Reporting and Evaluation of HIV-Related Clinical Endpoints in Two Multicenter International Clinical Trials

Abstract

Purpose: The processes for reporting and review of progression of HIV disease clinical endpoints are described for two large phase III international clinical trials. Method: SILCAAT and ESPRIT are multicenter randomized HIV trials evaluating the impact of interleukin-2 on disease progression and death in HIV-infected patients receiving antiretroviral therapy. We report definitions used for HIV progression of disease endpoints, procedures for site reporting of such events, processes for independent review of reported events by an Endpoint Review Committee (ERC), and the procedure for adjudication of differences of opinion between reviewers. Results: Of 473 events reported through May 1, 2006, 28% were judged by an ERC to meet "confirmed" criteria and 38% to meet "probable" criteria; 34% were classified "does not meet criteria." For diseases with >5 case reports, the proportion accepted as either "confirmed" or "probable" events was highest for cervical cancer (100%), non-Hodgkin's lymphoma (88%), cryptococcosis (82%), and cryptosporidiosis (80%) and was lowest for HIV encephalopathy (25%), HIV wasting syndrome (33%), and multidermatomal herpes zoster (35%). 25% of cases required adjudicaxstion between reviewers before diagnostic certainty was assigned. Conclusion: Important requirements for HIV trials using clinical endpoints include objective definitions of "confirmed" and "probable," a formal reporting process with adequate information and supporting source documentation, evaluation by independent blinded reviewers, and procedures for adjudication.     

Problems with Publishing Results of Interim Analyses of Randomized Clinical Trials

Abstract

Purpose: This purpose of this study was to illustrate how publication of interim analyses of randomized clinical trials (RCTs) can cause problems in the interpretation of final results. Method: The effect of publishing interim analyses on the results of a typical HIV RCT comparing regimens of registered antiretroviral drugs was illustrated using a simulation study. Simulations modeled an RCT comparing the effect of two treatment combinations on changes in log HIV viral load from baseline. Publication of interim results at 6 months was assumed to lead to 50% of patients switching from the poorer treatment if interim results were statistically significant (p < .05), 20% of patients switching from the poorer treatment if interim results were marginally significant (.05 < p < .20), and 10% of all patients switching treatment if interim results were not statistically significant. Three scenarios were simulated: a large treatment difference (0.4 log HIV viral load), a moderate difference (0.2 log), and no treatment difference (0.0 log). Results: The simulation study showed that if the true treatment difference was large (0.4 log) the power of the trial was reduced from over 80% at 6 months to under 37% at 12 months. Furthermore, given the statistical significance of the interim analysis results at 6 months, the simulations illustrated that the trial results would appear similar at 12 months, regardless of the true underlying treatment difference. Conclusion: The simulations reinforce the fact that publication of interim analyses of RCTs can affect the future conduct of a trial and make interpretation of final results difficult.     

Minorities Remain Underrepresented in HIV/AIDS Research Despite Access to Clinical Trials

Background and Objective: The reasons for minority underrepresentation in HIV/AIDS clinical trials remain unclear. We aimed to evaluate the knowledge, experience, and factors that influence minority participation in HIV/AIDS studies in the United States. Methods: An anonymous, bilingual, self-administered survey on study participation was given to HIV-infected adults attending AIDS Clinical Trials Group–affiliated clinics in the United States and Puerto Rico. Chi-square tests were used to evaluate differences by race, first language, and level of education. Logistic regression was used to estimate odds ratio (OR) and 95% confidence interval (CI) for factors associated with being talked to about participation in a study. Results: We analyzed 2,175 complete surveys (221 in Spanish). Among respondents, 31% were White, 40% were Black/African American (AA), and 21% were Hispanic. The overall rate of previous participation in any HIV/AIDS study was 48%. Hispanics were less likely to know about studies compared to Whites and AAs (67% vs 74% and 76%, respectively; P .001). Compared to Whites, AAs and Hispanics were less likely to have been talked to about participating in a study (76% vs 67% and 67%, respectively; P .001). The OR for being talked to about participating in a study was 0.65 (95% CI, 0.52–0.81) for AAs and 0.65 (95% CI, 0.49–0.85) for Hispanics, compared to Whites. AAs and Hispanics were more likely to state that studies were not friendly to their race (17% and 10% vs 4%; P .001). Conclusions: Minorities continue to face barriers for HIV/AIDS trial participation, even when clinical research is available. Enrollment strategies should better target minorities to improve recruitment in HIV/AIDS research.     

