Janet Masters

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.

Vertical transmission rates for HIV in the British Isles: estimates based on surveillance data

Abstract Objective: To estimate and interpret time trends in vertical transmission rates for HIV using data from national obstetric and paediatric surveillance registers. Design: Prospective study of HIV infected women reported through obstetric surveillance. HIV infection status of the child and onset of AIDS were reported through paediatric surveillance. Rates of vertical transmission and progression to AIDS rate were estimated by methods that take account of incomplete follow up of children with indeterminate infection status and delay in AIDS reporting. Setting: British Isles. Subjects: Pregnant women infected with HIV whose infection was diagnosed before delivery, and their babies. Main outcome measures: Mother to child transmission of infection and progression to AIDS in children. Results: By January 1999, 800 children born to diagnosed HIV infected women who had not breast fed had been reported. Vertical transmission rates rose to 19.6% (95% confidence interval 8.0% to 32.5%) in 1993 before falling to 2.2% (0% to 7.8%) in 1998. Between 1995 and 1998 use of antiretroviral treatment increased significantly each year, reaching 97% of live births in 1998. The rate of elective caesarean section remained constant, at around 40%, up to 1997 but increased to 62% in 1998. Caesarean section and antiretroviral treatment together were estimated to reduce risk of transmission from 31.6% (13.6% to 52.2%) to 4.2% (0.8% to 8.5%). The proportion of infected children developing AIDS in the first 6 months fell from 17.7% (6.8% to 30.8%) before 1994 to 7.2% (0% to 15.7%) after, coinciding with increased use of prophylaxis against Pneumocystis carinii pneumonia. Conclusions: In the British Isles both HIV related morbidity and vertical transmission are being reduced through increased use of interventions Key messages Reliable estimates of HIV vertical transmission rates can be derived from surveillance data Infected pregnant women are increasingly taking up elective caesarean section and antiretroviral treatment to reduce the risk of transmitting HIV to their babies Vertical transmission rates have fallen greatly over the past four years and progression to AIDS among infected children may also have slowed These benefits can occur only if infected women are diagnosed before or during pregnancy

Pneumocystis carinii pneumonia and cytomegalovirus infection in children with vertically acquired HIV infection

ObjectivesThe outcome of Pneumocystis carinii pneumonia (PCP) in HIV-infected infants is poor, and the role of cytomegalovirus (CMV) co-infection in the course and outcome of PCP is unclear. This study describes the prevalence, clinical characteristics, management and changes in survival over time of vertically HIV-infected infants developing PCP and/or CMV infection. MethodsData on children with HIV, born in the UK and Ireland and reported to the National Study of HIV in Pregnancy and Childhood, with PCP and/or CMV were combined with clinical information collected from reporting paediatricians. ResultsBy April 1998, 340 vertically HIV-infected children had been reported, of whom 93 had PCP and/or CMV, as their first AIDS indicator disease; 85 (91%) were infants. Among infants with PCP, 79% were born to mothers not diagnosed as HIV infected, and there was an independent and statistically significant association with breast-feeding, being black African, and developing CMV disease. Median survival after PCP and/or CMV was significantly better in those born between 1993 and 1998 compared with those born before 1993 (P = 0.009), and worse than after other AIDS diagnoses (P = 0.01). Infants with dual infection were more likely to be ventilated (P = 0.003) and receive corticosteroids (P = 0.002) than those with PCP alone. ConclusionAlthough survival from PCP and CMV has improved over time, these remain serious and potentially fatal infections among infants in whom maternal HIV status is not recognized in pregnancy. Breast-feeding increases the risk of combined PCP and CMV infection, which is associated with severe disease.

Persistence of antibody responses to Haemophilus influenzae type b polysaccharide conjugate vaccine in children with vertically acquired human immunodeficiency virus infection

BACKGROUND Recurrent bacterial sepsis is common in pediatric HIV infection and immunization against Haemophilus influenzae type b (Hib) is recommended. Long term persistence of anti-Hib antibody and the need for, or timing of, a booster dose has not been adequately studied. METHODS Immunogenicity during a 12-month period following immunization with Hib-tetanus conjugate vaccine (ACT-HIB; Merieux) was evaluated in 48 vertically HIV-infected children and 36 uninfected children, born to HIV-positive mothers. A titer of anti-Hib polysaccharide antibody of > or = 0.15 microgram/ml was considered to indicate short term and > or = 1 microgram/ml long term protection. RESULTS At 1 month postvaccination 36 (100%) uninfected and 42 (88%) HIV-infected children achieved titers of > or = 1 microgram/ml. However, by 1 year titers had dropped below this value in 18 (43%) infected compared with only 4 (11%) uninfected children (chi square, 9.7; P = 0.002). Although the rate of fall of antibody titer was greater in uninfected than in infected children, this was no longer the case after adjustment for the 1-month postimmunization titer. The rate of antibody titer decline was not significantly related to HIV disease status or to either the age-related CD4 count at the time of immunization or the change in age-adjusted CD4 count during the 12 months after immunization. CONCLUSIONS Not only was the initial antibody response to Hib conjugate vaccine decreased in children with HIV infection and AIDS but also 1 year later only 57% of the initial responders had persisting titers above the level associated with long term protection. The need for reimmunization of children with HIV infection against Hib requires further evaluation.

