mHealth app usage amongst paediatric department doctors in South Africa.

Background: Smartphone and mobile health (mHealth) applications (apps) have become an integral part of the day-to-day function of healthcare professionals, allowing quick, comprehensive, and up-to-date access to current clinical guidelines and other reference material. Objective: To evaluate the extent and nature of use of mHealth apps by paediatric department doctors in South Africa. Methods: E-mails requesting study participation were sent out to 285 paediatric department doctors employed at six hospitals affiliated to the University of the Witwatersrand. Willing participants were directed to complete the online study questionnaire. Results: A total of 150 respondents completed the questionnaire. All respondents owned a mobile device and already had one or more mHealth apps, 95.3% were unaware of any regulatory body responsible for regulating the use of mHealth apps, 86.0% did not have access to free Wi-Fi at work and 87.3% used an mHealth app at least once daily. Drug dosing (81.3%), diagnostic (59.3%) and clinical decision-making (44.7%) apps were the most common app categories with Medscape® (62.0%) and EMGuidance® (41.3%) being the most frequently used apps. Peer recommendation (76.0%), app credibility (74.0%) and app functionality (66.0%) were the most common factors that were considered by respondents prior to downloading or using an mHealth app. Conclusion: Medical apps are frequently used among paediatric medical doctors of all ranks. Drug dosing, diagnostic and clinical decision-making apps are the most common app categories in use. Improved awareness of the regulations pertaining to the use of mHealth apps amongst doctors is required.

Comparison of quantitative ultrasonography and dual X-ray absorptiometry for bone status assessment in South African children living with HIV.

Children living with HIV (CLHIV) have decreased bone mineral content (BMC) and density (BMD), increasing risk for fracture and future osteoporosis. While DXA is the gold-standard for bone assessments, it lacks availability in resource-constrained settings (RCS). Quantitative ultrasound (QUS) offers an alternative owing to its portability, low cost, ease of handling, and lack of ionizing radiation. While QUS has detected reduced bone quality in CLHIV, the relationship between QUS and DXA in this population remains unexplored. At baseline and 12 months, BMC and BMD of the whole body, lumbar spine, and radius were measured by DXA in a longitudinal cohort of CLHIV in Johannesburg, South Africa. Calcaneal speed of sound (SOS) and broadband ultrasound attenuation (BUA) and radius SOS were obtained by QUS, and calcaneal stiffness index (SI) was calculated. Spearman correlations, with and without HIV stratification, were performed between QUS and DXA measurements at each visit and for absolute difference in measurements between visits. At baseline and 12-months, calcaneal BUA and SI displayed strong positive correlations with DXA, with only modest correlations between radial QUS and DXA at baseline. Longitudinal measures of QUS did not correlate with DXA. At both baseline and 12-months, individuals with DXA whole-body BMD z-score < -1 displayed significantly lower calcaneal BUA and SI. Cross-sectionally, calcaneal QUS correlates strongly with whole body DXA and may represent a viable diagnostic alternative in RCS. Longitudinally, the two methods do not correlate well, possibly reflecting that each method assesses distinct aspects of bone architecture.

Addressing the migrant gap: maternal healthcare perspectives on utilising prevention of mother to child transmission (PMTCT) services during the COVID-19 pandemic, South Africa.

BACKGROUND: The COVID-19 pandemic has interrupted the prevention of mother-to-child transmission of HIV (PMTCT) programming in South Africa. In 2020, it was estimated that there were 4 million cross-border migrants in South Africa, some of whom are women living with HIV (WLWH), who are highly mobile and located within peripheral and urban areas of Johannesburg. Little is known about the mobility typologies of these women associated with different movement patterns, the impact of the COVID-19 pandemic on mobility typologies of women utilising PMTCT services and on how changes to services might have affected adherence. OBJECTIVE: To qualitatively explore experiences of different mobility typologies of migrant women utilising PMTCT services in a high mobility context of Johannesburg and how belonging to a specific typology might have affected the health care received and their overall experiences during the COVID-19 pandemic. METHODS: Qualitative semi-structured interviews with 40 pregnant migrant WLWH were conducted from June 2020-June 2021. Participants were recruited through purposive sampling at a public hospital in Johannesburg. A thematic approach was used to analyse interviews. RESULTS: Forty interviews were conducted with 22 cross-border and 18 internal migrants. Women in cross-border migration patterns compared to interprovincial and intraregional mobility experienced barriers of documentation, language availability, mistreatment, education and counselling. Due to border closures, they were unable to receive ART interrupting adherence and relied on SMS reminders to adhere to ART during the pandemic. All 40 women struggled to understand the importance of adherence because of the lack of infrastructure to support social distancing protocols and to provide PMTCT education. CONCLUSIONS: COVID-19 amplified existing challenges for cross-border migrant women to utilise PMTCT services. Future pandemic preparedness should be addressed with differentiated service delivery including multi-month dispensing of ARVs, virtual educational care, and language-sensitive information, responsive to the needs of mobile women to alleviate the burden on the healthcare system.

