Publications

28

Dec, 2011

Age and CD4 Count at Initiation of Antiretroviral Therapy in HIV-InfectedChildren: Effects on Long-term T-Cell Reconstitution

 

Authors: Lewis J, Walker AS, Castro H, et al.

Published in: J Infect Dis. 2011;205(4):548-556

Background Effective therapies and reduced AIDS-related morbidity and mortality have shifted the focus in pediatric human immunodeficiency virus (HIV) from minimizing short-term disease progression to maintaining optimal long-term health. We describe the effects of children’s age and pre-antiretroviral therapy (ART) CD4 count on long-term CD4 T-cell reconstitution.

Methods CD4 counts in perinatally HIV-infected, therapy-naive children in the Paediatric European Network for the Treatment of AIDS 5 trial were monitored following initiation of ART for a median 5.7 years. In a substudy, naive and memory CD4 counts were recorded. Age-standardized measurements were analyzed using monophasic, asymptotic nonlinear mixed-effects models.

Results One hundred twenty-seven children were studied. Older children had lower age-adjusted CD4 counts in the long term and at treatment initiation (P < .001). At all ages, lower counts before treatment were associated with impaired recovery (P < .001). Age-adjusted naive CD4 counts increased on a timescale comparable to overall CD4 T-cell reconstitution, whereas age-adjusted memory CD4 counts increased less, albeit on a faster timescale.

Conclusions It appears the immature immune system can recover well from HIV infection via the naive pool. However, this potential is progressively damaged with age and/or duration of infection. Current guidelines may therefore not optimize long-termimmunological health.

 

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28

Nov, 2011

Early antiretroviral therapy in HIV-1 infected infants, 1996-2008: treatment response and duration of first-line regimens

 

Authors: The European Pregnancy and Paediatric HIV Cohort Collaboration (EPPICC) study group in EuroCoord.

Published in: AIDS 2011; 25(18): 2279-2287

Background Durable and tolerable first-line antiretroviral therapy (ART) regimens are needed for HIV-infected infants who may need life-long treatment. We investigated virological and immunological response to ART, and predictors of switching and interrupting treatment among infants starting ART in the European Pregnancy and Paediatric HIV Cohort Collaboration.

Methods 9 cohorts from 13 European countries contributed data on HIV-infected infants born 1996-2008 and starting ART before age 12 months. Logistic and linear regression, and competing risks methods were used to assess predictors of virological (viral load <400c/mL) and immunological (change in CD4 Z-score) response, switching to second-line ART and treatment interruptions with viral load <400c/mL.

Findings 437 infants were followed for median 5.9 (interquartile range 2.3-7.6) years after starting ART; 30% had an AIDS diagnosis prior to ART initiation. Virological response improved with calendar year of ART initiation; 53% had suppressed viral load <400c/mL at 12 months in 1996-1999, increasing to 77% in 2004-2008. Virological and immunological responses at 12 months varied by initial ART type (p<0.001 and p=0.03 respectively), with 4-drug NNRTI-based regimens being superior (virological response <400c/mL adjusted OR 3.00, 95%CI 1.24-7.23; mean increase in CD4 Z-score coefficient 0.64, 95%CI 0.10-1.17) to both 3-drug NNRTI-based (reference) and boosted PI regimens which were similar. Rates of switching to second-line ART were lower among children starting 4-drug NNRTI-based and boosted PI-based regimens compared to 3-drug NNRTI regimens (p=0.03). 65% of infants remained on first-line ART without treatment interruption after five years.

Interpretation Effective and prolonged responses to first-line ART can now be achieved in infants starting early ART outside trial settings. Superior responses to 4-drug NNRTI compared

 

 

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30

Aug, 2011

A comparison of the pharmacokinetics of raltegravir during pregnancy and post-partum

 

Authors: Colbers A, Taylor G, Moltó J, Ivanovic J, Taylor G, Branco T, Wyen C, van der Ende I, Gomes da Silva H, Burger D; on behalf of the PANNA network

Published: 12th International Workshop on Clinical Pharmacology of HIV Therapy, 2011 April 13th-15th, Miami. P_18

 

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18

Jul, 2011

Long Term consequences of planned treatment interruptions in HIV infected children: Results from the TICCH (Treatment Interruption in Children with Chronic HIV-Infection )/PENTA 11 trial.

