WHEN TO START ANTIRETROVIRAL THERAPY IN INFANTS AND CHILDREN CL IN ICAL

T H E S O U T H E R N A F R I C A N J O U R NA L O F H I V M E D I C I N E When to initiate antiretroviral therapy (ART) in children and adults has been determined by disease stage and CD4 count or percentage. The starting criteria were based on cohort data and clinical experience. The main groups determining paediatric guidelines are from the USA, Europe (PENTA Paediatric European Network for Treatment of AIDS) and the World Health Organization (WHO). With the advent of effective triple therapy from 1995, guidelines have adapted to new data. Initial staging clinical and immunological criteria were those of the Centers for Diseases Control and Prevention (CDC). The staging criteria were based on North American experience and were not always appropriate for Africa. For example, failure to thrive, bronchiectasis and pulmonary tuberculosis were not adequately addressed.

When to initiate antiretroviral therapy (ART) in children and adults has been determined by disease stage and CD4 count or percentage.The starting criteria were based on cohort data and clinical experience.2][3] With the advent of effective triple therapy from 1995, guidelines have adapted to new data.Initial staging clinical and immunological criteria were those of the Centers for Diseases Control and Prevention (CDC). 4The staging criteria were based on North American experience and were not always appropriate for Africa.For example, failure to thrive, bronchiectasis and pulmonary tuberculosis were not adequately addressed.
Although the CDC classification included CD4 depletion, it was only with the HIV Prognostic Markers Collaborative Study (HPMCS), representing the combined data of 3 941 HIV-infected infants and children from the USA and Europe in the pre-highly active antiretroviral therapy (HAART) era, that the relationship between age and CD4 percentage became clearer. 5The study showed that the younger the infant, the higher the CD4 percentage or absolute count at which there was a high risk of disease progression or death within the next 12 months.As the CD4 count normally declines with age until 5 years of age and the CD4 percentage remains stable, the CD4 percentage is used as a guideline until then (in the absence of lymphopenia).However, the CD4 count is an extremely accurate predictor of outcome. 6These findings were subsequently incorporated into all paediatric guidelines.
The establishment of a WHO classification system in 2006 helped to focus on conditions more frequently encountered in Africa. 7The system has 4 stages, with ART recommended for stages 3 and 4. The special vulnerability of young infants to rapid disease progression and death was not fully appreciated at this time, although allowance was made for initiating ART in HIV antibody-positive infants with severe disease before confirmation by HIV DNA polymerase chain reaction (PCR).
The decision on when to initiate ART in infants and children has always been influenced by fears of long-term toxicity or antiretroviral (ARV) resistance if therapy is started too soon.Also, ARV choices for children are far more limited than for adults.Second-line therapy is especially unsatisfactory.
However, there is increasing realisation, especially from adult data, that delaying ART until the CD4 cell count falls below 350 cells/µl is associated with increased morbidity and mortality. 8,9ART is therefore recommended at higher CD4 thresholds than previously.
Mortality in HIV-infected infants is exceedingly high.The first data came from a study of combined outcome in nine vertical transmission prevention (VTP) studies conducted in sub-Saharan Africa. 10Thirty-five per cent of HIV-infected infants had died by 1 year of age and 52.5% by 2 years of age.The ZVITAMBO study in Zimbabwe showed a similar but slightly higher mortality in the first 2 years of life. 11For both studies, co-tri- The Children with HIV Early Antiretroviral (CHER) trial is the first ARV trial to prospectively evaluate ART strategies to inform ARV guidelines. 12Before this, limited cohort studies favoured early ART.For example, Faye et al. reported an improved outcome in 40 infants commencing ART before 6 months of age compared with 43 starting later.In the early group there was no disease progression versus 7 events, including 3 cases of encephalopathy, in those treated later. 13ER commenced in July 2005 in two South African sites, the Perinatal HIV Research Unit (PHRU) in Soweto and the Children's Infectious Diseases Clinical Research Unit (KID-CRU) at Tygerberg in the Western Cape.The hypothesis of the study is that early ART will have long-term benefit by delaying the need for continuous therapy.At the time of planning and initiation, the standard practice in infants was to initiate ART for a low CD4 percentage (<20% until August 2006 and 25% thereafter, in the first year of life) or evidence of severe clinical disease. 3,14In the first part of the study, infants with baseline CD4 >25% were randomised to deferred ART (arm 1), where ART was initiated once treatment criteria were reached (CD4 <20% until August 2006 and <25% thereafter or severe HIV disease), or early ART commencing before 12 weeks of age until either the first (arm 2) or second (arm 3) birthdays, with interruption of ART until indicated through CD4 depletion (<20% after the first birthday) or clinical disease progression.For the first year of the study, deferred ART (arm 1) was compared with early ART (arms 2 and 3).

