Zhongfu Liu

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.

Association between missed early visits and mortality among patients of china national free antiretroviral treatment cohort.

Background:Chinas National Free Antiretroviral Treatment program has scaled-up rapidly since 2002, leading to a significant reduction of mortality among its participants. However, few studies have evaluated indicators for patient access to medical care and their association with mortality. Methods:Patients enrolled into this national program between June 2002 and June 2009 for at least 7.5 months were retrospectively analyzed. Results:Twenty-seven thousand five hundred four patients were included into the analysis, among whom 10,034 (37%) had at least 1 missed visit during the first 6 months of treatment. In Cox proportional hazard regression analysis, controlled for baseline demographic and clinical factors, patients with more missed visits had a higher risk of mortality, with an adjusted hazard ratio of 1.3 (95% confidence interval: 1.1 to 1.5) for 1–2 missed visits and 1.7 (95% confidence interval 1.4 to 2.2) for ≥3 missed visits compared with patients with no missed visits. In multivariate logistic regression models, factors independently associated with a higher likelihood of early missed visits included female gender, age >60, HIV transmission via injection drug use or via plasma donation compared with sexual transmission, baseline alanine aminotransferase >100 IU/L, having more symptoms at antiretroviral therapy initiation and receiving a didanosine-based regimen compared with lamivudine-based regimen. Lower baseline CD4 count was protective against missed visits. Conclusions:Missing early visits occurred in a sizable number of patients in this cohort and was associated with a higher mortality rate. Early missed visits may serve as an early warning indicator to trigger additional outreach effort.

Mortality and Treatment Outcomes of China's National Pediatric Antiretroviral Therapy Program

BACKGROUND The aim of this study was to describe 3-year mortality rates, associated risk factors, and long-term clinical outcomes of children enrolled in Chinas national free pediatric antiretroviral therapy (ART) program. METHODS Records were abstracted from the national human immunodeficiency virus (HIV)/AIDS case reporting and national pediatric ART databases for all HIV-positive children ≤15 years old who initiated ART prior to December 2010. Mortality risk factors over 3 years of follow-up were examined using Cox proportional hazards regression models. Life tables were used to determine survival rate over time. Longitudinal plots of CD4(+) T-cell percentage (CD4%), hemoglobin level, weight-for-age z (WAZ) score, and height-for-age z (HAZ) score were created using generalized estimating equation models. RESULTS Among the 1818 children included in our cohort, 93 deaths were recorded in 4022 child-years (CY) of observed time for an overall mortality rate of 2.31 per 100 CY (95% confidence interval [CI], 1.75-2.78). The strongest factor associated with mortality was baseline WAZ score <-2 (adjusted hazard ratio [HR] = 9.1; 95% CI, 2.5-33.2), followed by World Health Organization stage III or IV disease (adjusted HR = 2.4; 95% CI, 1.1-5.2), and hemoglobin <90 g/L (adjusted HR = 2.2; 95% CI, 1.2-3.9). CD4%, hemoglobin level, WAZ score, and HAZ score increased over time. CONCLUSIONS Our finding that 94% of children engaged in this program are still alive and of improved health after 3 years of treatment demonstrates that Chinas national pediatric ART program is effective. This program needs to be expanded to better meet treatment demands, and efforts to identify HIV-positive children earlier must be prioritized.

Decreasing Excess Mortality of HIV-infected Patients Initiating Antiretroviral Therapy: Comparison with Mortality in General Population in China, 2003 – 2009

