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.




Apr, 2007

3TC+ABC maintains virological superiority over ZDV+3TC and ZDV+ABC beyond 5 years in children: the PENTA 5 trial


Authors: Gibb DM, Green H, Saidi Y, et al; on behalf of PENTA 5.

Published in: AIDS.2007;21(8):947-955

Objective To describe the long-term efficacy over 5 years of regimens including combinations of abacavir, lamivudine and/or zidovudine in previously untreated children in the PENTA 5 trial.

Design PENTA 5 was a 48-week randomised controlled trial comparing three dual nucleoside reverse transcriptase inhibitor (NRTI) combinations as part of first triple antiretroviral therapy (ART).

Methods 128 ART-naïve children were randomised to zidovudine\lamivudine (n = 36), zidovudine\abacavir (45) or lamivudine\abacavir (47). Asymptomatic children (n = 55) were also randomised to nelfinavir or placebo; all other children received open-label nelfinavir. Analyses are intent-to-treat and adjusted for minor baseline imbalances and receipt of nelfinavir/placebo.

Results Median follow-up was 5.8 years. By 5 years, 17 (47%), 28 (64%) and 18 (39%) children had changed their randomised NRTIs in the zidovudine\lamivudine, zidovudine\abacavir and lamivudine\abacavir groups respectively, but 18%, 50% and 50% of these changes were either early single drug substitutions for toxicity or switches with viral suppression (HIV-1 RNA < 400 copies/ml; e.g. to simplify regimen delivery). At 5 years, 55%/32% zidovudine\lamivudine, 50%/25% zidovudine\abacavir and 79%/63% lamivudine\abacavir had HIV-1 RNA < 400/< 50 copies/ml respectively (p = 0.03/p = 0.003). Mean increase in height-for-age 0.42, 0.68, 1.05 (p = 0.02); weight-for-age 0.03, 0.13, 0.75 (p = 0.02). Reverse transcriptase resistance mutations emerging on therapy differed between the groups: zidovudine\lamivudine (M41L, D67N, K70R, M184V, L210W, T215Y); zidovudine\abacavir (M41L, D67N, K70R, L210W, T215F/Y, K219Q); lamivudine\abacavir (K65R, L74V, Y115F, M184V).

Conclusions Five year data demonstrate that lamivudine\abacavir is more effective in terms of HIV-1 RNA suppression and growth changes, with lower rates of switching with detectable HIV-1 RNA than zidovudine\lamivudine or zidovudine\abacavir, and should be preferred as first-line NRTI backbone.


Apr, 2005

Relationship between changes in thymic emigrants and cell-associated HIV-1 DNA in HIV-1 infected children initiating antiretroviral therapy


Authors: De Rossi A, Walker AS, De Forni D, Klein N, Dibb DM. Paediatric European Network for Treatment of AIDS (PENTA)

Published in: Antivir Ther. 2005;10(1):63-71

Objectives and Methods To investigate the relationship between cell-associated HIV-1 dynamics and recent thymic T-cell emigrants, HIV-1 DNA and T-cell receptor rearrangement excision circles (TREC, a marker of recent thymic emigrants) were measured in peripheral blood mononuclear cells in 181 samples from 33 HIV-1-infected children followed for 96 weeks after antiretroviral therapy(ART) initiation.

Results At baseline, HIV-1 DNA was higher in children with higher TREC (P=0.02) and was not related to age, CD4 or HIV-1 RNA in multivariate analyses (P>0.3). Overall, TREC increased and HIV-1 DNA decreased significantly after ART initiation, with faster HIV-1DNA declines in children with higher baseline TREC (P=0.009). The greatest decreases in HIV-1 DNA occurred in children with the smallest increases in TREC levels during ART (P=0.002). However, this inverse relationship between changes in HIV-1 DNA and TREC tended to vary according to the phase of HIV-1 RNA decline (P=0.13); for the same increase in TREC, HIV-1 DNA decline was much smaller during persistent or transient viraemia compared with stable HIV-1 RNA suppression.

Conclusions Overall, these findings indicate that TREC levels predict HIV-1 DNA response to ART and suggest that immune repopulation by thymic emigrants adversely affects HIV-1 DNA decline in the absence of persistent viral suppression, possibly by providing a cellular source for viral infection and replication.



Apr, 2004

Maintaining the nelfinavir trough concentration above 0.8 mg/L improves virologic response in HIV-1-infected children


Authors: Burger DM, Bergshoeff A, de Groot R, et al; on behalf of the PENTA 5 study group.

Published in: J Paediatr 2004;145(3):403-405

Abstract Differences in virologic response were compared in 32 HIV-infected children with a nelfinavir trough concentration either below (n=7) or above (n=25) 0.8 mg/L. Virologic response at week 48 was observed in 29% of children with subtherapeutic nelfinavir troughs versus 80% in children with therapeutic nelfinavir troughs (P=.02)


Apr, 2004

Effect of concurrent zidovudine use on the resistance pathway selected by abacavir-containing regimens


Authors: Lanier ER, Givens N, Stone C, et al.

