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Background The aim of this study was to compare quantitative ultrasound (QUS) and dual energy X-ray absorptiometry (DXA) for determining bone mineral density (BMD) among children living with HIV (CLWH) who were switching to second-line antiretroviral therapy (ART). Methods We conducted a cross-sectional study among CLWH as a sub-study of the CHAPAS-4 trial. Total body less head (TBLH) BMD and lumbar spine (LS) BMD were determined by DXA while the sound of speed (SOS), broad band ultrasound attenuation (BUA) and bone quality index (BQI) were determined by QUS. We evaluated the correlation between the DXA and QUS measurements using spearman correlation coefficient. Results A total of 167 children were enrolled; the median age was 9.4 (interquartile range = 6.0–12.0) years. Eighty-five (50.9%) were male. The median weight- for- age Z- score (IQR) was − 1.29(-2.16, -0.49) and height for age Z-score was − 1.03(-1.56, 0.01). SOS was weakly correlated with TBLH BMD R  = 0.35, P  < 0.001), lumbar spine bone apparent density (LSBMAD) ( R  = 0.19, P  = 0.01) and LS bone mineral content (BMC) ( R  = 0.31, P  < 0.001). BUA was moderately correlated with TBLH BMD ( R  = 0.50, P  < 0.001), BMC ( R  = 0.47, P  = 0.001), and LS BMC ( R  = 0.43, P  < 0.001) but weakly correlated with LSBMAD ( R  = 0.28, P  < 0.001). BQI was moderately correlated with TBLH BMC ( R  = 0.46, P  < 0.001), TBLH BMD ( R  = 0.46, P  < 0.001) and LSBMC ( R  = 0.41, P  < 0.001). There was weak correlation between LSBMAD and BUA ( R  = 0.28, P  < 0.001) BQI ( R  = 0.29, P  < 0.001). QUS Z-score was weakly correlated with TBLH BMD and ( R  = 0.30, P  < 0.01) and no correlation with LSBMAD ( R  = 0.07, P  = 0.35). Conclusion In CLWH, there was moderate correlation observed for TBLH measurements when comparing DXA to QUS, and weak correlation was found between LSBMAD and QUS measurements. There was a moderate correlation detected between the LSBMC and QUS.QUS may not be an appropriate substitute for DXA scan.

Although WHO recommends viral load (VL) monitoring for those on antiretroviral therapy (ART), availability in low-income countries remains limited. We investigated long-term VL and resistance in HIV-infected children managed without real-time VL monitoring. In the ARROW factorial trial, 1,206 children initiating ART in Uganda and Zimbabwe between 15 March 2007 and 18 November 2008, aged a median 6 years old, with median CD4% of 12%, were randomised to monitoring with or without 12-weekly CD4 counts and to receive 2 nucleoside reverse transcriptase inhibitors (2NRTI, mainly abacavir+lamivudine) with a non-nucleoside reverse transcriptase inhibitor (NNRTI) or 3 NRTIs as long-term ART. All children had VL assayed retrospectively after a median of 4 years on ART; those with >1,000 copies/ml were genotyped. Three hundred and sixteen children had VL and genotypes assayed longitudinally (at least every 24 weeks). Overall, 67 (6%) switched to second-line ART and 54 (4%) died. In children randomised to WHO-recommended 2NRTI+NNRTI long-term ART, 308/378 (81%) monitored with CD4 counts versus 297/375 (79%) without had VL <1,000 copies/ml at 4 years (difference = +2.3% [95% CI -3.4% to +8.0%]; P = 0.43), with no evidence of differences in intermediate/high-level resistance to 11 drugs. Among children with longitudinal VLs, only 5% of child-time post-week 24 was spent with persistent low-level viraemia (80-5,000 copies/ml) and 10% with VL rebound ≥5,000 copies/ml. No child resuppressed <80 copies/ml after confirmed VL rebound ≥5,000 copies/ml. A median of 1.0 (IQR 0.0,1.5) additional NRTI mutation accumulated over 2 years' rebound. Nineteen out of 48 (40%) VLs 1,000-5,000 copies/ml were immediately followed by resuppression <1,000 copies/ml, but only 17/155 (11%) VLs ≥5,000 copies/ml resuppressed (P < 0.0001). Main study limitations are that analyses were exploratory and treatment initiation used 2006 criteria, without pre-ART genotypes. In this study, children receiving first-line ART in sub-Saharan Africa without real-time VL monitoring had good virological and resistance outcomes over 4 years, regardless of CD4 monitoring strategy. Many children with detectable low-level viraemia spontaneously resuppressed, highlighting the importance of confirming virological failure before switching to second-line therapy. Children experiencing rebound ≥5,000 copies/ml were much less likely to resuppress, but NRTI resistance increased only slowly. These results are relevant to the increasing numbers of HIV-infected children receiving first-line ART in sub-Saharan Africa with limited access to virological monitoring. ISRCTN Registry, ISRCTN24791884.

