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Cell-Mediated Immune Predictors of Vaccine Effect on Viral Load and CD4 Count in a Phase 2 Therapeutic HIV-1 Vaccine Clinical Trial.

ABSTRACT: In a placebo-controlled trial of the peptide-based therapeutic HIV-1 p24Gag vaccine candidate Vacc-4x, participants on combination antiretroviral therapy (cART) received six immunizations over 18weeks, followed by analytical treatment interruption (ATI) between weeks 28 and 52. Cell-mediated immune responses were investigated as predictors of Vacc-4x effect (VE) on viral load (VL) and CD4 count during ATI.All analyses of week 28 responses and fold-changes relative to baseline considered per-protocol participants (Vacc-4x:placebo=72:32) resuming cART after week 40. Linear regression models with interaction tests were used. VE was estimated as the Vacc-4x-placebo difference in log10-transformed VL (VEVL) or CD4 count (VECD4).A lower fold-change of CD4+ T-cell proliferation was associated with VECD4 at week 48 (p=0.036, multiplicity adjusted q=0.036) and week 52 (p=0.040, q=0.080). A higher fold-change of IFN-? in proliferation supernatants was associated with VEVL at week 44 (p=0.047, q=0.07). A higher fold-change of TNF-? was associated with VEVL at week 44 (p=0.045, q=0.070), week 48 (p=0.028, q=0.070), and week 52 (p=0.037, q=0.074). A higher fold-change of IL-6 was associated with VEVL at week 48 (p=0.017, q=0.036). TNF-? levels (>median) were associated with VECD4 at week 48 (p=0.009, q=0.009).These exploratory analyses highlight the potential value of investigating biomarkers in T-cell proliferation supernatants for VE in clinical studies.

SUBMITTER: Huang Y

PROVIDER: S-EPMC5652289 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Cell-Mediated Immune Predictors of Vaccine Effect on Viral Load and CD4 Count in a Phase 2 Therapeutic HIV-1 Vaccine Clinical Trial.

Huang Yunda Y Pantaleo Giuseppe G Tapia Gonzalo G Sanchez Brittany B Zhang Lily L Trondsen Monica M Hovden Arnt-Ove AO Pollard Richard R Rockstroh Jürgen J Ökvist Mats M Sommerfelt Maja A MA

EBioMedicine 20170922

<h4>Background</h4>In a placebo-controlled trial of the peptide-based therapeutic HIV-1 p24<sup>Gag</sup> vaccine candidate Vacc-4x, participants on combination antiretroviral therapy (cART) received six immunizations over 18weeks, followed by analytical treatment interruption (ATI) between weeks 28 and 52. Cell-mediated immune responses were investigated as predictors of Vacc-4x effect (VE) on viral load (VL) and CD4 count during ATI.<h4>Methods</h4>All analyses of week 28 responses and fold-ch ...[more]

PMID: 28970080

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Project description:BACKGROUND:Despite the success of prevention of mother to child transmission (PMTCT) program in South Africa, the 30% HIV prevalence among women of childbearing age requires the PMTCT program to be maximally efficient to sustain gains in the prevention of vertical HIV transmission. We aimed to determine the immunologic and virologic status at entry into antenatal care (ANC) and at childbirth among HIV positive women who conceived under the CD4<500 cells/?l antiretroviral therapy (ART) eligibility threshold and universal test and treat (UTT) policies in the Gauteng province of South Africa. METHOD:We conducted a retrospective cohort study of 692 HIV positive adult (>18 years) postpartum women who gave birth between September 2016 and December 2017. Demographic, viral load (VL) and CD4 data at ANC start (3-9 months before delivery) and delivery (3 months before/after) were obtained from medical records of consenting women. We compared CD4?500 cell/?l and viral load (VL) suppression (<400 copes/ml) rates at ANC start and delivery among women with a pre-pregnancy ART, women known HIV positive but with in-pregnancy ART and newly diagnosed women with in-pregnancy ART. Predictors of having a high CD4 and suppressed VL were assessed by log-binomial regression. RESULTS:Of the 692 participants, 394 (57.0%) had CD4 data and 326 (47.1%) had VL data. Overall women with a pre-pregnancy ART were more likely to start ANC with CD4 count?500 cell/?l (46.3% vs 24.8%, adjusted risk ratio (aRR) = 1.9; 95% confidence interval (95% CI): 1.4-2.5), compared to newly diagnosed women. This difference was no longer apparent at the time of delivery (aRR 1.2 95% CI: 0.4-3.7). Similarly, viral suppression at delivery was higher among women with pre-pregnancy ART (87.2% vs 69.3%, aRR 1.3, 95% CI: 1.1-1.6) as compared to the newly diagnosed women. Viral suppression rate among newly diagnosed women increased substantially by the time of delivery from 43.5% to 69.3% (p = 0.001). CONCLUSION:These results show that pre-pregnancy ART improves immunologic and virologic control during pregnancy and call for renewed efforts in HIV testing, linkage to ART and viral monitoring.

