Neurocognition and quality of life after reinitiating antiretroviral therapy in children randomized to planned treatment interruption

Objective: Understanding the effects of antiretroviral treatment (ART) interruption on neurocognition and quality of life (QoL) are important for managing unplanned interruptions and planned interruptions in HIV cure research. Design: Children previously randomized to continuous (continuous ART, n=41) vs. planned treatment interruption (PTI, n=47) in the Pediatric European Network for Treatment of AIDS (PENTA) 11 study were enrolled. At study end, PTI children resumed ART. At 1 and 2 years following study end, children were assessed by the coding, symbol search and digit span subtests of Wechsler Intelligence Scale for Children (6-16 years old) or Wechsler Adult Intelligence Scale ( 6517 years old) and by Pediatrics QoL questionnaires for physical and psychological QoL. Transformed scaled scores for neurocognition and mean standardized scores for QoL were compared between arms by t-test and Mann-Whitney U test, respectively. Scores indicating clinical concern were compared (<7 for neurocognition and <70 for QoL tests). Results: Characteristics were similar between arms with a median age of 12.6 years, CD4 + of 830 cells/\u3bcl and HIV RNA of 1.7 log 10 copies/ml. The median cumulative ART exposure was 9.6 in continuous ART vs. 7.7 years in PTI (P=0.02). PTI children had a median of 12 months off ART and had resumed ART for 25.2 months at time of first assessment. Neurocognitive scores were similar between arms for all tests. Physical and psychological QoL scores were no different. About 40% had low neurocognitive and QoL scores indicating clinical concern. Conclusion: No differences in information processing speed, sustained attention, short-term memory and QoL functioning were observed between children previously randomized to continuous ART vs. PTI in the PENTA 11 trial

Interruptions of tenofovir/emtricitabine-based antiretroviral therapy in patients with HIV/hepatitis B virus co-infection

Thai patients enrolled in STACCATO with HIV/hepatitis B virus (HBV) co-infection and tenofovir/emtricitabine-based antiretroviral therapy (ART) were randomly assigned to continuous treatment or CD4 cell count-guided interruptions. HBV replication was suppressed below detection in 15/16 patients. Structured treatment interruption increased transaminases and HBV viraemia in five of six patients; one flare was severe. Conversion to anti-hepatitis Be occurred with continuous treatment only. Tenofovir/emtricitabine-containing ART is highly effective in controlling chronic HIV/HBV co-infection but treatment should not be interrupted

Changes in metabolic toxicity after switching from stavudine/didanosine to tenofovir/lamivudine : a Staccato trial substudy

OBJECTIVES: Stavudine is widely used in Thailand and is associated with mitochondrial toxicity. Here, we evaluated the effect of switching from stavudine/didanosine to tenofovir/lamivudine on measures of metabolic and mitochondrial toxicity in Thai patients. METHODS: Thirty-five Thai patients with full HIV RNA suppression were switched from stavudine/didanosine to tenofovir/lamivudine while receiving saquinavir/ritonavir 1600/100 mg once daily. Patients were assessed at the time of switch and 24 and 48 weeks after for lipids, liver enzymes, lactate, mitochondrial DNA content and limb/total fat mass by dual energy X-ray absorptiometry (DEXA) scanning. RESULTS: Forty-eight weeks after the switch, there were significant reductions in lipids and lactate, but no change in liver enzymes. There was reversal of lipoatrophy, as shown by rises in limb fat mass (+0.38 kg, P = 0.006) and total fat mass (+0.69 kg, P = 0.02) on DEXA scan. Patients perceived weight improvement, but did not report reversal of lipoatrophy of individual body parts. The mitochondrial DNA/nuclear DNA ratio rose (+1.06, P > 0.0001). CONCLUSIONS: After the nucleoside reverse transcriptase inhibitor switch, reversal of mitochondrial toxicity was consistent with switch studies of mainly Caucasian patients, although the peripheral mononuclear cell mitochondrial DNA rise exceeded previous reports

Ferritin levels during structured treatment interruption of highly active antiretroviral therapy

