Fujie Zhang

Five-Year Outcomes of the China National Free Antiretroviral Treatment Program

Context In 2002, China began the National Free Antiretroviral Treatment Program, which included more than 52000 persons by 2008. Contribution Among 48785 program participants over 5 years, mortality was highest in the 3 months after highly active antiretroviral therapy (HAART) initiation, decreased to 4 to 5 deaths per 100 person years by 6 months, and stayed stable through year 5. The cumulative rate of immunologic treatment failure, measured by CD4 cell count, was 50% by year 5. Implication The program to implement HAART for HIV infection in 1 developing country was associated with a reduction in mortality, but immunologic failure was common in the setting of a limited range of HAART regimens. The Editors In China, an estimated 700000 persons are infected with HIV, of whom approximately 85000 have developed AIDS (1). Of these, a cumulative 223501 and 62838 persons, respectively, had been identified as of October 2007 (2). Before 2002, when China initiated its National Free Antiretroviral Treatment Program as a pilot project among former plasma donors (3, 4), antiretroviral therapy (ART) was not readily available. Treatment was rapidly scaled up, and by August 2008, more than 52000 persons had received first-line highly active antiretroviral therapy (HAART). A few nongovernmental organizations also provide treatment in Chinaand some patients self-paybut an estimated 97% of patients in China receive free treatment through the national program. Currently, all HIV-infected individuals who meet the national treatment criteria are eligible for treatment, and patients have been treated in all 31 provinces, autonomous regions, and municipalities in China. Multiple studies (510) have demonstrated the feasibility of implementing HAART in developing countries, with 1-year outcomes often similar to those in developed countries. Longer-term data on the sustainability of such outcomes have also been reported (1122), but these studies have had either relatively small sample sizes or only slightly longer treatment durations. We report the 5-year outcomes on mortality, immunologic treatment failure rates, and risk factors of all previously treatment-naive adult patients enrolled in the China National Free Antiretroviral Treatment Program. Methods Study Design and Setting The National Free Antiretroviral Treatment Program and its observational database have been previously described (3, 4, 23, 24). Briefly, all HIV-positive patients in China who meet the national treatment guidelines of a CD4 cell count less than 0.200109 cells/L, total lymphocyte count less than 1.2109 cells/L, or World Health Organization (WHO) stage 3 or 4 disease are eligible to receive HAART (25). The first-line treatment regimen consists of zidovudine or stavudine with nevirapine, all generically produced in China. Didanosine (generic) was used as the third drug until 2005, when lamivudine (branded) became available. After treatment initiation, visits are scheduled at 2 weeks, 1 month, 2 months, 3 months, and then every 3 months thereafter. Local health care providers from the program complete visit-specific forms at each visit. Patient Selection All patients who were in the database from June 2002 through 30 August 2008 were eligible. We excluded patients if they did not receive treatment through the national program, were not previously naive to ART, were younger than 18 years at treatment initiation, had not initially received appropriate triple therapy, or had missing treatment dates. We considered 35 CD4 cell counts greater than 3.000109 cells/L to be inaccurate and excluded them as well. We considered patients without a treatment termination date to be active if their most recent follow-up visit was within 6 months of 30 August 2008 and late if it was not. Because Henan province did not participate in the national treatment database until July 2006, we instead collected baseline CD4 cell counts for patients from Henan before July 2006 from the national HIV epidemiology database, which is independently maintained at the Chinese Center for Disease Control and Prevention (China CDC). Variables and Data Collection Case report forms from each visit were forwarded to the China CDC through DataFax (Clinical DataFax Systems, Hamilton, Ontario, Canada). Data collected included demographic characteristics, current symptoms, laboratory results, treatment regimen start and stop dates and the reason for change, and reasons for treatment termination (25). Two reviewers manually compared each data field of each form with the faxed digital image to ensure accurate electronic transcription of data. We sent quality control queries to each site to resolve missing or discrepant data. We considered patients with a prefectural or city-level address to be urban and those with a district, county, or lower-level address to be rural. We calculated survival from the date of ART initiation until death or the date of the last