroviral treatment among patients co-infected with hepatitis B virus (HBV) and/or hepatitis C virus (HCV) in the Australian HIV Observational Database (AHOD). METHODS: Analysis was based on 805 of the 2218 patients recruited to the AHOD by March 2003, who had commenced HAART after 1 January 1997, who had recorded test results for HBV surface antigen and anti-HCV antibody, and who had follow-up of more than 3 months. The effect of hepatitis co-infection on the rate of antiretroviral treatment change after commencing HAART was assessed using a random-effect Poisson regression model. RESULTS: Among those included in the analyses, the prevalences of HBV and HCV were 4.8% and 12.8%, respectively. The overall rate of combination antiretroviral treatment change was 0.74 combinations per year. Factors independently associated with an increased rate of change of combination antiretroviral treatment were: prior AIDS-defining illness; prior exposure to double combination antiretroviral therapy; and antiretroviral treatment class. Co-infection with HBV and/or HCV was not found to be significantly associated with the rate of combination antiretroviral treatment change. CONCLUSIONS: While both HBV and HCV co-infections are relatively common in the AHOD, they do not appear to be serious impediments to the treatment of HIV-infected patients.     

Treatment and disease outcomes of migrants from low- and middle-income countries in the Australian HIV Observational Database cohort

People from culturally and linguistically diverse backgrounds, including low- and middle-income countries, account for a third of new HIV diagnoses in Australia and are a priority for HIV prevention and treatment programs. We describe the demographic and clinical characteristics of participants in the Australian HIV Observational Database (AHOD) and compare disease outcomes, progression to AIDS and treatment outcomes of those born in low- and middle-income countries, with those born in high-income countries and Australia. All participants enrolled in AHOD sites where country of birth is routinely collected were included in the study. Age, CD4 count, HIV viral load, antiretroviral therapy, hepatitis co-infection, all-cause mortality and AIDS illness were analysed. Of 2403 eligible participants, 77.3% were Australian born, 13.7% born in high-income countries and 9.0% born in middle- or low-income countries. Those born in Australia or high-income countries were more likely to be male (96%) than those from middle- or low-income countries (76%), p?p?p?p?=?.19.There was no difference in adjusted incidence risk ratios for all-cause mortality and AIDS incidence in all three groups, p?=?.39. These findings reflect successful outcomes of people born in low- and middle-income countries once engaged in HIV care.     

Prevalence of and risk factors for lipodystrophy among HIV-infected patients receiving combined antiretroviral treatment in the Asia-Pacific region: results from the TREAT Asia HIV Observational Database (TAHOD)

The prevalence of and risk factors for lipodystrophy (LD) among patients receiving combined antiretroviral treatment (cART) in the Asia-Pacific region are largely unknown. LD diagnosis was based on the adverse event definition from the US NIH Division of AIDS (2004 version), and only cases with a severity grade of ≥ 3 were included. TAHOD patients who had recently commenced cART with ≥ 3 drugs after 1996 from sites which had ever reported LD were included in the analysis. Covariates for the forward multivariate logistic regression model included demographic variables, CDC disease classification, baseline CD4 and viral load, hepatitis B/C virus co-infection, and regimen and duration of cART. LD was diagnosed in 217 (10.5%) of 2072 patients. The median duration of cART was 3.8 (interquartile range, 2.2-5.3) years [stavudine, 2.0 (1.0-3.5) years; zidovudine, 1.8 (0.6-3.9) years; and protease inhibitors (PI), 2.6 (1.3-4.5) years]. In the multivariate model, factors independently associated with LD included use of stavudine (≤ 2 years vs. no experience: OR 25.46, p<0.001, > 2 years vs. no experience: OR 14.92, p<0.001), use of PI (> 2.6 years vs. no experience: OR 0.26, p<0.001), and total duration of cART (> vs. ≤ 3.8 years: OR 4.84, p<0.001). The use of stavudine was strongly associated with LD in our cohort. Stavudine-sparing cART strategies are warranted to prevent the occurrence of LD in the Asia-Pacific region.     

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.     

AIDS-defining illnesses among patients with HIV in Singapore, 1985 to 2001: results from the Singapore HIV Observational Cohort Study (SHOCS)

Background  

The objective was to describe the causes of initial and overall AIDS-defining disease episodes among HIV patients in Singapore.     

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.     

Causes of death among patients with HIV in Singapore from 1985 to 2001: results from the Singapore HIV Observational Cohort Study (SHOCS)

OBJECTIVES: To investigate the major primary and contributory causes of death among HIV patients in Singapore. DESIGN: A retrospective observational cohort study of all adult patients seen at the national referral centre for HIV in Singapore between 1985 and 2001. METHODS: Data were extracted from the patients' records by 10 trained health care workers. AIDS-defining conditions were established using predefined criteria. For each case, a single principal cause of death and up to three contributory causes were identified. RESULTS: A total of 1504 patients aged 17 years or over were seen before the end of 2001, of whom 504 have died. The most frequent principal causes of death were Mycobacterium avium (17.5%), Mycobacterium tuberculosis (9.7%), pneumonia (cause unknown) (6.5%) and Cryptococcus neoformans (6.7%). Three hundred and eighteen patients (63.1%) died from an AIDS-defining condition. CONCLUSIONS: The causes of death were similar to those found in Western cohorts, except that disseminated M. avium was a more frequent cause of death.     

Das Strengthening the Reporting of Observational Studies in Epidemiology (STROBE-) Statement

Much of biomedical research is observational. The reporting of such research is often inadequate, which hampers the assessment of its strengths and weaknesses and of a study's generalizability. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Initiative developed recommendations on what should be included in an accurate and complete report of an observational study. We defined the scope of the recommendations to cover three main study designs: cohort, case-control, and cross-sectional studies. We convened a 2-day workshop in September 2004, with methodologists, researchers, and journal editors to draft a checklist of items. This list was subsequently revised during several meetings of the coordinating group and in e-mail discussions with the larger group of STROBE contributors, taking into account empirical evidence and methodological considerations. The workshop and the subsequent iterative process of consultation and revision resulted in a checklist of 22 items (the STROBE Statement) that relate to the title, abstract, introduction, methods, results, and discussion sections of articles. Eighteen items are common to all three study designs and four are specific for cohort, case-control, or cross-sectional studies. A detailed Explanation and Elaboration document is published separately and is freely available on the web sites of PLoS Medicine, Annals of Internal Medicine, and Epidemiology. We hope that the STROBE Statement will contribute to improving the quality of reporting of observational studies.