Andrew Riordan

Decline in mortality, AIDS, and hospital admissions in perinatally HIV-1 infected children in the United Kingdom and Ireland

Abstract Objective To describe changes in demographic factors, disease progression, hospital admissions, and use of antiretroviral therapy in children with HIV. Design Active surveillance through the national study of HIV in pregnancy and childhood (NSHPC) and additional data from a subset of children in the collaborative HIV paediatric study (CHIPS). Setting United Kingdom and Ireland. Participants 944 children with perinatally acquired HIV-1 under clinical care. Main outcome measures Changes over time in progression to AIDS and death, hospital admission rates, and use of antiretroviral therapy. Results 944 children with perinatally acquired HIV were reported in the United Kingdom and Ireland by October 2002; 628 (67%) were black African, 205 (22%) were aged ≥ 10 years at last follow up, 193 (20%) are known to have died. The proportion of children presenting who were born abroad increased from 20% in 1994-5 to 60% during 2000-2. Mortality was stable before 1997 at 9.3 per 100 child years at risk but fell to 2.0 in 2001-2 (trend P < 0.001). Progression to AIDS also declined (P < 0.001). From 1997 onwards the proportion of children on three or four drug antiretroviral therapy increased. Hospital admission rates declined by 80%, but with more children in follow up the absolute number of admissions fell by only 26%. Conclusion In children with HIV infection, mortality, AIDS, and hospital admission rates have declined substantially since the introduction of three or four drug antiretroviral therapy in 1997. As infected children in the United Kingdom and Ireland are living longer, there is an increasing need to address their medical, social, and psychological needs as they enter adolescence and adult life.

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.

Comparison of interferon-{gamma} release assays and tuberculin skin test in predicting active tuberculosis (TB) in children in the UK: a paediatric TB network study

Background The value of interferon-γ release assays (IGRA) to diagnose active tuberculosis (TB) in children is not established, but these assays are being widely used for this purpose. The authors examined the sensitivity of commercially available IGRA to diagnose active TB in children in the UK compared with the tuberculin skin test (TST). Methods The authors established a paediatric tuberculosis network and conducted a retrospective analysis of data from children investigated for active TB at six large UK paediatric centres. All centres had used TST and at least one of the commercially available IGRA (T-Spot.TB or Quantiferon-Gold in Tube) in the diagnostic work-up for active TB. Data were available from 333 children aged 2 months to 16 years. The authors measured the sensitivity of TST and IGRA in definite (culture confirmed) and probable TB in children, agreement between TST and either IGRA, and their combined sensitivity. Results Of 333 children, 49 fulfilled the criteria of definite TB, and 146 had probable TB. Within the definite cohort, TST had a sensitivity of 82%, Quantiferon-Gold in tube (QFT-IT) had a sensitivity of 78% and T-Spot.TB of 66%. Neither IGRA performed significantly better than a TST with a cut-off of 15 mm. Combining the results of TST and IGRA increased the sensitivity to 96% for TST plus T-Spot.TB and 91% for TST plus QFG-IT in the definite TB cohort. Conclusions A negative IGRA does not exclude active TB disease, but a combination of TST and IGRA increases the sensitivity for identifying children with active TB.

Outcomes for human immunodeficiency virus-1-infected infants in the United kingdom and Republic of Ireland in the era of effective antiretroviral therapy.

Background: There are few data about disease progression and response to antiretroviral therapy (ART) in vertically HIV-infected infants in the era of effective therapy. Design: Cohort study. Methods: We examined progression to acquired immunodeficiency syndrome (AIDS) and death over calendar time for infants reported to the National Study of HIV in Pregnancy and Childhood in the United Kingdom/Ireland. The use of ART and CD4 and HIV-1 RNA responses were assessed in a subset in the Collaborative HIV Pediatric Study. Results: Among 481 infants, mortality was lower in those born after 1997 (HR 0.30; P < 0.001), with no significant change in progression to AIDS. Of 174 infants born since 1997 in the Collaborative HIV Pediatric Study, 41 (24%) were followed from birth, 77 (44%) presented pre-AIDS and 56 (32%) presented with AIDS. Of 125 (72%) children on 3- or 4-drug ART by the age of 2 years, 59% had HIV-1 RNA <400 at 12 months; median CD4 percentage increased from 24% to 35%. Among 41 infants followed from birth, 12 progressed to AIDS (5 while ART naive) and 3 died; 1 of 10 infants initiating ART before 3 months of age progressed clinically. Conclusion: Mortality in HIV-infected infants is significantly lower in the era of effective ART, but symptomatic disease rates remain high. Infrequent clinic attendance and poor compliance with cotrimoxazole prophylaxis and/or ART in infants born to diagnosed HIV-infected women and late presentation of infants identified after birth appear to be major contributors. Poor virologic response to ART during infancy is of concern because of increased likelihood of early development of resistance.