Objective:To evaluate excess mortality across calendar time comparing HIV-infected patients receiving combination antiretroviral therapy (cART) with the general Chinese population. Methods:Patients receiving free cART through the National Free Antiretroviral Therapy Program (NFATP) between January 1, 2003, and December 31, 2009, were included. Observed mortality rates, excess mortality rates, and standardized mortality ratios were calculated by calendar periods. Factors associated with excess mortality across calendar time were evaluated in multivariable Poisson regression models. Results:Among 64,836 HIV-infected patients, the observed and excess mortality rates in 2003–2004 were 9.5 deaths per 100 person-years [95% confidence interval (CI): 8.8 to 10.2] and 9.1 (95% CI: 8.5 to 9.8); in 2008–2009, these decreased to 5.6 (95% CI: 5.4 to 5.8) and 5.2 (95% CI: 5.0 to 5.4), respectively. The adjusted excess hazard ratio (eHR) for 2003–2004 in comparison to 2008–2009 was 1.27 (95% CI: 1.11 to 1.45). Patients initiating cART at CD4 cell counts <50 cells per microliter in comparison with ≥350 cells per microliter had an adjusted eHR of 9.92 (95% CI: 8.59 to 11.44). Patients starting cART at older ages also had greater excess mortality with an eHR of 1.63 (95% CI: 1.47 to 1.82) comparing ages ≥45 to 18–29 years. Standardized mortality ratio results were consistent with those for excess mortality. Conclusions:Substantial decreases in excess mortality were observed from 2003 to 2009 in China among HIV-infected patients receiving free cART. However, mortality among HIV-infected patients remained higher than the general Chinese population. As more efficacious first- and second-line cART regimens become increasingly available to Chinese HIV-infected patients, further reductions in overall and excess mortality are likely.

Attrition among Human Immunodeficiency Virus (HIV)- Infected Patients Initiating Antiretroviral Therapy in China, 2003–2010

Background Mortality and morbidity from HIV have dramatically decreased in both high- and low-income countries. However, some patients may not benefit from combination antiretroviral therapy (cART) because of inadequate access to HIV care, including attrition after care initiation. Methodology/Principal Findings The study population included all HIV-infected patients receiving cART through the Chinese National Free Antiretroviral Treatment Program from 1 January 2003 to 31 December 2010 (n = 106,542). We evaluated retention in HIV care and used multivariable Cox proportional hazard models to identify independent factors predictive of attrition. The cumulative probability of attrition from cART initiation was 9% at 12 months, 13% at 18 months, 16% at 24 months and 24% at 60 months. A number of factors were associated with attrition, including younger age, male gender, and being single or divorced. Patients with higher CD4 cell counts at cART initiation were more likely to drop out of HIV care. The proportion of patients remaining in HIV care increased in more recent calendar years and among patients who initiated modern cART regimens. Conclusions/Significance Retention in HIV care is essential for optimizing individual and public health outcomes. Attrition, even the degree observed in our study, can lead to premature morbidity and mortality, and possibly affect further transmission of HIV and HIV resistant drug variants. Effective strategies to promote retention in HIV care programs are needed. In China these strategies may include focusing particularly on younger male patients and those with higher CD4 cell counts at therapy initiation.

Progress of the National Pediatric Free Antiretroviral Therapy program in China

Abstract In 2003, the Chinese Government initiated a free antiretroviral therapy (ART) program focusing on adult AIDS patients. Pediatric antiretroviral (ARV) formulations were yet unavailable. It was not until July 2005, with the initiation of a two-stage program implemented by the Chinese Ministry of Health, that pediatric formulations became accessible in China. Initially, the pediatric ART program was piloted in six provinces with the highest incidences of pediatric HIV/AIDS. The pilot stage allowed the Chinese Center for Disease Control and Prevention (CCDC) to finalize entry criteria, treatment regimen, and patient monitoring and follow-up procedures. The second stage commenced at the end of 2006 when the program was scaled-up nationally. In order to guarantee treatment of pediatric patients, extensive training in the selection of appropriate ARV drug regimen and dosage was provided to doctors, often through on-site collaboration with domestic and international experts. The CCDC simultaneously established a pediatric ARV management system and a pediatric ART information system. CD4 count and other laboratory tests are being routinely performed on these pediatric patients. By the end of June 2009, 1529 pediatric patients had received ARV under the national program. However, challenges remain. Firstly, many children infected with HIV/AIDS live in rural areas where the treatment quality is hindered by the limited number of medical facilities and skilled medical workers. Secondly, much of the pediatric ARV drug supply depends on donation. An effort needs to be made by the Chinese Government to establish Chinas own drug procurement and supply system.