Published in: HIV Med. 2004;5(6):394-399

Objectives Abacavir (ABC) selects for four mutations (K65R, L74V, Y115F and M184V) in HIV‐1 reverse transcriptase (RT), both in vitro and during monotherapy in vivo. The aim of this analysis was to compare the selection of these and other nucleoside reverse transcriptase inhibitor (NRTI)‐associated mutations by ABC‐containing therapies in the presence and absence of concurrent lamivudine (3TC) and/or zidovudine (ZDV) and to assess the effect of these mutations on phenotypic susceptibility to the NRTIs.

Design This study was a retrospective analysis of the patterns of NRTI‐associated mutations selected following virological failure in six multicentre trials conducted during the development of ABC.

Methods Virological failure was defined as confirmed vRNA above 400 HIV‐1 RNA copies/mL. RT genotype and phenotype were determined using standard methods.

Results K65R was selected infrequently by ABC‐containing regimens in the absence of ZDV (13 of 127 patients), while L74V/I was selected more frequently (51 of 127 patients). Selection of both K65R and L74V/I was significantly reduced by co‐administration of ZDV with ABC (one of 86 and two of 86 patients, respectively). Y115F was uncommon in the absence (seven of 127 patients) or presence (four of 86 patients) of ZDV. M184V was the most frequently selected mutation by ABC alone (24 of 70 patients) and by ABC plus 3TC (48 of 70 patients). Thymidine analogue mutations were associated with ZDV use. The K65R mutation conferred the broadest phenotypic cross‐resistance of the mutations studied.

Conclusions The resistance pathway selected upon virological failure of ABC‐containing regimens is significantly altered by concurrent ZDV use, but not by concurrent 3TC use. These data may have important implications for the efficacy of subsequent lines of NRTI therapies.




Apr, 2003

Three year follow-up of the PENTA 5 trial


Authors: Gibb DM, Giaquinto C, Walker AS, Harper L, Compagnucci A, Saidi Y, Moulinier C, Aboulker JP, Babiker AG, Debré M, Darbyshire JH on behalf of the PENTA 5 Executive Committee

Published: 10th Conference on Retroviruses and Opportunistic Infections February 10th – 14th, 2003 – Boston. Poster G1-12



Apr, 2003

Relationship between Cell-Associated HIV-1 DNA and Thymic Output in HIV-1 infected Children Initiating Antiretroviral Therapy in the PENTA 5 Trial


Authors: De Rossi A, Walker AS, De Forni D, Gibb DM on behalf of PENTA.

Published in: 10th Conference on Retroviruses and Opportunistic Infections February 10th – 14th, 2003 – Boston. Poster P-17



Apr, 2003

Adherence to Prescribed Antiretroviral Therapy in Human Immunodeficiency Virus-Infected Children in the PENTA 5 Trial


Author: Gibb DM, Goodall RL, Giacomet V, McGee L, Compagnucci A, Lyall H. Paediatric European Network for Treatment of AIDS Steering Committee.

Published in: Pediatr Infect Dis J. 2003;22(1):56-62

Background Most studies of adherence to highly active antiretroviral therapy in children have been retrospective or cross-sectional. Factors relating to the caregiver, the child and the medication are all considered to be important for good adherence.
Methods Adherence with taking prescribed medication was assessed by questionnaires completed at 4, 12, 24 and 48 weeks by caregivers of previously untreated HIV-infected children participating in the PENTA 5 trial, which was designed to evaluate different dual nucleoside reverse transcriptase inhibitor therapy combinations with and without the protease inhibitor nelfinavir. The effects of several factors on adherence and the effect of adherence on virologic suppression were assessed by multivariate logistic regression.
Results Caregivers returned 266 questionnaires including at least 1 for 108 (84%) children in the trial. Nelfinavir was reported to be the most difficult drug to take (38% of questionnaires), but the difficulty decreased over time, P = 0.02. Comments on difficulties in taking and remembering drugs related to fear of disclosure and to unpleasant characteristics of the drugs. Full adherence was reported in 74% of questionnaires, did not change over time and was reported more frequently in children older than 10 years and those with symptomatic HIV disease. More children reporting full adherence achieved HIV RNA <400 copies/ml (e.g. at 48 weeks 79%vs. 50% reporting some nonadherence; overall P = 0.01).
Conclusion Good adherence with taking prescribed medication was associated with virologic response. Social factors were important in explaining nonadherence.



Sep, 2002

Zidovudine (ZDV) appears to prevent selection of K65R and L74V, mutations normally selected by Abacavir (ABC) mono- or combination therapies not containing ZDV


Authors: Ait-Khaled M, Lanier R, Richards N, Stone C, Griffin P, Gibb DM, Walker AS, Craig C, Loeliger E, Tisdale M

Published in: 2002 International Meeting of the Institute of Human Virology, September 9th-13th, 2002, Baltimore


Jul, 2002

Adherence to HAART in children: results from a questionnaire study of children in PENTA 5 trial


Authors: Giacomet V, Gibb DM, Goodall R, McGee L, Walker AS, Giaquinto C.

Published in: XIV World AIDS Conference, 7th-12th July 2002, Barcelona, Spain. Poster TuPpB2050


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