Liver transient elastography values in healthy South African children.

BACKGROUND: Transient elastography (TE) is a rapid noninvasive ultrasound-based technology that measures liver stiffness as a surrogate for liver fibrosis and controlled attenuation parameter (CAP) as a measure of liver steatosis. However, normal ranges in children are not well defined in all populations. The aim of this study was to determine transient elastography values in healthy South African children. METHODS: From April 2019 to December 2021, children were recruited from the HIV negative control group of a cohort study. Only children neither overweight nor obese, without evidence of liver disease, no medical condition or medication associated with hepatic steatosis or fibrosis and normal metabolic profile were included in this cross-sectional analysis. Clinical data, anthropometry and blood samples were collected on the same day as transient elastography with controlled attenuation parameter was performed. RESULTS: 104 children (median age 12.8 years [IQR 11.4-14.8, range 7.9-17.7 years]; 59 [57%] boys) were included. Liver stiffness was positively correlated with age (Pearson's r = 0.39, p < 0.001). Median liver stiffness in boys (5.2 kPa [5th to 95th percentiles 3.6 to 6.8 kPa]) was greater than in girls (4.6 kPa [5th to 95th percentiles 3.6 to 6.1 kPa; p = 0.004]), but there was no difference by ethnicity. Median CAP was 179dB/m (5th to 95th percentiles 158 to 233dB/m). There was a positive correlation between CAP and body mass index (BMI) z-score, but no difference by age, sex, ethnicity or pubertal status. CONCLUSION: Liver stiffness values increase with age and are higher in healthy South African boys than girls, whereas CAP values vary with BMI, but not with age or sex.

Longitudinal controlled attenuation parameter and liver stiffness in children with and without perinatal HIV infection in South Africa.

OBJECTIVES: Metabolic dysfunction-associated steatotic liver disease (MASLD) is an emerging cause of liver disease in HIV. Transient elastography (TE) with controlled attenuation parameter (CAP) measures liver stiffness as a marker of liver fibrosis and CAP as a measure of hepatic steatosis. Our aim was to evaluate longitudinal CAP and liver stiffness in children with perinatally acquired HIV (PHIV) on antiretroviral therapy (ART) from early life compared to children without HIV (HU). DESIGN: Prospective cohort study. METHODS: PHIV and HU were followed annually for two years. During the study, 60% of PHIV switched from older ART regimens to tenofovir disoproxil, lamivudine and dolutegravir (TLD). Longitudinal evolution of CAP and liver stiffness were investigated in two PHIV groups - on older ART and on TLD - compared to HU children using linear mixed effects models. RESULTS: 263 children and adolescents (112 PHIV, 151 HU) aged 7-20 years were followed. PHIV on older ART had CAP 8.61% (95% CI 4.42-12.97, P  < 0.001) greater than HU and no significant difference in CAP between PHIV on TLD and HU. No significant difference in liver stiffness was found between PHIV on older ART regimens and PHIV on TLD compared to HU. CONCLUSION: PHIV on older ART had higher CAP than HU, whereas in PHIV switched to TLD there was no difference in CAP compared to HU. There was no difference in liver stiffness between either PHIV group and HU. This suggests starting ART early in life might protect PHIV from developing hepatic fibrosis.

Decreased Hepatic Steatosis in South African Adolescents With Perinatal HIV Switching to Dolutegravir-containing Regimens.

BACKGROUND: Although dolutegravir (DTG) has a favorable metabolic profile, it has been linked to excess weight gain. We evaluated changes in hepatic steatosis in adolescents with perinatally acquired HIV switching to DTG-containing antiretroviral therapy (ART). METHODS: Virologically suppressed adolescents switched to dolutegravir for a minimum of 4 months or on unchanged ART (84% protease inhibitor) were assessed prospectively with anthropometry, transient elastography with controlled attenuation parameter (CAP) and fasting metabolic profiles. ART regimens were determined independently of the study. RESULTS: In total 68 adolescents [baseline median age 13.5 years [interquartile range (IQR): 12.5-14.4 years]; 42 (62%) female] were recruited. However, 38 remained on the same regimen and were followed for a median of 98 weeks (IQR: 48-108 weeks), and 30 switched to DTG and were followed for a median of 52 weeks (IQR: 49-101). There was no baseline difference in CAP between groups. There was no significant change in body mass index z-score in either group, but the median CAP in the DTG group decreased by -40dB/m (IQR: -51 to -31 dB/m) after a median of 44 weeks (IQR: 28-50 weeks) on DTG, compared to +1dB/m (IQR: -29 to +14 dB/m) in adolescents not switched ( P < 0 .01). Cholesterol and triglycerides were lower in those switched. Whereas hepatic steatosis prevalence decreased from 17% to 3% in adolescents who switched to dolutegravir, its prevalence doubled from 8% to 16% in those not switched ( P = 0.1). CONCLUSIONS: In this exploratory study, adolescents switched to DTG-containing regimens had reduced hepatic steatosis, cholesterol and triglycerides with no excess weight gain compared to those on unchanged ART.

Prevalence and Risk Factors for Hepatic Steatosis in Children With Perinatal HIV on Early Antiretroviral Therapy Compared to HIV-Exposed Uninfected and HIV-Unexposed Children.

