Influence of age and co-medication on dolutegravir glucuronidation in paediatric patients.

Dolutegravir (DTG) is primarily metabolized by uridine diphosphate glucuronosyltransferases, forming the pharmacologically inactive DTG glucuronide (DTG-gluc). We described the dolutegravir metabolic ratio (DTG-MR; DTG-gluc AUC0-24h divided by DTG AUC0-24h) in 85 children with HIV aged 3 months to 18 years receiving DTG in the CHAPAS-4 (ISRCTN22964075) and ODYSSEY (NCT02259127) trials. Additionally, we assessed the influence of age, body weight, nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) backbone, rifampicin use and kidney function on DTG-MR. The overall geometric mean (CV%) DTG-MR was 0.054 (52%). Rifampicin use was the only significant factor associated with DTG-MR (P < .001) in multiple linear regression. DTG-MR geometric mean ratio was 1.81 (95% CI: 1.57-2.08) for children while on vs. off rifampicin. This study showed that overall DTG-MR in children was similar to adults, unaffected by age or NRTI backbone, and increased with rifampicin co-administration. These findings support future paediatric pharmacokinetic modelling and extrapolation from adult data.

Cognitive Function in Young Persons With and Without Perinatal HIV in the AALPHI Cohort in England: Role of Non-HIV-Related Factors.

BACKGROUND: There is limited evidence about the cognitive performance of older adolescents with perinatally acquired human immunodeficiency virus (HIV) compared with HIV-negative (HIV-) adolescents. METHODS: A total of 296 perinatally HIV-infected (PHIV+) and 97 HIV- adolescents (aged 12-21 and 13-23 years, respectively) completed 12 tests covering 6 cognitive domains. The HIV- participants had PHIV+ siblings and/or an HIV-infected mother. Domain-specific and overall (NPZ-6) z scores were calculated for PHIV+ participants, with or without Centers for Disease Control and Prevention (CDC) stage C disease, and HIV- participants. Linear regression was performed to explore predictors of NPZ-6. RESULTS: One hundred twenty-five (42%) of the PHIV+ and 31 (32%) of the HIV- participants were male; 251 (85%) and 69 (71%), respectively, were black African; and their median ages (interquartile range) were 16 (15-18) and 16 (14-18) years, respectively. In PHIV+ participants, 247 (86%) were receiving antiretroviral therapy, and 76 (26%) had a previous CDC C diagnosis. The mean (standard deviation) NPZ-6 score was -0.81 (0.99) in PHIV+ participants with a CDC C diagnosis (PHIV+/C), -0.45 (0.80) in those without a CDC C diagnosis (PHIV+/no C), and -0.32 (0.76) in HIV- participants (P < .001). After adjustment, there was no difference in NPZ-6 scores between PHIV+/no C and HIV- participants (adjusted coefficient, -0.01; 95% confidence interval, -.22 to .20). PHIV+/C participants scored below the HIV- group (adjusted coefficient, -0.44; -.70 to -.19). Older age predicted higher NPZ-6 scores, and black African ethnicity and worse depression predicted lower NPZ-6 scores. In a sensitivity analysis including PHIV+ participants only, no HIV-related factors apart from a CDC C diagnosis were associated with NPZ-6 scores. CONCLUSIONS: Cognitive performance was similar between PHIV+/no C and HIV- participants and indicated relatively mild impairment compared with normative data. The true impact on day-to-day functioning needs further investigation.

National policy development for cotrimoxazole prophylaxis in Malawi, Uganda and Zambia: the relationship between Context, Evidence and Links.