Providing HIV Prevention of Mother to Child Transmission (PMTCT) Services to Migrants During the COVID-19 Pandemic in South Africa: Insights of Healthcare Providers.

BACKGROUND: In March 2020, COVID-19 entered South Africa, resulting in 2.9 million cases, the country took preventative and precautionary measures to control the spread of COVID-19 infection. These measures limited population mobility especially for migrant women living with HIV (WLWH) and the provision of PMTCT services. The purpose of this research was to explore the challenges of the COVID-19 pandemic on PMTCT provision by healthcare providers and understand what strategies could be implemented with lifelong antiretroviral therapy (ART) for migrants to better manage the program. METHODS: Twelve in-depth interviews were conducted with healthcare providers across city and provincial levels on how the changes to the healthcare system with COVID-19 affected highly mobile patients' adherence and utilization of PMTCT services. A thematic content analysis was used for emerging themes and guided by The Utilization of PMTCT Services conceptual framework. RESULTS: Five main themes emerged: (1) Facilitators and barriers to adherence, which included the need for multi-month dispensing for the long term supply of antiretrovirals (ARVs) and the fear of contracting COVID-19 at the hospital that disrupted patients' continuum of care; (2) Healthcare providers work environment, where participants felt overwhelmed with the high patient demand and the lack of infrastructural resources to follow social distancing protocols; (3) Financial challenges and opportunity costs, PMTCT proved difficult for migrants due to border closures and documentation required to receive care, this resulted in treatment interruption and left many unable to receive support at the facility due to capacity restrictions; (4) Interpersonal interactions, mistreatment, and xenophobic attitudes existed toward the migrant HIV population; and (5) "Program sustainability" revealed three key areas for strengthening: longer duration of time allocated with counseling for same-day initiation, the increased use of technology, and translation services for migrants. CONCLUSIONS: It is important to take what was learned during the pandemic and integrate it into routine service delivery, which includes long-term medication supply to reduce risk with multiple visits to collect medication, and the use of technology to alleviate the high-burden of patient demand. Healthcare policies that work toward inclusion and sustainability for migrants are needed to improve the integration of safer and practical methods of PMTCT provision into health systems.

Persistently lower bone mass and bone turnover among South African children living with well controlled HIV.

OBJECTIVE: We evaluated longitudinal trends and associations between bone mass, bone turnover and inflammatory markers among South African children living with HIV (CLHIV) and controls. DESIGN: We previously reported decreased bone mass among CLHIV independent of marked inflammation and increased bone turnover. The goal of this study was to evaluate longitudinal changes in bone mass, bone turnover and inflammation over 2 years. METHODS: Longitudinal analyses were conducted among 220 CLHIV and 220 controls. Anthropometric measurements, physical activity, antiretroviral regimen, virologic and immunologic status, whole body (WB) and lumbar spine (LS) bone mineral content (BMC) and bone mineral density (BMD) were collected (enrollment, 12 and 24 months). Bone turnover markers including C-telopeptide of type I collagen (CTx) and procollagen type I N-terminal propeptide (P1NP) and inflammatory markers including interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), soluble CD14 and high-sensitivity C-reactive protein (hsCRP) were collected at enrollment and 24 months. RESULTS: Compared with controls, CLHIV had significantly lower mean WB-BMC, WB-BMD, WB-BMC z scores, LS-BMC and LS-BMD as well as lower bone formation (P1NP) and resorption (CTx), and higher hsCRP and soluble CD14 over 24 months. CLHIV on efavirenz (EFV) had consistently lower TNF-alpha and IL-6 compared with those on ritonavir-boosted lopinavir (LPV/r) at all time points. CONCLUSION: Over 2 years of follow-up, South African CLHIV had persistently lower bone mass, bone turnover, and macrophage activation. Lower bone mass and higher pro-inflammatory cytokine profiles were consistently observed among those on LPV/r-based compared with EFV-based regimens.

