The benefit of immediate compared with deferred antiretroviral therapy on CD4+ cell count recovery in early HIV infection.
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ABSTRACT:
SUBMITTER: Sharma S
PROVIDER: S-EPMC6561661 | biostudies-literature | 2019 Jul
REPOSITORIES: biostudies-literature
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Project description:BackgroundThere is conflicting evidence on the immunologic benefit of treating helminth co-infections ("deworming") in HIV-infected individuals. Several studies have documented reduced viral load and increased CD4 count in antiretroviral therapy (ART) naïve individuals after deworming. However, there are a lack of data on the effect of deworming therapy on CD4 count recovery among HIV-infected persons taking ART.Methodology/principal findingsTo estimate the association between empiric deworming therapy and CD4 count after ART initiation, we performed a retrospective observational study among HIV-infected adults on ART at a publicly operated HIV clinic in southwestern Uganda. Subjects were assigned as having received deworming if prescribed an anti-helminthic agent between 7 and 90 days before a CD4 test. To estimate the association between deworming and CD4 count, we fit multivariable regression models and analyzed predictors of CD4 count, using a time-by-interaction term with receipt or non-receipt of deworming. From 1998 to 2009, 5,379 subjects on ART attended 21,933 clinic visits at which a CD4 count was measured. Subjects received deworming prior to 668 (3%) visits. Overall, deworming was not associated with a significant difference in CD4 count in either the first year on ART (? = 42.8; 95% CI, -2.1 to 87.7) or after the first year of ART (? = ?-9.9; 95% CI, -24.1 to 4.4). However, in a sub-analysis by gender, during the first year of ART deworming was associated with a significantly greater rise in CD4 count (? = 63.0; 95% CI, 6.0 to 120.1) in females.Conclusions/significanceEmpiric deworming of HIV-infected individuals on ART conferred no significant generalized benefit on subsequent CD4 count recovery. A significant association was observed exclusively in females and during the initial year on ART. Our findings are consistent with recent studies that failed to demonstrate an immunologic advantage to empirically deworming ART-naïve individuals, but suggest that certain sub-populations may benefit.
| S-EPMC4125278 | biostudies-literature
Project description:ObjectiveTo determine if immediate compared to deferred initiation of antiretroviral therapy (ART) in healthy persons living with HIV had a more favorable impact on health-related quality of life (QOL), or self-assessed physical, mental, and overall health status.DesignQOL was measured in the Strategic Timing of Antiretroviral Therapy study, which randomized healthy ART-naive persons living with HIV with CD4 cell counts above 500 cells/μl from 35 countries to immediate versus deferred ART.MethodsAt baseline, months 4 and 12, then annually, participants completed a visual analog scale (VAS) for 'perceived current health' and the Short-Form 12-Item Health Survey version 2 from which the following were computed: general health perception; physical component summary (PCS); and mental component summary (MCS); the VAS and general health were rated from 0 (lowest) to 100 (highest).ResultsQOL at study entry was high (mean scores: VAS = 80.9, general health = 72.5, PCS = 53.7, MCS = 48.2). Over a mean follow-up of 3 years, changes in all QOL measures favored the immediate group (P < 0.001); estimated differences were as follows: VAS = 1.9, general health = 3.6, PCS = 0.8, MCS = 0.9. When QOL changes were assessed across various demographic and clinical subgroups, treatment differences continued to favor the immediate group. QOL was poorer in those experiencing primary outcomes; however, when excluding those with primary events, results remained favorable for immediate ART recipients.ConclusionIn an international randomized trial in ART-naive participants with above 500 CD4 cells/μl, there were modest but significant improvements in self-assessed QOL among those initiating ART immediately compared to deferring treatment, supporting patient-perceived health benefits of initiating ART as soon as possible after an HIV diagnosis.