OBJECTIVE: The aim of the study was to investigate the influence of highly active antiretroviral therapy (HAART) on iron status and, conversely, the influence of iron status on the response to HAART. METHODS: Ferritin levels were retrospectively determined in stored plasma from 138 HAART-naive, moderately immunosuppressed HIV-infected Thai patients participating in a structured treatment interruption trial. Ferritin levels were determined at three predefined time-points: (1) HAART initiation; (2) HAART discontinuation; and (3) HAART resumption. Results: At baseline, 31% and 16% of the HIV-infected patients included in the study had high (>200 ng/mL) and low (<30 ng/mL) ferritin levels, respectively. Ninety-five per cent of patients with low ferritin levels were female. Ferritin decreased significantly during the interruption phase of HAART (-8.8 ng/mL; P=0.0005) but remained elevated in 62% of the patients with high baseline levels. A low baseline ferritin level was associated with a shorter time (P=0.041) to reach the CD4 cell target for HAART interruption (350 cells/microL), compared with a normal or high baseline ferritin level. Moreover, in a multivariate model, the relative risk (RR) of arriving at this CD4 cell target was significantly higher [RR 1.81; 95% confidence interval (CI) 1.05-3.14] in patients with low baseline ferritin. It is unlikely that inflammation affected ferritin in our patients, as mean levels of C-reactive protein were not elevated in patients with either high or low ferritin levels. CONCLUSIONS: Both high and low ferritin levels were highly prevalent in moderately immunosuppressed HIV-positive Thai patients. Structured treatment interruption of HAART resulted in a significant decrease in overall ferritin levels. Furthermore, subjects with low baseline ferritin levels had a faster and greater CD4 response to HAART, suggesting a potential beneficial effect of iron deficiency on immunological recovery after initiation of HAART

Reduced Time to Suppression Among Neonates With HIV Initiating Antiretroviral Therapy Within 7 Days After Birth

There are limited data on infants with HIV starting antiretroviral therapy (ART) in the neonatal period. We investigated the association between the timing of ART initiation and time-tosuppression among infants who tested HIV-positive and initiated ART within the first 28 days of life. The effect was estimated using cumulative probability flexible parametric spline models and a multivariable generalized additive mixed model was performed to test nonlinear associations. Forty-four neonates were included. Nineteen (43.2%) initiated ART within 7 days of life and 25 (56.8%) from 8 to 28 days. Infants treated within 7 days were 4-fold more likely to suppress earlier than those treated after 7 days [Hazard ratio (HR) 4.01 (1.7-9.5)]. For each week the ART initiation was delayed, the probability of suppression decreased by 35% (HR 0.65 [0.46-0.92]). Age at ART start was linearly associated with time-to-suppression. However, a linear association with normally distributed residuals was not found between baseline viral load and time-to-suppression, with no association found when baseline viral loads were &lt;5 log(10) copies/mL, but with exponential increase in time-to-suppression with &gt; log5 copies/mL at baseline. Starting ART within 7 days of life led to 4-fold faster time to viral suppression, in comparison to initiation from 8 to 28 days

Pharmacokinetics and 48 week efficacy of low-dose lopinavir/ritonavir in HIV-infected children.

