The South African early infant diagnosis of HIV (EID) programme
South Africa has one of the longest-standing, leading EID programmes globally, and has been providing EID to HIV exposed infants and children since 2000. The South African National Health Laboratory System (NHLS) established a network of molecular testing facilities supported by 10 accredited referral laboratories. These PCR laboratories are linked to a network of referral facilities, making EID accessible to 4000 health services nationally. The sampling method in the South Africa EID programme, dried blood spot (DBS) sampling, led to this method becoming the international EID standard. The centralised model of EID services through the NHLS has permitted data collation and analysis of EID service performance.51
HIV-PCR testing at 6 weeks postpartum coincides with the EPI visit to the clinic. This is, however, too late for rapid intervention and early treatment of HIV-infected infants (before the age of 7.4 weeks) as demonstrated in the CHER trial.50 Furthermore, treatment initiation is often further delayed or missed as a result of loss to follow-up, which is of particular concern in many PMTCT programs in developing countries.76
Modeling the ideal timing of PCR tests in early infant diagnosis for South Africa, by considering birth, 6-, 10- and 14- week EPI visits, demonstrated that when using one PCR test the same number of HIV-positive infants is identified at birth or at 6 weeks of age. When using two PCR tests, the greatest number of HIV-infected infants can be identified at birth and 10 weeks of age.58 The SAPMTCT programme adopted the birth- and 10-week testing strategy in 2015.
Although EID services were available in most (>95%) South African health care and EPI service centers, a review of these services in 2010 reported many missed opportunities. Poor documentation of maternal and infant HIV test results in the infant’s Road-to-Health Chart (RTHC), maternal non-reporting, poor adherence to cART, inadequate maternal knowledge about MTCT, fear of discrimination, and lack of provider-initiated HIV retesting were some of the factors that needed to be addressed.
INFANT-HIV TREATMENT CONSIDERATIONS AND CHALLENGES
A case report published in 2013 of an HIV-infected child in Mississippi who achieved viral control despite interruption of antiretroviral therapy, raised many challenging questions, and also afforded research opportunities.78 This case report started the concept of a ‘functional cure’ in infants if they started on cART “hours” after birth. Shiau and Kuhn reviewed important research questions that need to be addressed around the clinical management of HIV-infected infants and young children.79 These topics include timing of treatment initiation, indication and expected outcome of ARV therapy, type and combination ARV, and accurate and timely HIV diagnosis in infants. The traditional goal of early cART initiation for children was to reduce mortality and morbidity, as well as to achieve normal growth and development and improve quality of life. Birth PCR-testing in the window period from < 30 hours is an important new strategy, requiring further research to guide protocol change if a “functional cure” is to be considered.80
Managing HIV-infected neonates is complex. Circumstances that have led to poor maternal antenatal care and access to PMTCT strategies are likely to continue, and will complicate the infant’s management plan. Follow-up rates vary due to different service locations for maternal-infant postpartum care, and migratory patterns.81
The choice of newborn cART drugs is limited. There is a lack of formulations that can be used and given at small-weighted-dosages. Drugs that are currently used for 1st line cART in young children in South Africa are abacavir (ABC), lamivudine (3TC) and ritonavir-boosted lopinavir (LPV/r).82 Abacavir is only labelled for use after 3 months of age and LPV/r is not recommended for use before 42 weeks postmenstrual age, due to its high ethanol and propylene glycol content in the liquid formulation that can lead to propylene glycol-associated adverse events, especially in preterm infants.83 Current 1st line regimens are therefore appropriate for use in infants where the HIV diagnosis is confirmed after 6 weeks of age. Due to limited pharmacokinetic data for newborns, the optimal dosing to reach adequate therapeutic drug levels is also not well established for the first 4 weeks of life. Zidovudine (AZT) has dosing recommendations for both term and preterm infants. Lamivudine and AZT requires regular dose adjustments when prescribed during the first weeks of life. Although nevirapine is extensively used in PMTCT programmes and can be used in treatment regimens of newborns, the correct therapeutic dose and need for an induction dosage are less clear. Drug resistance is another factor that should be taken into account. Children exposed to non-nucleoside reverse transcriptase inhibitors (NNRTIs) for PMTCT have a risk of both viral resistance and virological failure on a nevirapine-containing regimen.84,85 Phylogenetic reconstruction and drug resistance profiles of mother-infant pairs at baseline can provide evidence of either transmitted or acquired drug resistance to the infant, and should be requested if available.86 In the 2014 South African guidelines, all positive HIV-PCR results require urgent action. Confirmation of the HIV status on a new blood sample and immediate initiation of cART should be carried out.39 This requires good communication between health care facilities and the laboratory to access positive results within 2-7 days. Patient follow-up is vital to ensure all HIV-PCR-positive patients are appropriately managed as soon as possible.56 It is further recommended in the guidelines that cART initiation and treatment regimens should be discussed with experts in the field of infant HIV.39 Treatment guidelines are being developed at leading tertiary centres in South Africa, and include the Neonatal ART Guidance Document of Rahima Moosa Mother and Child Hospital87 and, following a meeting by the South African HIV Society, Neonatal Diagnosis and Treatment Consultation Group, neonatal treatment guidelines were reviewed and published.
CHAPTER 1: INFANTS AFFECTED BY HIV: PROVIDING A FULL PACKAGE OF CARE
1.1 HIV ACQUISITION IN INFANTS
1.2 INFANT-HIV PREVENTION: MTCT STRATEGIES; EXAMINING THE EVIDENCE
1.3 GLOBAL AND LOCAL PMTCT POLICY FRAMEWORKS
1.4 INFANT-HIV DIAGNOSTIC TOOLS AND ALGORITHMS
1.5 INFANT-HIV TREATMENT CONSIDERATIONS AND CHALLENGES
1.6 SPECIAL CONSIDERATIONS IN HIV EXPOSED UNINFECTED INFANTS
1.7 SUMMARY AND KEY QUESTIONS RELATING TO INFANTS AFFECTED BY HIV
CHAPTER 2: AN EARLY-INFANT HIV-RISK SCORE FOR TARGETED HIV TESTING AT BIRTH: RESULTS FROM THE VERY EARLY INFANT DIAGNOSIS OF HIV (VEID) STUDY, SOUTH AFRICA.
2.8 ARTICLE ADDENDUM
CHAPTER 3: LATER OUTCOMES OF BIRTH PCR TESTED, HIV EXPOSED PCR NEGATIVE INFANTS WITH UNIVERSAL MATERNAL CART EXPOSURE.
CHAPTER 4: SEROREVERSION IN A BIRTH PCR TESTED, HIV EXPOSED PCR NEGATIVE PMTCT OPTION B/B+ COHORT UP TO 9 MONTHS OF AGE USING RAPID HIV TESTS KITS AND HIV ELISA: FOLLOW-UP COHORT FROM THE VERY EARLY INFANT DIAGNOSIS OF HIV (VEID) STUDY, GAUTENG, SOUTH AFRICA.
GENERAL DISCUSSION AND CONCLUSIONS