| S-EPMC5373969 | biostudies-literature
Project description:ObjectiveTo investigate CD4 cell count recovery following ART initiation in perinatally HIV-infected children diagnosed in later childhood.DesignObservational prospective cohort study of newly diagnosed children aged 6-15 in Harare, Zimbabwe.MethodsParticipants were enrolled into a cohort at seven primary healthcare clinics between January 2013 and January 2015. ART was initiated according to national guidelines and CD4 cell counts were performed 6-monthly over 18 months. The relationship between CD4 cell count and time on ART was investigated using regression analysis with fixed (population) and random (individual) effects, and age at ART initiation as a covariate.ResultsOf the 307 participants who initiated ART, the median age at initiation was 11.7 years (interquartile range 9.6-13.8). The addition of an individual intercept and slope as random effects significantly improved the model fit compared with a fixed effects-only model. CD4 response (using a square-root transformation) was best modelled using a two-knot linear spline, with significant effects of time on ART and age at ART initiation. Younger children had a higher CD4 cell count at ART initiation (-17.9?cells/?l per year of age), an accelerated increase during the first 3 months on ART (-38.9?cells/?l per year of age at day 84), and a sustained higher CD4 cell count.ConclusionEarlier ART initiation in older children is associated with accelerated CD4 cell count recovery and lasting immune reconstitution. Our findings support WHO guidance recommending ART initiation in all children, irrespective of disease stage and CD4 cell count.
| S-EPMC6125740 | biostudies-literature
Project description:BackgroundThe optimal stage for initiating antiretroviral therapies in HIV-1 bearing patients is still a matter of debate.MethodsWe present computer simulations of HIV-1 infection aimed at identifying the pro et contra of immediate as compared to deferred Highly Active Antiretroviral Therapy (HAART).ResultsOur simulations highlight that a prompt specific CD8+ cytotoxic T lymphocytes response is detected when therapy is delayed. Compared to very early initiation of HAART, in deferred treated patients CD8+ T cells manage to mediate the decline of viremia in a shorter time and, at interruption of therapy, the virus experiences a stronger immune pressure. We also observe, however, that the immunological effects of the therapy fade with time in both therapeutic regimens. Thus, within one year from discontinuation, viral burden recovers to the value at which it would level off in the absence of therapy.In summary, simulations show that immediate therapy does not prolong the disease-free period and does not confer a survival benefit when compared to treatment started during the chronic infection phase.ConclusionOur conclusion is that, since there is no therapy to date that guarantees life-long protection, deferral of therapy should be preferred in order to minimize the risk of adverse effects, the occurrence of drug resistances and the costs of treatment.
| S-EPMC2771028 | biostudies-literature
Project description:BackgroundThe optimal time for the initiation of antiretroviral therapy for asymptomatic patients with human immunodeficiency virus (HIV) infection is uncertain.MethodsWe conducted two parallel analyses involving a total of 17,517 asymptomatic patients with HIV infection in the United States and Canada who received medical care during the period from 1996 through 2005. None of the patients had undergone previous antiretroviral therapy. In each group, we stratified the patients according to the CD4+ count (351 to 500 cells per cubic millimeter or >500 cells per cubic millimeter) at the initiation of antiretroviral therapy. In each group, we compared the relative risk of death for patients who initiated therapy when the CD4+ count was above each of the two thresholds of interest (early-therapy group) with that of patients who deferred therapy until the CD4+ count fell below these thresholds (deferred-therapy group).ResultsIn the first analysis, which involved 8362 patients, 2084 (25%) initiated therapy at a CD4+ count of 351 to 500 cells per cubic millimeter, and 6278 (75%) deferred therapy. After adjustment for calendar year, cohort of patients, and demographic and clinical characteristics, among patients in the deferred-therapy group there was an increase in the risk of death of 69%, as compared with that in the early-therapy group (relative risk in the deferred-therapy group, 1.69; 95% confidence interval [CI], 1.26 to 2.26; P<0.001). In the second analysis involving 9155 patients, 2220 (24%) initiated therapy at a CD4+ count of more than 500 cells per cubic millimeter and 6935 (76%) deferred therapy. Among patients in the deferred-therapy group, there was an increase in the risk of death of 94% (relative risk, 1.94; 95% CI, 1.37 to 2.79; P<0.001).ConclusionsThe early initiation of antiretroviral therapy before the CD4+ count fell below two prespecified thresholds significantly improved survival, as compared with deferred therapy.
