We examined changes in soluble inflammatory cytokines and T-cell activation after antiretroviral therapy (ART) initiation in an AIDS Clinical Trials Group (ACTG) nested case-control study. Cases were 143 human immunodeficiency virus (HIV)–infected adults who developed a non-AIDS event; 315 controls remained event-free. Specimens were tested pre-ART, year 1 post-ART, and at the visit preceding the event. Conditional logistic regression evaluated the associations of biomarker changes with non-AIDS events. Inflammatory and most activation biomarkers declined from pre-ART to year 1 for cases and controls. Subsequently, inflammatory biomarkers remained mostly stable in controls but not cases. Cellular activation markers generally declined for both cases and controls between year 1 and the pre-event sampling. Controls with greater pre-ART RNA levels or lower CD4+ levels had higher biomarker levels while also experiencing greater biomarker declines in the first year of ART. Changes in biomarkers to year 1 showed no significant associations with non-AIDS events. Cases, however, had significantly greater increases in all plasma biomarkers (but not cellular activation) from year 1 to the visit preceding the event. Inflammation increases prior to non-AIDS events in treated HIV-infected adults. These biomarker changes may reflect subclinical disease processes or other alterations in the inflammatory environment that causally contribute to disease. NCT00001137.
HLA class I molecules are ligands for killer cell immunoglobin like receptors (KIR) that control the antiviral response of natural killer (NK) cells. However, the effects of KIR and HLA (KIR/HLA) alleles on HIV disease of children have not been studied.993 antiretroviral naïve children with symptomatic HIV infection from PACTG protocols P152 and P300 were genotyped for KIR and HLA alleles using the Luminex platform. Linear regression was used to test the association between genotypes and baseline pre-ART HIV RNA, CD4+ lymphocyte count, and cognitive score, adjusting for age, race/ethnicity and study. The interaction between genetic markers and age was investigated. To account for multiple testing the false discovery rate (FDR) was controlled at 0.05.Children with the KIR2DS4*ALL FULL LENGTH (KIR2DS4*AFL) allele had higher CD4+ lymphocyte counts. Among children ≤2 years of age, the KIR2DS4*AFL was associated with lower plasma HIV RNA and higher cognitive index scores. KIR Cent2DS3/5_1 had lower CD4+ lymphocyte counts in children ≤2 years of age, while the presence of Tel1, Tel2DS4_2, Tel2DS4_4, Tel8, Tel2DS4_6 had higher CD4+ lymphocyte counts in all children. Presence of Cent2, Cent4 and Cent8 was associated with increased HIV RNA load in children ≤2 years. Presence of KIR3DL1+Bw4 was associated with higher CD4+ lymphocyte counts in all children. Among children >2 years old, KIR3DS1+Bw4-80I was associated with higher plasma HIV RNA, and Bw6/Bw6 was associated with lower plasma HIV RNA compared to children with KIR3DS1+Bw4-80I.Presented data show for the first time that specific KIR alleles independently or combined with HLA ligands are associated with HIV RNA and CD4+ lymphocyte counts in infected, antiretroviral naive children; and many of these effect estimates appear to be age dependent. These data support a role for specific KIR alleles in HIV pathogenesis in children.
Background: Most clinical trials comparing treatments evaluate the separate effects on each of several efficacy and toxicity outcomes. However, population-averaged summary measures of treatment differences may not accurately reflect individual responses to treatment, and drawing conclusions about which treatment is “best” is straightforward if one treatment is superior across all outcomes, but challenging when this is not the case. Methods: We created a study outcome based on expert opinion, which captures the risk/benefit profile of response to a treatment. Treatments were compared using this ordered outcome with standard statistical techniques. To illustrate the approach, we used as an example a study designed to evaluate initial antiretroviral therapy (ART) in human immunodeficiency virus-1–infected infants, in which results were contradictory across the study’s primary and secondary efficacy and toxicity outcomes. The proposed risk/benefit outcome was evaluated retrospectively in each participant. Results: In the International Maternal Pediatric Adolescent AIDS Clinical Trials P1060 study, one treatment regimen (lopinavir/ritonavir-based ART) was superior to the other (nevirapine-based ART) in reducing viral load (primary outcome) but inferior for immunologic and growth outcomes (important secondary outcomes in resource-limited settings). Treatment comparisons using the risk/benefit outcome indicated that the lopinavir/ritonavir-based ART regimen had a higher proportion of participants with the best overall response to treatment. Comparisons focusing on individual-level responses for the secondary outcomes also favored lopinavir/ritonavir-based ART, results that differed from the original population-averaged analyses ones. Conclusions: Designing studies prospectively using risk/benefit outcomes focusing on an individual’s responses to treatment more closely matches the needs of clinicians making decisions about how best to treat patients in clinical settings.
