Thymic Function Failure Is Associated With Human Immunodeficiency Virus Disease Progression.

Background: Thymic function has been mainly analyzed with surrogate peripheral markers affected by peripheral T-cell expansion, making it difficult to assess the role of thymic failure in human immunodeficiency virus (HIV) disease progression. The assay of signal-joint/DßJß T-cell rearrangement excision circles (sj/ß-TREC ratio) overcomes this limitation but has only been assayed in small cohorts. Thus, the aim of this study was to determine the role of thymic function, measured by the sj/ß-TREC ratio, on CD4 T-cell maintenance in prospective HIV cohorts that include patients with a wide age range and different immunological phenotypes. Methods: Seven hundred seventy-four patients including typical progressors, long-term nonprogressors (LTNPs), and vertically HIV-infected subjects were analyzed. Thymic function was quantified in peripheral blood samples using the sj/ß-TREC ratio. Associations between thymic function and CD4 T-cell dynamics and combination antiretroviral therapy (cART) onset were analyzed using linear, logistic, and Cox proportional hazard models. Results: Thymic function failure (sj/ß-TREC ratio <10) was independently associated with HIV progression. In agreement, patients with distinctive high CD4 T-cell levels and low progression rates (vertically HIV-infected patients and LTNPs, including HIV controllers) had significantly higher thymic function levels whereas patients with thymic function failure had lower CD4 T-cell levels, lower nadir, and faster CD4 T-cell decay. Conclusions: This work establishes the relevance of thymic function, measured by sj/ß-TREC ratio, in HIV disease progression by analyzing a large number of patients in 3 cohorts with different HIV disease progression phenotypes. These results support and help to understand the mechanisms underlying the rationale of early cART onset.

Off-label use of rilpivirine in combination with emtricitabine and tenofovir in HIV-1-infected pediatric patients: A multicenter study.

To assess the safety and efficacy of rilpivirine in combination with emtricitabine and tenofovir (RPV/FTC/TDF) as a once-daily single-tablet regimen (STR) in HIV-1-infected children and adolescents we performed a multicenter case series study of HIV-1-infected patients. Inclusion criteria were initiation of therapy with RPV/FTC/TDF before the age of 18. Patients were divided into undetectable viral load (uVL) group, HIV-1 RNA < 20 copies/mL on stable combined antiretroviral therapy (cART), and detectable viral load (dVL) group, HIV-1 RNA ≥ 20 copies/mL at RPV/FTC/TDF initiation. Patients were monitored from the date of RPV/FTC/TDF initiation until June 30, 2015, RPV/FTC/TDF discontinuation or failure to follow-up. Seventeen patients (8 in uVL and 9 in dVL group) with age between 11.6 and 17.6 were included. Reasons for switching were toxicity (n = 4) and simplification (n = 4) in uVL; viral failure (n = 8) and cART initiation (n = 1) in the dVL group. After a median follow-up of 90 (uVL) and 40 weeks (dVL), 7/8 (86%) patients maintained and 8/9 (89%) achieved and maintained HIV-1 suppression. Median CD4 count increased from 542 to 780/µL (uVL, P = 0.069) and 480 to 830/µL (dVL, P = 0.051). Five patients (2 in uVL and 3 in dVL) improved their immunological status from moderate to no immunosuppression. Serum lipid profiles improved in both groups; cholesterol dropped significantly in the dVL group (P = 0.008). Grade 1 laboratory adverse events (AEs) were observed in 3 patients. No clinical AEs occurred. Adherence was complete in 9 patients (5 in uVL and 4 in dVL); 1 adolescent interrupted treatment. Once-daily STR with RPV/FTC/TDF may be a safe and effective choice in selected HIV-1-infected adolescents and children.

Off-label use of maraviroc in HIV-1-infected paediatric patients in clinical practice.

Maraviroc (MVC) is not approved for HIV-1-infected paediatric patients. This is the first assessment of the use of MVC-based salvage therapy in vertically HIV-1-infected paediatric patients in clinical settings. The results suggest that MVC-based salvage therapy is useful in children and adolescents with extensive resistance profile leading to maintained virological suppression in up to 88% of the patients with CCR5-tropic virus. The likelihood of treatment success might increase when MVC is combined with other active drugs.

Determinants of highly active antiretroviral therapy duration in HIV-1-infected children and adolescents in Madrid, Spain, from 1996 to 2012.

