Chronic lung disease in HIV-infected children established on antiretroviral therapy.

Respiratory disease is a major cause of morbidity and mortality in HIV-infected children. Despite antiretroviral therapy (ART), children suffer chronic symptoms. We investigated symptom prevalence, lung function, and exercise capacity among older children established on ART, and an age-matched HIV-uninfected group. A cross-sectional study in Zimbabwe of: 1) HIV-infected children aged 6-16 years receiving ART for over six months; 2) HIV-uninfected children attending primary health clinics from the same area. Standardised questionnaire, spirometry, Incremental Shuttle Walk Testing (ISWT), CD4 count, HIV viral load, and sputum culture for tuberculosis were performed. 202 HIV-infected and 150 uninfected participants (median age 11.1 years in each group) were recruited. Median age at HIV diagnosis and ART initiation was 5.5 (IQR 2.8-7.5) and 6.1 years (IQR 3.6-8.4) respectively. Median CD4 count was 726 cells/μl, and 79% had HIV viral load<400copies/ml. Chronic respiratory symptoms were rare in HIV-uninfected children (n = 1 [0.7%]), but common in HIV-infected participants (51 [25%]), especially cough (30 [15%]) and dyspnoea (30 [15%]). HIV-infected participants were more commonly previously treated for tuberculosis (76 [38%] versus 1 [0.7%], p < 0.001), had lower exercise capacity (mean ISWT distance 771m versus 889m respectively, p < 0.001), and more frequently abnormal spirometry (43 [24.3%] versus 15 [11.5%], p = 0.003) compared to HIV-uninfected participants. HIV diagnosis at an older age was associated with lung function abnormality (p = 0.025). No participant tested positive for M. tuberculosis. In children, despite ART, HIV is associated with significant respiratory symptoms and functional impairment. Understanding pathogenesis is key, as new treatment strategies are urgently required

History of tuberculosis is associated with lower exhaled nitric oxide levels in HIV-infected children

Objective: HIV disrupts host defense mechanisms and maintains chronic inflammation in the lung. Nitric oxide is a marker of lung inflammation and can be measured in the exhaled air. We investigated the relationship between exhaled nitric oxide (eNO), HIV status and airway abnormalities in perinatally HIV-infected children aged 6–19 years. Design: A cross-sectional study. Methods: HIV-infected individuals on antiretroviral therapy and HIV-uninfected children with no active tuberculosis (TB) or acute respiratory tract infection were recruited from a public hospital in Harare, Zimbabwe. Clinical history was collected and eNO testing and spirometry was performed. The association between eNO and explanatory variables (HIV, FEV1 z-score, CD4+ cell count, viral load, history of TB) was investigated using linear regression analysis adjusted for age, sex and time of eNO testing. Results: In total, 222 HIV-infected and 97 HIV-uninfected participants were included. Among HIV-infected participants, 57 (25.7%) had a history of past TB; 56 (25.2%) had airway obstruction, but no prior TB. HIV status was associated with lower eNO level [mean ratio 0.79 (95% confidence interval, 95% CI 0.65–0.97), P = 0.03]. Within the HIV-infected group, history of past TB was associated with lower eNO levels after controlling for age, sex and time of eNO testing [0.79 (95% CI 0.67–0.94), P = 0.007]. Conclusion: HIV infection and history of TB were associated with lower eNO levels. eNO levels may be a marker of HIV and TB-induced alteration in pulmonary physiology; further studies focused on potential causes for lower eNO levels in HIV and TB are warranted

The effect of perinatal HIV and antiretroviral therapy on vascular structure and function in young people: A systematic review and meta-analysis.

BACKGROUND AND AIMS: Perinatal HIV infection (PHIV) and prolonged use of antiretroviral therapy (ART) may increase the likelihood of developing subclinical vascular dysfunction at an early age. We conducted a systematic review to assess the effect of PHIV and ART on intima-media thickness (IMT), arterial stiffness and endothelial function in individuals aged 6-25 years. METHODS: Medline, Embase and Web of Science were searched, and studies screened by two independent reviewers. We performed a meta-analysis on selected studies reporting on IMT. RESULTS: A total of 680 studies were retrieved from the databases, with 21 studies deemed eligible for qualitative analysis. There were few studies assessing IMT, arterial stiffness and endothelial function. More than half of the studies found either increased IMT, stiffer arteries or impaired endothelial function in PHIV compared to uninfected controls. A minority of the studies reported that the two groups had similar vascular parameters, a conflicting finding. There was a lack of standardisation for IMT assessment and reporting in numerous studies. In a meta-analysis of seven studies with matching methodologies, IMT was higher in PHIV compared to uninfected controls, (mean difference, 0.05 (0.01-0.09; p = 0.01) but heterogeneity between the studies was substantial (I2, 96.7%; p < 0.001). CONCLUSIONS: PHIV may affect vascular structure and function. Existing studies are generally small, often contradictory, and predominantly cross-sectional in design. Further studies are required to understand vascular health in PHIV to identify cardiovascular disease risk and improve interventional strategies aimed at prevention and treatment of early vascular changes in this population

Shorter granulocyte telomeres among children and adolescents with perinatally-acquired HIV infection and chronic lung disease in Zimbabwe