BACKGROUND: Several frameworks have been constructed to analyse the factors which influence and shape the uptake of evidence into policy processes in resource poor settings, yet empirical analyses of health policy making in these settings are relatively rare. National policy making for cotrimoxazole (trimethoprim-sulfamethoxazole) preventive therapy in developing countries offers a pertinent case for the application of a policy analysis lens. The provision of cotrimoxazole as a prophylaxis is an inexpensive and highly efficacious preventative intervention in HIV infected individuals, reducing both morbidity and mortality among adults and children with HIV/AIDS, yet evidence suggests that it has not been quickly or evenly scaled-up in resource poor settings. METHODS: Comparative analysis was conducted in Malawi, Uganda and Zambia, using the case study approach. We applied the 'RAPID' framework developed by the Overseas Development Institute (ODI), and conducted a total of 47 in-depth interviews across the three countries to examine the influence of context (including the influence of donor agencies), evidence (both local and international), and the links between researcher, policy makers and those seeking to influence the policy process. RESULTS: Each area of analysis was found to have an influence on the creation of national policy on cotrimoxazole preventive therapy (CPT) in all three countries. In relation to context, the following were found to be influential: government structures and their focus, donor interest and involvement, healthcare infrastructure and other uses of cotrimoxazole and related drugs in the country. In terms of the nature of the evidence, we found that how policy makers perceived the strength of evidence behind international recommendations was crucial (if evidence was considered weak then the recommendations were rejected). Further, local operational research results seem to have been taken up more quickly, while randomised controlled trials (the gold standard of clinical research) was not necessarily translated into policy so swiftly. Finally the links between different research and policy actors were of critical importance, with overlaps between researcher and policy maker networks crucial to facilitate knowledge transfer. Within these networks, in each country the policy development process relied on a powerful policy entrepreneur who helped get cotrimoxazole preventive therapy onto the policy agenda. CONCLUSIONS: This analysis underscores the importance of considering national level variables in the explanation of the uptake of evidence into national policy settings, and recognising how local policy makers interpret international evidence. Local priorities, the ways in which evidence was interpreted, and the nature of the links between policy makers and researchers could either drive or stall the policy process. Developing the understanding of these processes enables the explanation of the use (or non-use) of evidence in policy making, and potentially may help to shape future strategies to bridge the research-policy gaps and ultimately improve the uptake of evidence in decision making.

Morbidity, mortality, and response to treatment by children in the United Kingdom and Ireland with perinatally acquired HIV infection during 1996-2006: planning for teenage and adult care.

BACKGROUND: 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. METHODS: We analyzed prospective cohort data reported to the National Study of HIV in Pregnancy and Childhood (NSHPC) and the Collaborative HIV Paediatric Study. RESULTS: 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. CONCLUSIONS: 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.

Who Gets Severe Gynecomastia Among HIV-infected Children in the United Kingdom and Ireland?

There are few data on gynecomastia in HIV-infected children. Within the UK/Ireland's national cohort, 56 of 1873 (3%) HIV-infected children had gynecomastia, of which 10 (0.5%) were severe. All 10 had received antiretroviral therapy for a median of 27.5 (21, 42) months; 4 of 10 had received efavirenz, 7 of 10 and 6 of 10 had received stavudine and/or didanosine respectively. Five were nonreversible, despite changing antiretroviral therapy, and required breast reduction surgery.

Outcomes after viral load rebound on first-line antiretroviraltreatment in children with HIV in the UK and Ireland: an observational cohort study.

BACKGROUND: About a third of children with HIV have virological failure within 2 years of beginning antiretroviral treatment (ART). We assessed the probability of switch to second-line ART or virological re-suppression without switch in children who had virological rebound on first-line ART in the UK and Ireland. METHODS: In this study, we used data reported to the Collaborative HIV Paediatric Study (CHIPS), a national multicentre observational cohort. We included children with virological rebound (confirmed viral load>400 copies per mL after suppression<400 copies per mL) on first-line ART. We did a competing-risk analysis to estimate the probability of switch to second-line treatment, confirmed resuppression (two consecutive viral load measurments<400 copies per mL) without switch, and continued viral load above 400 copies per mL without switch. We also assessed factors that predicted a faster time to switch. FINDINGS: Of the 900 children starting first-line ART who had a viral load below 400 copies per mL within a year of starting treatment, 170 (19%) had virological rebound by a median of 20·6 months (IQR 9·7­40·5). At rebound, median age was 10·6 years (5·6­13·4), median viral load was 3·6 log10 copies per mL (3·1­4·2), and median CD4% was 24% (17­32). 89 patients (52%) switched to second-line ART at a median of 4·9 months (1·7­13·4) after virological rebound, 53 (31%) resuppressed without switch (19 [61%] of 31 patients on a first-line regimen that included a protease inhibitor and 31 [24%] of 127 patients on a first-line regimen that included a non-nucleoside reverse transcriptase inhibitor; NNRTI), and 28 (16%) neither resuppressed nor switched. At 12 months after rebound, the estimated probability of switch was 38% (95% CI 30­45) and of resuppression was 27% (21­34). Faster time to switch was associated with a higher viral load (p<0·0001), later calendar year at virological rebound (p=0·02), and being on an NNRTI-based or triple nucleoside reverse transcriptase inhibitor-based versus protease-inhibitor-based first-line regimen (p=0·001). INTERPRETATION: A third of children with virological rebound resuppressed without switch. Clinicians should consider the possibility of resuppression with adherence support before switching treatment in children with HIV. FUNDING: NHS England (London Specialised Commissioning Group).

