The optimal time to test for sero-reversion in HIV-exposed uninfected infants: the later the better?

OBJECTIVES: HIV-exposed uninfected (HEU) infants are tested for loss of maternal antibody (sero-reversion) at 18 months of age. Highly sensitive fourth-generation antigen/antibody assays can detect very low levels of antibody, leading to retesting. We audited serological screening outcomes in HEU infants at two National Health Service (NHS) Trusts. METHODS: HEU infants born between January 2013 and August 2016 were identified via case records. Data collected included gestation; age at testing; test results and assay type. RESULTS: One hundred and forty-two infants were identified, of whom 21 were excluded from analysis. One hundred and one (83%) were born at term and 20 (17%) preterm (< 37/40 weeks of gestation), and the median age at first serology was 19.1 [interquartile range (IQR) 18.1; 21.4] months. Initial serology was positive in 10 of 121 infants (8.3%), and the median age of these 10 infants was 18.3 (IQR 18.1; 18.8) months, whereas those with negative serology (n = 111) had a median age of 19.2 (IQR 18.1; 21.5) months (P = 0.12). All infants with positive HIV serology were born at term. Seven of 10 infants had reactive serology on two fourth-generation assays. Subsequent serology was available for eight of 10 infants, with a median age of 21.3 months. Five of the eight (63%) were negative. One was reactive but HIV RNA polymerase chain reaction (PCR) was negative, and one was reactive on screening but negative on confirmatory testing. The remaining child was still seropositive at 24.7 months but had a non-reactive result at 29.4 months. CONCLUSIONS: Overall, 8.3% of HEU infants required repeat testing to confirm loss of antibody. Delaying testing until 22 months of age reduces retesting to < 2%, with associated resource and emotional implications. Positive serology at 22 months should prompt an HIV RNA PCR to exclude infection.

Persistence of HIV reservoir following successful haematopoietic stem cell transplant for juvenile myelomonocytic leukaemia in a child with perinatally acquired HIV.

This report describes a case of juvenile myelomonocytic leukaemia (JMML) on a background of both perinatally acquired HIV infection and congenital cytomegalovirus, and management of antiretroviral therapy during haematopoietic stem cell transplant. Peripheral blood HIV viral load remained below the lower limit of detection throughout and following transplant and is currently <20 RNA copies/mL. The child is currently in remission from JMML, but HIV DNA remains detectable despite myeloablative conditioning and sustained plasma HIV viral suppression.

Paediatric European Network for Treatment of AIDS (PENTA) guidelines for treatment of paediatric HIV-1 infection 2015: optimizing health in preparation for adult life.

The 2015 Paediatric European Network for Treatment of AIDS (PENTA) guidelines provide practical recommendations on the management of HIV-1 infection in children in Europe and are an update to those published in 2009. Aims of treatment have progressed significantly over the last decade, moving far beyond limitation of short-term morbidity and mortality to optimizing health status for adult life and minimizing the impact of chronic HIV infection on immune system development and health in general. Additionally, there is a greater need for increased awareness and minimization of long-term drug toxicity. The main updates to the previous guidelines include: an increase in the number of indications for antiretroviral therapy (ART) at all ages (higher CD4 thresholds for consideration of ART initiation and additional clinical indications), revised guidance on first- and second-line ART recommendations, including more recently available drug classes, expanded guidance on management of coinfections (including tuberculosis, hepatitis B and hepatitis C) and additional emphasis on the needs of adolescents as they approach transition to adult services. There is a new section on the current ART 'pipeline' of drug development, a comprehensive summary table of currently recommended ART with dosing recommendations. Differences between PENTA and current US and World Health Organization guidelines are highlighted and explained.

Etravirine in treatment-experienced, HIV-1-infected children and adolescents: 48-week safety, efficacy and resistance analysis of the phase II PIANO study.

