Publications

Authors: Klein N, Sefe D, Mosconi I, et al; on Behalf of the Paediatric European Network for Treatment of AIDS (PENTA) 11 Trial Team

Published in: PLoS One. 2013;8(10):e76582.

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 naïve 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.

Authors:  Colbers A, Brookie B, Wang J, Stek A, Hidalgo-Tenorio C, Hawkins D, Taylor G, Capparelli E, Burger D, Mirochnick M; on behalf of the PANNA network

Published: 20th Conference on Retroviruses and Opportunistic Infections, March 3rd-6th 2013, Atlanta. P_931

Authors: Turkova A, Thorne C, Galli L, Goetghebuer T, de Martino M, Oprea C, Ramos Amador JT, Giaquinto C; for the European Pregnancy and Paediatric HIV Cohort Collaboration in EuroCoord.

Published in: 7th International AIDS Society Conference (IAS 2013), Kuala Lumpur, 30th June – 3rd July 2013

Authors: Thorne C, Bailey H, Semenenko I, Tereschenko R, Adeyanova I, Kulakovskaya E, Ostrovskaya L, Malyuta R

Published in: 7th International AIDS Society Conference (IAS 2013), Kuala Lumpur, 30th June – 3rd July 2013

Authors: D Bastiaans, S Forcat, H Lyall, T Cressey, S Chalermpantmetagul, Y Saïdi, C Koenigs,  D Nayagam, A Compagnucci, S Montero, L Harper, C Giaquinto, E Colbers, D Burger.

Published in: 31^st Annual Meeting of the ESPID- May 28 – June 1, 2013, Milan: Poster discussion Abstract A-534-0018-00429. 

Authors: Aebi-Popp K, Mulcahy F, Glass T, Rudin C, Martinez de Tejada B, Bertisch B, Grawe C, Rickenbach M, Scheibner K, Hösli I and Thorne C  for the European Collaborative Study in EuroCoord and the Swiss Mother & Child HIV Cohort Study.

Published in: 5^th International HIV Pediatrics Workshop, Kuala Lumpur, 28-29 June 2013.

Authors: Aebi-Popp K, Mulcahy F, Glass TR, et al.; for the European Collaborative Study in EuroCoord and the Swiss Mother & Child HIV Cohort Study.

Published in: J Acquir Immune Defic Syndr. 2013;64(1):58-65

Introduction Most national guidelines for the prevention of mother-to-child transmission of HIV in Europe updated between 2001 and 2010 recommend vaginal deliveries for women with undetectable or very low viral load (VL). Our aim was to explore the impact of these new guidelines on the rates of vaginal deliveries among HIV-positive women in Europe.

Methods In a pooled analysis of data on HIV-positive pregnant women enrolled in the Swiss Mother & Child HIV Cohort Study and the European Collaborative Study 2000 to 2010, deliveries were classified as occurring pre- or postpublication of national guidelines recommending vaginal delivery.

Results Overall, 2663 women with 3013 deliveries were included from 10 countries; 28% women were diagnosed with HIV during pregnancy. Combination antiretroviral therapy was used in most pregnancies (2020, 73%), starting during the first or second trimester in 78% and during the third trimester in 22%; in 25% pregnancies, the woman conceived on combination antiretroviral therapy. Overall, in 86% pregnancies, a VL < 400 copies per milliliter was achieved before delivery. The proportion of vaginal deliveries increased from 17% (414/2377) before the change in guidelines to 52% (313/600) after; elective Caesarean section rates decreased from 65% to 27%. The proportion of women with undetectable VL having a Caesarean section was 55% after implementation of new guidelines. We observed a decrease of late preterm deliveries from 16% (377/2354) before to 7% (42/599) after the change in guidelines (P < 0.001).

Conclusion There are still missed opportunities for women with HIV to fully suppress their VL and to deliver vaginally in Europe.

Authors: Bailey H, Townsend CL, Cortina-Borja M, Thorne C; for the European Collaborative Study in EuroCoord.

Published in: AIDS 2013; 27:2312-2315

Abstract Among 396 HIV-infected women conceiving on combination antiretroviral therapy and enrolled in the European Collaborative Study in 2000–2011, the proportion with virological failure (>200 copies/ml after ≥24 weeks of treatment) declined substantially from 34% in 2000–2001 to 3% in 2010–2011. In adjusted analyses, younger women and those with at least two children were at increased risk of virological failure, highlighting the importance of close monitoring and adherence support.