 

Authors: Compagnucci A. on behalf of the PENTA Steering Committee

Published in: 3rd HIV Paediatric Workshop Rome 15-16 July 2011.

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23

May, 2011

Effect of transmitted drug resistance on virological and immunological response to initial combination antiretroviral therapy for HIV (EuroCoord-CHAIN joint project): a European multi-cohort study.

 

Authors: Wittkop L, Günthard HF, de Wolf F, et al. EuroCoord-CHAIN study group.

Published in: Lancet Infectious Diseases 2011; 11(5): 363-71

Background The effect of transmitted drug resistance (TDR) on first-line combination antiretroviral therapy (cART) for HIV-1 needs further study to inform choice of optimum drug regimens. We investigated the effect of TDR on outcome in the first year of cART within a large European collaboration.

Methods HIV-infected patients of any age were included if they started cART (at least three antiretroviral drugs) for the first time after Jan 1, 1998, and were antiretroviral naive and had at least one sample for a genotypic test taken before the start of cART. We used the WHO drug resistance list and the Stanford algorithm to classify patients into three resistance categories: no TDR, at least one mutation and fully-active cART, or at least one mutation and resistant to at least one prescribed drug. Virological failure was defined as time to the first of two consecutive viral load measurements over 500 copies per mL after 6 months of therapy.

Findings Of 10 056 patients from 25 cohorts, 9102 (90·5%) had HIV without TDR, 475 (4·7%) had at least one mutation but received fully-active cART, and 479 (4·8%) had at least one mutation and resistance to at least one drug. Cumulative Kaplan-Meier estimates for virological failure at 12 months were 4·2% (95% CI 3·8–4·7) for patients in the no TDR group, 4·7% (2·9–7·5) for those in the TDR and fully-active cART group, and 15·1% (11·9–19·0) for those in the TDR and resistant group (log-rank p<0·0001). The hazard ratio for the difference in virological failure between patients with TDR and resistance to at least one drug and those without TDR was 3·13 (95% CI 2·33–4·20, p<0·0001). The hazard ratio for the difference between patients with TDR receiving fully-active cART and patients without TDR was 1·47 (95% CI 0·19–2·38, p=0·12). In stratified analysis, the hazard ratio for the risk of virological failure in patients with TDR who received fully-active cART that included a non-nucleoside reverse transcriptase inhibitor (NNRTI) compared with those without TDR was 2·0 (95% CI 0·9–4·7, p=0·093).

Interpretation These findings confirm present treatment guidelines for HIV, which state that the initial treatment choice should be based on resistance testing in treatment-naive patients.

 

15

May, 2011

Risk of triple-class virological failure in children with HIV: a retrospective cohort study

 

Authors: Castro H, Judd A, Gibb DM, et al. Pursuing Later Treatment Options II (PLATO II) project team for the Collaboration of Observational HIV Epidemiological Research Europe (COHERE).

Published in: Lancet 2011; 377(9777): 1580-1587

Background: In adults with HIV treated with antiretroviral drug regimens from within the three original drug classes (nucleoside or nucleotide reverse transcriptase inhibitors [NRTIs], non-NRTIs [NNRTIs], and protease inhibitors), virological failure occurs slowly, suggesting that long-term virological suppression can be achieved in most people, even in areas where access is restricted to drugs from these classes. It is unclear whether this is the case for children, the group who will need to maintain viral suppression for longest. We aimed to determine the rate and predictors of triple-class virological failure to the three original drugs classes in children.

Methods: In the Collaboration of Observational HIV Epidemiological Research Europe, the rate of triple-class virological failure was studied in children infected perinatally with HIV who were aged less than 16 years, starting antiretroviral therapy (ART) with three or more drugs, between 1998 and 2008. We used Kaplan-Meier and Cox regression methods to investigate the risk and predictors of triple-class virological failure after ART initiation.