OBJECTIVES: PIANO (Paediatric study of Intelence As an NNRTI Option; TMC125-C213; NCT00665847) assessed the safety/tolerability, antiviral activity and pharmacokinetics of etravirine plus an optimized background regimen (OBR) in treatment-experienced, HIV-1-infected children (≥ 6 to < 12 years) and adolescents (≥ 12 to < 18 years) over 48 weeks. METHODS: In a phase II, open-label, single-arm study, 101 treatment-experienced patients (41 children; 60 adolescents) with screening viral load (VL) ≥ 500 HIV-1 RNA copies/mL received etravirine 5.2 mg/kg (maximum dose 200 mg) twice a day (bid) plus OBR. RESULTS: Sixty-seven per cent of patients had previously used efavirenz or nevirapine. At week 48, the most common treatment-related grade ≥ 2 adverse event (AE) was rash (13%); 12% experienced grade 3 AEs. Only two grade 4 AEs occurred (both thrombocytopaenia, not etravirine related). At week 48, 56% of patients (68% children; 48% adolescents) achieved a virological response (VL<50 copies/mL; intent-to-treat, noncompleter=failure). Factors predictive of response were adherence > 95%, male sex, low baseline etravirine weighted genotypic score and high etravirine trough concentration (C0h ). Seventy-six patients (75%) completed the trial; most discontinuations occurred because of protocol noncompliance or AEs (8% each). Sixty-five per cent of patients were > 95% adherent by questionnaire and 39% by pill count. Forty-one patients experienced virological failure (VF; time-to-loss-of-virological-response non-VF-censored algorithm) (29 nonresponders; 12 rebounders). Of 30 patients with VF with paired baseline/endpoint genotypes, 18 (60%) developed nonnucleoside reverse transcriptase inhibitor (NNRTI) mutations, most commonly Y181C. Mean etravirine area under the plasma concentration-time curve over 12 h (AUC0-12h ; 5216 ng h/mL) and C0h (346 ng/mL) were comparable to adult target values. CONCLUSIONS: Results with etravirine 5.2 mg/kg bid (with OBR) in this treatment-experienced paediatric population and etravirine 200 mg bid in treatment-experienced adults were comparable. Etravirine is an NNRTI option for treatment-experienced paediatric patients.

British HIV Association and Children's HIV Association position statement on infant feeding in the UK 2011.

To prevent the transmission of HIV infection during the postpartum period, the British HIV Association and Children's HIV Association (BHIVA/CHIVA) continue to recommend the complete avoidance of breast feeding for infants born to HIV-infected mothers, regardless of maternal disease status, viral load or treatment.

Presentation, diagnosis and management of tuberculosis in HIV-infected children in the UK.

OBJECTIVES: Management of HIV-infected children with tuberculosis (TB) is challenging. The objective of this study was to assess current treatment and outcomes in a resource-rich setting in the era of highly active antiretroviral therapy (HAART). METHODS: A retrospective case-note review of coinfected children was carried out in a large UK-based HIV family clinic. RESULTS: Of 328 HIV-infected children, 18 were diagnosed and treated for active TB. TB presentation led to HIV diagnosis in eight of these 18 children. TB was confirmed microbiologically in 33% of children. Fifteen of the 18 children presented with pulmonary TB, and three with extrapulmonary TB (EPTB). Immunological status at TB diagnosis did not predict EPTB. The mean CD4 T-cell count at TB presentation was 402 cells/microL (mean CD4 percentage 16%), with a range of 0-790 cells/microL (0-34%). In seven children concurrently treated with HAART and anti-tuberculous therapy (ATT), therapeutic drug monitoring (TDM) guided management. No immune reconstitution disease occurred. There was one death, unrelated to TB, 2 years after completion of ATT. CONCLUSIONS: An HIV test should be considered in all children diagnosed with TB, especially if there are epidemiological risk factors. Our experience shows that, even with deferral of HAART in concurrently infected children, good therapeutic responses to ATT can be achieved. Where necessary, TDM guiding concurrent HAART and ATT can facilitate good clinical and virological responses.

Infant HIV infection despite "universal" antenatal testing.