Authors: Chiappini E, Galli L, Giaquinto C, et al. European Pregnancy and Paediatric HIV Cohort Collaboration (EPPICC) study group in EuroCoord.

Published in: AIDS 2013; 27(6): 991-1000

Objectives To evaluate use of combination neonatal prophylaxis (CNP) in infants at high risk for mother-to-child transmission(MTCT) of HIV in Europe and investigate whether CNP is more effective in preventing MTCT than single drug neonatal prophylaxis (SNP).

Design Individual patient-data meta-analysis across eight observational studies.

Methods Factors associated with CNP receipt and with MTCT were explored by logistic regression using data from non-breastfed infants, born between 1996 and 2010 and at high risk for MTCT.

Results In 5285 mother-infant pairs, 1463 (27.7%) had no antenatal or intrapartum antiretroviral prophylaxis, 915 (17.3%) had only intrapartum prophylaxis and 2907 (55.0%) mothers had detectable delivery viral load despite receiving antenatal antiretroviral therapy. Any neonatal prophylaxis was administered to 4623 (87.5%) infants altogether; 1105 (23.9%) received CNP. Factors significantly associated with the receipt of CNP were later calendar birth year, no elective caesarean section, maternal CD4 cell count less than 200 cells/μl, maternal delivery viral load more than 1000 copies/ml, no antenatal antiretroviral therapy, receipt of intrapartum single-dose nevirapine and cohort. After adjustment, absence of neonatal prophylaxis was associated with higher risk of MTCT compared to neonatal prophylaxis [adjusted odds ratio (aOR) 2.29; 95% confidence interval (95% CI) 1.46-2.59; P < 0.0001]. Further, there was no association between CNP and MTCT compared to SNP (aOR 1.41; 95% CI 0.97-2.5; P = 0.07).

Conclusion In this European population, CNP use is increasing and associated with presence of MTCT risk factors. The finding of no observed difference in MTCT risk between one drug and CNP may reflect residual confounding or the fact that CNP may be effective only in a subgroup of infants rather than the whole population of high-risk infants.

Authors: Colbers AP, Hawkins DA, Gingelmaier A, et al.

Published in: Aids. 2013; 27(5):739-748.

Objective To describe the pharmacokinetics of tenofovir and emtricitabine in the third trimester of pregnant HIV-infected women and at postpartum.

Design A nonrandomized, open-label, multicentre phase IV study in HIV-infected pregnant women recruited from HIV treatment centres in Europe.

Methods HIV-infected pregnant women treated with the nucleotide/nucleoside analogue reverse transcriptase inhibitors (NRTIs) tenofovirdisoproxil fumarate (TDF 300 mg; equivalent to 245 mg tenofovir disoproxil) and/or emtricitabine (FTC 200 mg) were included in the study. Twenty-four-hour pharmacokinetic curves were recorded in the third trimester (preferably week 33) and postpartum (preferably week 4-6). Collection of a cord blood sample and maternal sample at delivery was optional. Pharmacokinetic parameters were calculated using WinNonlin software version 5.3. Statistical analysis was conducted using SPSS version 16.0.

Results Thirty-four women were included in the analysis. Geometric mean ratios of third trimester vs. postpartum [90% confidence interval (CI)] were 0.77 (0.71-0.83) for TDF area under the curve (AUC0-24 h); 0.81 (0.68-0.96) for TDF Cmax and 0.79 (0.70-0.90) for TDF C24 h and 0.75 (0.68-0.82) for FTC AUC0-24 h; and 0.87 (0.77-0.99) for FTC Cmax and 0.77 (0.52-1.12) for FTC C24 h. The viral load close to delivery was less than 200  copies/ml in all but one patient, the average gestational age at delivery was 38 weeks. All children were tested HIV-negative and no congenital abnormalities were reported.

Conclusion Although pharmacokinetic exposure of the NRTIs TDF and FTC during pregnancy is approximately 25% lower, this was not associated with virological failure in this study and did not result in mother-to-child transmission.

Authors: Bunupuradah T, Duong T, Compagnucci A, et al; on behalf of the PENTA 11 Extension Study Group

Published in: AIDS. 2013;27(4):579-89

Background Excess risks for death/opportunistic disease in adults randomized to CD4-driven planned treatment interruption (PTI) in the Strategies for Management of Antiretroviral Therapy (SMART) trial remained after antiretroviral therapy (ART) re-initiation. Risks for childrenfollowing PTI were evaluated in long-term follow-up of children in the PENTA 11 trial.

