Di Gibb

Medical Research Council (UK), London, ENG, United Kingdom

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Publications (9)51.85 Total impact

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    ABSTRACT: BACKGROUND:: Uncertainty surrounds the correct dosing of lopinavir/r (LPV/r) in HIV-infected children not receiving NNRTIs. The licensed total daily dose is 460mg/m, whilst the original study, reporting excellent viral load (VL) suppression, used a higher 600mg/m dose. METHODS:: We calculated LPV/r daily doses prescribed from 2000-2009 within the UK/Irish national Collaborative HIV Paediatric Study (CHIPS) cohort. Logistic and binomial mixed models were used to explore whether higher LPV/r doses affected VL suppression. RESULTS:: 444/1201 (37%) children on antiretroviral therapy in CHIPS had taken lopinavir/r without NNRTIs. Of 1065 recorded doses, 48% were syrup, 27% capsules and 25% tablets. 10% of doses were >10% below 460mg/m per day, and 12% were >10% above 600mg/m. In multivariable models, predictors of lower doses were: once vs. twice daily dosing (32mg/m lower); syrup vs. tablets/capsules (33mg/m lower); higher weight- and height-for-age (24mg/m and 13mg/m lower per unit higher, respectively); and older age (13mg/m lower per year older for those >10 years old) (p<0.05). Dosing varied widely by hospital (p=0.0004), with some targeting higher and others lower doses. For those receiving lopinavir/r for ≥6 months there was a greater chance of VL<400 copies/mL with higher doses (OR=1.15 95%CI 1.06-1.25 per 50mg/m higher, p=0.001). CONCLUSIONS:: Findings suggest substantial variation and large hospital-level effects in the LPV/r dose prescribed to HIV-infected children in the UK/Ireland. Higher doses appeared to improve long-term VL suppression, which may be critical in children who need life-long therapy. Results highlight the importance of optimizing dosing in HIV-infected children of all ages.
    The Pediatric Infectious Disease Journal 10/2012; · 3.57 Impact Factor
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    ABSTRACT: To investigate the association between tenofovir disoproxil fumarate (TDF) use and renal abnormality in a large cohort of HIV-1-infected children on antiretroviral therapy (ART). Nested case-control study. Patients were from the Collaborative HIV Paediatric Study, a cohort of approximately 95% of HIV-1-infected children in the UK/Ireland. Serum (but not urine) biochemistry results for 2002-2008 were obtained for 456 ART-exposed children (2-18 years) seen at seven hospitals. Cases had either confirmed hypophosphataemia DAIDS grade at least 2 or estimated glomerular filtration rate (eGFR) less than 60 ml/min per 1.73 m; three controls per case were matched by hospital. Conditional logistic regression identified risk factors for renal abnormality. Twenty of 456 (4.4%) had hypophosphataemia, and one had eGFR less than 60 ml/min per 1.73 m. Ten of 20 (50%) cases versus 11 of 60 (18%) controls had taken TDF-containing ART for a median [interquartile range (IQR)] of 18 [17-20] months, as part of second-line or salvage therapy. The hypophosphataemia incidence rate was 4.3/100 person-years in the TDF group versus 0.9/100 person-years in those not exposed to TDF. In multivariable analysis, only TDF exposure in the previous 6 months was associated with hypophosphataemia [odds ratio (OR) = 4.81, 95% confidence interval (CI) 1.45-16.0, P = 0.01]. In six of 10 children with hypophosphataemia and at least four subsequent phosphate measurements, phosphate values returned to normal when TDF was stopped; in four with three measures or less, values rose but remained subnormal. Hypophosphataemia was uncommon (4%), but was associated with prolonged TDF use, and was generally reversible following TDF withdrawal. Findings highlight the importance of continuing to monitor longer-term renal function, in particular tubular function, especially in those taking TDF. Further studies assessing urine biochemistry measures which more accurately indicate renal tubular damage are required.