Low Pretreatment Viral Loads in Infants With HIV in an Era of High-maternal Antiretroviral Therapy Coverage.

BACKGROUND: With expansion of antiretroviral therapy (ART) programs, transmission rates are low but new infant infections still occur. We investigated predictors of pre-ART viral load (VL) and CD4+ T-cell counts and percentages in infants diagnosed with HIV at birth in a setting with high coverage of maternal ART and infant prophylaxis. METHODS: As part of an early treatment study, 97 infants with confirmed HIV-infection were identified at a hospital in Johannesburg, South Africa. Infant VL and CD4+ T-cell parameters were measured before ART initiation. Data were collected on maternal characteristics, including VL, CD4+ T-cell counts and ART, and infant characteristics, including sex, birth weight, and mode of delivery. RESULTS: Pre-ART, median infant VL was 28,405 copies/mL [interquartile range (IQR): 2515-218,150], CD4+ T-cell count 1914 cells/mm (IQR: 1474-2639) and percentage 40.8% (IQR: 32.2-51.2). Most (80.4%) infants were born to mothers who received ART during pregnancy and 97.9% of infants received daily nevirapine prophylaxis until ART initiation at median of 2 days of age (IQR: 1-7). Infant pre-ART VL was more likely to be ≥1000 copies/mL when their mothers had VL ≥1000 copies/mL [Odds Ratio (OR): 6.88, 95% confidence interval (CI): 2.32-20.41] and was higher in boys than girls (OR: 3.29, 95% CI: 1.07-9.95). Lower maternal CD4+ T-cell count (<350 cells/mm) was associated with lower infant CD4+ T-cell count (<1500 cells/mm) (OR: 3.59, 95% CI: 1.24-10.43). CONCLUSIONS: Pre-ART VL and CD4+ T-cell parameters of intrauterine-infected infants were associated with VL and CD4+ T-cell counts of their mothers. Maternal ART during pregnancy may begin treatment of intrauterine infection and may mask the severity of disease in infected infants identified in the current era with high-maternal ART coverage.

Switch to Efavirenz Attenuates Lipoatrophy in Girls With Perinatal HIV.

OBJECTIVES: Children with HIV (CHIV) have lifetime exposure to antiretrovirals (ART); therefore, optimizing their regimens to have the least impact on fat redistribution is a priority. METHODS: This is a cross-sectional study of 219 perinatally infected CHIV and 219 HIV-uninfected controls from similar socioeconomic backgrounds in Johannesburg, South Africa. We compared total body and regional fat distribution in CHIV on suppressive ART regimens with controls and, among CHIV, between ritonavir-boosted lopinavir (LPV/r)-based and efavirenz (EFV)-based regimens. RESULTS: The mean age of the 219 uninfected children (45% girls) and the 219 CHIV (48% girls) was 7.0 and 6.4 years, respectively. CHIV had lower adjusted total body fat (P = 0.005) and lower percentage fat at the trunk (P = 0.020), arms (P = 0.001), and legs (P < 0.001) than uninfected children. CHIV on LPV/r had similar body composition as those on EFV, except for arm fat mass (P = 0.030). When stratified by sex, girls with HIV on LPV/r had lower adjusted total (P = 0.007), trunk (P = 0.002), arms (P = 0.008), legs (P = 0.048) fat mass; trunk-to-total body fat (P = 0.044); and higher legs-to-total body fat (P = 0.011) than those on EFV. CONCLUSIONS: South African CHIV receiving ART had lower global and partial fat mass and percentage fat than healthy controls. In girls with HIV with sustained virologic suppression on ART, switching from LPV/r to EFV could attenuate fat mass loss, indicating that EFV-based regimen may be a better option in this group of individuals.

Option B+ Program for the Prevention of Vertical Transmission of HIV: A Case Study in Johannesburg, South Africa.