Methods Children with HIV RNA below 50 copies/ml and CD4 at least 30% (2-6 years) or at least 500 cells/μl (7-15 years) were randomized to continuous ART (cART) or PTI in PENTA 11 (ISRCTN 36694210). After the end of the trial, all were recommended to resume ART. Data were collected annually and analysed up to the second year of visit.

Results One hundred and one (51 cART, 50 PTI; median baseline age 9.2 years) children had median overall follow-up 4.6 (range 3.7-5.0) years. During 2-year post-trial period, there were no deaths or new Centers for Disease Control and Prevention (CDC) stage B/C events. Rate of clinical grade of at least two events was similar between PTI and cART [relative risk (RR) 1.03; 95% confidence interval (CI) 0.43, 2.50; P = 0.94]. At 2 years, difference in absolute CD4% between PTI and cART was -1.6% (-4.5%; 1.3%; P = 0.27), and proportions with HIV RNA below 50 copies/ml were 82 versus 86% (P = 0.57), respectively; no differences in growth or fasting lipids were observed. Key predictors of greater CD4% recovery after re-initiating ART were higher CD4% at baseline (P < 0.001) and longer time since ART re-initiation (P < 0.001). During overall follow-up, 4 (8%) PTI versus 5 (10%) CT children switched ART for failure (P = 0.75) and 9 (18%) versus 1 (2%) (P = 0.008) substituted ART for simplification.

Conclusions No adverse clinical, immunological or virological consequences of PTI were observed 2 years after the end of PENTA 11 trial. Although ART interruption is not generally recommended, it may be an acceptable option for children, particularly when there is high risk of unplanned treatment interruptions.

Authors: Harrison L, Ananworanich J, Hamadache D, et al; on Behalf of the Paediatric European Network for Treatment of AIDS (PENTA) 11 Trial Team

Published in: AIDS Behav. 2013;17(1):193-202.

Abstract There have been no paediatric randomised trials describing the effect of planned treatment interruptions (PTIs) of antiretroviral therapy (ART) on adherence, or evaluating acceptability of such a strategy. In PENTA 11, HIV-infected children were randomised to CD4-guided PTIs (n = 53) or continuous therapy (CT, n = 56). Carers, and children if appropriate, completed questionnaires on adherence to ART and acceptability of PTIs. There was no difference in reported adherence on ART between CT and PTI groups; non-adherence (reporting missed doses over the last 3 days or marking <100 % adherence since the last clinical visit on a visual analogue scale) was 18 % (20/111) and 14 % (12/83) on carer questionnaires in the CT and PTI groups respectively (odds ratios, OR (95 % CI) = 1.04 (0.20, 5.41), χ(2) (1) = 0.003, p = 0.96). Carers in Europe/USA reported non-adherence more often (31/121, 26 %) than in Thailand (1/73, 1 %; OR (95 % CI) = 54.65 (3.68, 810.55), χ(2) (1) = 8.45, p = 0.004). The majority of families indicated they were happy to have further PTIs (carer: 23/36, 64 %; children: 8/13, 62 %), however many reported more clinic visits during PTI were a problem (carer: 15/36, 42 %; children: 6/12, 50 %).

Authors: Colbers A, Taylor G, Moltó J, Ivanovic J, Wyen C, Schwarze-Zander C, Weizsäcker K, Gingelmaier A, Hawkins D, Sadiq T, Kabamba K, Burger D; on behalf of the PANNA network

Published: 13th International Workshop on Clinical Pharmacology of HIV Therapy, 2012 April 16th-18th, Barcelona

Authors: Colbers A, Moltó J, Ivanovic J, Hidalgo-Tenori C, Weizsäcker K, van der Ende I, Hawkins D, Taylor G, Sadiq T,  Burger D; on behalf of the PANNA network

Published: 19th Conference on Retroviruses and Opportunistic Infections, March 5th-8th 2012, Seattle. P_103

Authors: European Collaborative Study in Eurocord

Published in: Antivir Ther, 2011,16: 859-903.

Background: Although mother-to-child transmission (MTCT) rates are at an all-time low in Western Europe, potentially preventable transmissions continue to occur. Duration of antenatal combination antiretroviral therapy (ART) is strongly associated with MTCT risk.

Methods: Data on pregnant HIV-infected women enrolled in the Western and Central European sites of the European Collaborative Study between January 2000 and July 2009 were analysed. The proportion of women receiving no antenatal ART or 1-13 days of treatment was investigated, and associated factors explored using logistic regression models.