    AIDS (London, England) 02/2010; 24(4):525-34. · 4.91 Impact Factor
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    ABSTRACT: Children with perinatally acquired HIV-1 infection are surviving into adolescence and increasingly transitioning toward adult services. Planning appropriate services in adult life requires an understanding of their progress through pediatric care. We describe the demographic features, disease progression, antiretroviral therapy (ART), and resistance in young people aged 10 years or more living in the United Kingdom and Ireland reported to the National Study of HIV in Pregnancy and Childhood (NSHPC) with prospective annual follow-up in the Collaborative HIV Paediatric Study (CHIPS) between 1996 and September 2007. Six hundred fifty-four perinatally infected young people were identified; 76% black African, 57% born abroad. Median age at presentation and duration of follow-up was 1 and 11 years, respectively, if born in the United Kingdom/Ireland, and 8 and 5 years if born elsewhere. One hundred sixty-nine (26%) ever had an AIDS-defining illness. Ten died during adolescence. At last follow-up, 64% were on ART, 18% off treatment having previously received ART and 18% were ART naive. Of 518 who had received highly active antiretroviral therapy (HAART), 47% were triple class experienced. At last follow-up 77 (12%) had CD4 counts less than 200 per microliter; of those on HAART, 78% had HIV-1 RNA </=400 copies per milliliter, median CD4 count 554 (interquartile range [IQR] 324-802). Among 166 with resistance assays on HAART, 52% and 12% had dual- and triple-class HIV-1-associated resistance mutations, respectively. One hundred three (16%) young people had transferred to adult services. Young adults with perinatally acquired HIV-1 infection require coordinated multidisciplinary transitional care services and careful long-term follow-up in adult life.
    AIDS patient care and STDs 03/2009; 23(3):159-66. · 2.68 Impact Factor
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    ABSTRACT: Tenofovir disoproxil fumarate (TDF) is neither licensed for use nor extensively studied in HIV-infected children. The only available formulation is an adult tablet, introducing the possibility of dosing errors in children. TDF interacts with other antiretrovirals and has been associated with decline in renal function and CD4 count. We describe the use of TDF in a cohort of HIV-1-infected children in the United Kingdom and Ireland. Children ever prescribed TDF and followed in the Collaborative HIV Pediatric Study cohort since 2001 were included in analyses of dosing, adverse events, and virologic and immunologic response. Suspected adverse drug reactions to TDF reported to the Medicines and Healthcare products Regulatory Agency during the same time were also reviewed. One hundred fifty-nine of 1253 children had taken TDF. They were older and had clinically more advanced disease than the rest of the cohort. Eighteen percent received >120% and 37% received <80% of the suggested pediatric dose (8 mg/kg). Thirty-seven percent of new TDF regimens contained didanosine (ddI), though few since 2005. Twelve of 159 (7.5%) children experienced serious adverse events and stopped TDF permanently, 11 taking concurrent lopinavir-ritonavir, and 10 ddI; 5 had renal toxicity. Viral load suppressed to < or =50 copies/mL at 12 months in 38% of those starting TDF. Median increase in CD4 count at 12 months was +110 cells/mL (interquartile range, 9-270), but only 3 cells/mL in those taking concurrent ddI. TDF seems to be an effective antiretroviral drug in this pediatric cohort, although considerable underdosing and overdosing occurs. A small number of children experienced serious adverse events while taking TDF; half were renal toxicity, most associated with concurrent ddI and lopinavir-ritonavir use.
    The Pediatric Infectious Disease Journal 01/2009; 28(3):204-9. · 3.57 Impact Factor
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    ABSTRACT: We reviewed HIV-1 genotypes from 200 of 979 (20%) HIV-infected children in the U.K. Collaborative HIV in Pediatric Study (CHIPS) cohort (343 resistance tests). Three of 44 samples had major primary resistance mutations before antiretroviral therapy. Three-class resistance was noted in 42 samples (14.1%). Our study also highlighted underutilization of testing and the need for prompt genotyping after drug discontinuation which may have lead to an underestimation of HIV-1 resistance.
    The Pediatric Infectious Disease Journal 06/2008; 27(5):457-9. · 3.57 Impact Factor
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    Steven B Welch, Di Gibb
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    ABSTRACT: Background to the debate: The advent of highly active antiretroviral therapy (HAART) dramatically improved the prognosis for both adults and children infected with HIV who had access to treatment. However, the optimal timing for initiating treatment remains controversial, particularly in children. This debate lays out the case for deferred treatment against the case for early initiation of HAART in children.
    PLoS Medicine 04/2008; 5(3):e73. · 15.25 Impact Factor
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    ABSTRACT: Currently, there are no comparable estimates of the short-term risk of disease progression in the absence of effective antiretroviral therapy for human immunodeficiency virus (HIV)-infected adults and children. A joint analysis of 2 large studies of children with vertically acquired HIV infection (the HIV Paediatric Prognostic Markers Collaborative Study) and adults with seroconversion (the CASCADE [Concerted Action on Sero-Conversion to AIDS and Death in Europe] collaboration) was conducted. Follow-up was censored at the end of 1995, before the introduction of combination antiretroviral therapy. The incidence rates of death and AIDS or death (AIDS/death) were estimated on the basis of age and current CD4 cell count. A total of 1260 deaths (over 20,500 person-years of follow-up) and 1894 initial AIDS events (over 17,200 person-years of follow-up) were observed among 6741 patients (3244 children [i.e., patients < or =15 years of age] and 3497 adults). Young children (age, <5 years) experienced high morbidity and mortality rates. After adjustment for the CD4 cell count, the effect of age on disease progression was not significant among older children, whereas the risk increased markedly in association with increasing age among adults. Death rates were similar among older children and adults aged approximately 20 years, as were the rates of progression to AIDS/death when cases of serious recurrent bacterial infection, which has a more restrictive case definition in adults, were excluded. Similar CD4 cell count criteria for initiation of antiretroviral therapy can be applied to adults and children > or = 5 years of age.