Long-term virological outcome in children on antiretroviral therapy in the UK and Ireland.

OBJECTIVE: To assess factors at the start of antiretroviral therapy (ART) associated with long-term virological response in children. DESIGN: Multicentre national cohort. METHODS: Factors associated with viral load below 400 copies/ml by 12 months and virologic failure among children starting 3/4-drug ART in the UK/Irish Collaborative HIV Paediatric Study were assessed using Poisson models. RESULTS: Nine hundred and ninety-seven children started ART at a median age of 7.7 years (inter-quartile range 2.9­11.7), 251 (25%) below 3 years: 411 (41%) with efavirenz and two nucleoside reverse transcriptase inhibitors (EFVþ2NRTIs), 264 (26%) with nevirapine and two NRTIs (NVPþ2NRTIs), 119 (12%; 106 NVP, 13 EFV) with non-nucleoside reverse transcriptase inhibitor and three NRTIs (NNRTIþ3NRTIs), and 203 (20%) with boosted protease inhibitor-based regimens. Median follow-up after ART initiation was 5.7 (3.0­8.8) years. Viral load was less than 400 copies/ml by 12 months in 92% [95% confidence interval (CI) 91­94%] of the children. Time to suppression was similar across regimens (P»0.10), but faster over calendar time, with older age and lower baseline viral load. Three hundred and thirtynine (34%) children experienced virological failure. Although progression to failure varied by regimen (P<0.001) and was fastest for NVPþ2NRTIs regimens, risk after 2 years on therapy was similar for EFVþ2NRTIs and NVPþ2NRTIs, and lowest for NNRTIþ3NRTIs regimens (P-interaction»0.03). Older age, earlier calendar periods and maternal ART exposure were associated with increased failure risk. Early treatment discontinuation for toxicity occurred more frequently for NVP-based regimens, but 5-year cumulative incidence was similar: 6.1% (95% CI 3.9­8.9%) NVP, 8.3% (95% CI 5.6­11.6) EFV, and 9.8% (95% CI 5.7­15.3%) protease inhibitor-based regimens (P»0.48). CONCLUSION: Viral load suppression by 12 months was high with all regimens. NVPþ3NRTIs regimens were particularly efficacious in the longer term and may be a good alternative to protease inhibitor-based ART in young children.

Lopinavir dosing in HIV-infected children in the United Kingdom and Ireland.

BACKGROUND: Uncertainty surrounds the correct dosing of lopinavir/r (LPV/r) in HIV-infected children not receiving non-nucleoside reverse transcriptase inhibitors. The licensed total daily dose is 460 mg/m², whereas the original study, reporting excellent viral load (VL) suppression, used a higher 600 mg/m² dose. METHODS: We calculated LPV/r daily doses prescribed from 2000 to 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: Four hundred forty-four of 1201 (37%) children on antiretroviral therapy in CHIPS had taken lopinavir/r without non-nucleoside reverse transcriptase inhibitors. Of 1065 recorded doses, 48% were syrup, 27% capsules and 25% tablets. Ten percent of doses were >10% below 460 mg/m² per day, and 12% were >10% above 600 mg/m². In multivariable models, predictors of lower doses were: once versus twice daily dosing (32 mg/m² lower); syrup versus tablets/capsules (33 mg/m² lower); higher weight-for-age and height-for-age (24 mg/m² and 13 mg/m² lower per unit higher, respectively); and older age (13 mg/m lower per year older for those aged >10 years, 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 (odds ratio = 1.15 [95% confidence interval: 1.06-1.25 per 50 mg/m² 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 United Kingdom/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.

Effect of tenofovir disoproxil fumarate on risk of renal abnormality in HIV-1-infected children on antiretroviral therapy: a nested case-control study.

OBJECTIVE: 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). DESIGN: Nested case-control study. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.