Ute Dagmar Feucht

Early diagnosis is critical to ensure good outcomes in HIV-infected children: outlining barriers to care

HIV-infected children require early initiation of antiretroviral therapy (ART) to ensure good outcomes. The aim was to investigate missed opportunities in childhood HIV diagnosis leading to delayed ART initiation. Baseline data were reviewed of all children aged <15 years referred over a 1-year period for ART initiation to the Kalafong Hospital HIV services in Gauteng, South Africa. Of the 250 children, one-quarter (24.5%) was of school-going age, 34.5% in the preschool group, 18% between 6 and 12 months old and 23% below 6 months of age (median age = 1.5 years [interquartile range 0.5–4.8]). Most children (82%) presented with advanced/severe HIV disease, particularly those aged 6–12 months (95%). Malnutrition was prominent and referrals were mostly from hospital inpatient services (61%). A structured caregiver interview was conducted in a subgroup, with detailed review of medical records and HIV results. The majority (≥89%) of the 65 interviewed caregivers reported good access to routine healthcare, except for postnatal care (26%). Maternal HIV-testing was mostly done during the second and third pregnancy trimesters (69%). Maternal non-disclosure of HIV status was common (63%) and 83% of mothers reported a lack of psychosocial support. Routine infant HIV-testing was not done in 66%, and inadequate reporting on patient-held records (Road-to-Health Cards/Booklets) occurred frequently (74%). Children with symptomatic HIV disease were not investigated at primary healthcare in 53%, and in 68% of families the siblings were not tested. One-third of children (35%) had a previous HIV diagnosis, with 77% of caregivers aware of these prior results, while 50% acknowledged failing to attend ART services despite referral. In conclusion, a clear strategy on paediatric HIV case finding, especially at primary healthcare, is vital. Multiple barriers need to be overcome in the HIV care pathway to reach high uptake of services, of which especially maternal reasons for not attending paediatric ART services need further exploration.

Factors Associated with the Development of Drug Resistance Mutations in HIV-1 Infected Children Failing Protease Inhibitor-Based Antiretroviral Therapy in South Africa.

Objective Limited data are available from the developing world on antiretroviral drug resistance in HIV-1 infected children failing protease inhibitor-based antiretroviral therapy, especially in the context of a high tuberculosis burden. We describe the proportion of children with drug resistance mutations after failed protease inhibitor-based antiretroviral therapy as well as associated factors. Methods Data from children initiated on protease inhibitor-based antiretroviral therapy with subsequent virological failure referred for genotypic drug resistance testing between 2008 and 2012 were retrospectively analysed. Frequencies of drug resistance mutations were determined and associations with these mutations identified through logistic regression analysis. Results The study included 65 young children (median age 16.8 months [IQR 7.8; 23.3]) with mostly advanced clinical disease (88.5% WHO stage 3 or 4 disease), severe malnutrition (median weight-for-age Z-score -2.4 [IQR -3.7;-1.5]; median height-for-age Z-score -3.1 [IQR -4.3;-2.4]), high baseline HIV viral load (median 6.04 log10, IQR 5.34;6.47) and frequent tuberculosis co-infection (66%) at antiretroviral therapy initiation. Major protease inhibitor mutations were found in 49% of children and associated with low weight-for-age and height-for-age (p = 0.039; p = 0.05); longer duration of protease inhibitor regimens and virological failure (p = 0.001; p = 0.005); unsuppressed HIV viral load at 12 months of antiretroviral therapy (p = 0.001); tuberculosis treatment at antiretroviral therapy initiation (p = 0.048) and use of ritonavir as single protease inhibitor (p = 0.038). On multivariate analysis, cumulative months on protease inhibitor regimens and use of ritonavir as single protease inhibitor remained significant (p = 0.008; p = 0.033). Conclusion Major protease inhibitor resistance mutations were common in this study of HIV-1-infected children, with the timing of tuberculosis treatment and subsequent protease inhibitor dosing strategy proving to be important associated factors. There is an urgent need for safe, effective, and practicable HIV/tuberculosis co-treatment in young children and the optimal timing of treatment, optimal dosing of antiretroviral therapy, and alternative tuberculosis treatment strategies should be urgently addressed.

Persistence of HIV drug resistance among South African children given nevirapine to prevent mother-to-child-transmission

Objectives: We set out to examine the prevalence and persistence of mutations conferring high-level nonnucleoside reverse transcriptase (NNRTI)-resistance in a cohort of HIV-infected children who had failed prophylaxis to prevent mother-to-child-transmission (PMTCT). Design: A prospective observational cohort study at the Pediatric HIV Clinic at Kalafong Provincial Tertiary Hospital in Pretoria, South Africa. Methods: Children referred for initiation of antiretroviral therapy (ART) were enrolled from July 2010 through February 2013. HIV drug resistance testing was performed using the oligonucleotide ligation assay (OLA) on dried blood spots (DBS) collected at enrolment and monthly follow-up visits for 2 years. Results: South African children who failed HIV-prophylaxis had a high prevalence of NNRTI-resistant HIV (46/88; 52%). Among children with NNRTI-resistance, the frequency of the predominant resistant variant in each childs HIV-quasispecies was high (median 96%) at study entry (median age 7.5 months), and in 26 out of 27 followed a median of 13 months persisted at a high frequency (median 89%). Conclusion: Our finding that infants who fail HIV-prophylaxis frequently have long-lived NNRTI-resistant HIV suggests that resistance will likely persist through 36 months of age, when children qualify for NNRTI-based ART. These children may benefit from HIV drug resistance testing to guide selection of their treatment.