In this clinical trial of second-line antiretroviral therapy in children with HIV in Africa, regimens including tenofovir alafenamide fumarate as the backbone and dolutegravir as the anchor drug were most effective.

In sub-Saharan Africa, individuals infected with HIV who are severely immunocompromised have high mortality (about 10%) shortly after starting antiretroviral therapy (ART). This group also has the greatest risk of morbidity and mortality associated with immune reconstitution inflammatory syndrome (IRIS), a paradoxical response to successful ART. Integrase inhibitors lead to significantly more rapid declines in HIV viral load (VL) than all other ART classes. We hypothesised that intensifying standard triple-drug ART with the integrase inhibitor, raltegravir, would reduce HIV VL faster and hence reduce early mortality, although this strategy could also risk more IRIS events. In a 2×2×2 factorial open-label parallel-group trial, treatment-naive adults, adolescents, and children >5 years old infected with HIV, with cluster of differentiation 4 (CD4) <100 cells/mm3, from eight urban/peri-urban HIV clinics at regional hospitals in Kenya, Malawi, Uganda, and Zimbabwe were randomised 1:1 to initiate standard triple-drug ART, with or without 12-week raltegravir intensification, and followed for 48 weeks. The primary outcome was 24-week mortality, analysed by intention to treat. Of 2,356 individuals screened for eligibility, 1,805 were randomised between 18 June 2013 and 10 April 2015. Of the 1,805 participants, 961 (53.2%) were male, 72 (4.0%) were children/adolescents, median age was 36 years, CD4 count was 37 cells/mm3, and plasma viraemia was 249,770 copies/mL. Fifty-six participants (3.1%) were lost to follow-up at 48 weeks. By 24 weeks, 97/902 (10.9%) raltegravir-intensified ART versus 91/903 (10.2%) standard ART participants had died (adjusted hazard ratio [aHR] = 1.10 [95% CI 0.82-1.46], p = 0.53), with no evidence of interaction with other randomisations (pheterogeneity > 0.7) and despite significantly greater VL suppression with raltegravir-intensified ART at 4 weeks (343/836 [41.0%] versus 113/841 [13.4%] with standard ART, p < 0.001) and 12 weeks (567/789 [71.9%] versus 415/803 [51.7%] with standard ART, p < 0.001). Through 48 weeks, there was no evidence of differences in mortality (aHR = 0.98 [95% CI 0.76-1.28], p = 0.91); in serious (aHR = 0.99 [0.81-1.21], p = 0.88), grade-4 (aHR = 0.88 [0.71-1.09], p = 0.29), or ART-modifying (aHR = 0.90 [0.63-1.27], p = 0.54) adverse events (the latter occurring in 59 [6.5%] participants with raltegravir-intensified ART versus 66 [7.3%] with standard ART); in events judged compatible with IRIS (occurring in 89 [9.9%] participants with raltegravir-intensified ART versus 86 [9.5%] with standard ART, p = 0.79) or in hospitalisations (aHR = 0.94 [95% CI 0.76-1.17], p = 0.59). At 12 weeks, one and two raltegravir-intensified participants had predicted intermediate-level and high-level raltegravir resistance, respectively. At 48 weeks, the nucleoside reverse transcriptase inhibitor (NRTI) mutation K219E/Q (p = 0.004) and the non-nucleoside reverse transcriptase inhibitor (NNRTI) mutations K101E/P (p = 0.03) and P225H (p = 0.007) were less common in virus from