Predictors for tuberculosis co-infection in people living with HIV/AIDs

Background/aimTuberculosis (TB) is one of the most common chronic infectious conditions causing mortality and severe outcomes, particularly in people living with HIV/AIDS (PLWHA). In this study, we aimed to determine the prevalence and predictors of TB among PLWHA.Materials and MethodsWe conducted a retrospective and single-center study of adults (≥18 years) PLWHA registered at our tertiary teaching and research hospital between 2000 and 2016.ResultsA total of 711 PLWHA were included. Of whom, 633 (89.0%) were male. Mean age was 36.53 ±11.55 years (range, 17–79). Thirty-eight (5.3%) patients were diagnosed with active TB. TB development was associated with low CD4+ lymphocyte count (p<0.001), high viral load (p=0.040) and alcohol consumption (p=0.004) but no association with age (p=0.392), gender (p=0.928) and duration since anti-retroviral therapy initiation (p=0.788) was found. Also, a receiver operating characteristic analysis showed that the area under the curves of CD4+ lymphocyte count as a predictor for TB development in PLWHA was 0.717 (p<0.001).ConclusionThere are still clinical challenges to predict TB diagnosis. However, CD4+ lymphocyte count and viral load may be considered as valuable predictors for TB development. Also, community strategies to reduce harmful effect of alcohol use should be developed.     

Lymphocyte immunophenotype reference ranges in healthy Indian adults: implications for management of HIV/AIDS in India

With the advent and application of standard and sensitive flow cytometry methods, it became essential to establish reference intervals in healthy individuals to demarcate between health and disease. A reference range of lymphocyte populations for normal individuals is important in the diagnosis and prognosis of immunodeficiency diseases like AIDS. We tried to accomplish this by studying the values for T lymphocyte subsets for 200 healthy North Indian adults between 18 and 55 years. We obtained the following reference ranges for various T lymphocyte subsets: CD4 count (304-1864 cells/microl with the median of 666 cells/microl), CD4% (17.5-50.6% with the median of 35%), CD8% (14-53% with the median of 32.3%), CD3% (43-89% with the median of 70.5%), and CD4/CD8 ratio (0.04-3.5 with the median of 1.04). Significant variations were observed for normal reference intervals for T lymphocyte subsets according to the race, ethnic origin, age group, and gender.     

Correlation between baseline CD4 + T-Lymphocyte count and plasma viral load in AIDS patients and their early clinical and immunological response to HAART: a preliminary study

The aim of this study was to determine the clinical, immunological and virological status of newly diagnosed AIDS cases and to monitor their clinical and immunological response to HAART after a minimum period of three months. Forty three drug naive AIDS patients were enrolled. The most common presenting complaints were weight loss (74.4%), cough (72.1%) and diarrhoea (67.4%). Mean baseline CD4 cell count was 112 +/- 60 cells/microL and mean baseline plasma viral load of 31 patients studied was 192,686 copies/mL. Baseline plasma viral load was higher among patients with lower baseline CD4 cell count. During follow-up, 80.8% patients showed clinical improvement, while a CD4 cell count increased by > or =50 cells/microL in 84.6% cases. Mean CD4 cell count increased from 126 +/- 16.6 cells/microL at baseline to 278 +/- 196.7 cells/microL.     

Impact of CD4+ blood cell count and HIV viral load on treatment response with direct acting antivirals in HIV and HCV coinfected patients: insights from the German Hepatitis C-Registry

Background: Direct-acting antivirals (DAAs) lead to high cure rates of Hepatitis C Virus (HCV) infections in HIV/HCV coinfected patients. Recent data suggest that treatment failures occur more often in HIV/HCV coinfected persons.

Objective: We aimed to identify risk factors for treatment failure in coinfected patients.

Methods: We analyzed data collected from the German Hepatitis C-Registry (DHC-R, Trials Registration number DRKS00009717). 437 HIV/HCV coinfected patients were included. Sustained virological response (SVR) rates and the impact of CD4+ count, HIV viral load, liver cirrhosis and splenomegaly were evaluated.

Results: 83.5% (365/437) of the patients were male (average age: 46.6?±?9.2 y). Most patients received antiretroviral therapy (ART) (88.1%; 385/437), had a HIV RNA ≤40 copies/ml (88.5%; 285/322) and were infected with HCV genotype (GT) 1 (77.6%; 339/437). Overall SVR12 rate was 92% (402/437). In patients with HIV RNA ≤40 copies/ml and >40 copies/ml SVR12 rates were 93.2% (272/292) and 85.3%, respectively (29/34; p?=?.11). SVR12 rates were 91.8% (45/49) and 92.7% (253/273; p?=?.84) in patients with a CD4+ <350/µl and ≥350/µl. We observed no difference in either of the subgroups in patients with cirrhosis or splenomegaly. In the univariate logistic regression analysis none of the analyzed HIV or HCV specific parameters, liver cirrhosis or splenomegaly were associated with treatment outcome.