Background: South Africa's National Department of Health adopted WHO's 2013 consolidated guidelines on ARVs for HIV treatment and prevention in 2015, including changes for Prevention from Mother-to-Child Transmission (PMTCT) through Option B+, aimed to reduce the HIV prevalence rate amongst women by placing them on lifelong treatment, irrespective of their CD4 count. As a result, these guidelines were implemented for the PMTCT program at Rahima Moosa Hospital. Little is known about the impact of these guidelines on the work of healthcare workers (HCWs) and no research had focused on how these changes have affected adherence for the patients. Objectives: The purpose of this research project was (1) to explore the impact of the Option B+ PMTCT program on the work of healthcare professionals, and (2) to understand pregnant HIV-positive women views and experiences with ART for life, as a way to better manage the Option B+ PMTCT program. Design: Qualitative semi-structured interviews with a phenomenological approach was used. Setting: Data collection at the antenatal/postnatal clinics/wards, OBGYN and Department of Pediatrics at RMMCH in Johannesburg. Method: A qualitative study design is used with a phenomenological approach. The methodology used semi-structured interviews with healthcare professionals and patients. The thematic analysis was used within an Accessibility Framework to guide the identification of domains that emerged from all transcribed data. A convenience sample in the antenatal clinic, postnatal clinic, antenatal ward, OBGYN, and Department of Pediatrics and Child Health at RMMCH. The study is situated in Johannesburg, South Africa. Results: The findings demonstrated that work has become difficult to manage for all healthcare professionals because of (1) the need for strengthening indicators for tracking to decrease loss to follow-up (LTFU); (2) inconsistency in delivery of counseling and support services and the need for communication across clinical departments; and (3) the lack of compassion and understanding by service providers. The difficult healthcare environment has affected overall views and experiences of pregnant HIV-positive women going on ART for life. All patient participants (n = 55) responded that they chose to take the fixed-dose combination (FDC) for life to protect the health of the baby and felt ART for life can be stopped after giving birth, unaware of the long-term benefits to the mother. Conclusion: The Option B+ program emphasized a need for the provision of continuous counseling and support services for women with same day initiation of ART. There is a need for better internal communication and collaboration amongst HCWs across all units of RMMCH for attainment in treatment outcomes. HCWs communication to patients is essential in helping patients build trust in service delivery, decreasing the LTFU and promoting adherence. The ability to understand functions of the work environment in which a PMTCT program operates in is essential in addressing policy implementation and program issues for ease of adaptability of Option B+ programming on a larger scale across all units of RMMCH. Implications for future research include the need to address changes within the healthcare system at both clinical and management levels. It is crucial to incorporate the perspective of patients in policy implementation; uptake and adherence are key indicators in informing whether the Option B+ PMTCT program is being adapted into state hospitals effectively. There needs to be extensive research on how to strengthen indicators for long term scalability and sustainability of the program. Future evaluations need to address how interdisciplinary collaboration within healthcare facilities improves the management and understanding of Option B+ program.

Behavioral Functioning and Quality of Life in South African Children Living with HIV on Antiretroviral Therapy.

This study examined behavioral functioning and quality of life in South African children living with perinatally acquired HIV. Compared with controls, children living with perinatally acquired HIV had a higher mean total difficulties score assessed by the Strengths and Difficulties Questionnaire and lower mean quality of life scores assessed by the Pediatric Quality of Life Inventory.

Bone turnover markers in children living with HIV remaining on ritonavir-boosted lopinavir or switching to efavirenz.

INTRODUCTION: We previously found lower bone mass but similar bone turnover in pre-pubertal children living with HIV (CLWH) on a ritonavir-boosted lopinavir (LPV/r)-based vs. efavirenz-based antiretroviral therapy regimen 2 years after switch. Here, we evaluate if bone turnover differed between the groups close to the time of switch. METHODS: Samples from 108 children remaining on LPV/r and 104 children switched to efavirenz were available for analysis 8 weeks post-randomization. Bone turnover markers, including C-telopeptide of type 1 collagen (CTx), procollagen type-I N-terminal propeptide (P1NP), and osteocalcin were measured. Markers of immune activation were also measured, including IL-6, TNF-alpha, soluble CD14 and high-sensitivity C-reactive protein (CRP). RESULTS: Eight weeks post-randomization, we did not detect differences in CTx (1.42 vs. 1.44 ng/mL, p = 0.85) or P1NP concentrations (622 vs. 513 ng/mL, p = 0.68) between treatment groups. At 8 weeks, the treatment groups also had similar levels of IL-6, TNF-alpha, soluble CD14 and high-sensitivity CRP. Osteocalcin (ng/mL) was higher in the LPV/r than efavirenz group both at 8 weeks (88.6 vs. 67.3, p = 0.001) and 2 years (67.6 vs. 49.8, p = 0.001). CONCLUSIONS: Overall, we failed to detect difference in bone turnover by P1NP and CTx in virologically-suppressed CLWH on different regimens at a time point close to the switch. We did observe higher levels of total osteocalcin in children remaining on LPV/r compared to children switched to efavirenz. Future studies should focus on uncovering the mechanism and determining whether perturbation in undercarboxylated osteocalcin could explain some of the bone side effects noted with protease inhibitors.