Results: Of 2148 women, 142 (7%) received no antenatal ART, decreasing from 8% in 2000-03 to 5% in 2004-09 (χ² =8.73, p<0.01). A further 41 (2%) received 1-13 days of ART. A third (64/171) of women with “insufficient” (no or 1-13 days) antenatal ART had a late HIV diagnosis (in the third trimester or intrapartum), but half (85/171) were diagnosed pre-conception. Preterm delivery <34 weeks was associated with receipt of no and 1-13 days antenatal ART (AOR 2.9 p<0.01 and AOR 4.5 p<0.01 respectively). Injecting drug use history was associated with an increased risk of no ART (AOR 2.9 p<0.01) and severe symptomatic HIV disease with a decreased risk (AOR 0.2, p<0.01). MTCT rates were 1.1% (15/1318) among women with ≥14 days antenatal ART and 7.4% (10/136) among those with insufficient ART.

Conclusions: Over the last 10 years, around 1 in 11 women in this study received insufficient antenatal ART, accounting for 40% of mother-to-child transmissions. Half of these women were diagnosed pre-conception, suggesting disengagement from care.

Authors: Bastiaans DET, Forcat S, Lyall HEG, Cressey TR, Chalermpantmetagul S, Saïdi Y, Noguera T, Fortuny C, Compagnucci A, Bleier J, Giaquinto C, Colbers EP, Burger DM.

Published in: 4th International Workshop on HIV pediatrics 2012. July 20-21, 2012. L’Enfant Plaza Hotel, Washington DC, USA. 4th International Workshop on HIV pediatrics. July 20-21, 2012. L’Enfant Plaza Hotel, Washington DC, USA.

Authors: Ramos J., Melvin D, Medin G, Compagnucci A, Bleier J, Boscolo V, Barclay L, Ory S, Giaquinto C, Gibb D. on behalf of the PENTA Steering Committee.

Published in: 19th Conference on Retroviruses and Opportunistic Infections, San Francisco, 5-8 March 2012, Poster

Authors: Antinori A., Marcotullio S., Ammassari A., Andreoni M., Angarano G., Armignacco O., Carosi G., Cinque P., d’Arminio Monforte A., Di Perri G., Ensoli B., Florida M., Galli M., Mastroianni C., Matteelli A., Mazzotta F., Moroni M., Pal G., Puoti M., Puro V., Rizzardini G., Sagnelli E., Vella S., Vullo V., Lazzarin A., Italian HIV Guidelines Working Group (Giaquinto C.  member of Study Group)

Published in: New Microbiol 2012, 35: 113 – 59

Abstract: This short version complies with the intention expressed in the methodological introduction to the full text Italian Guidelines for the use of antiretroviral drugs and the diagnostic-clinical management of people with HIV-1 infection. By definition, this version should not be considered completely exhaustive with respect to the full text version of the Guidelines available at the website: http://www.salute.gov.it/imgs/C_17_pubblicazioni_1301_allegato.pdf.

Authors: Mbisa JL, Hue S, Buckton AJ, et al.

Published in: AIDS Res Hum Retroviruses. 2012;28(9):1161-1166

Abstract In the late 1980s an HIV-1 epidemic emerged in Romania that was dominated by subtype F1. The main route of infection is believed to be parenteral transmission in children. We sequenced partial pol coding regions of 70 subtype F1 samples from children and adolescents from the PENTA-EPPICC network of which 67 were from Romania. Phylogenetic reconstruction using the sequences and other publically available global subtype F sequences showed that 79% of Romanian F1 sequences formed a statistically robust monophyletic cluster. The monophyletic cluster was epidemiologically linked to parenteral transmission in children. Coalescent-based analysis dated the origins of the parenteral epidemic to 1983 [1981–1987; 95% HPD]. The analysis also shows that the epidemic’s effective population size has remained fairly constant since the early 1990s suggesting limited onward spread of the virus within the population. Furthermore, phylogeographic analysis suggests that the root location of the parenteral epidemic was Bucharest.

Authors: D Bastiaans, S. Forcat, H.E.G. Lyall, T.R. Cressey, S. Chalermpantmetagul, Y. Saïdi, H.J. Scherpbier, A. Warris, A. Compagnucci, C. Giaquinto, E.P. Colbers, D.M. Burger on behalf of PENTA KONCERT Study Group.