participants with raltegravir-intensified ART, with weak evidence of less intermediate- or high-level resistance to tenofovir (p = 0.06), abacavir (p = 0.08), and rilpivirine (p = 0.07). Limitations of the study include limited clinical, radiological, and/or microbiological information for some participants, reflecting available services at the centres, and lack of baseline genotypes. Although 12 weeks of raltegravir intensification was well tolerated and reduced HIV viraemia significantly faster than standard triple-drug ART during the time of greatest risk for early death, this strategy did not reduce mortality or clinical events in this group and is not warranted. There was no excess of IRIS-compatible events, suggesting that integrase inhibitors can be used safely as part of standard triple-drug first-line therapy in severely immunocompromised individuals. ClinicalTrials.gov NCT01825031. International Standard Randomised Controlled Trials Number ISRCTN 43622374.

Background. Identifying determinants of morbidity and mortality may help target future interventions for human immunodeficiency virus (HIV)-infected children. Methods. CD4⁺ T-cell count, HIV viral load, and levels of biomarkers (C-reactive protein, tumor necrosis factor 6 [TNF-6], interleukin 6 [IL-6], and soluble CD14) and interleukin 7 were measured at antiretroviral therapy (ART) initiation in the ARROW trial (case-cohort design). Cases were individuals who died, had new or recurrent World Health Organization clinical stage 4 events, or had poor immunological response to ART. Results. There were 115 cases (54 died, 45 had World Health Organization clinical stage 4 events, and 49 had poor immunological response) and 485 controls. Before ART initiation, the median ages of cases and controls were 8.2 years (interquartile range [IQR], 4.4-11.4 years) and 5.8 years (IQR, 2.3-9.3 years), respectively, and the median percentages of lymphocytes expressing CD4 were 4% (IQR, l%-9%) and 13% (IQR, 8%-18%), respectively. In multivariable logistic regression, cases had lower age-associated CD4⁺ T-cell count ratio (calculated as the ratio of the subject's CD4⁺ T-cell count to the count expected in healthy individuals of the same age; P < .0001) and higher IL-6 level (P = .002) than controls. Clustering biomarkers and age-associated CD4⁺ and CD8⁺ T-cell count ratios identified 4 groups of children. Group 1 had the highest frequency of cases (41% cases; 16% died) and profound immunosuppression; group 2 had similar mortality (23% cases; 15% died), but children were younger, with less profound immunosuppression and high levels of inflammatory biomarkers and malnutrition; group 3 comprised young children with moderate immunosuppression, high TNF-α levels, and high age-associated CD8⁺ T-cell count ratios but lower frequencies of events (12% cases; 7% died); and group 4 comprised older children with low inflammatory biomarker levels, lower HIV viral loads, and good clinical outcomes (11% cases; 5% died). Conclusions. While immunosuppression is the major determinant of poor outcomes during ART, baseline inflammation is an additional important factor, identifying a subgroup of young children with similar mortality. Antiinflammatory interventions may help improve outcomes.