Deficits in Bone Architecture and Strength in Children Living With HIV on Antiretroviral Therapy.

BACKGROUND: Reduced bone mineral mass by dual x-ray absorptiometry is reported in children living with HIV (CLWH), but few studies of bone microarchitecture, particularly in sub-Saharan Africa, have been conducted. Here, we compare bone architecture and strength in black South African CLWH and uninfected control children by peripheral quantitative computed tomography (pQCT). SETTING AND METHODS: One hundred seventy-two CLWH on antiretroviral therapy (ART) and 98 controls in the CHANGES Bone Study in Johannesburg, South Africa received pQCT scans of the radius and tibia. Measurements included trabecular and cortical volumetric bone mineral density (vBMD) and bone strength, estimated by the polar strength strain index (SSI), a validated measure of fracture risk. RESULTS: CLWH (51% boys) and controls (63% boys) were an average of age 10.4 years. Mean ART duration for CLWH was 9.5 years, with 70.9% on an efavirenz-based, 28.5% on a lopinavir/ritonavir-based, and 1 child on an atazanavir/ritonavir-based regimen. Male CLWH had lower trabecular vBMD at the radius than controls after adjustment for age, radial length, and Tanner stage (ß = -17.3, standard error = 7.2, P = 0.018). Bone strength by polar SSI was lower in CLWH than controls (778 vs. 972 mm, P < 0.01). CLWH on an LPV/r-based regimen had lower trabecular vBMD (199 vs. 222 mg/cm, P < 0.001) and cortical vBMD (1074 vs. 1093 mg/cm, P = 0.004) than those on an efavirenz-based regimen. No difference in bone strength by polar SSI was observed between treatment groups. CONCLUSION: CLWH initiated on ART early in life with well-controlled HIV have deficits in bone architecture and reductions in bone strength as detected by pQCT.

Negative Diagnostic PCR Tests in School-Aged, HIV-Infected Children on Antiretroviral Therapy Since Early Life in Johannesburg, South Africa.

BACKGROUND: Younger age at antiretroviral therapy (ART) initiation has been associated with smaller HIV reservoirs. We investigated whether younger age of ART initiation is associated with testing negative and weaker signal on a standard HIV diagnostic test in treated children. METHODS: At exit from a longitudinal study at 2 sites in Johannesburg, South Africa, 316 school-aged, HIV-infected children on continuous ART started at a median age of 6.3 months, were tested with standard total nucleic acid PCR used for infant diagnosis. All negative results were repeated. Simultaneous viral load (VL) and CD4 T-cell counts/percentages, along with data collected over the prior 4 years, were used in multivariable regression to predict negative PCR results and higher cycle threshold (Ct) values (weaker signal). RESULTS: Seven children (2.2%, 95% confidence interval: 0.6 to 3.8) in the full cohort had negative PCR results; all 7 were in a subset of 102 (6.9%, 95% confidence interval: 2.0 to 11.8) who had initiated ART at age 0-4 months and had VL <50 copies/mL at the time of PCR testing. Only one repeat tested as negative. Younger age at ART initiation, VL <50 copies/mL at time of test, sustained VL <400 copies/mL, lower CD4 T-cell counts, and ever treated with efavirenz were significant predictors of weaker signal on the diagnostic test. CONCLUSIONS: In a small proportion of children who start ART in the first months of life and remain on continuous therapy, standard diagnostic HIV PCR tests may result as negative. Repeat testing may resolve uncertainty of diagnosis.

Early antiretroviral treatment of infants to attain HIV remission.