Contains fulltext : 79493.pdf (publisher's version ) (Closed access)BACKGROUND: Lopinavir/ritonavir is a common protease inhibitor (PI) used for second-line regimens in children. Several studies have shown higher plasma concentrations of antiretroviral agents in Thai adults than in Caucasians, suggesting that lower doses may be used. METHODS: An open label study in 24 HIV-infected children between the age of 2 and 18 years, naive to PIs, randomized to receive either the WHO-recommended dose of lopinavir/ritonavir or a low dose (70% of the standard dose) twice daily in combination with zidovudine and lamivudine. A 12 h pharmacokinetic study was done at 4-6 weeks after starting treatment. Treatment outcomes were evaluated at week 48. The clinical trial number of the study is NCT00887120. RESULTS: The medians [interquartile ranges (IQRs)] of age, body surface area, percentage CD4 and plasma HIV RNA were 9.5 years (7.0-12.3), 0.9 m(2) (0.8-1.1), 17% (11%-24%) and 4.6 log(10) copies/mL (4.1-4.9), respectively. The median (IQR) lopinavir dose was 279 mg/m(2)/dose (263-294) and 194 mg/m(2)/dose (176-206) in the standard and low-dose arms, respectively. Median (IQR) AUC(0-12) and C(trough) of lopinavir were 117.6 mg.h/L (74.0-128.5) and 4.9 mg/L (2.7-8.0) for the standard arm and 83.8 mg.h/L (56.0-112.9) and 3.4 mg/L (2.7-5.4) for the low-dose arm. One child in the low-dose arm had a lopinavir pre-dose level of <1.0 mg/L. At week 48, the median percentage CD4 was 22% (15%-28%) and 27% (21%-31%) in the standard and low-dose arms, respectively, while 50% and 83% of children had HIV RNA <50 copies/mL, respectively (P = 0.19). CONCLUSIONS: Low-dose lopinavir displayed adequate pharmacokinetic parameters and good efficacy as compared with standard-dose lopinavir in Thai children. A larger study to investigate the efficacy of low-dose lopinavir is warranted

Long-term efficacy and safety of first-line therapy with once-daily saquinavir/ritonavir

BACKGROUND: The aim of this study was to assess the long-term efficacy and safety of first-line treatment with once-daily saquinavir/ritonavir plus two nucleoside reverse transcriptase inhibitors (NRTIs). METHODS: A total of 272 antiretroviral-naive patients with a CD4+ T-cell count of 200-350 cells/mm3 were treated with two NRTIs and saquinavir/ritonavir 1,600/100 mg per day for 400 copies/ml, with a median HIV RNA decline of -2.89 (IQR 3.31--2.37) log10 copies/ml (P > 0.001) and a median rise in CD4+ T-cell count of 192 (IQR 117-317) cells (P > 0.001). At weeks 24, 48, 72 and 96, 249/272 (91.5%), 157/164 (95.7%), 113/126 (89.7%) and 84/90 (93.3%) had HIV RNA > 400 copies/ml, respectively; at the same time points, 83.8%, 92.7%, 85.7% and 85.6% had HIV RNA > 50 copies/ml. Drug-related adverse events were reported in 6.30%. Significant rises in total cholesterol, triglyceride, low-density lipoprotein and high-density lipoprotein were seen. CONCLUSION: First-line highly active antiretroviral therapy with once-daily saquinavir/ritonavir plus two NRTIs showed strong antiviral efficacy

The immunological and virological consequences of planned treatment interruptions in children with HIV infection

Contains fulltext : 126098.pdf (publisher's version ) (Open Access)OBJECTIVES: To evaluate the immunological and viral consequences of planned treatment interruptions (PTI) in children with HIV. DESIGN: This was an immunological and virological sub-study of the Paediatric European Network for Treatment of AIDS (PENTA) 11 trial, which compared CD4-guided PTI of antiretroviral therapy (ART) with continuous therapy (CT) in children. METHODS: HIV-1 RNA and lymphocyte subsets, including CD4 and CD8 cells, were quantified on fresh samples collected during the study; CD45RA, CD45RO and CD31 subpopulations were evaluated in some centres. For 36 (18 PTI, 18 CT) children, immunophenotyping was performed and cell-associated HIV-1 DNA analysed on stored samples to 48 weeks. RESULTS: In the PTI group, CD4 cell count fell rapidly in the first 12 weeks off ART, with decreases in both naive and memory cells. However, the proportion of CD4 cells expressing CD45RA and CD45RO remained constant in both groups. The increase in CD8 cells in the first 12 weeks off ART in the PTI group was predominantly due to increases in RO-expressing cells. PTI was associated with a rapid and sustained increase in CD4 cells expressing Ki67 and HLA-DR, and increased levels of HIV-1 DNA. CONCLUSIONS: PTI in children is associated with rapid changes in CD4 and CD8 cells, likely due to increased cell turnover and immune activation. However, children off treatment may be able to maintain stable levels of naive CD4 cells, at least in proportion to the memory cell pool, which may in part explain the observed excellent CD4 cell recovery with re-introduction of ART