study design and setting
This study is a prospective, open-labelled, randomized controlled trial (RCT) that will performed at 17 hospitals in 12 provinces in mainland China: Chongqing Public Health Medical Center, Beijing You’an Hospital of Capital Medical University, the Forth Affiliated Hospital of Harbin Medical University, the Second People's Hospital of Tianjin, the First Hospital of Changsha, the Eighth People's Hospital of Guangzhou, Liuzhou General Hospital, the Third People's Hospital of Guilin, the Third People’s Hospital of Shenzhen, Guiyang Public Health Clinical Center, Public Health Clinical Center of Chengdu, the Third People’s Hospital of Kunming, Yunnan Provincial Infectious Disease Hospital, the Fourth People’s Hospital of Nanning, Guangxi Longtan Hospital, the First Affiliated Hospital of Zhejiang University, and Xixi Hospital of Hangzhou.
A total of 300 AIDS/CMVR patients will be recruited for this prospective trial. Participants will be randomized into two groups: an early ART initiation group (initiation of ART within 2 weeks after anti-CMV therapy), and the deferred ART group (initiation of ART more than 2 weeks after anti-CMV therapy). Enrolled subjects will be assessed during a 48-week follow-up period at day 0, week 4, week 8, week 12, week 24, week 36, and week 48. Aqueous or vitreous humor fluid, blood, and urine samples will be collected for laboratory testing, including for hematological analysis, liver and kidney function tests, blood/ aqueous and vitreous humor CMV DNA testing, lymphocyte subset, and HIV-1 RNA viral load test. An experienced ophthalmologist will regularly examine subjects and record individual retinal changes. Table 1. represents a complete schedule of study activities during the 48-week follow-up period. Schematic outlines of this study design and procedures are shown in Figure 1. This protocol was approved by the Ethics Committee of Chongqing Public Health Medical Center (2019-003-02-KY) and has been registered as one of the twelve trials under the name of a general project at the Chinese clinical trials registry, the trial registration number being ChiCTR1900021195.
The study aims to investigate the optimal timing for ART initiation in AIDS/CMVR patients.
According to the 2019 DHHS Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents, and the 2018 Chinese Guidelines for Diagnosis and Treatment of HIV/AIDS, the diagnostic criteria for HIV infection and AIDS will have to be met.
The diagnosis of CMVR will have to meet the following criteria:
(1) Characteristic retinal changes observed at baseline through a dilated pupil during an ophthalmoscopic examination performed by two experienced ophthalmologists.
(2) With or without visual symptoms such as floaters, scotomata, blurred vision, decreased visual acuity, loss of peripheral or central vision.
(3) In rare cases, diagnosis of CMVR may be difficult, and reverse-transcriptase polymerase chain reaction (PCR) of aqueous humor or vitreous humor specimens for CMV testing may be useful for establishing the diagnosis.
IRU will be diagnosed according to the following criteria:
- Anti-CMV drug treatment is effective, and symptoms and signs of CMVR have improved or disappeared prior to ART initiation;
- ART is effective, resulting in a decrease in plasma HIV RNA level ＞1 log10 copies/ml, or an increase in CD4+ count of ≥25 cells/μl after ART initiation;
- Patients show worsening clinical symptoms or ophthalmoscopic signs of CMVR after ART initiation, and the worsening signs may not be explained by therapeutic drug toxicity or newly acquired disease.
The study will include HIV-infected patients who are ART-naïve, 18 years or older, and have been diagnosed with CMVR. Prospective participants must be willing to complete and sign informed consent documentation. All of the above criteria will have to be met before inclusion in the study.
Participants will be excluded from this study if: (1) they are intolerant or have allergies to any therapeutic drugs; (2) they have laboratory anomalies viz. hemoglobin (Hb) <60g/L, white blood cell count (WBC) <1.0×109/L, neutrophil count (N) <0.5×109/L, platelet count (PLT) <50×109/L, blood amylase (AMS) >2×upper normal limit (UNL), serum creatinine (Scr) >1.5×UNL, aspartate aminotransferase (AST), alanine aminotransferase (ALT) or alkaline phosphatase (ALP) >5×UNL, total bilirubin (TB) >2×UNL, serum creatine phosphokinase (CK) >2×UNL; (3) they have other serious disease that may adversely affect the evaluation of the efficacy of therapeutic drugs and prognosis of patients; (4) they are pregnant or breast-feeding women; (5) they have mental illness, are intravenous recreational drug users, or are non-Chinese nationals.
Our study will include participants from 17 different hospitals in mainland China, and investigators will strive to ensure that the proposed sample size is attained and maintained. Attending doctors will evaluate and select patients according to inclusion and exclusion criteria specified in this protocol.