| S-EPMC2854555 | biostudies-literature
Project description:ObjectivesCertain prescribed opioids have immunosuppressive properties, yet their impact on clinically relevant outcomes, including antiretroviral therapy (ART) response among HIV-infected patients, remains understudied.MethodsUsing the Veterans Aging Cohort Study data, we conducted a longitudinal analysis of 4358 HIV-infected patients initiating ART between 2002 and 2010 and then followed them for 24 months. The primary independent variable was prescribed opioid duration, categorized using pharmacy data as none prescribed, short-term (< 90 days) and long-term (≥ 90 days). Outcomes included CD4 cell count over time. Analyses adjusted for demographics, comorbid conditions, ART type and year of initiation, and overall disease severity [ascertained with the Veterans Aging Cohort Study (VACS) Index]. Sensitivity analyses examined whether effects varied according to baseline CD4 cell count, achievement of viral load suppression, and opioid properties (i.e. dose and known immunosuppressive properties).ResultsCompared to those with none, patients with short-term opioids had a similar increase in CD4 cell count (mean rise per year: 74 vs. 68 cells/μL; P = 0.11), as did those with long-term prescribed opioids (mean rise per year: 74 vs. 75 cells/μL; P = 0.98). In sensitivity analysis, compared with no opioids, the effects of short-term prescribed opioids were statistically significant among those with a baseline CD4 cell count ≥ 500 cells/μL (mean rise per year: 52 cells/μL for no opioids vs. 20 cells/μL for short-term opioids; P = 0.04); findings were otherwise unchanged.ConclusionsDespite immunosuppressive properties intrinsic to opioids, prescribed opioids appeared to have no effect on CD4 cell counts over 24 months among HIV-infected patients initiating ART.
| S-EPMC5053822 | biostudies-literature
Project description:The role of antiretroviral therapy (ART) in reducing or contributing to liver fibrosis in persons with human immunodeficiency virus (HIV) is unclear. We evaluated participants in the Strategic Timing of AntiRetroviral Treatment (START) trial for liver fibrosis using the AST to Platelet Ratio Index (APRI) and Fibrosis-4 Index (FIB-4), and assessed for a benefit of early versus delayed ART on liver fibrosis progression. ART-naïve persons with high CD4 counts (>500 cells/µL) from 222 clinical sites in 35 countries were randomized to receive ART either at study enrollment (immediate treatment arm) or when their CD4 count fell below 350 cells/µL (deferred treatment arm). The following outcomes were evaluated: fibrosis (APRI > 0.5 or FIB-4 > 1.45), significant fibrosis (APRI > 1.5 or FIB-4 > 3.25), hepatic flare, and resolution of elevated APRI and FIB-4 scores. Of the 4,684 enrolled into the START study, 104 did not have APRI or FIB-4 results and were excluded. Among 4,580 participants (2,273 immediate treatment; 2,307 deferred treatment), the median age was 36 years, 26.9% were female, and 30.4% were black. Three percent had an alcoholism or substance abuse history, 6.4% had hepatitis B and/or C, and 1.1% had significant fibrosis at baseline. The median CD4 count was 651, and 5.3% had HIV RNA ≤ 200. Immediate arm participants were at lower risk of developing increased fibrosis scores than deferred arm participants (hazard ratio [HR] = 0.66; 95% confidence interval [CI] = 0.57-0.78; P < 0.001) and more likely to have resolution of elevated baseline scores (HR 1.6; 95% CI 1.3-1.9; P < 0.001). Conclusions: Significant liver fibrosis was rare among ART-naïve HIV-positive persons with high CD4 counts. Our findings suggest a benefit of early ART in preventing the development of liver fibrosis.