Conclusion: We found high SVR12 rates in HIV/HCV coinfected patients and no significant difference was observed due to the patients CD4+ cell count, HIV viral load, portal hypertension or liver cirrhosis.     

Interferon-γ release assay in people infected with immunodeficiency virus

The present study aimed to use QuantiFERON TB Gold in tube (Cellestis Limited, Carnegie, Victoria, Australia) as a tool for the screening for tubercular infection in HIV-positive patients. Seventy-three HIV-positive subjects were tested. For each individual, QuantiFERON TB in tube was performed. The immunoassay was negative in 53 subjects, positive in eight and indeterminate in 12. The data obtained indicate that factors such as the CD4 cell count and their percentage, as well as the stage of the disease, could affect the performance of the interferon-γ release assay in populations at risk such as HIV-positive subjects.     

Baseline CD4+ T-Cell Counts Predict HBV Viral Kinetics to Adefovir Treatment in Lamivudine-Resistant HBV-Infected Patients with or without HIV Infection

Abstract

Background: Coinfection with HIV and hepatitis B virus (HBV) substantially alters the course of HBV. Directly acting anti-HBV agents suppress HBV viral levels; however, the kinetics of HBV decline in mono- and coinfected persons have not been evaluated. We investigated the role of baseline CD4+ T-cell counts as a predictor of HBV response to adefovir (ADV) therapy in chronic HBV with and without HIV coinfection. Methods: We conducted a double-blind, randomized, placebo-controlled study of HIV-infected (n = 12) and uninfected (n = 5) chronic HBV patients treated with ADV. Five HIV uninfected patients received ADV; the HIV+ patients received ADV or placebo for a total of 48 weeks. At the end of 48 weeks, all patients received open-label ADV for an additional 48 weeks. HBV, HIV viral loads, CD4+ T-cell counts, and safety labs were performed on days 0, 1, 3, 5, 7, 10, 14, and 28 and then every 4 weeks. Results: Lower HBV slopes were observed among coinfected compared to monoinfected patients (P = .027 at 4 weeks, P = .019 at 24 weeks, and P = .045 at 48 weeks). Using a mixed model analysis, we found a significant difference between the slopes of the 2 groups at 48 weeks (P = .045). Baseline CD4+ T-cell count was the only independent predictor of HBV decline in all patients. Conclusion: HIV coinfection is associated with slower HBV response to ADV. Baseline CD4+ T-cell count and not IL28B genotype is an independent predictor of HBV decline in all patients, emphasizing the role of immune status on clearance of HBV.     

Causes and Consequences of Incomplete HIV RNA Suppression in Clinical Trials

Abstract

The current goal of antiretroviral treatment is suppression of HIV RNA below 50 copies/mL. However, there is evidence for residual low-level plasma viraemia below 50 copies/mL for people with HIV RNA suppression on antiretroviral treatment. It is not clear whether more profound suppression of HIV RNA would lead to a lower risk of virological failure on antiretroviral treatment or emergent drug resistance. There is high variability in the currently used HIV RNA PCR assays for samples with HIV RNA levels close to the detection lower limit of 40–50 copies/mL. For patients who have HIV RNA levels just above 50 copies/mL (often called “single blips”), a repeat sample should be taken to investigate the possibility of technical error. In a systematic review of 48-week effi cacy from randomized clinical trials (N = 8,083), patients were signifi cantly more likely to show HIV RNA levels between 50–400 copies/mL while taking fi rst-line boosted PI-based HAART (7.3%) compared with fi rst-line NNRTI-based HAART (4.5%) (p < 0.01). However in a systematic review of emergent drug resistance at failure in the same trials, there was also a signifi cantly lower risk of emerging drug resistance after virological failure of boosted PI-based HAART (p < 0.01). Therefore, HIV RNA blips between 50–400 copies/mL may have different consequences for different classes of antiretrovirals. The most widely used method to analyse HIV RNA in clinical trials — time to loss of virological response (TLOVR) — uses two consecutive HIV RNA measurements to define both virological success and failure. However, other methods may improve precision and increase statistical power.     

Continuing debate over HIV therapy initiation

Abstract

Initiation of highly active antiretroviral therapy (HAART) in human immunodeficiency virus (HIV) infection has changed the landscape of HIV/AIDS care. However, the potential for long-term complications from therapy has emerged, and the risk/benefit associated with usage now merits more extensive evaluation. As data from ongoing and future clinical trials continue to accumulate, individualization of therapy may be the appropriate option for HIV-infected individuals.     