OBJECTIVES: To investigate the duration of sequential HAART regimens and predictors of first-line regimen discontinuation among HIV-1 vertically infected children and adolescents. DESIGN: Multicentre survey of antiretroviral-naïve patients enrolled in the HIV-Paediatric Cohor,t CoRISpeS-Madrid Cohort, Spain. METHODS: Patients with a follow-up of ≥ 1 month spent on HAART, with available baseline CD4 count and HIV-viral load (VL) were included. Time spent on sequential HAART regimens was estimated and multivariable regression was used to identify predictors of time to first-line regimen discontinuation. RESULTS: 104 patients were followed for a median 8 years after starting HAART among 1996-2012; baseline %CD4 was 21.5 (12.3-34.0)and viral load was 5.1 (4.6-5.6) log10 copies/mL. Patients received a mean of 1.9 regimens. Median time on first-line HAART (n = 104) was 64.5 months; second HAART (n = 56) 69.8 months; and third HAART (n = 21) 66.5 months. Eleven (11%) patients were lost to follow-up while on first-line HAART and 54% discontinued (cumulative incidence of 16% and 38% by 1 and 3-year, respectively). The main predictor of first-line regimen discontinuation was suboptimal adherence to antiretrovirals (AHR: 2.60; 95% CI: 1.44-4.70). CONCLUSIONS: Adherence to therapy was the main determinant of the duration of the first-line HAART regimen in children. It is important to identify patients at high risk for non-adherence, such as very young children and adolescents, in provide special care and support to those patients.

Potent and sustained antiviral response of raltegravir-based highly active antiretroviral therapy in HIV type 1-infected children and adolescents.

BACKGROUND: There are pediatric patients receiving many highly active antiretroviral therapy (HAART) regimens entailing drug resistance mutations that complicate HAART effective therapies. METHODS: This was a multicenter retrospective study of 19 multidrug-resistant children and adolescents enrolled from July 2007 to October 2009. Patients were nonresponders because no reduction in HIV type 1 (HIV-1) RNA to undetectable levels was observed during their previous antiretroviral treatment history. The long-term effectiveness of raltegravir (RAL)-based salvage therapy was assessed through a longitudinal analysis of immunologic, virologic, and clinical status of the patients. RESULTS: Median age was 16.0 (15.0-18.0) years. At baseline, median HIV-1 RNA was 10,000 (4.0 log10 copies/mL) (interquartile range [IQR]: 4300-83,000), and median CD4T-cell count was 329 (18.2% cells/µL) (IQR: 175-452). The backbone regimen included at least 1 fully active drug in 17/19 (89%) patients. Median follow-up with HAART including RAL was 80.1 weeks (IQR: 49.4-96.4): 16/19 (84%) exposed for >120 weeks and 6/19 (32%) >100 weeks. After RAL-based therapy, 4/19 (21%) patients achieved HIV-1 RNA <400 copies and 13/17 (68%) reached HIV-1 RNA <50 copies: 6 (32%) within the first month and 7 (37%) within the first 4 months. CD4+ T-cell recovery (70% to 90% of the baseline values) was observed in 17/19 (89%) patients. No deaths, AIDS-defining illnesses, or symptoms of severe intolerance were recorded. Only 2 patients experienced mild-moderate short-term skin rash. Two (11%) patients had sustained and optimum adherence to HAART. No patients showed resistance mutations to RAL after follow-up. CONCLUSIONS: We observed a sustained antiviral response and improved immunologic indices in multidrug-resistant pediatric patients, most of whom had received RAL as part of salvage regimens with at least 1 fully active drugs.

Long-term efficacy and safety of fosamprenavir in human immunodeficiency virus-infected pediatric patients.

Fosamprenavir (FPV) efficacy in human immunodeficiency virus (HIV)-infected pediatric patients is still being evaluated in ongoing clinical trials. The long-term efficacy and safety of FPV boosted with ritonavir (FPV/r) was evaluated in 20 antiretroviral-naive and antiretroviral-experienced HIV-vertically infected pediatric patients. Analyses of CD4(+) T-cells, HIV-ribonucleic acid (RNA), and clinical status were performed during a median of 180 weeks. Initially, median HIV-RNA was 4.6 log(10) in naive and 4.4 log(10) in pretreated patients. Median CD4(+) T-cell was 17% and 31%, respectively. After FPV/r treatment, 18 of 20 patients achieved undetectable HIV-RNA and 4 of 20 experienced adverse events. To date, FPV/r treatment has shown sustained antiviral response and immunologic improvement in our 20 patients.