All eligible participants will be randomly assigned to one of two groups (ART initiation within 2 weeks vs ART initiation later than 2 weeks) at a 1:1 ratio by an online medical research tool called Medical Research Platform (http://www.51yyt.org/FrontPage/Index.aspx). Randomization will be performed by the research manager at each treatment center, who will have access to the next subject allocation number, but not the entire subject list. Drug treatment will be dispensed to participants in an open-labelled fashion (neither participants nor investigators will be blinded to drug treatment allocation).
Withdrawal and endpoints
Patients may refuse to take part in, or withdraw their participation from this study at any time. If participants meet any of the following criteria, they should withdraw from further participation in the study: (1) Development of serious adverse events or serious adverse reactions; (2) Non-adherence to the research protocol; (3) Non- compliance with the follow-up schedule. Should any one of the following occur, the end point of the study will be reached: (1) Completion of the prescribed 48-week follow-up schedule as per the research protocol; (2) Discontinuation of ART during the study period; (3) Death.
According to the recommendations of the 2018 Chinese Guidelines for Diagnosis and Treatment of HIV/AIDS, all participants will receive systemic anti-CMV therapy comprising ganciclovir (intravenous 5mg/kg every 12 hours for 14-21 days, followed by a maintenance dose of ganciclovir at 5mg/kg/day), or foscarnet (intravenous 60mg/kg every 8 hours for 14-21 days, followed by a maintenance dose of foscarnet at 90mg/kg/day) for treatment of CMVR. Systemic anti-CMV therapy may be combined with intraocular administration of 1-4 doses of ganciclovir (2mg/injection), or foscarnet (2.4mg/injection) for over a period of 7-10 days, should that be necessary. After completion of anti-CMV therapy, all participants will receive conventional prophylactic antiviral drug therapy until CD4+ T-cell counts increase to >100 cells/μL, and continue prophylactic treatment for 3-6 months. In accordance with local HIV treatment guidelines, Tenofovir (300mg/d) + Lamivudine (300mg/d) + Efavirenz (600mg/d) is the preferred drug combination for AIDS; however other guideline-prescribed drug regimen combinations are optional.
The incidence of visual loss (to worse than 20/40 and to 20/200 or worse) in the two study groups during 48 weeks of treatment.
(1) Comparison of the difference in CD4+ T-cell counts between the two study groups from baseline to week 48;
(2) Comparison of virological suppression (HIV RNA ＜50 copies/mL) between the two study groups at different follow-up points from baseline to week 48;
(3) Comparison of the difference in the incidence of IRU between the two study groups during the study period;
(4) Comparison of the occurrence of adverse events between the two study groups during the study period;
(5) The incidence of other opportunistic infections (OIs) in the two study groups during the 48 weeks of follow-up;
(6) The incidence of retinitis progression and retinal detachment between the two study groups during the study period;
(7) The overall mortality in the two study groups at week 48.
All data will be recorded on case report forms (CRFs) by appropriately-trained nurses. Data will simultaneously be uploaded into our database at Medical Research Platform by two investigators, independently. The participants' clinical information will be collected from baseline to end of follow-up for this study. The study monitor will consult and review the required clinical research data. After reviewing all the study data and confirming that the uploaded data is accurate, the project leader and the statistical analysts will perform a data lock.
The sample size will be 150 subjects per intervention arm, based on a power of 80%, and a level of confidence of 95%. We hypothesized that our study would detect a 15% survival benefit in relation to visual loss in the deferred ART group. The drop-out rate is expected to be 20%. We will perform a descriptive statistical analysis of organizational and socio-demographic characteristics at baseline in order to assure comparability between the two study groups. Baseline measurements and changes in outcome variables for each study-arm will be presented as means or median. All variables that differ significantly between groups will be adjusted for baseline. Categorical variables will be recorded as numbers and percentages, and will be compared using the chi-squared test or Fisher’s exact test. The time-to-event method, using Cox proportional-hazards models, will be used to compare mortality at week 48. All data will be analyzed by Statistical Package for the Social Sciences (SPSS) software, Version 20.0 (IBM SPSS Inc., Chicago, IL, USA). Statistical significance will be assumed if p <0.05.
Safety will be monitored for 48 weeks in this study, and this monitoring will include occurrence of adverse events (AEs), serious adverse events (SAEs), discontinuation of treatment due to AEs, deaths, individual changes in the monitoring data from baseline, all indicators of drug toxicity in laboratory tests, and ECG changes. The time of AE occurrence, AE duration, and AE severity (mild, moderate, or severe) will be accurately documented in individual participant CRFs. Any prolonged hospitalization, persistent or significant disability or incapacity, or unexpected medical occurrence that results in death will be reported as an SAE, and will be required to be reported to the principal investigator (PI) and the ethics committee within 24 hours.