follow-up. For the analysis of immunologic treatment failure and CD4 cell count response, we included only patients with 1 or more follow-up CD4 cell count. We defined immunologic treatment failure by using WHO criteria: CD4 cell count less than 0.100109 cells/L after receiving treatment for 6 months, CD4 cell count at or less than pretreatment level after receiving treatment for 6 months, or CD4 cell count less than 50% of peak on-treatment level (26). We considered treatment to have failed for any patients who met any of these criteria. We defined time to failure as treatment initiation date to the first CD4 cell count date when the patient met 1 of the 3 criteria. We censored data for other patients on the date of their last follow-up visit. We also performed a sensitivity analysis, for which we used 1 year as the treatment failure cut-point instead of 6 months. For the analysis of CD4 cell count response, we used a 3-month window around each time point (6 weeks before and after) to define the CD4 cell count for that interval. We included the initial 6 weeks after treatment within the 3-month time point. If more than 1 CD4 cell count was done during any interval, we used the one closest to each 3-month time point. We defined the last pretreatment CD4 cell count as the baseline. Because of the difficulty in definitively diagnosing opportunistic infections in rural settings, we used easily identified signs and symptoms as a proxy. These were collected as part of a general review of systems and a physical examination during the baseline patient visit and were categorized as fever, pulmonary (cough, dyspnea, chest pain, night sweats, or lymphadenopathy), gastrointestinal (nausea, vomiting, or diarrhea), skin or mucosal (rash, thrush, or oral hairy leukoplakia), or central nervous system (headache or visual changes). Statistical Analysis We compared baseline characteristics between cohorts by using the MannWhitney test for continuous variables, because none fulfilled the KolmogorovSmirnov test for normality. We used the Pearson chi-square statistic for dichotomous and categorical variables. We used Cox proportional hazards modeling to assess hazard ratios (HRs) between the outcome (mortality or treatment failure) and potential risk factors. We entered covariates that we predetermined to be clinically significant into full multivariate Cox models. We calculated survival curves by using life tables and assessed statistical significance between groups by using the log-rank test because the assumption of proportionality was fulfilled. We modeled CD4 cell counts over time by using the mixed linear model with maximum likelihood estimation. We used SPSS, version 13.0 (SPSS, Chicago, Illinois), and SAS, version 9.13 (SAS Institute, Cary, North Carolina), for all analyses. All hypothesis testing was 2-sided, with an level of 0.05. The institutional review board of the China CDC approved this analysis. Role of the Funding Source This study was funded by the applied research program on AIDS prevention and treatment of the China Ministry of Health, the U.S. National Institutes of Health, and a cooperative agreement from the U.S. Centers for Disease Control and Prevention Global AIDS Program to the China CDC. The U.S. sponsors were involved in the study design, data analysis and interpretation, writing of the manuscript, and decision to submit the paper for publication. Results Of 52191 patients with AIDS in the National Free Antiretroviral Treatment Program database through 30 August 2008, 3406 were excluded (Figure 1). Of the 48785 patients we included, 70% were active, 10% were late, and 13% died (90% of these deaths were AIDS related). Seven percent terminated treatment because of medication adverse effects (46%), patient request (35%), poor adherence (9%), or other (10%). Forty-seven percent of included patients were from Henan province; 15% from Yunnan; 11% from Guangxi; 5% from Anhui; and 3% each from Xinjiang, Hubei, and Guangdong, with the remaining 13% distributed among the other 24 provinces, autonomous regions, and municipalities. Median follow-up time was 17 months (interquartile range [IQR], 5 to 37), with a median of 7 follow-up visits (IQR, 4 to 9). Median age was 38 years, 58% were men, 75% were married, and 53% were infected through plasma or blood (Table 1). We classified 82% as rural, with 91% of plasma donors and 72% of those infected through other routes as rural (P for difference< 0.001). Baseline median CD4 cell count was 0.118109 cells/L (among those with a baseline CD4 cell count), and 81% of patients had at least 1 baseline symptom category. Treatment regimens consisted of zidovudine or stavudine and nevirapine as 2 of the 3 drugs, with similar rates of zidovudine and stavudine use. Didanosine was the third drug for 46% of patients and lamivudine for 43%. These 4 regimens made up 89% of all initial regimens. Patients who received a diagnosis of HIVtuberculosis co-infection (9%) received efavirenz instead of nevirapine. Figure 1. Study flow d