INFANTS BELOW 12 MONTHS OF AGE
On 20 June 2007, after the study had been open for 2 years, the Data Safety Monitoring Board for CHER, noting significantly improved survival in subjects in the early ART arms, recommended that no infants be randomised to deferred ART and that data until this time point be released. 12The difference in mortality and disease progression is shown in Fig. 1.
A key finding in CHER was high early mortality, mainly in the deferred arm, which diminished as the infants became older (Table I).Also of note, however, is that mortality was also higher early on in the early ART group, diminishing over time in the first year of the study.Subsequently, ARV guidelines for children throughout the world incorporated the findings of CHER and recommended that all HIV-infected children below 12 months of age start ART irrespective of CD4 status or disease progression. 1,2,15 e recently, a study by Bourne and colleagues, using birth and death data from Statistics South Africa between 1997 and 2002, showed a peak in post-neonatal mortality, rising each year directly proportional to the rising HIV antenatal seroprevalence. 16These data are shown in Fig. 2. Also of note is that neonatal deaths are not addressed.It is possible that HIV may contribute significantly to neonatal deaths as well.These data, together with CHER, illustrate the enormous dilemma and problems for child health programmes.In CHER the diagnostic HIV DNA PCR was done from 4 weeks of age with a 7-day turnaround time.In the public sector, the PCR is done at 6 weeks of age, to coincide with the 6-week immunisation visit.Turnaround time for the test results and then communication to the caregiver all take time during a period of great vulnerability.   ).
the importance of the caregiver in giving ARVs, previous guidelines emphasised adequate preparation and training over a number of weeks.Because of the new recognition of early infancy as a period of high mortality, there is a need to 'fast-track' preparation and also to continue training and support after having initiated ARVs.
Practical difficulties are illustrated by experience in the Tshwane district.In 2009, 82% of children newly referred to the Kalafong ART site had stage 3 or 4 disease, the majority being referred from the in-and outpatient service.Of the 14 000 -22 000 HIV-infected children thought to be in Tshwane, only between 3 000 and 4 000 are receiving ART or are in care.
In this group there is less certainty on when to initiate ART.Ideally, decisions must be based on randomised studies.The PREDICT is underway in Thailand and Cambodia and will assess the CD4 thresholds for therapy in children between 1 and 12 years of age.
All guidelines recommend using absolute CD4 counts from 5 years of age.For simplicity, the WHO regards 1 -5 years of age as a single group, while the PENTA guidelines have 1 -3 and 3 -5 years of age.This group of children also represents a wide age spectrum.Clinical disease stage is extremely important and the majority of children are symptomatic.The dissociation of CD4 from disease severity has been well documented in South African children. 17The HPMCS data, although showing a low risk of disease progression for higher CD4 percentages, still showed notable death and disease progression with CD4 >30% up to 6 years of age. 5,6itial data suggested that young children show excellent immune restoration once ART is initiated, but more recent studies suggest a poorer response if therapy is delayed to CD4 <15%.Initial reports also suggested that viral suppression was difficult to achieve, especially in younger infants with extremely high viral loads.However, potent regimens and a better understanding of pharmacokinetics have improved outcomes.
Importantly, health care providers caring for children often do not fully appreciate the extent of end-organ damage.Mild cognitive and behavioural changes, milder forms of chronic lung disease, renal and hepatic disease and poor growth may easily be overlooked, leading to irreversible organ damage, growth failure and delayed puberty.
In the 3C4KIDS, 2 510 children over a year of age from Africa and Brazil contributed 357 deaths and 3 769 child-years at risk. 18None had access to ART, with 81% follow-up occurring on co-trimoxazole.The 12-month risk of death was higher than in the HPMCS for CD4 count and percentage.Most importantly, when anaemia and failure to thrive were included, the CD4 thresholds for predicting death or severe disease were much higher (Fig. 3).Both of these conditions are markers for advanced HIV disease.Most importantly, there was a real risk of death at high CD4 counts and percentages.For these reasons, our guidelines favour earlier ART between 1 and 5 years of age, in keeping with current US recommendations. 2 There has been much progress in refining and improving ARV guidelines for children.More changes can be expected as knowledge advances.Most important, however, is the realisation that each child is unique and his or her individual and family circumstances need to be considered for maximum benefit.

CHILDREN >12 MONTHS OF AGE CONCLUSION
d e c e m b e r 2 0 0 9 moxazole prophylaxis for prevention of Pneumocystis pneumonia (PCP) was not given.

Fig. 1 .
Fig. 1.Deferred ART is associated with a) a higher probability of death or b) first HIV event in the CHER trial.

Fig. 3 .
Fig. 3.Estimated risk of death within 12 months for a child on co-trimoxazole prophylaxis by age, weight-for-age zscore and haemoglobin and CD4 percentage or count.(a) CD4% at 2 years of age; (b) CD4% at 5 years of age; (c) CD4 count at 2 years of age; and (d) CD4 count at 5 years of age(reproduced with permission from AIDS18 ).

TABLE I . HIGH EARLY MORTALITY RATE IN THE CHER STUDY
Fig. 2. Early peak in infant mortality proportional to rising antenatal HIV seroprevalence, 1997 -2002 (reproduced with permission from AIDS