BACKGROUND: Studies in adults and children suggested that starting antiretroviral therapy (ART) soon after infection positively influences early events in HIV infection raising the possibility that remission may be achieved in some. METHODS: We designed an analytic treatment interruption (ATI) trial to test the hypothesis that a sizable minority of HIV-infected neonates who initiated ART <14 days of birth and maintained on ART would be able to maintain viral suppression when ART was withdrawn. To yield the target cohort for this trial, 73 HIV-infected neonates identified at one hospital in Johannesburg, South Africa, were initiated on ART <14 days of birth and maintained on ART tracking viral load (VL) decline and immune recovery (clinicaltrials.gov # NCT02431975). FINDINGS: Three HIV-infected infants (4.1%) died and nine (12.3%) were lost to follow-up before 48 weeks of age. Of those surviving on study, 52.5% attained and sustained VL <50 copies/ml and half of these sustained CD4+ T-cell percentage >30% which were the primary entry criteria for the ATI trial. Proportions achieving ATI eligibility criteria were similar in the 46 infants starting ART <48 h (19.6%) to 27 infants starting 2-14 days (25.9%) (p = 0.567). INTERPRETATION: Very early ART on its own, using regimens available when the trial was designed, is insufficient to attain minimum entry criteria needed to justify our trial of ART interruption. Decisions about how quickly to start ART should be based on optimizing standard clinical outcomes rather than with the expectation that remission can be attained. FUNDING: NICHD/NIAID (U01HD080441), South African Research Chairs Initiative of DST and NRF (South Africa).

Educational delays among children living with perinatally-acquired HIV in Johannesburg, South Africa.

Little is known about how growing up with HIV impacts educational outcomes in sub-Saharan African children. We evaluated if South African children living with HIV (CLWH) were in the appropriate school grade-for-age compared to uninfected control children. We observed higher rates of not being in the correct grade-for-age in CLWH compared with controls (OR 3.32, 95% CI: 2.07-5.34), adjusted for study site, sex, whether the child's biological father was alive, and caregiver education. Initiation of ART before 6 months of age reduced but did not eliminate this association. Whether these associations are due to biological factors or other social and environmental determinants, and how best to support CLWH to achieve educational goals, warrants further investigation.

Mitochondrial Impairment in Well-Suppressed Children with Perinatal HIV-Infection on Antiretroviral Therapy.

Mitochondrial impairment is reported in HIV-infected children receiving antiretroviral therapy (ART), as well as those naive to ART. Whether mitochondrial function recovers with early initiation of ART and sustained viral suppression on long-term ART is unclear. In this study, we evaluate mitochondrial markers in well-suppressed perinatally HIV-infected children initiated on ART early in life. We selected a cross-sectional sample of 120 HIV-infected children with viral load <400 copies/mL and 60 age-matched uninfected children (22 HIV-exposed uninfected) enrolled in a cohort study in Johannesburg, South Africa. Complex IV (CIV) and citrate synthase (CS) activity were measured by spectrophotometry. Mitochondrial DNA (mtDNA) content relative to nuclear DNA (nDNA) was measured by quantitative real-time polymerase chain reaction and expressed as copies/nDNA. Mitochondrial markers were impaired in HIV-infected children, including lower mean CIV activities [1.76 vs. 1.40 optical densities (OD)/min], higher risk of a CIV/CS ratio ≤0.22 (third quartile; odds ratio = 3.03, 95% confidence interval: 1.38-6.66), and lower mtDNA content. Children with shorter versus longer ART duration (<6.3 vs. ≥6.3 years) had lower means of CIV activity (1.22-1.58 OD/min) and mtDNA content (386-907 copies/nDNA). There were no differences in mitochondrial markers between children who started ART earlier (<6 months) or later (6-24 months). CIV activity was impaired in children with lower height-for-age Z-scores (HAZs). Despite early treatment and prolonged viral suppression, HIV-infected children had detectable mitochondrial impairment, particularly among those with stunted growth. Further study is required to determine if continued treatment will lead to full recovery of mitochondrial function in HIV-infected children.

Bone Quality Measured Using Calcaneal Quantitative Ultrasonography Is Reduced Among Children with HIV in Johannesburg, South Africa.

We evaluated bone quality among South African children with HIV over a 2-year period by quantitative ultrasound (QUS). Children with HIV have persistently lower bone quality compared with controls reflecting increased porosity, reduced strength, and possibly an increased short- and long-term risk of fracture.