The Chinese free antiretroviral treatment program: challenges and responses.

To respond to the HIV/AIDS epidemic in China, the National Center for AIDS/STD Control and Prevention established the Division of Treatment and Care in late 2001. The pilot for the National Free ART Program began in Henan Province in 2002, and the program fully began in 2003. Treatment efforts initially focused on patients infected through illicit blood and plasma donation in the mid-1990s and subsequently expanded to include HIV-infected injection drug users, commercial sex workers, pregnant women, and children. The National Free ART Database was established in late 2004, and includes data on current patients and those treated before 2004. Over 31 000 adult and pediatric patients have been treated thus far. Challenges for the program include integration of drug treatment services with ART, an under-resourced health care system, co-infections, stigma, discrimination, drug resistance, and procurement of second-line ART. The merging of national treatment and care, epidemiologic, and drug resistance databases will be critical for a better understanding of the epidemic, for earlier identification of patients requiring ART, and for improved patient follow-up. The Free ART Program has made considerable progress in providing the necessary care and treatment for HIV-infected people in China and has strong government support for continued improvement and expansion.

The TREAT Asia HIV Observational Database: baseline and retrospective data.

Background:Relatively little is known regarding HIV disease natural history and response to antiretroviral treatments among Asian people infected with HIV. The Therapeutics Research, Education, and AIDS Training in Asia (TREAT Asia) HIV Observational Database (TAHOD) is a recently established collaborative observational cohort study that aims to assess HIV disease natural history in treated and untreated patients in the Asia-Pacific region. Methods:Observational data are collected on HIV-infected patients from 11 sites in the Asia-Pacific region. Data are centrally aggregated for analyses, with the first baseline and retrospective data transferred in September 2003. Retrospective data were analyzed to assess the response to highly active antiretroviral treatment (HAART) over a 6-month period in terms of changes in CD4 count and proportions of patients achieving an undetectable HIV viral load (<400 copies/mL). Results:By the end of May 2004, 1887 patients had been recruited to the TAHOD. Seventy-two percent of patients were male, with median age 36 years. Seventy-eight percent of patients reported HIV infection through heterosexual contact. Forty-three percent of patients had a previous AIDS diagnosis, of whom 55% had tuberculosis. The mean 6-month CD4 count increase was 115 cells/μL (SD = 127) after starting triple-combination therapy. Smaller CD4 count increases were associated with a higher CD4 count before starting treatment, prior treatment with monotherapy or double therapy, and treatment with a HAART regimen containing a nucleoside reverse transcriptase inhibitor (NRTI) and/or protease inhibitor (PI) but without a nonnucleoside reverse transcriptase inhibitor (NNRTI). Five hundred and ninety-eight patients started HAART and had a viral load assessment at 6 months, with 69% attaining an undetectable viral load. Older patients, patients not exposed to HIV through heterosexual contact, and patients treated with HAART containing NRTIs and NNRTIs but without PIs were found to be more likely to achieve an undetectable level. Conclusion:Analyses of retrospective data in the TAHOD suggest that the overall response to HAART in Asian populations is similar to that seen in Western countries.

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

BackgroundPneumocystis 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.MethodsTAHOD 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.ResultsThere 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.ConclusionsApproximately 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.

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

Background and Aim:u2002 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.

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

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.

Chinese pediatric highly active antiretroviral therapy observational cohort: a 1-year analysis of clinical, immunologic, and virologic outcomes.

Background:Few data are available on the outcomes of pediatric antiretroviral therapy (ART) in the developing world. Methods:Eighty-three children were followed prospectively in China from July 2005 to August 2006 and received (zidovudine or stavudine) plus lamivudine plus (nevirapine or efavirenz). Results:Fifty-one children were ART naive at enrollment, and 32 were ART experienced. After 12 months, median weight increased by 0.3 weight for age z-score, median CD4 count increased from 116 to 340 cells/mm3 (P < 0.0001), and median viral load decreased from 5.53 to <2.60 log10 copies/mL (P < 0.0001) in the previously ART-naive children. In the ART-experienced children, median CD4 count increased from 193 to 318 cells/mm3 (P = 0.13), despite little change in median viral load (4.85 to 4.58 log10 copies/mL; P = 0.83). The viral load was <400 copies/mL in 55% of the previously ART-naive children and in 16% of the ART-experienced children. Conclusions:Weight and CD4 cell counts improved, and more than half of previously ART-naive patients had undetectable viral loads at 1 year. Future efforts should focus on improved virologic suppression through improved adherence and access to second-line regimens.