We reviewed the antenatal HIV testing history, clinical presentation and outcome of 25 infants diagnosed with HIV between 1 January 2001 and 31 December 2005 in a tertiary referral hospital in London. Of the 25 cases, 21 had received antenatal care in the UK. Twelve mothers had not had an antenatal HIV test, four had tested positive antenatally, while five had had a negative HIV test on antenatal booking, implying seroconversion in pregnancy. When mothers had not been diagnosed antenatally, infants presented with severe infections, which were fatal in six cases. The majority (65%) of the children have long-term neurological sequelae. HIV seroconversion is an important cause of infant HIV in the UK.

Panton-Valentine leukocidin-secreting Staphylococcus aureus causing severe musculoskeletal sepsis in children. A new threat.

Panton-Valentine leukocidin secreted by Staphylococcus aureus is known to cause severe skin, soft tissue and lung infections. However, until recently it has not been described as causing life-threatening musculoskeletal infection. We present four patients suffering from osteomyelitis, septic arthritis, widespread intravascular thrombosis and overwhelming sepsis from proven Panton-Valentine leukocidin-secreting Staphylococcus aureus. Aggressive, early and repeated surgical intervention is required in the treatment of these patients. The Panton-Valentine leukocidin toxin not only destroys host neutrophils, immunocompromising the patient, but also increases the risk of intravascular coagulopathy. This combination leads to widespread involvement of bone with glutinous pus which is difficult to drain, and makes the delivery of antibiotics and eradication of infection very difficult without surgical intervention.

Neurodevelopmental outcomes in children with HIV infection under 3 years of age.

Following the introduction of combination antiretroviral therapy, children vertically infected with the human immunodeficiency virus (HIV-1) living in the developed world are surviving into adult life. This paper reviews the neurodevelopmental outcomes of 62 consecutively-presenting children with HIV-1 infection diagnosed before 3 years of age (32 males, 30 females; median age at presentation 6 mo). Neurological and developmental data are presented with immunological and virological responses to antiretroviral therapy. Fourteen children (22%) had abnormal neurological signs and 25 (40%) demonstrated significant developmental delay on standardized developmental assessments. Children presenting with more severe HIV-1 disease and immune compromise had significantly more abnormal neurological signs and developmental delays than children presenting with milder HIV-1 symptomatology. Immune function, control of HIV-1 viral replication, and growth parameters improved with antiretroviral therapy (median age at last follow-up 7 y 3 mo); however, abnormal neurological signs and significant gross motor difficulties persisted.

Effects of highly active antiretroviral therapy on paediatric metabolite levels.

OBJECTIVES: Highly active antiretroviral therapy (HAART) has extended survival of HIV-infected children into adulthood, raising concerns about long-term metabolic changes in childhood. METHODS: A longitudinal study of metabolite levels in paediatric HIV-infected patients before and after starting HAART (January 2000 to June 2003). The effects of HAART on nonfasting blood levels of total (TC), high-density lipoprotein (HDL), and low-density lipoprotein (LDL) cholesterol, cholesterol ratio and lactate were analysed using mixed-effects regression. RESULTS: A total of 146 children attended 1208 appointments (median 6.7/child). Of these, 99 (68%) were African. At baseline, 75 (51%) were on HAART and had higher TC (4.19 vs 3.49 mmol/L, P<0.0001), HDL (1.03 vs 0.82 mmol/L, P<0.0001), and LDL (2.54 vs 2.11 mmol/L, P=0.0003) than those not on HAART. Metabolites increased with time on HAART exposure and then stabilized. At 2 years, TC had increased by 0.93 mmol/L (P<0.0001), with 29 children (20%) having repeated TC levels above the 95th centile. LDL and HDL had increased by 0.69 and 0.31 mmol/L at 2 years, respectively (both P<0.0001). Lactates declined with increasing age (-0.06 mmol/L/year, P=0.0001). CONCLUSIONS: This is the first cohort study to demonstrate significant elevations of HDL as well as LDL in children on HAART. This rise in cardio-protective HDL may represent a positive effect of treatment.

Cytomegalovirus Retinitis in infancy.