Randomized Trials Stopped Early for Harm in HIV/AIDS: A Systematic Survey

Abstract

Purpose: The decision to stop trials early because of the harmful effects of the intervention is complex and requires weighing statistical, logistical, and ethical considerations. We assessed the prevalence of randomized clinical trials (RCTs) stopped early for harm in HIV/AIDS and determined the quality of reporting of methods to inform the decision to stop the trial. Method: We searched 11 electronic databases and major conference abstract databases, contacted trialist and advocacy groups, and searched the Internet. We selected RCTs stopped early for harm. We extracted data on journal and year of publication, reporting of methods and funding, planned sample size, number and planning of interim analyses, stopping rules, and effect size of the harm outcomes. Results: We found 10 RCTs stopped early for harm (median, n = 85; range, 7-1227). Most interventions (n = 9) were antiviral drugs; one trial studied vitamins to prevent vertical transmission of HIV. Five studies reported a priori defined adverse events, and only 1 trial reported planned stopping guidelines. The primary harm outcomes reported across trials included toxicity, death, and increased mother-to-child transmission. Two trials were stopped due to sudden unanticipated adverse events (Stevens-Johnson syndrome, death, and encephalopathy). Relative risk point estimates for harm ranged from 1 to 6.18. Six studies reported the presence of a data safety and monitoring board. Conclusion: The reporting of methods to inform the decision to stop trials for harm in this population is deficient in a variety of ways, including lack of stopping guidelines. Clinicians should interpret RCTs stopped early for harm with caution and interpret the results in light of related evidence. Trialists should improve the transparency of their decision-making regarding early stopping for harmful effects.     

存放温度及时间对于HIV/AIDS患者外周血CD4+、CD8+细胞测定结果的影响

目的　研究HIV AIDS患者外周血CD4 、CD8 淋巴细胞数在不同条件下 (时间、温度和处理过程 )的变化。方法　选取HIV AIDS患者 34例 ,用流式细胞术检测在 4℃条件下放置不同时间(2、2 4、4 8、72h)的外周血CD4 、CD8 细胞数的变化 ,对经过处理的外周血 (处理过的血样 )CD4 、CD8 细胞数的变化进行比较 ;对室温条件下放置不同时间 (2、2 4、4 8、72h)处理过的血样CD4 、CD8 细胞数的变化进行比较。结果　在 4℃时 ,全血放置 2、2 4、4 8、72h的CD4 细胞计数差异无显著意义(P >0 0 5 ) ,而CD8 细胞数放置 72h时则差异有显著意义 (P <0 0 5 ) ;处理过的样品放置 72hCD4 细胞计数差异才有显著意义 (P <0 0 5 ) ,而CD8 细胞数在 2 4h时差异就有显著意义 (P <0 0 5 )。在室温时 ,处理过血样放置 2、2 4、4 8、72h的CD4 细胞计数差异无显著意义 (P >0 0 5 ) ,而CD8 细胞数在 4 8h则差异有显著意义 (P <0 0 5 )。结论　抗凝全血在 4℃放置 4 8h ,检测CD4 、CD8 淋巴细胞数 ,结果是可靠的。处理过血样在室温放置 2 4h ,检测CD4 、CD8 淋巴细胞数 ,结果是可靠的。 2 4～4 8h虽然CD4 淋巴细胞没有变化 ,但CD8 淋巴细胞却发生明显的变化 ,两者比例必然发生变化。     

Clinical and immunological status of a newly diagnosed HIV positive population, in Marrakech, Morocco

Objective

To evaluate the clinical and the immune status of newly HIV diagnosed patients, in Marrakech city and its neighboring area, in Morocco.

Methods

We performed a retrospective study on 235 patients who have been previously confirmed for HIV infection, and underwent a CD4 T cells using flow cytometry (FacsCount, Becton Dickinson®).

Results

The mean age of patients was 34,3 ± 8,4 years (range: 14–55), with a male predominance (sex-ratio M/F=1.4). On basis of clinical data of the patients, 62% (n=146) of them were categorized as “category C”, 18.4% (n=43) as “category B”, and 19.6% (n=46) as “category A” according to CDC (Center for Disease Control) HIV classification. Among all of them, 60.4% (n=142) had less than 200 CD4T cells, 26% (n=61) had between 200 and 499 CD4T cells, and only 13.6% (n=32) showed a number of CD4T cells less or equal to 500/mm³.