The relationship of specific psychiatric conditions to adherence has not been examined in longitudinal studies of youth with perinatal HIV infection (PHIV). We examined associations between psychiatric conditions and antiretroviral nonadherence over 2 years.Longitudinal study in 294 PHIV youth, 6-17 years old, in the United States and Puerto Rico.We annually assessed three nonadherence outcomes: missed above 5% of doses in the past 3 days, missed a dose within the past month, and unsuppressed viral load (>400 copies/ml). We fit multivariable logistic models for nonadherence using Generalized Estimating Equations, and evaluated associations of psychiatric conditions (attention deficit hyperactivity disorder, disruptive behavior, depression, anxiety) at entry with incident nonadherence using multivariable logistic regression.Nonadherence prevalence at study entry was 14% (3-day recall), 32% (past month nonadherence), and 38% (unsuppressed viral load), remaining similar over time. At entry, 38% met symptom cut-off criteria for at least one psychiatric condition. Greater odds of 3-day recall nonadherence were observed at week 96 for those with depression [adjusted odds ratio (aOR) 4.14, 95% confidence interval (CI) 1.11-15.42] or disruptive behavior (aOR 3.36, 95% CI 1.02-11.10], but not at entry. Those with vs. without attention deficit hyperactivity disorder had elevated odds of unsuppressed viral load at weeks 48 (aOR 2.46, 95% CI 1.27-4.78) and 96 (aOR 2.35, 95% CI 1.01-5.45), but not at entry. Among 232 youth adherent at entry, 16% reported incident 3-day recall nonadherence. Disruptive behavior conditions at entry were associated with incident 3-day recall nonadherence (aOR 3.01, 95% CI 1.24-7.31).In PHIV youth, comprehensive adherence interventions that address psychiatric conditions throughout the transition to adult care are needed.
Background. The International Maternal Pediatric Adolescent AIDS Clinical Trials Network (IMPAACT) P1060 study demonstrated short-term superiority of lopinavir/ritonavir (LPV/r) over nevirapine (NVP) in antiretroviral therapy (ART), regardless of prior NVP exposure. However, NVP-based ART had a marginal benefit in CD4 percentage (CD4%) and growth. We compared 5-year outcomes from this clinical trial. Methods. Human immunodeficiency virus (HIV)–infected, ART-eligible children were enrolled into 2 cohorts based on prior NVP exposure and randomized to NVP- or LPV/r-based ART. The data safety monitoring board recommended unblinding results in both cohorts due to superiority of LPV/r for the primary endpoint: stopping randomized treatment, virologic failure (VF), or death by 6 months. Participants were offered a switch in regimens (if on NVP) and continued observational follow-up. We compared time to VF or death, death, and CD4% and growth changes using intention-to-treat analyses. Additionally, inverse probability weights were used to account for treatment switching and censoring. Results. As of September 2014, 329 of the 451 (73%) enrolled participants were still in follow-up (median, 5.3 years; interquartile range [IQR], 4.3–6.4), with 52% on NVP and 88% on LPV/r as originally randomized. NVP arm participants had significantly higher risk of VF or death (adjusted hazard ratio [aHR], 1.90; 95% confidence interval [CI], 1.37–2.65) but not death alone (aHR, 1.65; 95% CI, .72–3.76) compared with participants randomized to LPV/r. Mean CD4% was significantly higher in the NVP arm up to 1 year after ART initiation, but not beyond. Mean weight-for-age z scores were marginally higher in the NVP arm, but height-for-age z scores did not differ. Similar trends were observed in sensitivity analyses. Conclusions. These findings support the current World Health Organization recommendation of LPV/r in first-line ART regimens for HIV-infected children. Clinical Trials Registration. NCT00307151.
Desirability of outcome ranking and response adjusted for duration of antibiotic risk (DOOR/RADAR) are novel and innovative methods of evaluating data in antibiotic trials. We analyzed data from a noninferiority trial of short-course antimicrobial therapy for intra-abdominal infection (STOP-IT), and results suggest global superiority of short-duration therapy for intra-abdominal infections.