Published in: 6th Netherlands Conference on HIV Pathogenesis, Prevention and Treatment. November 27, 2012. 

Authors:  Chiappini E., Galli L., Tovo P.A., Gabiano C., Lisi C., Giacomet V., Bernardi S., Esposito S., Rosso R., Giaquinto C ., Badolato R., Guarino A., Maccabruni A., Masi M., Cellini M., Salvini F., Di Bari C., Dedoni M., Dodi I., De Martino M for the Italian Register for HIV infection in children

Published in: Acta Paediatr, 2012, 101: 287-295

Background:  Information on the use of new antiretroviral drugs in children in the real setting of clinical fields is largely unknown.

Methods:  Data from 2554 combined antiretroviral therapy (cART) regimens administered to 911 children enrolled in the Italian Register for HIV infection in children, between 1996 and 2009, were analysed. Factors potentially associated with undetectable viral load and immunological response to cART were explored by Cox regression analysis.

Results:  Proportion of protease inhibitor (PI)-based regimens significantly decreased from 88.0% to 51.2% and 54.9%, while proportion on non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens increased from 4.5% to 38.8% and 40.2% in 1996–1999, 2000–2004 and 2005–2009, respectively (p < 0.0001). Significant change in the use of each antiretroviral drug occurred over the time periods (p < 0.0001). Factors independently associated with virological and immunological success were as follows: later calendar periods, younger age at regimen (only for virological success) and higher CD4⁺ T-lymphocyte percentage at baseline. Use of unboosted PI was associated with lower adjusted hazard ratio (aHR) of virological or immunological success with respect to NNRTI- and boosted PI-based regimens, with no difference among these two latter types.

Conclusion:  Use of new generation antiretroviral drugs in Italian HIV-infected children is increasing. No different viro-immunological outcomes between NNRTI- and boosted PI-based cART were observed.

Authors: Alam N., Cortina – Borja M., Goetghebuer T., et al. European Paediatr HIV & Lipodystrop (Giaquinto C.  member of the Study Group)

Published in: JAIDS, 2012, 59: 314 – 32

Objectives: To estimate the prevalence of and identify risk factors for lipodystrophy syndrome (LS) and body fat abnormality in a population of HIV-infected children and adolescents.

Design: Cross-sectional observational study.

Methods: HIV-infected subjects aged 2-18 years were recruited from 15 HIV centers in Belgium, Italy, and Poland between January 2007 and December 2008. Standardized assessments by the patient’s long-term clinician were performed to establish the presence of abnormality. Risk factors were explored in logistic regression models for fat abnormality outcomes and LS (abnormality plus dyslipidemia).

Results: Among 426 subjects (70% white), median age was 12.2 years (interquartile range: 9.0-15.0 years) and median duration of antiretroviral therapy was 5.2 years (interquartile range: 2.2-8.8 years). Prevalence was 57% (n = 235) for LS and 42% (n = 176) for fat abnormality; 90 subjects with abnormality were affected in ≥3 locations. Lipoatrophy occurred in 28% (n = 117) of subjects and lipohypertrophy in 27% (n = 115), most commonly in the face and trunk, respectively. In multivariable analysis, white ethnicity, body mass index, ritonavir/lopinavir, and nonnucleoside reverse transcriptase inhibitors were each associated with an increased risk of LS (P < 0.05). White ethnicity, history of Centers for Disease Control and Prevention-defined disease, and stavudine were associated with risk of lipoatrophy (P < 0.05). Increased risk of lipohypertrophy was associated with body mass index and prior HIV disease.

Conclusions: Fat abnormality was prevalent in close to half of children and adolescents, who had accumulated long treatment durations. Risk of fat abnormality was associated with specific drugs, including stavudine and ritonavir, and other variables. Our results underline the importance of continued surveillance of children treated with antiretroviral therapy.

Authors: Goetghebuer T, Le Chenadec J, Haelterman E, et al.

Published in: Clinical Infectious Diseases 2012; 54(6): 878-881

Abstract The clinical benefit of antiretroviral therapy in infants is established. In this cohort collaboration, we compare immunological and virological response to treatment started before or after 3 months of age. Early initiation provides a better short-term response, although evolution after 12 months of age is similar in both groups.

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

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

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

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

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

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

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.

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.

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.

Authors: HIV Paediatric Prognostic Markers Collaborative Study

Published in: AIDS 2010, 24, 1213–1217

Authors: Paediatric European Network for Treatment of AIDS (PENTA)

Published in: Antivir Ther. 2010;15(3):297-305.