Risk and prognostic significance of tuberculosis in patients from The TREAT Asia HIV Observational Database

BackgroundTo assess the risk and the prognostic significance of tuberculosis (TB) diagnosis in patients from The TREAT Asia HIV Observational Database, a multi-centre prospective cohort of HIV-infected patients receiving HIV care in the Asia-Pacific region.MethodsThe risk of TB diagnosis after recruitment was assessed in patients with prospective follow-up. TB diagnosis was fitted as a time-dependent variable in assessing overall survival.ResultsAt baseline, 22% of patients were diagnosed with TB. TB incidence was 1.98 per 100 person-years during follow up, with predictors including younger age, lower recent CD4 count, duration of antiretroviral treatment, and living in high TB burden countries. Among 3279 patients during 6968 person-years, 142 died (2.04 per 100 person-years). Compared to patients with CDC category A or B illness only, mortality was marginally higher in patients with single Non-TB AIDS defining illness (ADI), or TB only (adjusted HR 1.35, p = 0.173) and highest in patients with multiple non-TB AIDS or both TB and other ADI (adjusted HR 2.21, p < 0.001).ConclusionThe risk of TB diagnosis was associated with increasing immunodeficiency and partly reduced by antiretroviral treatment. The prognosis of developing TB appeared to be similar to that following a diagnosis of other non-TB ADI.

Hepatitis B and hepatitis C seroprevalence in children receiving antiretroviral therapy for human immunodeficiency virus-1 infection in China, 2005-2009.

Background:Coinfection of hepatitis B virus (HBV) or hepatitis C virus (HCV) may compromise pediatric antiretroviral therapy (ART) in China. In this study, we evaluated the seroprevalence of HBV and HCV in children receiving ART and associated factors. Methods:Patients were selected from HIV-1-infected children under age 16 enrolled in China National Pediatric ART Cohort since July 2005. Medical assessments, hepatitis B surface antigen (HBsAg), and anti-HCV antibody serologies, and transaminase levels were obtained for analysis. Results:A total of 53 of 1082 children tested were HBsAg seropositive [4.9%; 95% confidence interval (CI): 3.6% to 6.2%], and 90 of 938 children tested were anti-HCV antibody positive (9.6%; 95% CI: 7.7% to 11.5%). No other serologic assays were performed for HBV detection. Age was associated with HBV coinfection in univariate analysis; older children were more likely to be HBsAg positive. Multivariate analysis revealed that children infected with HIV through transfusion of contaminated blood or blood products were more likely to be anti-HCV antibody positive than those infected with HIV through other routes (adjusted odds ratio = 6.2; 95% CI: 3.3% to 11.7%). Conclusions:The high prevalence of HBV and HCV coinfection in HIV-infected children in China receiving ART demands routine screening for viral hepatitis coinfection, intensive prevention of childhood HBV and HCV transmission, and modification of the management of pediatric HIV infection.

Short-Term Clinical Disease Progression in HIV-Infected Patients Receiving Combination Antiretroviral Therapy: Results from the TREAT Asia HIV Observational Database

OBJECTIVEnThe 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.nnnMETHODSnInclusion 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.nnnRESULTSnIn 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) <or= 18 were at very high risk, and patients who were aged <40 years or were male and had mild anemia were at high risk. In the CD4 cell count model, patients with a CD4 cell count <50 cells/microL, severe anemia, or a BMI <or=18 were at very high risk, and patients who had a CD4 cell count of 51-200 cells/microL, were aged <40 years, or were male and had mild anemia were at high risk. In the CD4 cell count and HIV RNA level model, patients with a CD4 cell count <50 cells/microL, a detectable viral load, severe anemia, or a BMI <or=18 were at very high risk, and patients with a CD4 cell count of 51-200 cells/microL and mild anemia were at high risk. The incidence of new AIDS or death in the clinical model was 1.3, 4.9, and 15.6 events per 100 person-years in the low-risk, high-risk, and very high-risk groups, respectively. In the CD4 cell count model the respective incidences were 0.9, 2.7, and 16.02 events per 100 person-years; in the CD4 cell count and HIV RNA level model, the respective incidences were 0.8, 1.8, and 6.2 events per 100 person-years.nnnCONCLUSIONSnThese models are simple enough for widespread use in busy clinics and should allow clinicians to identify patients who are at high risk of AIDS or death in Asia and the Pacific region and in resource-poor settings.