Abstract Background Tenofovir disoproxil fumarate (TDF) in combination with other antiretroviral (ARV) drugs has been in clinical use for HIV treatment since its approval in 2001. Although the effectiveness of TDF in preventing perinatal HIV infection is well established, information about renal safety during pregnancy is still limited. Trial design The IMPAACT PROMISE study was an open-label, strategy trial that randomized pregnant women to one of three arms: TDF based antiretroviral therapy (ART), zidovudine (ZDV) based ART, and ZDV alone (standard of care at start of enrollment). The P1084s substudy was a nested, comparative study of renal outcomes in women and their infants. Methods PROMISE participants (n = 3543) were assessed for renal dysfunction using calculated creatinine clearance (CrCl) at study entry (> 14 weeks gestation), delivery, and postpartum weeks 6, 26, and 74. Of these women, 479 were enrolled in the P1084s substudy that also assessed maternal calcium and phosphate as well as infant calculated CrCl, calcium, and phosphate at birth. Results Among the 1338 women who could be randomized to TDF, less than 1% had a baseline calculated CrCl below 80 mL/min. The mean (standard deviation) maternal calculated CrCl at delivery in the TDF-ART arm [147.0 mL/min (51.4)] was lower than the ZDV-ART [155.0 mL/min (43.3); primary comparison] and the ZDV Alone [158.5 mL/min (45.0)] arms; the mean differences (95% confidence interval) were − 8.0 mL/min (− 14.5, − 1.5) and − 11.5 mL/min (− 18.0, − 4.9), respectively. The TDF-ART arm had lower mean maternal phosphate at delivery compared with the ZDV-ART [− 0.14 mg/dL (− 0.28, − 0.01)] and the ZDV Alone [− 0.17 mg/dL (− 0.31, − 0.02)] arms, and a greater percentage of maternal hypophosphatemia at delivery (4.23%) compared with the ZDV-ART (1.38%) and the ZDV Alone (1.46%) arms. Maternal calcium was similar between arms. In infants, mean calculated CrCl, calcium, and phosphate at birth were similar between arms (all CIs included 0). Conclusions Although mean maternal calculated CrCl at Delivery was lower in the TDF-ART arm, the difference between arms is unlikely to be clinically significant. During pregnancy, the TDF-ART regimen had no observed safety concerns for maternal or infant renal function. Trial Registration : NCT01061151 on 10/02/2010 for PROMISE (1077BF). NCT01066858 on 10/02/2010 for P1084s.
Background: IMPAACT PROMISE 1077BF/FF was a randomized study of antiretroviral therapy (ART) strategies for pregnant and postpartum women with high CD4+ T-cell counts. We describe postpartum outcomes for women in the study who were randomized to continue or discontinue ART after delivery.Methods: Women with pre-ART CD4+ cell counts ≥350 cells/mm3 who started ART during pregnancy were randomized postpartum to continue or discontinue treatment. Women were enrolled from India, Malawi, South Africa, Tanzania, Uganda, Zambia, and Zimbabwe. The primary outcome was a composite of progression to AIDS-defining illness or death. Log-rank tests and Cox regression models assessed treatment effects. Incidence rates were calculated per 100 person-years. A post hoc analysis evaluated WHO Stage 2/3 events. All analyses were intent-to-treat.Findings: 1611 women were enrolled (June 2011–October 2014) and 95% were breastfeeding. Median age at entry was 27 years, CD4+ count 728 cells/mm3 and the majority of women were Black African (97%). After a median follow-up of 1.6 years, progression to AIDS-defining illness or death was rare and there was no significant difference between arms (HR: 0·55; 95%CI 0·14, 2·08, p = 0.37). WHO Stage 2/3 events were reduced with continued ART (HR: 0·60; 95%CI 0·39, 0·90, p = 0.01). The arms did not differ with respect to the rate of grade 2, 3, or 4 safety events (p = 0.61).Interpretation: Serious clinical events were rare among predominately breastfeeding women with high CD4+ cell counts over 18 months after delivery. ART had significant benefit in reducing WHO 2/3 events in this population.
IMPAACT PROMISE 1077BF/FF was a sequentially randomized study of pregnant and postpartum women living with HIV to investigate the efficacy and safety of antiretroviral therapy (ART). This Maternal Health Component investigated efficacy for the risk of developing AIDS or death; and safety among women randomized to continue ART (CTART: N = 289) or discontinue ART (N = 268) after cessation of breastfeeding or after confirmation of infant infection. No AIDS-defining illnesses were reported during follow-up in either arm. Adverse events of grade 3 or higher were more frequent in the CTART arm [hazard ratio = 1.78, 95% confidence interval: (1.05 to 3.02), P-value = 0.03]. The difference in adverse events in the 2 groups was mostly driven by moderate weight loss for women on the CTART arm.
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