Background Once-daily dosing of abacavir and lamivudine has been approved for adults, but paediatric data are insufficient. We conducted a pharmacokinetic study of once-daily and twice-daily abacavir and lamivudine in children aged 3-<36 months.

Methods Children with stable HIV type-1 (HIV-1) RNA levels after 12 weeks treatment with twice-daily abacavir (8 mg/kg) with or without lamivudine (4 mg/kg) underwent plasma pharmacokinetic sampling. Children then switched to once-daily abacavir (16 mg/kg) with or without lamivudine (8 mg/kg), and sampling was repeated 4 weeks later. The area under the plasma concentration-time curve over 24 h (AUC(0-24)) and the maximum concentration (C(max)) were compared using geometric mean ratios (GMRs); 90% confidence intervals (CIs) within the range of 0.80-1.25 were considered bioequivalent.

Results A total of 18 children (4, 6 and 8 in the 3-<12, 12-<24 and 24-<36 month age ranges, respectively) provided pharmacokinetic data for abacavir (17 for lamivudine). The GMR of AUC(0-24), once-daily versus twice-daily, was 1.07 (90% CI 0.92-1.23) for abacavir and 0.91 (90% CI 0.79-1.06) for lamivudine. C(max) almost doubled on once-daily versus twice-daily dosing: abacavir and lamivudine GMRs were 2.04 (90% CI 1.73-2.42) and 1.78 (90% CI 1.52-2.09), respectively. At baseline, 12, 24 and 48 weeks, 89%, 94%, 100% and 89% of children had HIV-1 RNA<400 copies/ml, respectively.

Conclusions Bioequivalence was demonstrated on AUC(0-24) between twice-daily and once-daily abacavir; very similar AUC(0-24) values were seen for twice-daily and once-daily lamivudine. Given that viral load suppression rates were maintained, these data suggest that once-daily abacavir and lamivudine might be an option for children aged 3-<36 mont

Authors: Cella M, Gorter de Vries F, Burger D, Danhof M, Della Pasqua O.

Published in: Clinical Pharmacology and Therapeutics, 2010, 87(3):294-302.

Authors: Sefe D, Klein N, Mosconi I, Ricci E, Castro, H (nee Green), Jacobsen M, Bernardi S, Pillay D, Gibb DM, and De Rossi A, on behalf of the PENTA Steering Committee

Published in: 17th Conference on Retroviruses and Opportunistic Infections, San Francisco, 16-19 February 2010, Poster

PENTA and IMPAACT: A phase II/III randomised, open-label trial of combination antiretroviral regimens and treatment-switching strategies in HIV-1-infected antiretroviral naïve children

Published in: XVIII International AIDS Conference, 22nd July 2010, Vienna Austria.

Authors: Lodwick R, Costagliola D, Reiss P, et al. Pursuing Later Treatment Options II (PLATO II) Project Team for the Collaboration of Observational HIV Epidemiological Research Europe (COHERE).

Published in: Archives of Internal Medicine. 2010; 170(5):410-419

Background: Life expectancy in people with HIV is now estimated to approach that in the general population in some successfully treated subgroups. However, to attain these life expectancies, viral suppression must be maintained for decades.

Methods: We studied the rate of triple class virologic failure (TCVF) in patients within the Collaboration of Observational HIV Epidemiological Research Europe (COHERE) who started antiretroviral therapy (ART) with an NNRTI- or PI/r-containing regimen from 1998 onwards. We also focussed on TCVF in patients who started a PI/r-containing regimen after virologically failing a first-line NNRTI-containing regimen.

Results: Of 45937 patients followed for a median (IQR) 3.0 (1.5-5.0) years, 980 (2.1%) developed TCVF. By 5 and 9 years after starting ART, an estimated 3.4% (95% CI:3.1%-3.6%) and 8.6% (95% CI:7.5%-9.8%) of patients had developed TCVF. The incidence of TCVF rose during the first 3-4 years on ART, but plateaued thereafter. There was no significant difference in the risk of TCVF according to whether the initial regimen was NNRTI- or PI/r-based (p=0.11). By 5 years after starting a PI/r as second-line, 46% of patients had developed TCVF.

Conclusions: The rate of virologic failure of the three original drug classes is low, but not negligible, and does not appear to diminish over time from starting ART. If this trend continues, many patients are likely to need newer drugs to maintain viral suppression. The rate of TCVF from start of a PI/r after NNRTI failure provides a comparator for studies of response to secondline regimens in resource-limited settings.