PURPOSE: To describe the presentation of cytomegalovirus retinitis (CMVR) in a series of infants. METHODS: Immunocompromised infants with either HIV or systemic cytomegalovirus (CMV) were examined for CMVR. Ocular involvement was recorded and monitored by digital imaging. RESULTS: Five infants were detected to have CMVR. All the infants demonstrated changes within the macula. One infant progressed from a fine granular pattern to fulminant CMVR. CONCLUSION: Infants under a year with CMVR have a predilection for the disease to present at the macula, in contrast to the presentation in adults, which tends to involve more peripheral parts of the retina.

HIV evolution: CTL escape mutation and reversion after transmission.

Within-patient HIV evolution reflects the strong selection pressure driving viral escape from cytotoxic T-lymphocyte (CTL) recognition. Whether this intrapatient accumulation of escape mutations translates into HIV evolution at the population level has not been evaluated. We studied over 300 patients drawn from the B- and C-clade epidemics, focusing on human leukocyte antigen (HLA) alleles HLA-B57 and HLA-B5801, which are associated with long-term HIV control and are therefore likely to exert strong selection pressure on the virus. The CTL response dominating acute infection in HLA-B57/5801-positive subjects drove positive selection of an escape mutation that reverted to wild-type after transmission to HLA-B57/5801-negative individuals. A second escape mutation within the epitope, by contrast, was maintained after transmission. These data show that the process of accumulation of escape mutations within HIV is not inevitable. Complex epitope- and residue-specific selection forces, including CTL-mediated positive selection pressure and virus-mediated purifying selection, operate in tandem to shape HIV evolution at the population level.

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

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 > or = 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.

Paediatric HIV infection: correlates of protective immunity and global perspectives in prevention and management.

The impact of the HIV epidemic on child health globally is beginning to be appreciated. With the burden of new infections falling on young women, there is a skyrocketing number of AIDS orphans, and a rapidly increasing number of children infected via mother-to-child-transmission (MTCT). An estimated 600,000 new paediatric infections occur each year, of which some 1500/day (> 90%) occur in sub-Saharan Africa. But whereas children account for only 4% of those currently living with HIV infection, 20% of AIDS deaths have been in children. This reflects the rapid progression to disease in paediatric HIV infection. Whereas a dramatic reduction in viraemia follows acute adult infection, corresponding to the appearance of a vigorous anti-HIV cytotoxic T lymphocyte response, virtually no impact of the immune response is observed in acute paediatric infection following MTCT. Two specific challenges for the paediatric immune response are: (i) infection occurs before the immune system itself is fully developed; and (ii) the viruses transmitted by MTCT have already evaded an immune system sharing close genetic relatedness to that of the child. Accumulating evidence indicates that the immune system is potentially capable of effective control of HIV infection, and that events occurring in acute infection critically determine the ultimate outcome. Technological advances that have transformed the study of T-cell immunity now enable the developing immune system in childhood to be better understood. Via novel immunotherapeutic approaches described, it may be possible to modulate the infant's immune response to reach effective and durable suppression of HIV, as can be achieved by the rare long-term non-progressors of HIV infection. The feasibility of adopting these approaches globally are as yet untested. Finally, the striking disparity between the burden of paediatric HIV infection and access to the necessary infrastructure and therapeutic options required for its optimal management is addressed in a comparison between three sites of paediatric HIV care: Durban, South Africa; London, UK; and Boston, USA.

MMR vaccine in HIV-infected children -- potential hazards?

Although given routinely as prophylaxis against wild-type measles to HIV-infected children, the live attenuated measles component of the MMR triple vaccine also possesses potential for disease. We document a case of measles proven to be caused by vaccine strain in a HIV-infected child here in the UK and discuss the clinical and immunological aspects. We also consider the new guidelines for MMR vaccination in HIV-infected children adopted last year in the USA.

Pharmacological implications of lengthened in-utero exposure to nevirapine.

Given as a single dose to the mother during labour, nevirapine can protect the neonate from HIV-1 infection for up to 7 days. However, after maternal nevirapine therapy during pregnancy, neonatal plasma concentrations of nevirapine decline more rapidly, suggesting in-utero liver enzyme induction.