Distinct epigenetic profiles in children with perinatally-acquired HIV on antiretroviral therapy.

Perinatally-acquired HIV has persistent effects on long-term health outcomes, even after early treatment. We hypothesize that epigenetic indicators, such as DNA methylation, may elucidate cellular processes that explain these effects. Here, we compared DNA methylation profiles in whole blood from 120 HIV-infected children on antiretroviral therapy (ART) and 60 frequency age-matched HIV-uninfected children aged 4-9 years in Johannesburg, South Africa. Using an individual CpG site approach, we found 1,309 differentially-methylated (DM) CpG sites between groups, including 1,271 CpG sites that were hyper-methylated in the HIV-infected group and 38 CpG sites that were hypo-methylated in the HIV-infected group. Six hyper-methylated CpG sites were in EBF4, which codes for a transcription factor involved in B-cell maturation. The top hypomethylated site was in the promoter region of NLRC5, encoding a transcription factor that regulates major histocompatibility complex (MHC) class I molecule expression. Using a differentially-methylated region (DMR) approach, we found 315 DMRs between groups, including 28 regions encompassing 686 CpG sites on chromosome 6. A large number of the genes identified in both the CpG site and DMR approaches were located in the MHC region on chromosome 6, which plays an important role in the adaptive immune system. This study provides the first evidence that changes in the epigenome are detectable in children with perinatally-acquired HIV infection on suppressive ART started at an early age.

Cost-Effectiveness of Preemptive Switching to Efavirenz-Based Antiretroviral Therapy for Children With Human Immunodeficiency Virus.

BACKGROUND: The NEVEREST-3 (South Africa) and MONOD-ANRS-12206 (Côte d'Ivoire, Burkina Faso) randomized trials found that switching to efavirenz (EFV) in human immunodeficiency virus-infected children >3 years old who were virologically suppressed by ritonavir-boosted lopinavir (LPV/r) was noninferior to continuing o LPV/r. We evaluated the cost-effectiveness of this strategy using the Cost-Effectiveness of Preventing AIDS Complications-Pediatric model. METHODS: We examined 3 strategies in South African children aged ≥3 years who were virologically suppressed by LPV/r: (1) continued LPV/r, even in case of virologic failure, without second-line regimens; continued on LPV/r with second-line option after observed virologic failure; and preemptive switch to EFV-based antiretroviral therapy (ART), with return to LPV/r after observed virologic failure. We derived data on 24-week suppression (<1000 copies/mL) after a switch to EFV (98.4%) and the subsequent risk of virologic failure (LPV/r, 0.23%/mo; EFV, 0.15%/mo) from NEVEREST-3 data; we obtained ART costs (LPV/r, $6-$20/mo; EFV, $3-$6/mo) from published sources. We projected discounted life expectancy (LE) and lifetime costs per person. A secondary analysis used data from MONOD-ANRS-12206 in Côte d'Ivoire. RESULTS: Continued LPV/r led to the shortest LE (18.2 years) and the highest per-person lifetime cost ($19 470). LPV/r with second-line option increased LE (19.9 years) and decreased per-person lifetime costs($16 070). Switching led to the longest LE (20.4 years) and the lowest per-person lifetime cost ($15 240); this strategy was cost saving under plausible variations in key parameters. Using MONOD-ANRS-12206 data in Côte d'Ivoire, the Switch strategy remained cost saving only compared with continued LPV/r, but the LPV/r with second-line option strategy was cost-effective compared with switching. CONCLUSION: For children ≥3 years old and virologically suppressed by LPV/r-based ART, preemptive switching to EFV can improve long-term clinical outcomes and be cost saving. CLINICAL TRIALS REGISTRATION: NCT01127204.

Field Performance and Diagnostic Accuracy of a Low-Cost Instrument-Free Point-of-Care CD4 Test (Visitect CD4) Performed by Different Health Worker Cadres among Pregnant Women.