Project description:BACKGROUND: HCV RNA viral load is an important predictor of sustained virological response and, recently, a significant correlation with liver fibrosis was described. We investigated on possible influence of clinical and viro-immunological variables on HCV viral load in HIV-HCV co-infected patients over a study time of three years (2009-2012). METHODS: We retrospectively enrolled 98 adult patients with a diagnosis of chronic HIV infection in 2009, a diagnosis of chronic HCV infection with a detectable plasma HCV RNA in 2009 and 2012, HCV therapy-naïve or with failed and stopped antiviral treatment before June 2008. The following variables were recorded: age, gender, HCV genotype, IL28B rs12979860 CC genotype, HCV treatment status, advanced liver fibrosis diagnosis, antiretroviral therapy, CD4+ cell count, HCV viral load, HIV RNA (plasma HIV-1 RNA levels were measured from blood samples every three months at least). The correlation was established using linear regression analysis, analysis of variance and Fisher's exact test. Comparisons between groups were performed using Fisher's exact test, the independent samples t-test and the t-test for paired data, as appropriate, for continuous variables. A mixed mode (ME) maximum likelihood linear regression model was constructed to evaluate the dependence of HCV viral load. RESULTS: HCV RNA levels did not change significantly from 2009 to 2012 (from 3924650?±?5320177 IU/ml to 3085128?±?3372347 IU/ml, p?=?0.13); the CD4+ count increased significantly (from a mean of 576 to a mean of 654, p?=?0.003). Using linear regression, a positive correlation was observed for HCV load and genotype 1 (p?=?0.002), nonresponder status (p?=?0.04) and with interleukin 28B CC allele (p?=?0.05). Other studied covariates failed to reach a significant correlation. CONCLUSIONS: The HCV RNA load, a known pretreatment predictor of response to antiviral therapy, was independent of the two main parameters of HIV disease, plasma HIV RNA and CD4 cell count, over an observation time of 3 years in patients with recovered or spontaneously maintained immunocompetence.

Project description:BackgroundViral load (VL) is recommended for monitoring the response to highly active antiretroviral therapy (HAART) but is not routinely available in most low- and middle-income countries. The purpose of the study was to determine whether a CD4-based monitoring and switching strategy would provide a similar clinical outcome compared to the standard VL-based strategy in Thailand.Methods and findingsThe Programs for HIV Prevention and Treatment (PHPT-3) non-inferiority randomized clinical trial compared a treatment switching strategy based on CD4-only (CD4) monitoring versus viral-load (VL). Consenting participants were antiretroviral-naïve HIV-infected adults (CD4 count 50-250/mm(3)) initiating non-nucleotide reverse transcriptase inhibitor (NNRTI)-based therapy. Randomization, stratified by site (21 public hospitals), was performed centrally after enrollment. Clinicians were unaware of the VL values of patients randomized to the CD4 arm. Participants switched to second-line combination with confirmed CD4 decline >30% from peak (within 200 cells from baseline) in the CD4 arm, or confirmed VL >400 copies/ml in the VL arm. Primary endpoint was clinical failure at 3 years, defined as death, new AIDS-defining event, or CD4 <50 cells/mm(3). The 3-year Kaplan-Meier cumulative risks of clinical failure were compared for non-inferiority with a margin of 7.4%. In the intent to treat analysis, data were censored at the date of death or at last visit. The secondary endpoints were difference in future-drug-option (FDO) score, a measure of resistance profiles, virologic and immunologic responses, and the safety and tolerance of HAART. 716 participants were randomized, 356 to VL monitoring and 360 to CD4 monitoring. At 3 years, 319 participants (90%) in VL and 326 (91%) in CD4 were alive and on follow-up. The cumulative risk of clinical failure was 8.0% (95% CI 5.6-11.4) in VL versus 7.4% (5.1-10.7) in CD4, and the upper-limit of the one-sided 95% CI of the difference was 3.4%, meeting the pre-determined non-inferiority criterion. Probability of switch for study criteria was 5.2% (3.2-8.4) in VL versus 7.5% (5.0-11.1) in CD4 (p=0.097). Median time from treatment initiation to switch was 11.7 months (7.7-19.4) in VL and 24.7 months (15.9-35.0) in CD4 (p=0.001). The median duration of viremia >400 copies/ml at switch was 7.2 months (5.8-8.0) in VL versus 15.8 months (8.5-20.4) in CD4 (p=0.002). FDO scores were not significantly different at time of switch. No adverse events related to the monitoring strategy were reported.ConclusionsThe 3-year rates of clinical failure and loss of treatment options did not differ between strategies although the longer-term consequences of CD4 monitoring would need to be investigated. These results provide reassurance to treatment programs currently based on CD4 monitoring as VL measurement becomes more affordable and feasible in resource-limited settings.Trial registrationClinicalTrials.govNCT00162682 Please see later in the article for the Editors' Summary.

Dataset Information

Cell-Mediated Immune Predictors of Vaccine Effect on Viral Load and CD4 Count in a Phase 2 Therapeutic HIV-1 Vaccine Clinical Trial.

Publications

Cell-Mediated Immune Predictors of Vaccine Effect on Viral Load and CD4 Count in a Phase 2 Therapeutic HIV-1 Vaccine Clinical Trial.

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