    The Journal of Infectious Diseases 02/2008; 197(3):398-404. · 5.85 Impact Factor
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    ABSTRACT: Recent evidence suggests that decreases in morbidity and mortality in cohorts of adults infected with human immunodeficiency virus (HIV) are showing signs of reversal. We describe changes over time in these characteristics and in the response to treatment among children in the United Kingdom and Ireland with perinatally acquired HIV infection, many of whom are now adolescents. We analyzed prospective cohort data reported to the National Study of HIV in Pregnancy and Childhood (NSHPC) and the Collaborative HIV Paediatric Study. By mid 2006, 1441 HIV-infected children were reported to NSHPC; 40% were > or = 10 years old at their most recent follow-up visit, and 34% were receiving care outside London. The proportion of children born abroad increased from 24% during 1994-1996 to 64% during 2003-2006. The percentage of total child time during which children received highly active antiretroviral therapy (HAART) increased from 36% during 1997-1999 to 61% during 2000-2002 and 63% during 2003-2006. Of children who were naive to antiretroviral therapy at the start of HAART, the percentage with an HIV-1 RNA load of < 400 copies/mL after 12 months increased from 52% during 1997-1999 to 79% during 2003-2006. In multivariate analysis, only calendar time predicted virological response, whereas both younger age and lower CD4 cell percentage at HAART initiation predicted increases of > 10% in the CD4 cell percentage. A total of 31% of children aged 5-14 years and 38% aged > or = 15 years at their most recent follow-up visit had been exposed to drugs from each of the 3 main HAART classes. The rate of AIDS and mortality combined decreased from 13.3 cases per 100 person-years before 1997 to 3.1 and 2.5 cases per 100 person-years, respectively, during 2000-2002 and 2003-2006; rates of hospital admission also declined during this interval. Of 18 children known to have died since 2003, 9 died within 1 month after presentation. Morbidity and mortality rates among HIV-infected children continue to decrease over time. Because these children are increasingly dispersed outside London, specialist care is now provided in national clinical networks. Transition pathways to adolescent and adult services and long-term observation to monitor the effects of prolonged exposure to both HIV and HAART are required.
    Clinical Infectious Diseases 10/2007; 45(7):918-24. · 9.37 Impact Factor
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    ABSTRACT: There are few data on plasma and intracellular pharmacokinetics (PK) of once-daily (q24h) nucleoside analogues in HIV-infected children. Children aged 2-13 years receiving combination treatment containing lamivudine (3TC) (4 mg/kg) and/or abacavir (ABC) (8 mg/kg) twice daily (q12h) were included in this single-arm, open-label, crossover study. Intensive plasma PK sampling was performed at steady state, after which children switched to q24h dosing and PK sampling was repeated 4 weeks later. Daily area under the curve (AUC0-24) and peak level (Cmax) of q24h and q12h regimens were compared by geometric mean ratios (GMRs) with 90% confidence intervals (CIs). Children were followed for 24 weeks to evaluate safety and virological response. 24 children were enrolled, of whom 20 [median age (range) 5.6 (2.1-12.8) years] had evaluable PK data for 3TC (n=19) and/or ABC (n=14). GMRs of 3TC and ABC AUC0-24 and Cmax q24h versus q12h significantly exceeded 1.0. GMRs were not significantly different between children aged 2-6 versus 6-13 years old (P>0.08). Of note, 3TC Cmax values for both q12h and q24h were significantly lower in children aged 2-6 versus 6-13 years old. No child discontinued due to adverse events. At baseline, 16 out of 20 children had a viral load <100 copies/ml compared with 17 out of 19 at week 24. AUC0-24 and Cmax of both 3TC and ABC q24h were not inferior to q12h dosing in children. Insufficient results were obtained concerning intracellular levels of the active triphosphate moieties of both agents. Virological data did not indicate a marked difference in antiviral activity between q12h and q24h regimens.
    Antiviral therapy 01/2005; 10(2):239-46. · 3.07 Impact Factor