Objectives: We evaluated the prevalence and risk factors for hepatic steatosis in South African children with perinatally acquired HIV (PHIV) who started treatment early and remain on long-term antiretroviral therapy (ART) compared to HIV-uninfected children. Design: A cross-sectional study from April 2019 to October 2021. PHIV, HIV-exposed uninfected (HEU) and HIV-unexposed (HU) children were enrolled from an ongoing cohort study. Methods: All children had transient elastography (TE) with controlled attenuation parameter (CAP). Liver enzymes, lipogram, insulin and glucose were sent after an overnight fast. Multivariable linear regression analyses identified predictors of CAP. Hepatic steatosis was defined as CAP>248kPa. Results: 215 children (111 [52%] male; median age 14.1 years; IQR 12.7-14.9) participated in the study, 110 PHIV, 105 HIV-uninfected (36 HEU, 69 HU). PHIV initiated ART at a median age of 2.7 months (IQR 1.8-8.5). Hepatic steatosis prevalence was 9% in PHIV, 3% in HEU and 1% in HU children (p = 0.08). However, 8% of lean (body mass index z-score ≤ +1) PHIV had hepatic steatosis compared to zero lean HEU or HU children (p = 0.03). In multivariable linear regression analysis of all PHIV, body mass index (BMI) z-score was positively associated with CAP (p = 0.001) while CD4 count (p = 0.02) and duration of suppression of HIV viraemia (p = 0.009) were negatively associated with CAP, adjusting for age, sex and ethnicity. Conclusions: Hepatic steatosis prevalence was higher in lean PHIV than lean HIV-uninfected South African children. Longer suppression of HIV viraemia and higher CD4 count were associated with lower CAP and might be protective factors for hepatic steatosis in PHIV children.

Effect of Coadministration of Lidocaine on the Pain and Pharmacokinetics of Intramuscular Amikacin in Children With Multidrug-Resistant Tuberculosis: A Randomized Crossover Trial.

BACKGROUND: Currently recommended treatment for multidrug-resistant (MDR) tuberculosis (TB) includes 4-8 months of an injectable medication, which is poorly tolerated. We evaluated the impact of coadministering lidocaine on pain and pharmacokinetics of intramuscular injections of amikacin in children with MDR-TB. METHODS: Children 8-18 years of age, receiving amikacin for MDR-TB treatment in Cape Town, South Africa, were eligible for this randomized crossover trial. Participants received a 15 mg/kg dose of intramuscular amikacin with and without additional lidocaine (0.2-0.4 mg/kg) on different days and were randomized to the order of the treatments (the sequence). Participants and staff completing evaluations were blinded to sequence. Samples were drawn predose, and at 1, 2, 4, 6 and 8 hours postdose for measurement of plasma amikacin concentrations. Pain was assessed by participants using the Wong Baker FACES pain scale (0-5) predose, immediately after the injection and then at 30 and 60 minutes. Pharmacokinetic measures were calculated using noncompartmental analysis. RESULTS: Twelve children were included, median age 11.5 years (interquartile range [IQR], 9.9-13.4 years). Participant-reported pain scores immediately after the amikacin injection were lower when lidocaine was coadministered: 1.0 (IQR, 0.5-2.0) with lidocaine versus 2.5 (1.0-4.0) without lidocaine (P = 0.004). The median area under the concentration time curve0-8 and median maximum plasma concentration of amikacin were 109.0 µg × h/mL (IQR, 84.7-121.3) and 36.7 µg/mL (IQR, 34.1-40.5) with lidocaine compared with 103.3 µg × h/mL (IQR, 81.7-135.0; P = 0.814) and 34.1 µg/mL (IQR, 35.6-46.4; P = 0.638) without lidocaine, respectively. CONCLUSIONS: The coadministration of lidocaine resulted in reduced pain immediately after the injection and did not alter amikacin area under the concentration time curve or maximum plasma concentration.

Linezolid for the treatment of drug-resistant tuberculosis in children: a review and recommendations.

Options for the treatment of children with drug-resistant tuberculosis (DR-TB) are limited. Emerging evidence in adults from systematic reviews and a randomized trial has shown good efficacy of linezolid in difficult cases of DR-TB but with frequent serious adverse effects. Published data in children are limited and we are unaware of formal guidelines for linezolid in treatment of paediatric DR-TB, though it will likely be an important component of DR-TB treatment for a growing number of children. We performed a structured review of existing literature on the efficacy, adverse effects, pharmacokinetics and pharmacodynamics of linezolid in DR-TB, highlighting the key evidence from the adult literature and systematically evaluating published paediatric data. Our search identified 8 reports of 18 children receiving linezolid for difficult to treat DR-TB. All 18 had culture conversion and 15 of 18 had successful long-term treatment outcomes. Adverse events were reported in 9 of 18; a linezolid dose reduction was required in 5 of 18, and 2 of 18 permanently discontinued linezolid because of adverse events. We make specific recommendations for the use of linezolid in children with DR-TB, and identify priority questions for future research. For children with multidrug-resistant (MDR)-TB with additional resistance or with extensively drug-resistant (XDR)-TB, linezolid may make the difference between a successful or poor outcome, and until newer antituberculosis agents with better efficacy and safety become available in children, linezolid will be an important component of treatment for children with the worst forms of DR-TB.