Background Chronic lung disease (CLD) has been reported among African children with perinatally acquired human immunodeficiency virus (HIV) infection (C-PHIV), despite combination antiretroviral therapy (cART). In adults, shorter telomere length (TL) has been reported in association with both CLD and HIV. As little is known in children, our objective was to compare TL in HIV-positive (cART-naive or -treated) and HIV-negative children with and without CLD. Methods Participants included Zimbabwean C-PHIV, aged 6–16, who were either newly diagnosed and cART-naive, or on cART for >6 months, and HIV-negative controls of similar age and sex. Packed blood cell (granulocyte) TLs from 621 children were compared cross-sectionally between groups. For a subset of newly diagnosed C-PHIV, changes in TL following cART initiation were evaluated. Results C-PHIV had shorter granulocyte TL compared with uninfected peers, regardless of cART. Among 255 C-PHIV without CLD, TL was shorter in cART-naive participants. In multivariable analyses adjusted for age, sex, CLD, and HIV/cART status, shorter TL was independently associated with older age, being HIV positive, and having reduced forced vital capacity (FVC). Last, cART initiation increased TL. Conclusions In this cohort, C-PHIV and those with reduced FVC have shorter granulocyte TL, possibly the result of increased immune activation and cellular turnover due to longstanding HIV infection with delayed cART initiation

Unexpectedly high prevalence of cytomegalovirus DNAemia in older children and adolescents with perinatally acquired human immunodeficiency virus infection

BACKGROUND:Older children and adolescents with perinatally acquired human immunodeficiency virus (PHIV) infection in Africa experience multiple comorbidities that are not typical of HIV-associated opportunistic infections, including growth impairment and chronic lung disease. We examined associations between plasma cytomegalovirus (CMV) DNA and lung function and growth. METHODS:Plasma CMV DNA loads were measured children aged 6-16 years with PHIV (n = 402) and HIV-uninfected controls (n = 224). The HIV-infected children were either newly diagnosed or known HIV infected and stable on antiretroviral therapy (ART) for &gt;6 months. CMV DNA loads were measured using quantitative polymerase chain reaction. CMV DNAemia was modeled as a time-varying outcome using longitudinal mixed-effects logistic regression. RESULTS:At enrollment, CMV DNAemia ≥1000 copies/mL (defined as "clinically significant") was detected in 5.8% of uninfected children, 14.7% of HIV-infected participants stable on ART, and 22.6% of HIV-infected ART-naive children (χ2 = 23.8, P &lt; .001). The prevalence of CMV DNAemia ≥1000 copies/mL was associated with CD4 counts &lt;350 cells/µL. Among HIV-infected ART-naive children, the presence of CMV DNAemia of ≥1000 copies/mL was independently associated with reduced lung function (adjusted odds ratio [aOR] = 3.23; 95% confidence interval [CI], 1.23-8.46; P = .017). Among ART-treated children, stunting was associated with CMV DNAemia of ≥1000 copies/mL (aOR = 2.79; 95% CI, 0.97-8.02; P = .057). CONCLUSIONS:Clinically significant levels of CMV DNAemia were common in older children with PHIV, even those on ART, suggesting a role for inadequately controlled CMV infection in the pathogenesis of PHIV comorbidities in Africa

Enhanced infection prophylaxis reduces mortality in severely immunosuppressed HIV-infected adults and older children initiating antiretroviral therapy in Kenya, Malawi, Uganda and Zimbabwe: the REALITY trial

Meeting abstract FRAB0101LB from 21st International AIDS Conference 18–22 July 2016, Durban, South Africa. Introduction: Mortality from infections is high in the first 6 months of antiretroviral therapy (ART) among HIV‐infected adults and children with advanced disease in sub‐Saharan Africa. Whether an enhanced package of infection prophylaxis at ART initiation would reduce mortality is unknown. Methods: The REALITY 2×2×2 factorial open‐label trial (ISRCTN43622374) randomized ART‐naïve HIV‐infected adults and children >5 years with CD4 <100 cells/mm3. This randomization compared initiating ART with enhanced prophylaxis (continuous cotrimoxazole plus 12 weeks isoniazid/pyridoxine (anti‐tuberculosis) and fluconazole (anti‐cryptococcal/candida), 5 days azithromycin (anti‐bacterial/protozoal) and single‐dose albendazole (anti‐helminth)), versus standard‐of‐care cotrimoxazole. Isoniazid/pyridoxine/cotrimoxazole was formulated as a scored fixed‐dose combination. Two other randomizations investigated 12‐week adjunctive raltegravir or supplementary food. The primary endpoint was 24‐week mortality. Results: 1805 eligible adults (n = 1733; 96.0%) and children/adolescents (n = 72; 4.0%) (median 36 years; 53.2% male) were randomized to enhanced (n = 906) or standard prophylaxis (n = 899) and followed for 48 weeks (3.8% loss‐to‐follow‐up). Median baseline CD4 was 36 cells/mm3 (IQR: 16–62) but 47.3% were WHO Stage 1/2. 80 (8.9%) enhanced versus 108(12.2%) standard prophylaxis died before 24 weeks (adjusted hazard ratio (aHR) = 0.73 (95% CI: 0.54–0.97) p = 0.03; Figure 1) and 98(11.0%) versus 127(14.4%) respectively died before 48 weeks (aHR = 0.75 (0.58–0.98) p = 0.04), with no evidence of interaction with the two other randomizations (p > 0.8). Enhanced prophylaxis significantly reduced incidence of tuberculosis (p = 0.02), cryptococcal disease (p = 0.01), oral/oesophageal candidiasis (p = 0.02), deaths of unknown cause (p = 0.02) and (marginally) hospitalisations (p = 0.06) but not presumed severe bacterial infections (p = 0.38). Serious and grade 4 adverse events were marginally less common with enhanced prophylaxis (p = 0.06). CD4 increases and VL suppression were similar between groups (p > 0.2). Conclusions: Enhanced infection prophylaxis at ART initiation reduces early mortality by 25% among HIV‐infected adults and children with advanced disease. The pill burden did not adversely affect VL suppression. Policy makers should consider adopting and implementing this low‐cost broad infection prevention package which could save 3.3 lives for every 100 individuals treated