Zhihui Dou

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

Antiretroviral therapy to prevent HIV transmission in serodiscordant couples in China (2003–11) : a national observational cohort study

BACKGROUND On the basis of the results of the randomised clinical trial HPTN 052 and observational studies, WHO has recommended that antiretroviral therapy be offered to all HIV-infected individuals with uninfected partners of the opposite sex (serodiscordant couples) to reduce the risk of transmission. Whether or not such a public health approach is feasible and the outcomes are sustainable at a large scale and in a developing country setting has not previously been assessed. METHODS In this retrospective observational cohort study, we included treated and treatment-naive HIV-positive individuals with HIV-negative partners of the opposite sex who had been added to the national HIV epidemiology and treatment databases between Jan 1, 2003 and Dec 31, 2011. We analysed the annual rate of HIV infection in HIV-negative partners during follow-up, stratified by treatment status of the index partner. Cox proportional hazards analyses were done to examine factors related to HIV transmission. FINDINGS Based on data from 38,862 serodiscordant couples, with 101,295·1 person-years of follow-up for the seronegative partners, rates of HIV infection were 2·6 per 100 person-years (95% CI 2·4-2·8) among the 14,805 couples in the treatment-naive cohort (median baseline CD4 count for HIV-positive partners 441 cells per μl [IQR 314-590]) and 1·3 per 100 person-years (1·2-1·3) among the 24,057 couples in the treated cohort (median baseline CD4 count for HIV-positive partners 168 cells per μl [62-269]). We calculated a 26% relative reduction in HIV transmission (adjusted hazard ratio 0·74, 95% CI 0·65-0·84) in the treated cohort. The reduction in transmission was seen across almost all demographic subgroups and was significant in the first year (0·64, 0·54-0·76), and among couples in which the HIV-positive partner had been infected by blood or plasma transfusion (0·76, 0·59-0·99) or heterosexual intercourse (0·69, 0·56-0·84), but not among couples in which the HIV-positive partner was infected by injecting drugs (0·98, 0·71-1·36). INTERPRETATION Antiretroviral therapy for HIV-positive individuals in serodiscordant couples reduced HIV transmission across China, which suggests that the treatment-as-prevention approach is a feasible public health prevention strategy on a national scale in a developing country context. The durability and generalisability of such protection, however, needs to be further studied. FUNDING Chinese Governments 12th Five-Year Plan, the National Natural Science Foundation of China, and the Canadian International Development Research Centre.

The Effect of Highly Active Antiretroviral Therapy on Mortality among HIV-Infected Former Plasma Donors in China

BACKGROUND In China, many former plasma donors were infected with the human immunodeficiency virus (HIV) in the early-mid-1990s. Highly active antiretroviral therapy (HAART) was provided for former plasma donors beginning in 2002. The effect of HAART on mortality in this cohort has not been described. METHODS This study is a retrospective analysis of the national HIV epidemiology and treatment databases for the period 1993-2006. All HIV-infected subjects from 10 counties with a high prevalence of HIV infection in 6 provinces were eligible. Inclusion criteria were: (1) history of plasma donation, (2) positive Western blot result, (3) clinical diagnosis of AIDS or CD4(+) cell count <200 cells/microL at any time, and (4) age >or=18 years at AIDS diagnosis. RESULTS Of 9059 eligible subjects, 4093 met the inclusion criteria. Mean age was 41 years, 51% were male, 99% were farmers, and 87% were from Henan Province. Overall mortality decreased from 27.3 deaths per 100 person-years in 2001 to 4.6 deaths per 100 person-years in 2006. Conversely, the percentage of patient-years receiving HAART increased from 0% in 2001 to 70.5% in 2006. In a multivariate Cox proportional hazards analysis, not receiving HAART was the greatest risk factor for mortality (hazard ratio, 2.8; 95% confidence interval, 2.4-3.3). Among treated patients, those who had lower CD4(+) cell counts and higher numbers of opportunistic infections at the initiation of therapy were at greater risk of death. CONCLUSIONS The national treatment program has significantly reduced the mortality rate among HIV-infected former plasma donors through the use of generic drugs in a rural treatment setting with limited laboratory monitoring. Treatment success can be improved through increased coverage and earlier initiation of therapy.

Predictors of virologic failure in HIV-1-infected adults receiving first-line antiretroviral therapy in 8 provinces in China.

BACKGROUND Despite poor primary health care systems, free antiretroviral therapy (ART) has been available in China for >5 years. Virologic outcomes in Chinese patients receiving ART have not been described on a national level. METHODS A multistage cluster design was used in 8 provinces to randomly select patients who had been receiving first-line ART for at least 6 months, who were stratified into 3 treatment-duration groups. Viral load testing and patient interviews were conducted, and data were linked with national treatment database information. Collected data were analyzed for association with viral suppression by means of multivariate modeling. Adequate viral suppression was defined as a viral load of <400 copies/mL. RESULTS Of 5256 patients receiving ART, 3894 met the eligibility criteria, among whom 1153 were analyzed. Overall, 72% demonstrated viral suppression, and 82%, 73%, and 67% of the participants receiving ART for 6-11, 12-23, and > or = 24 months, respectively, experienced viral suppression (P < .001). In a multivariate model, treatment given at locations other than county-level hospitals was less likely to achieve viral suppression, with greater odds for inadequate virologic response found at village clinics (odds ratio [OR], 5.4; 95% confidence interval [CI], 2.9-10.1), township health centers (OR, 3.1; 95% CI, 1.7-5.6), and public health clinics (OR, 3.1; 95% CI, 1.7-5.6). Patients receiving didanosine-based regimens were more likely to experience an inadequate virologic response than were those receiving lamivudine-based regimens (OR, 3.9; 95% CI, 2.7-5.7). CONCLUSIONS Chinas national ART program is largely successful at suppressing viral load. Care received outside of hospitals and regimens containing didanosine were associated with less favorable virologic outcomes.