In sub-Saharan Africa, 20%-25% of people starting antiretroviral therapy (ART) have severe immunosuppression; approximately 10% die within 3 months. In the Reduction of EArly mortaLITY (REALITY) randomized trial, a broad enhanced anti-infection prophylaxis bundle reduced mortality vs cotrimoxazole. We investigate the contribution and timing of different causes of mortality/morbidity. Participants started ART with a CD4 count <100 cells/µL; enhanced prophylaxis comprised cotrimoxazole plus 12 weeks of isoniazid + fluconazole, single-dose albendazole, and 5 days of azithromycin. A blinded committee adjudicated events and causes of death as (non-mutually exclusively) tuberculosis, cryptococcosis, severe bacterial infection (SBI), other potentially azithromycin-responsive infections, other events, and unknown. Median pre-ART CD4 count was 37 cells/µL. Among 1805 participants, 225 (12.7%) died by week 48. Fatal/nonfatal events occurred early (median 4 weeks); rates then declined exponentially. One hundred fifty-four deaths had single and 71 had multiple causes, including tuberculosis in 4.5% participants, cryptococcosis in 1.1%, SBI in 1.9%, other potentially azithromycin-responsive infections in 1.3%, other events in 3.6%, and unknown in 5.0%. Enhanced prophylaxis reduced deaths from cryptococcosis and unknown causes (P < .05) but not tuberculosis, SBI, potentially azithromycin-responsive infections, or other causes (P > .3); and reduced nonfatal/fatal tuberculosis and cryptococcosis (P < .05), but not SBI, other potentially azithromycin-responsive infections, or other events (P > .2). Enhanced prophylaxis reduced mortality from cryptococcosis and unknown causes and nonfatal tuberculosis and cryptococcosis. High early incidence of fatal/nonfatal events highlights the need for starting enhanced-prophylaxis with ART in advanced disease. ISRCTN43622374.

BackgroundPaediatric second line antiretroviral therapy (ART) formulations are limited. CHAPAS-4 (ISRCTN22964075), a 2X4 factorial randomised trial investigated efficacy and safety of 4 anchor drugs. MethodsChildren from Uganda, Zambia and Zimbabwe on non-nucleoside reverse transcriptase inhibitor-based regimens, requiring second line ART, were randomised to dolutegravir (DTG) or ritonavir-boosted darunavir(DRV/r), atazanavir(ATV/r) or lopinavir(LPV/r) dosed according to WHO weight-bands. Primary endpoint was week-96 viral load(VL)<400copies/mL. We hypothesised ATV/r would be non-inferior to LPV/r(12% margin); both DRV/r and DTG superior to LPV/r and ATV/r arms combined (superiority threshold p≤0.03; multiple comparisons). Analysis was intention-to-treat, based on logistic regression. Results of second randomisation (tenofovir alafenamide(TAF)-based vs. SOC backbone) will be reported separately. Results919 children aged 3–15years (54%male, median[IQR] viral load 17,573copies/mL[5549, 55,700]; CD4 count 669[413, 971]) were randomised and spent 98% of time on allocated regimen. At week-96 208/226(92.0%) on DTG, 203/230(88.3%) on DRV/r, 193/229(84.3%) on ATV/r, 180/223(80.7%) on LPV/r had VL<400c/ml. DTG was superior to LPV/r and ATV/r (adjusted difference 9.7%[4.8, 14.5],p<0.0001); DRV/r showed a trend to superiority to LPV/r and ATV/r (5.6%[0.3, 11.0],p=0.04); ATV/r was non-inferior to LPV/r (3.4%[-3.4, 10.2],p=0.33). Results were similar for VL<60copies/mL and <1000copies/mL and at weeks 48 and 144. CD4 count improved in all arms. More grade 3/4 adverse events(AE), predominantly hyperbilirubinemia, occurred for ATV/r vs LPV/r(p<0.0001); DTG had fewer AE vs. LPV/r(p=0.02). There was no evidence of excess weight-gain. Improvement in growth parameters were lowest with LPV/r. Renal and bone health was similar between arms. One child died (treatment-unrelated); 3% had serious adverse events.ConclusionThese results supports current WHO guidelines for preferred and alternative second line ART. In the future children will require second line ART after first line DTG. Ongoing development of child-friendly boosted DRV and ATV will be key to ensure robust treatment options are available for children in Africa.