We performed a secondary analysis of data collected as part of two large prospective multicenter studies of adult patients with HIV in China carried out by the same collaborative research network. These studies recruited patients from regions of high HIV prevalence across China, and were established to systematically evaluate the efficacy, toxicities and co-morbidities associated with the first-line government-sponsored free ART regimens available at the time each study was initiated.
In brief, the first study, [China AIDS Clinical Trial (CACT) 1810; clinicaltrials.gov ID: NCT00872417], initiated in 2008, was carried out in 8 cities across China (Beijing, Shanghai, Zhengzhou, Fuzhou, Guangzhou, Shenzhen, Xi’an and Yunnan), and recruited a total of 543 treatment-naïve adult patients with HIV from November 8, 2008 to August 6, 2010 (16). This was an open-label trial comparing the efficacy and safety of three different ART treatment regimens over 96 weeks using government-sponsored first-line agents in 2008: Stavudine (d4T, 30 mg twice daily, Desano, Shanghai, China) or Zidovudine (AZT, 300 mg twice daily, Northeast General Pharmaceutical Factory, China) plus lamivudine (3TC, 300 mg once daily, GlaxoSmithKline, UK) and nevirapine (NVP, 200 mg once daily for the first 2 weeks and then 200 mg twice daily, Desano) or efavirenz (EFV, 600 mg once daily, MSD, Australia). Subsequent funding enabled an extension of this study beyond the initial 96-week follow-up period through the time of the present analysis.
The second study, (CACT1215 clinicaltrials.gov ID: NCT01844297), initiated in 2012, was carried out in 9 cities across China (Beijing, Shanghai, Guangzhou, Chengdu, Changsha, Nanning, Liuzhou, Zhengzhou, Shenyang) and recruited a total of 583 treatment-naïve adult patients with HIV from July 17, 2012 to July 3, 2014. This study was a cohort study examining the efficacy and safety at 96 weeks of the current first-line ART treatment regimen in China [tenofovir disoproxil fumarate (TDF, 300 mg once daily, Gilead Sciences, Inc, USA) plus 3TC and EFV]. Subsequent funding also allowed an extension of this study beyond the initial 96-week follow up period through the time of the present analysis.
Both studies collected sociodemographic data, clinical data related to HIV and HIV-related risk factors, and serologic biospecimens. Eligibility criteria at baseline included age 18-65 years, confirmed HIV-infection status via Western blot, CD4+ cell count <350 cells/mm3 (for CACT1810) or <500 cells/mm3 (for CACT1215), and lack of prior exposure to ART. After enrollment, participants initiated treatment with ART, and returned for follow-up evaluations at weeks 2, 4, 8, 12, 24, and once every 12 weeks thereafter for clinical and laboratory evaluations. Trained study staff at each study site performed detailed clinical evaluations and recorded data in an electronic study database.
Peking Union Medical College Hospital (PUMCH) in Beijing, China served as the primary study center for both studies, and training and monitoring of study sites was overseen by the same contract research organization. Both protocols were approved by the PUMCH institutional review board prior to initiation of study activities. All study participants provided written informed consent at the time of enrollment, and all procedures were performed in compliance with the ethical standards of The Declaration of Helsinki.
For the present analysis, we included patients enrolled in both parent studies in order to encompass ART treatment regimens utilized in China over the past decade. Patients who did not complete at least 2 visits (including the baseline visit) were excluded from our analysis (database cutoff date June 2015).
Hypertension was defined based upon the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure Recommendations (17), namely a systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg at two different time points, or receiving a prescription for antihypertensive medication. Trained study personnel at each site performed standardized blood pressure measurements using a sphygmomanometer at each study encounter. For each participant, blood pressure was measured using a manual sphygmomanometer with appropriate cuff size based on arm circumference after more than 5 minutes of seated rest and without smoking, exercise or feeding. One measurement was taken positioned at the level of the heart, and recorded as the blood pressure value.
We tabulated and reported descriptive data using means ± standard deviations and frequencies. The Student’s t-test for parametric continuous variables, Mann-Whitney U test for non-parametric continuous variables, and the Chi-squared test for categorical variables were used to compare the clinical characteristics between patients with and without hypertension. Incidence rates of hypertension per 100 PYs during the observation period were calculated. Stepwise Cox regression analysis was used to estimate hazard ratios (HR) with 95% confidence intervals (CI). Patients were censored at time of incident of hypertension, loss to follow-up, death, withdrawal from study during follow-up or end of study. The observation period began at the enrollment visit and ended at the date of hypertension diagnosis or the last clinical encounter for those who did not develop hypertension. Participants with hypertension at baseline were excluded from the longitudinal analyses.
Covariates analyzed included age, sex, BMI, Han ethnicity, current smoking, current alcohol use, eGFR, diabetes, dyslipidemia, hepatitis B virus (HBV) surface antigen (HBsAg), hepatitis C virus (HCV) antibody (HCV Ab), route of HIV transmission, years since HIV diagnosis, baseline CD4+ cell count, baseline VL, stavudine, zidovudine, and TDF exposure, recent CD4+ cell count, recent CD4+/CD8+ ratio, and recent VL. All statistical analyses were performed using SPSS 19.0 statistical software package (IBM Corporation, Armonk, New York, USA) and Prism version 6 (GraphPad Software, Inc., La Jolla, CA). For all tests, p<0.05 was considered statistically significant.