Measuring CD4 counts remains an important component of HIV care. The Visitect CD4 is the first instrument-free low-cost point-of-care CD4 test with results interpreted visually after 40 min, providing a result of ≥350 CD4 cells/mm3 The field performance and diagnostic accuracy of the test was assessed among HIV-infected pregnant women in South Africa. A nurse performed testing at the point-of-care using both venous and finger-prick blood, and a counselor and laboratory staff tested venous blood in the clinic laboratory (four Visitect CD4 tests/participant). Performance was compared to the mean CD4 count from duplicate flow cytometry tests on venous blood (FACSCalibur Trucount). In 2017, 156 patients were enrolled, providing a total of 624 Visitect CD4 tests (468 venous and 156 finger-prick samples). Of 624 tests, 28 (4.5%) were inconclusive. Generalized linear mixed modeling showed better performance of the test on venous blood (sensitivity = 81.7%; 95% confidence interval [CI] = 72.3 to 91.1]; specificity = 82.6%, 95% CI = 77.1 to 88.1) than on finger-prick specimens (sensitivity = 60.7%; 95% CI = 45.0 to 76.3; specificity = 89.5%, 95% CI = 83.2 to 95.8; P = 0.001). No difference in performance was detected by cadre of health worker (P = 0.113) or between point-of-care versus laboratory-based testing (P = 0.108). Adequate performance of Visitect CD4 with different operators and at the point of care, with no need of electricity or instrument, shows the potential utility of this device, especially for facilitating decentralization of CD4 testing services in rural areas.

Lopinavir-ritonavir super-boosting in young HIV-infected children on rifampicin-based tuberculosis therapy compared with lopinavir-ritonavir without rifampicin: a pharmacokinetic modelling and clinical study.

BACKGROUND: Rifampicin reduces lopinavir concentrations in HIV and tuberculosis co-treated patients. We hypothesised that adding ritonavir to co-formulated lopinavir-ritonavir (4:1) to achieve a one-to-one ratio would overcome this drug-drug interaction in young children. METHODS: We did a prospective, open-label, one-group, one-sequence study at five sites in three South African provinces. We included HIV-infected children with tuberculosis, a bodyweight of 3-15 kg, and a post-conceptional age of more than 42 weeks. Children received the standard four-to-one ratio of lopinavir-ritonavir in the absence of rifampicin-based anti-tuberculosis treatment, whereas super-boosting of lopinavir-ritonavir with additional ritonavir was given orally twice a day to achieve a one-to-one ratio during rifampicin treatment. The primary outcome was the comparison of the proportion of children with predicted lopinavir morning minimum concentrations (Cmin) of more than 1·0 mg/L during super-boosting with the proportion of more than 1·0 mg/L during standard lopinavir-ritonavir treatment without rifampicin. Lopinavir concentrations were determined before and at 1, 2, 4, 6, and 10 h after the morning dose during the second and the last month of tuberculosis co-treatment, and 4-6 weeks after stopping rifampicin. A non-linear mixed-effects model was implemented to interpret the data and Monte Carlo simulations were used to compare the percentage of lopinavir with morning Cmin values of less than 1·0 mg/L for the two dosing schemes. A non-inferiority margin of 10% was used. This study is registered with ClinicalTrials.gov, number NCT02348177. FINDINGS: Between Jan 30, 2013, and Nov 9, 2015, 96 children with a median age of 18·2 months (IQR 9·6-26·8) were enrolled. Of these 96 children, 80 (83%) completed the first three pharmacokinetic evaluations. Tuberculosis therapy was started before antiretrovirals in 70 (73%) children. The model-predicted percentage of morning Cmin of less than 1·0 mg/L after tuberculosis treatment without super-boosting was 8·8% (95% CI 0·6-19·8) versus 7·6% (0·4-16·2) during super-boosting and tuberculosis treatment. The difference of -1·1% (95% CI -6·9 to 3·2), at a non-inferiority margin of 10%, confirmed the non-inferiority of lopinavir trough concentrations during rifampicin co-treatment. 19 serious adverse events were reported in 12 participants. Three deaths and a temporary treatment interruption due to jaundice were unrelated to study treatment. INTERPRETATION: Lopinavir exposure with ritonavir super-boosting in a one-to-one ratio during rifampicin-based tuberculosis treatment was non-inferior to the exposure with lopinavir-ritonavir without rifampicin. Safe and effective, field application of super-boosting is limited by poor acceptability. Access to better adapted solid formulations will most likely facilitate public health implementation of this strategy. FUNDING: DNDi, French Development Agency, UBS Optimus Foundation, and Unitaid.