Antibody responses to Haemophilus influenzae type b and Streptococcus pneumoniae vaccines in children with human immunodeficiency virus infection.

Antibody responses to Haemophilus influenzae type b (Hib) conjugate (ActHIB; Pasteur Merieux) and pneumococcal (Pneumovax II; Morson) vaccines were measured in 56 infected children (VI) and 44 uninfected children (U) older than 18 months of age, born to human immunodeficiency virus-positive mothers. Preimmunization, 21% U and 20% VI had protective concentrations of anti-Hib polysaccharide antibodies. Postimmunization, 100% U and 86% VI achieved protective titers (P = 0.008). The geometric mean increase in anti-Hib polysaccharide antibody was 7.6 (95% confidence interval, 3.5 to 16.3; P = 0.0001) times higher in U than in VI children after adjusting for age and ethnicity. Sixty-one percent U compared to 54% VI showed a 2-fold increase in antibody levels to at least one of the four pneumococcal vaccine serotypes (3, 6, 19, 23) measured (P = 0.4). For both vaccines there was a significant trend toward poorer responses in children with acquired immunodeficiency syndrome but no correlation with age adjusted CD4 counts. These data suggest that human immunodeficiency virus-infected children should be immunized with these polysaccharide vaccines early in the course of their disease.

A family clinic--optimising care for HIV infected children and their families.

A family clinic providing specialist paediatric and adult medical, testing, counselling, and terminal care services for families living with HIV was set up at a paediatric tertiary care hospital in London in 1991. During the first five years, until April 1996, 185 children from 149 families attended, including 119 infected children, of whom 32 have died. Only 5% of mothers were born in the UK; the rest were born in 24 different countries, the majority in sub-Saharan Africa. Less than a quarter of children were cared for by both parents, 61% by mothers alone, and 11% by guardians or foster parents. Of the adult attendees, 76% were women, and more than half were untested when they first attended the clinic. Provision of a family planning service within the family clinic was initiated as a result of women presenting with unplanned pregnancies. Shared care with local clinics is increasing, but with the complexity around the management of paediatric HIV infection, particularly with regard to antiretroviral treatments, there is need for continued specialist input. Coordination among specialist and locally based family services is required to provide flexible, accessible, and up to date care for families living with HIV infection in London.

In utero exposure to antiretroviral therapy: feasibility of long-term follow-up

Abstract Most uninfected children born to diagnosed HIV-infected women in the United Kingdom (UK) are exposed to antiretroviral therapy (ART) in utero and neonatally, and concerns exist about potential adverse effects of such exposure. We explored the feasibility of using national clinic-based follow-up to investigate the association between ART exposure and adverse health events occurring after the neonatal period. Active surveillance of obstetric and paediatric HIV infection is conducted through the National Study of HIV in Pregnancy and Childhood (NSHPC). Between 2002 and 2005, health professionals enrolled previously notified uninfected children in a consented follow-up study (the CHildren exposed to AntiRetroviral Therapy (CHART) study). Follow-up information was collected opportunistically using a standard questionnaire. Of 2104 eligible uninfected children born in the UK between 1996 and 2004, 704 (33.5%) were enrolled in CHART; parents of 4.8% (100/2104) declined, 2.8% (59/2104) had gone abroad, 21.6% (455/2104) were not contactable, and the remaining 37.3% (786/2104) were not enrolled mainly because of lack of clinic resources or unwillingness of health professionals to approach the families. Demographic characteristics and type of ART exposure for enrolled and non-enrolled children were similar. Latest information on enrolled children was available at a median age of 24 months. Minor childhood ailments were reported in the majority of children, febrile seizures in 1.6% (11/704), and major health problems in 3.8% (27/704). It was reassuring that prevalence of these outcomes was within UK norms, but numbers were small and duration of follow-up was limited. The difficulties encountered in enrolling and retaining children in this study indicate that comprehensive clinic-based follow-up of ART-exposed uninfected children is not practical. Alternative approaches are required; a robust, secure data linkage protocol would provide a more feasible and sustainable system for long-term monitoring of in utero ART exposure.