Authors: Paediatric European Network for Treatment of AIDS.

Published in: AIDS. 2010;24(2):231-241.

Objective To evaluate clinical, immunological and virological consequences of CD4-guided antiretroviral therapy (ART) planned treatment interruptions (PTIs) compared with continuous therapy in children with chronic HIV infection in the Paediatric European Network for Treatment of AIDS 11 trial.

Design This was a multicentre, 72-week, open, randomized, phase II trial.Methods:One hundred and nine children with HIV-RNA below 50 copies/ml and CD4% of at least 30% (2–6 years) or at least 25% and CD4 cell count of at least 500 cells/μl (7–15 years) were randomized to continuous therapy (53) or PTI (56). In PTI, ART was restarted if confirmed CD4% was less than 20% or more than 48 weeks had been spent off ART. The primary outcome was Centers for Disease Control and Prevention (CDC) stage C event, death or CD4% less than 15% (and CD4 cell count less than 200 cells/μl for children aged 7–15 years).

Results At baseline, median (interquartile range) age was 9 (6–12) years, CD4% 37% (33–41), CD4 cell count 966 (793–1258) cells/μl, nadir CD4% before combination ART 18% (10–27), time on ART 6 (3–6) years and 26% were CDC stage C. After median (range) 130 (33–180) weeks of follow-up, 4 versus 48% of time was spent off ART in continuous therapy and PTI, respectively. No child died or had a new CDC stage C event; one (2%) continuous therapy versus four (7%) PTI children had a primary outcome based on CD4%/cell count (P = 0.2). Lower nadir CD4% predicted faster CD4% decline after stopping ART. Younger age and higher nadir CD4% predicted being off ART for at least 48 weeks and better CD4% recovery following PTI.

Conclusion In this first paediatric trial of PTI, there were no serious clinical outcomes. Younger children had better CD4% recovery after PTIs. Immunology substudies and long-term follow-up in Paediatric European Network for Treatment of AIDS 11 trial are ongoing. Further research into the role of treatment interruption in children is required, particularly, as guidelines now recommend early ART for all infected infants.

Authors: Jacqz-Aigrain, Farrelly L, Compagnucci A, Harrison L, Zhao W, Hamadache D, Welch S, Wintergerst U, Firtion G, Burger D

Published in: CROI 2009. February 8-11, 2009. Palais des Congres de Montreal, Canada , Poster S-154.

Authors: Zhao W, Farrelly L, Compagnucci A, Harrison L, Jacqz-Aigrain E, Hamadache D, Welch S, Wintergerst U, Burger D on behalf of the PENTA Trial Steering Committee .

Published in: 1st International Workshop on HIV Pediatrics, 17 – 18 July 2009, Cape Town, South Africa

Authors: Harrison L, Hamadache D, Bunupuradah T, Mazza A, Ramos Amador JT, Flynn J, Rampon O, Mellado Pena MJ, Floret D, Marczynska M, Puga A, Farrelly L, Riault Y, Lallemant M, Compagnucci A on behalf of the PENTA Trial Steering Committee.

Published in: 1st International Workshop on HIV Pediatrics, 17 – 18 July 2009, Cape Town, South Africa. (Poster P_90). 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention, Cape Town 19-22 July 2009

Authors: Goetghebuer T, Haelterman E, Le Chenadec J, et al. for the European infant collaboration group.

Published in: AIDS 2009;23:597-604

Objective: In the absence of treatment, rapid progression to AIDS occurs in approximately 20% of HIV-1-infected infants over the first year of life. The prognosis of these children has considerably improved with highly active antiretroviral therapy. As data from well resourced countries are lacking, the objective of this collaborative study was to evaluate the impact of early treatment in vertically infected infants.

Design: Children born to HIV-infected mothers between 1 September 1996 and 31 December 2004, who were diagnosed with HIV and free of AIDS before 3 months, were eligible. Demographics and pregnancy data, details of antiretroviral therapy, and clinical outcome were collected from 11 European countries.Methods:The risk of AIDS or death, by whether or not an infant started treatment before 3 months of age, was estimated by Kaplan–Meier survival analysis and Cox proportional hazards models.