HIV-Infected Former Plasma Donors in Rural Central China: From Infection to Survival Outcomes, 1985–2008

Background The HIV epidemic among former plasma donors (FPDs) in rural Central China in the early-mid 1990s is likely the largest known HIV-infected cohort in the world related to commercial plasma donation but has never been fully described. The objectives of this study are to estimate the timing and geographic spread of HIV infection in this cohort and to demonstrate the impact of antiretroviral therapy on survival outcomes. Methodology/Principal Findings HIV-infected FPDs were identified using the national HIV epidemiology and treatment databases. Locations of subjects were mapped. Dates of infection and survival were estimated using the midpoint date between initial-final plasma donation dates from 1985–2008 among those with plasma donation windows ≤2 years. Among 37084 FPDs in the two databases, 36110 were included. 95% were located in focal areas of Henan Province and adjacent areas of surrounding provinces. Midpoint year between initial-final plasma donation dates was 1994 among FPDs with known donation dates. Median survival from infection to AIDS was 11.8 years and, among those not treated, 1.6 years from AIDS to death. Among those on treatment, 71% were still alive after five years. Using Cox proportional hazard modeling, untreated AIDS patients were 4.9 times (95% confidence interval 4.6–5.2) more likely to die than those on treatment. Conclusions/Significance The epidemic of HIV-infected FPD in China was not widespread throughout China but rather was centered in Henan Province and the adjacent areas of surrounding provinces. Even in these areas, infections were concentrated in focal locations. Overall, HIV infections in this cohort peaked in 1994, with median survival of 13.4 years from infection to death among those not treated. Among AIDS patients on treatment, 71% were still alive after five years.

Cohort Profile: The Chinese national free antiretroviral treatment cohort

Overall, China does not have a big HIVproblem, with only 0.05% of the total populationinfected. With 1.3 billion people, however, thisequates to an estimated 700000 infected individuals,with high rates reported among the high-risk cohortsof FPD, injection drug users, female sex workers andmen who have sex with men. Among the estimated85000 with acquired immunodeficiency syndrome(AIDS), 62838 have been reported as of October2007.

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.

Changing baseline characteristics among patients in the China National Free Antiretroviral Treatment Program, 2002–09

Objective To improve HIV treatment in China by determining changes over time of patient characteristics (geographic, clinical and route of HIV infection) among patients enrolled in the China National Free Antiretroviral Treatment Program. Methods Patients in the national treatment database from 1 June 2002 to 1 June 2009 were eligible. Patients were excluded if <18 years old, not previously treatment-naïve, missing initial treatment date or not initiated on triple drug therapy. Results About 62 919 patients were included, located across 54.8% of counties/districts throughout mainland China; 86.4% were concentrated in 11.1% of counties/districts. Median age was 38 years, 41% female, 45.4% former plasma donors (FPDs), 33.9% sexually infected and 15.5% injection drug users (IDUs). Median baseline CD4 cell count was 129/µl. In 2002, 100% of treated were FPDs with no CD4 cell counts. By 2009, 59% of the treated were sexually infected and 96% had baseline CD4 cell counts. Injection drug users remained a minority of those treated. Conclusions Limited treatment resources can be focused on areas with more patients. Greater emphasis needs to be placed on earlier HIV diagnosis and treatment. New strategies must be identified to bring HIV-infected IDUs into treatment. Routine HIV testing would identify those at risk earlier.

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.

Gender Difference in 2-Year Mortality and Immunological Response to ART in an HIV-Infected Chinese Population, 2006–2008

Background Since it was initiated in 2002, the China Free Antiretroviral Treatment (ART) Program has been progressing from an emergency response to a standardized treatment and care system. As of December 31, 2009, a total of 81,880 patients in 31 provinces, autonomous regions, and special municipalities received free ART. Gender differences, however, in mortality and immunological response to ART in this cohort have never been described. Objective To understand whether women and men who enrolled in the China National Free ART Program responded equally well to the treatment. Methods A retrospective analysis of the national free ART databases from June 2006–December 2008 was performed. HIV-infected subjects who were 18 years or older, ART naïve at baseline, and on a 3TC regimen enrolled in the program from June 1 to December 31, 2006, were included in this study, then followed up to 2 years. Results Among 3457 enrolled subjects who met the inclusion criteria, 59.2% were male and 40.8% female. The majority of the subjects were 19–44 years old (77%) and married (72%). Over the full 24 months of follow-up, the mortality rate was 19.0% in males and 11.4% in females (p = 0.0014). Males on therapy for 3–24 months were more likely to die than females (HR = 1.46, 95% CI: 1.04–2.06, p = 0.0307) after adjusting for baseline characteristics. Compared to men, women had higher CD4+ counts over time after initiating ART (p<0.0001). Conclusions Our study showed that women had an overall lower mortality and higher CD4+ counts than men in response to ART treatment, which may be attributed to adherence, biological factors, social, cultural and economic reasons. Further study is needed to explore these factors that might contribute to the gender differences in mortality and immunological response to ART.