| S-EPMC6393919 | biostudies-literature
Project description:INTRODUCTION:HIV-tuberculosis (TB) co-infection remains an important cause of mortality in sub-Saharan Africa. Clinical trials have reported early (within 2 weeks of TB therapy) antiretroviral therapy (ART) reduces mortality among HIV-TB co-infected research participants with low CD4 cell counts, but this has not been consistently observed. We aimed to evaluate the current WHO recommendations for ART in HIV-TB co-infected patients on mortality in routine clinical settings. METHODS:We compared two cohorts before (2008-2010) and after (2012-2013) policy change on ART timing after TB and examined the effectiveness of early versus delayed ART on mortality in HIV-TB co-infected participants with CD4 cell count 100?cells/?l or less. We used inverse probability censoring-weighted Cox models on baseline characteristics to balance the study arms and generated hazard ratios for mortality. RESULTS:Of 356 participants with CD4 cell counts 100?cells/?l or less, 180 were in the delayed ART cohorts whereas 176 were in the early ART cohorts. Their median age (32.5 versus 32 years) and baseline CD4 cell counts (26.5 versus 26?cells/?l) respectively were similar. There was no difference in mortality rates of both cohorts. The risk of death increased in participants with a positive Cryptococcal antigen (CrAg) test in both the early ART cohort (aHR?=?2.6, 95% CI 1.0-6.8; P?=?0.045) and the delayed ART cohort (aHR?=?4.2, 95% CI 1.9-9.0; P?<?0.001 CONCLUSION:: Early ART in patients with HIV-TB co-infection was not associated with reduced risk of mortality in routine care. Asymptomatic Cryptococcal antigenaemia increased the risk of mortality in both cohorts.
| S-EPMC6136949 | biostudies-literature
Project description:OBJECTIVE:The Strategic Timing of AntiRetroviral Treatment (START) trial found a lower risk of a composite clinical outcome in HIV-positive individuals assigned to immediate initiation of antiretroviral therapy (ART) compared with those assigned to deferred initiation. However, 30% of those assigned to deferred initiation started ART earlier than the protocol specified. To supplement the published intention-to-treat (ITT) effect estimates, here we estimate the per-protocol effect of immediate versus deferred ART initiation in START. DESIGN:The START trial randomized 4685 HIV-positive participants with CD4 cell counts more than 500 cells/?l to start ART immediately after randomization (immediate initiation group) or to wait until the CD4 cell count dropped below 350 cells/?l or an AIDS diagnosis (deferred initiation group). METHODS:We used the parametric g-formula to estimate and compare the cumulative 5-year risk of the composite clinical outcome in the immediate initiation group, and deferred initiation groups had all the trial participants adhered to the protocol. RESULTS:We estimated that the 5-year risk of the composite outcome would have been 3.2% under immediate ART initiation and 7.0% under deferred initiation. The difference of 3.8% (95% confidence interval 1.5, 6.5) was larger than the ITT effect estimate of 3.1%, corresponding to a difference in effect estimates of 0.72% (-0.35, 2.35). CONCLUSION:The ITT effect estimate may underestimate the benefit of immediate ART initiation by 23%. This estimate can be used by patients and policy-makers who need to understand the full extent of the benefit of changes in ART initiation policies.
| S-EPMC5339063 | biostudies-literature
Project description:In a prospective randomized, controlled trial in Uganda comparing the efficacy of antiretroviral therapy during tuberculosis therapy with the efficacy of tuberculosis therapy alone in HIV-infected patients with tuberculosis who have a CD4(+) cell count >350 cells/microL, it was found that antiretroviral therapy did not accelerate microbiologic, radiographic, or clinical responses to tuberculosis therapy: 18% of participants had sputum smears positive for Mycobacterium tuberculosis after 5 months of tuberculosis therapy, despite having had negative culture results. Trial registration. ClinicalTrials.gov identifier: NCT00078247 .
| S-EPMC2919368 | biostudies-literature