Findings: Of 1007 children followed up for a median of 4·2 (IQR 2·4–6·5) years, 237 (24%) were triple-class exposed and 105 (10%) had triple-class virological failure, of whom 29 never had a viral-load measurement less than 500 copies per mL. Incidence of triple-class virological failure after ART initiation increased with time, and risk by 5 years after ART initiation was 12·0% (95% CI 9·4–14·6). In multivariate analysis, older age at ART initiation was associated with increased risk of failure (p=0·02). Of 686 children starting ART with NRTIs and either a NNRTI or ritonavir-boosted protease inhibitor, the rate of failure was higher than in adults with heterosexually transmitted HIV (hazard ratio 2·2 [95% CI 1·6–3·0, p<0·0001]).

Interpretation: Findings highlight the challenges of attaining long-term viral suppression in children who will be taking life-long ART. Early identification of children not responding to ART, adherence support, particularly for children and adolescents aged 13 years or older starting ART, and ART simplification strategies are all needed to attain and sustain virological suppression.

 

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18

Apr, 2011

First-line antiretroviral therapy initiation with a protease inhibitor versus non-nucleoside reverse transcriptase inhibitor combination and switch at higher versus low viral load in HIV-infected children: an open randomised controlled phase 2/3 trial.

 

Authors: The PENPACT-1 (PENTA 9 / PACTG 390) Study Team.

Published in: Lancet Infectious Diseases. April: 2011, 273-283

Background Children with HIV will be on antiretroviral therapy (ART) longer than adults, and therefore the durability of first-line ART and timing of switch to second-line are key questions. We assess the long-term outcome of protease inhibitor and non-nucleoside reverse transcriptase inhibitor (NNRTI) first-line ART and viral load switch criteria in children.

Methods In a randomised open-label factorial trial, we compared effectiveness of two nucleoside reverse transcriptase inhibitors (NRTIs) plus a protease inhibitor versus two NRTIs plus an NNRTI and of switch to second-line ART at a viral load of 1000 copies per mL versus 30,000 copies per mL in previously untreated children infected with HIV from Europe and North and South America. Random assignment was by computer-generated sequentially numbered lists stratified by age, region, and by exposure to perinatal ART. Primary outcome was change in viral load between baseline and 4 years. Analysis was by intention to treat, which we defined as all patients that started treatment. This study is registered with ISRCTN, number ISRCTN73318385.

Findings Between Sept 25, 2002, and Sept 7, 2005, 266 children (median age 6.5 years; IQR 2.8-12.9) were randomly assigned treatment regimens: 66 to receive protease inhibitor and switch to second-line at 1000 copies per mL (PI-low), 65 protease inhibitor and switch at 30,000 copies per mL (PI-higher), 68 NNRTI and switch at 1000 copies per mL (NNRTI-low), and 67 NNRTI and switch at 30,000 copies per mL (NNRTI-higher). Median follow-up was 5.0 years (IQR 4.2-6.0) and 188 (71%) children were on first-line ART at trial end. At 4 years, mean reductions in viral load were -3.16 log(10) copies per mL for protease inhibitors versus -3.31 log(10) copies per mL for NNRTIs (difference -0.15 log(10) copies per mL, 95% CI -0.41 to 0.11; p=0.26), and -3.26 log(10) copies per mL for switching at the low versus -3.20 log(10) copies per mL for switching at the higher threshold (difference 0.06 log(10) copies per mL, 95% CI -0.20 to 0.32; p=0.56). Protease inhibitor resistance was uncommon and there was no increase in NRTI resistance in the PI-higher compared with the PI-low group. NNRTI resistance was selected early, and about 10% more children accumulated NRTI mutations in the NNRTI-higher than the NNRTI-low group. Nine children had new CDC stage-C events and 60 had grade 3/4 adverse events; both were balanced across randomised groups.

Interpretation Good long-term outcomes were achieved with all treatments strategies. Delayed switching of protease-inhibitor-based ART might be reasonable where future drug options are limited, because the risk of selecting for NRTI and protease-inhibitor resistance is low.

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