Results: Among 210 children, 21 developed AIDS and three died. Baseline characteristics of the 124 infants treated before 3 months were similar to those of the 86 infants treated later. The risk of developing AIDS/death at 1 year was 1.6 and 11.7% in the two groups, respectively (P < 0.001). Deferring treatment was associated with increased risk of progression [crude hazard ratio 5.0; 95% confidence interval (CI) 2.0–12.6; P = 0.001] that persisted after adjusting for cohort in multivariate models (adjusted hazard ratio 3.0; 95% CI 1.2–7.9; P = 0.021).

Conclusion: In HIV-1 vertically infected infants, starting antiretroviral therapy before the age of 3 months is associated with a significant reduction in progression to AIDS and death.

Authors: Goetghebuer T, Haelterman E, Le Chenadec J, Dollfus C, Gibb D, Judd A, Green H, Galli L, Ramos JT, Giaquinto C, Warszawski J, Levy J; for the European Infant Collaboration group.

Published in:  AIDS 2009 Feb

Authors: Gibb DM, Compagnucci A, Green H, Lallemant M, et al.

Published in: Journal of the International AIDS Society 2008, 11(Suppl 1):O21 (10 November 2008)

Authors: Cressey TR, Green H, Khoo S, Treluyer J-M, Compagnucci A, Saidi Y, Lallement M, Gibb DM, Burger D.

Published in: Clin Infect Dis 2008. 15;46(10):1601-8 

Background The optimum strategy for stopping treatment with drugs that have different half-lives in a combination regimen to minimize the risk of selecting drug-resistant viruses remains unknown. We evaluated drug concentrations in plasma, human immunodeficiency virus (HIV) load, and development of drug resistance after a planned treatment interruption of a nonnucleoside reverse-transcriptase inhibitor (NNRTI)-containing regimen in HIV type 1-infected children.

Methods Children with viral loads <50 copies/mL and CD4 cell percentages > or =30% (for children aged 2-6 years) or CD4 cell percentages > or =25% and CD4 cell counts > or =500 cells/microL (for children aged 7-15 years) were randomized to either a planned treatment interruption or to continuous therapy. In the planned treatment interruption arm, either (1) treatment with nevirapine or efavirenz was stopped, and treatment with the remaining drugs was continued for 7-14 days, or (2) nevirapine or efavirenz were replaced by a protease inhibitor, and all drugs were stopped after 7-14 days. Sampling for determination of plasma drug concentrations, measurement of viral load, and drug resistance testing was scheduled at day 0, day 7 (drug concentrations only), day 14, and day 28 after interruption of treatment with an NNRTI.

Results Treatment with an NNRTI was interrupted for 35 children (20 were receiving nevirapine, and 15 were receiving efavirenz). Median time from NNRTI cessation to stopping all drugs was 9 days (range, 6-15 days) for nevirapine and 14 days (range, 6-18 days) for efavirenz. At 7 days, 1 (5%) of 19 and 4 (50%) of 8 children had detectable nevirapine and efavirenz concentrations, respectively; efavirenz remained detectable in 3 (25%) of 12 children at 14 days. At 14 days, viral load was > or =50 copies/mL in 6 of 16 children interrupting treatment with nevirapine (range, 52-7000 copies/mL) and in 2 of 12 children interrupting treatment with efavirenz (range, 120-1600 copies/mL). No new NNRTI mutations were observed.

Conclusions In children with virological suppression who experienced interruption of treatment with an NNRTI, staggered or replacement stopping strategies for a median of 9 days for nevirapine and 14 days for efavirenz were not associated with the selection of NNRTI resistance mutations.

Authors: Dunn DT, Woodburn P, Duong T, Phillips AN, Gibb D, Porter K on behalf of HIV Paediatric Prognostic Markers Collaborative Study (HPPMCS) and the CASCADE Collaboration.

Published in: J Infect Dis 2008, 197:398-404

Authors: Jacobsen MC, Thiebaut R, Fisher C, Sefe D, Clapson M, Klein NJ, Baxendale HE.

Published in: 5th Conference on Retroviruses and Opportunistic Infections, Boston, 2- 8 February 2008, Poster A-152 /453

Authors: Cross Continents Collaboration for Kids (3Cs4kids) Analysis and Writing Committee

Published in: AIDS. 2008 Jan 2;22(1):97-105.

Authors: Goetghebuer T for the European Infant Collaborative Study.

Published in: 4th Dominique Dormont International Conference, 13-15 December, 2007

Published in: American Academy of Pediatrics, 2007; 119: 838-845

Authors: Green H and Gibb DM.

Published in: Curr Opin HIV AIDS 2007; 2:62-68.