Consequences of prior use of full-dose ritonavir as single protease inhibitor as part of combination antiretroviral regimens on the future therapy choices in HIV-1-infected children

Background: South African HIV-infected infants below age 6 months and children younger than 3 years on concomitant antimycobacterial treatment received full-dose ritonavir single protease inhibitor (RTV-sPI), together with 2 nucleoside reverse transcriptase inhibitors, from 2004 until 2008. Use of RTV-sPI has been described as a risk factor for PI drug resistance, but the extent of this resistance is unknown. Aim: This research assesses clinical and virological outcome of a pediatric RTV-sPI cohort at a large South African antiretroviral therapy (ART) site in a high-burden tuberculosis setting, including resistance mutations in those failing ART. Methods: All children initiated at Kalafong hospital before December 2008, who ever received RTV-sPI–based regimens, were assessed for patient outcome, virological failure and drug resistance. HIV viral loads were done 6-monthly and HIV genotyping since 2009. Results: There were 178 children who ever received RTV-sPI, with a mean age at ART initiation of 1.4 years. Of the 135 children (76%) with >6 months follow-up, 17 children (13%) never had viral suppression, whereas another 25 (18%) developed virological failure later. Nineteen of 26 children (73%) with genotypic resistance results had major PI mutations. Conclusions: Treatment failure is not a universal feature in children with prior exposure to RTV-sPI regimens, but the significant proportion (31%) with virological failure is of concern due to high prevalence of major PI- and multiclass mutations. These children currently have no treatment options in the South African public sector, highlighting the urgent need for access to alternative ART regimens to ensure improved outcomes.

Keeping children alive and healthy in South Africa – how do we reach this goal? Perspectives from a paediatrician in a District Clinical Specialist Team

District Clinical Specialist Teams (DCSTs) are part of the primary healthcare re-engineering process in South Africa. These multidisciplinary clinical teams were established throughout the country in 2012, and their main role is reduction of maternal and childhood mortality and morbidity through improvement of service delivery at primary care level in their health districts. The Tshwane DCST is used as a case study to describe the challenges encountered in establishing the team within the complex district health system. On the other hand, the cross-disciplinary approach has proved itself a winning combination if the team shares a common vision and has a work plan to guide the priorities and facility support visits. Through their clinical expertise, and using extensive networking, DCSTs are well positioned in the health system to have a strong positive effect on child health.

Incorrectly diagnosing children as HIV-infected: Experiences from a large paediatric antiretroviral therapy site in South Africa

Objective. To assess the extent to which children may be falsely diagnosed as HIV-infected, using data from an antiretroviral therapy (ART) site in Pretoria, South Africa. Methods. This was a retrospective patient record review of all ART-naive children referred to Kalafong hospital’s paediatric HIV clinic between April 2004 and March 2010, with detailed review of those found to be HIV-uninfected. Results. There were 1 526 patient files analysed, with a male-to-female ratio of 1.01:1 and median age at first visit of 20 months (range 26 days - 17.5 years). Nearly half (n=715; 47%) of the children were aged <18 months. Fifty-one children were found to be HIV-uninfected after repeated diagnostic tests. Incorrect laboratory results for children aged <18 months included false-positive HIV DNA PCR tests (40), detectable HIV viral loads (4) and a false-positive HIV p24Ag test (1). One child above 18 months had false-positive HIV ELISA results. An additional 4 children were inappropriately referred after being incorrectly labelled as HIV-infected and 1 child aged <18 months was referred after an inappropriate diagnostic test for age was used. In summary, 1 in every 30 (3.3%) children was discharged HIV-uninfected, and below age 18 months, 1 in 16 children (6.3%) had false-positive HIV virological tests. Conclusions. Urgency in ART initiation in HIV-infected children is life-saving, especially in infants. However, HIV tests may produce false-positive results leading to misdiagnosis of children as HIV-infected, which has serious consequences. Meticulous checking of HIV-positive status is of utmost importance before committing any child to lifelong ART.

Taking kangaroo mother care forward in South Africa: The role of district clinical specialist teams.

The global agenda for improved neonatal care includes the scale-up of kangaroo mother care (KMC) services. The establishment of district clinical specialist teams (DCSTs) in South Africa (SA) provides an excellent opportunity to enhance neonatal care at district level and ensure translation of policies, including the requirement for KMC implementation, into everyday clinical practice. Tshwane District in Gauteng Province, SA, has been experiencing an increasing strain on obstetric and neonatal services at central, tertiary and regional hospitals in recent years as a result of growing population numbers and rapid up-referral of patients, with limited down-referral of low-risk patients to district-level services. We describe a successful multidisciplinary quality improvement initiative under the leadership of the Tshwane DCST, in conjunction with experienced local KMC implementers, aimed at expanding the districts KMC services. The project subsequently served as a platform for improvement of other areas of neonatal care by means of a systematic approach.

Community paediatrics and child health

In 2012, the Postgraduate Education Committee of the Health Professions Council of South Africa (HPCSA) supported the accreditation of Community Paediatrics and Child Health (CPCH) as a paediatric subspecialty; however, full HPCSA approval is outstanding. Consequently, by February 2015 there had been no visible progress towards implementation.