Monitoring HIV Drug Resistance Using Early Warning Indicators in China: Results From a Pilot Survey Conducted in 2008

Robust programmatic monitoring of factors associated with the emergence of human immunodeficiency virus (HIV) drug resistance is an essential component of antiretroviral therapy (ART) program evaluation and treatment optimization. China piloted World Health Organization HIV drug resistance early warning indicators to assess the feasibility and usefulness of results. Overall, early warning indicator monitoring showed high levels of appropriate ART prescribing, low rates of loss to follow-up 12 months after ART initiation, and high rates of retention of first-line ART at 12 months. On-time drug pick-up, which may signal treatment interruptions, was identified as a challenge. HIV drug resistance early warning indicator monitoring provides a valuable assessment of ART service delivery, and its application will be scaled up throughout China.

The Human Immunodeficiency Virus Care Continuum in China: 1985–2015

Background Human immunodeficiency virus (HIV) care continuum attrition is a major global public health challenge. Few studies have examined this problem in resource-limited settings. We aimed to assess cumulative, current, and historical achievement along Chinas HIV continuum of care. Methods A nationwide, serial cross-sectional study of all individuals with HIV infection diagnosed in China between 1 January 1985 and 31 December 2015 was conducted using data from Chinas HIV/AIDS information systems. Biennial estimates of the number of persons living with HIV were also used. We defined 7 steps in HIV care continuum as infected (estimated), diagnosed, linked, retained, enrolled, receiving antiretroviral therapy (ART), and virally suppressed. Cumulative, 30-year performance, and biennial performance during the most recent 10 years were examined. Results A total of 573529 persons diagnosed with HIV infection were included. Cumulatively, 94% were linked, 88% were retained, 73% were enrolled, 67% were receiving ART, and 44% were suppressed. Greatest attrition was observed for adolescents, minorities, and those who reported injecting drug use as their route of infection. Improvement was observed from 2005 to 2015. As of the end of 2015, 68% among those infected were diagnosed, 67% among diagnosed were receiving ART, and 65% among those receiving ART were virally suppressed. After adjusting for those without viral load testing, the proportion suppressed increased to 89%. Conclusions Despite dramatic improvements, China faces serious challenges in achieving the Joint United Nations Programme on HIV/AIDS 90-90-90 targets, because of substantial attrition along its continuum of HIV care.

Renal Function in Chinese HIV-Positive Individuals following Initiation of Antiretroviral Therapy.

Aim To identify the prevalence and predictors of abnormal renal function among HIV-positive Chinese patients prior to antiretroviral therapy (ART) initiation and to evaluate subsequent changes in renal function after ART exposure. Methods We conducted a nationwide cohort study of subjects who enrolled in the national Chinese ART program from January 1, 2012 to December 31, 2012. We estimated the glomerular filtration rate (eGFR) of subjects prior to and after initiating ART. Risk factors for abnormal renal function, as defined by eGFR <60 ml/min/1.73m2, at baseline and follow-up were assessed by logistic regression and Cox proportional hazards regression models, respectively. Results Among 41,862 subjects, at ART baseline, 3.3% had a baseline eGFR <60 ml/min/1.73m2 and 24.2% had eGFR = 60–90 ml/min/1.73m2. Adjusted baseline risk factors for baseline eGFR <60 ml/min/1.73m2 were older age (Adjusted odds ratio [AOR] = 5.19, 95% confidence interval [CI]: 4.52–5.67), female (AOR = 1.68, 95% CI: 1.47–1.93), hemoglobin <120g/L (AOR = 1.68, 95% CI: 1.47–1.93), blood glucose >6.1 mmol/L (AOR = 1.46, 95% CI: 1.25–1.72), and hepatitis C co-infection (AOR = 1.36, 95% CI: 1.06–1.73). Among subjects with baseline eGFR >90 ml/min/1.73m2, the incidence of the eGFR falling to <60 ml/min/1.73m2 was 0.92/100 person-years after a median of 15.0 months of ART. Being on a tenofovir with lopinavir/ritonavir regimen (Adjusted hazard ratio [AHR] = 3.02, 95% CI: 1.96–4.66) and having an unsuppressed viral load (AHR = 2.70, 95% CI: 1.80–4.03) were independent predictors for eGFR <60 ml/min/1.73m2 after ART initiation as well as older age, female, and hemoglobin <120 g/L. Conclusion A high proportion of HIV-positive subjects in China presented with abnormal renal function prior to ART initiation. But the incidence of the eGFR decrease after ART was low. Patient renal function should be regularly monitored by eGFR before initiating and during ART.