Long-term Mortality in HIV-Positive Individuals Virally Suppressed for >3 Years With Incomplete CD4 Recovery

BACKGROUND Some human immunodeficiency virus (HIV)-infected individuals initiating combination antiretroviral therapy (cART) with low CD4 counts achieve viral suppression but not CD4 cell recovery. We aimed to identify (1) risk factors for failure to achieve CD4 count >200 cells/µL after 3 years of sustained viral suppression and (2) the association of the achieved CD4 count with subsequent mortality. METHODS We included treated HIV-infected adults from 2 large international HIV cohorts, who had viral suppression (≤500 HIV type 1 RNA copies/mL) for >3 years with CD4 count ≤200 cells/µL at start of the suppressed period. Logistic regression was used to identify risk factors for incomplete CD4 recovery (≤200 cells/µL) and Cox regression to identify associations with mortality. RESULTS Of 5550 eligible individuals, 835 (15%) did not reach a CD4 count >200 cells/µL after 3 years of suppression. Increasing age, lower initial CD4 count, male heterosexual and injection drug use transmission, cART initiation after 1998, and longer time from initiation of cART to start of the virally suppressed period were risk factors for not achieving a CD4 count >200 cells/µL. Individuals with CD4 ≤200 cells/µL after 3 years of viral suppression had substantially increased mortality (adjusted hazard ratio, 2.60; 95% confidence interval, 1.86-3.61) compared with those who achieved CD4 count >200 cells/µL. The increased mortality was seen across different patient groups and for all causes of death. CONCLUSIONS Virally suppressed HIV-positive individuals on cART who do not achieve a CD4 count >200 cells/µL have substantially increased long-term mortality.

Encephalitis in children

Encephalitis is an uncommon but potentially devastating neurological syndrome with different aetiologies including direct central nervous system infection with different agents (most commonly viral) and those mediated by the immune system. Whilst there have been several recent publications and guidelines on the management of bacterial central nervous system infections in adults and children, viral infections have been relatively neglected. Guidelines have been published for adults with encephalitis (www.liv.ac.uk/braininfections) but none exist for children. For these reasons, we have reviewed the literature on encephalitis and have formulated a suggested management strategy for children with suspected, clinically diagnosed and proven encephalitis. We have excluded neonates, as encephalitis in this age group has different clinical features and is beyond the scope of this review.

Tenofovir use in human immunodeficiency virus-1-infected children in the United kingdom and Ireland.

Background: 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. Methods: 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. Results: 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 ≤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. Conclusions: 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.

Enter B and W: two new meningococcal vaccine programmes launched

In 2015, the UK became the first country in the world to have a comprehensive routine meningococcal vaccine programme targeting all of the main capsular groups of N. meningitidis. 1 An infant vaccine programme against meningococcal capsular group B Neisseria meningitidis (MenB) was launched from 1st September with an aim to reduce endemic MenB disease in early childhood. On 1st August 2015, an adolescent programme against groups A, C, W and Y meningococci (MenACWY) was rolled out to halt a growing outbreak of capsular group W disease (MenW) caused by a hypervirulent clone of N. meningitidis, in addition to maintaining control against MenC disease provided by the current adolescent programme. 2

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 m2; 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 m2. 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.

The management of infants and children treated with aciclovir for suspected viral encephalitis

Objective To investigate how infants and children with suspected viral encephalitis are currently managed in a UK tertiary children’s hospital. Methods Case notes of all infants and children who received intravenous aciclovir for suspected encephalitis over a 6-month period were reviewed. Suspected viral encephalitis was defined as a child with fever or history of febrile illness and a reduced level of consciousness, irritability or a change in personality or behaviour or focal neurological signs. Results Fifty one children were identified. Two had proven herpes simplex encephalitis (HSV) and two had clinically diagnosed viral encephalitis with no cause identified. Forty children had cerebrospinal fluid (CSF) analysis, but basic results were incomplete in 13 cases. CSF was sent for the detection of HSV DNA by PCR in 27 cases. The initial dose of aciclovir was incorrect in 38 cases. The median (range) length of intravenous aciclovir treatment was 4 (1–21) days. Six children were given a full course of aciclovir (10 or more days). For 14 children, there appeared to be no real indication for starting aciclovir. Case note documentation was generally inadequate. Conclusions The management of children with suspected viral encephalitis appears haphazard in many cases. Guidelines for the management of children with suspected viral encephalitis are needed.