Conclusion

The results of this study reflect a significant delay in the diagnosis of HIV infected patients. Therefore, this delay may compromise timely management of HIV infected individuals and enhances propagation of the epidemic in our country. These data confirm the need for intensifying prevention efforts among high-risk population. Moreover, continuing education in HIV/AIDS among healthcare providers should be reinforced.     

艾滋病临床用药分析

目的 探讨艾滋病临床用药方案与CD4细胞的关系,以期为艾滋病后续治疗起到积极的理论支持。方法 选取某临床医院2012年12月~2017年10月统计的732例艾滋病患者基线和随访数据,分析所有患者基线及随访治疗方案,将CD4个数作为评判标准,主要研究基线治疗以及随访治疗后患者CD4细胞个数的变化情况。结果 临床数据中患者的所有治疗方案中,有五组治疗方案:3TC+AZT+EFV、3TC+AZT+NVP、3TC+D4T+EFV、3TC+D4T+NVP和3TC+TDF+EFV占总方案的93.03%,且其中我国抗HIV治疗方案主要应用3TC+AZT+EFV和3TC+D4T+EFV,全部数据中未换药组占比79.97%;在治疗过程中,CD4提高的患者占64.30%。结论 艾滋病临床治疗中,治疗方案3TC+AZT+EFV、3TC+AZT+NVP、3TC+D4T+EFV、3TC+D4T+NVP和3TC+TDF+EFV被广泛应用,我国临床治疗以方案3TC+AZT+EFV和3TC+D4T+EFV为主,且各种治疗方案对于HIV病情有相对较好的稳定作用。     

HIV/AIDS患者疾病进程与CD4+CD25hi调节性T细胞之间相关性研究

目的 通过分析不同阶段HIV感染者外周血CD4+CD25hi调节性T细胞(CD4+CD25hiregulatory T cells,Treg cells)与外周血免疫状态和病毒载量的相关性,探讨Treg细胞对HIV/AIDS发病进程的影响.方法 采集116例HIV感染者和21例正常人对照外周血,用4色流式细胞术进行CD4+和CD8+T细胞绝对数计数;用3色流式细胞术进行Treg细胞测定;用荧光定量PCR法进行HIVRNA载晕测定.实验数据用回归统计学方法和T检验方法进行分析.结果 HIV感染者外周血Treg细胞频率在HIV感染初期显著下降,之后随着疾病的进程逐渐升高.在CD4+T细胞大于300/μl的患者低于正常对照组,在CD4+T细胞小于100/μl的患者高于正常对照组,差异具有统计学意义.Treg细胞频率与CD4+T淋巴细胞绝对数和CD4+/CD8+之间均呈负相关.其相关系数r和P值各为r=-0.564,P＜0.001和r=-0.377,P＜0.001;Treg细胞频率与血浆HIV病毒载量呈正相关,其相关系数r=0.514.P＜0.001.结论 CD4+CD25hi Treg细胞可能是参与艾滋病免疫发病机理的重要细胞,在HIV感染发病进程的不同阶段具有不同的意义,其确切机制有待进行进一步研究.     

Feasibility of using dried blood spots for HIV viral load testing among HIV-infected individuals in Thailand using QIAGEN QIAsymphony-artus HIV-1 platform

In settings where plasma preparation and sample centralization are not feasible or inconvenient, dried blood spots (DBS) could be used as an alternative specimen to plasma to assess antiretroviral treatment response among HIV-infected individuals. This study was aimed to (1) validate the recent QIAsymphony-artus assay for DBS HIV viral load (VL) and (2) assess the feasibility of measuring HIV VL on DBS using this assay in Thailand. Ethylenediaminetetraacetic acid-blood samples from 99 HIV-infected individuals were used to prepare paired DBS and plasma. Also, DBS samples were shipped to three distant hospitals in the northern region. After short-term storage, DBS were returned by regular post to the AMS laboratory and were re-tested for HIV VL using the same platform. HIV VL results were compared using Pearson's correlation and Bland-Altman analysis. DBS HIV VL fairly correlated to plasma HIV VL (R = 0.62) with a mean difference of 0.02 log₁₀IU/mL (SD = 1.06). A high correlation (R = 0.79) was observed between HIV VL in DBS before and after shipping (mean difference = 0.14 log₁₀IU/mL, SD = 0.74), indicating good stability of HIV RNA in DBS. DBS can be used as an alternative specimen for HIV VL monitoring in Thailand. However, measurement of HIV VL with the QIAGEN QIAsymphony-artus assay should be improved, especially the DBS pre-extraction process.