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Objectives: To assess baseline prevalence of cryptococcal antigen (CrAg) positivity; and its contribution to reductions in all-cause mortality, deaths from cryptococcus and unknown causes, and new cryptococcal disease in the REALITY trial. Design: Retrospective CrAg testing of baseline and week-4 plasma samples in all 1805 African adults/children with CD4+ cell count less than 100 cells/μl starting antiretroviral therapy who were randomized to receive 12-week enhanced-prophylaxis (fluconazole 100 mg/day, azithromycin, isoniazid, cotrimoxazole) vs. standard-prophylaxis (cotrimoxazole). Methods: Proportional hazards models were used to estimate the relative impact of enhanced-prophylaxis vs. standard-cotrimoxazole on all, cryptococcal and unknown deaths, and new cryptococcal disease, through 24 weeks, by baseline CrAg positivity. Results: Excluding 24 (1.4%) participants with active/prior cryptococcal disease at enrolment (all treated for cryptococcal disease), 133/1781 (7.5%) participants were CrAg-positive. By 24 weeks, 105 standard-cotrimoxazole vs. 78 enhanced-prophylaxis participants died. Of nine standard-cotrimoxazole and three enhanced-prophylaxis cryptococcal deaths, seven and two, respectively, were CrAg-positive at baseline. Among deaths of unknown cause, only 1/46 standard-cotrimoxazole and 1/28 enhanced-prophylaxis were CrAg-positive at baseline. There was no evidence that relative reductions in new cryptococcal disease associated with enhanced-prophylaxis varied between baseline CrAg-positives [hazard-ratio = 0.36 (95% confidence interval 0.13–0.98), incidence 19.5 vs. 56.5/100 person-years] and CrAg-negatives [hazard-ratio = 0.33 (0.03–3.14), incidence 0.3 vs. 0.9/100 person-years; Pheterogeneity = 0.95]; nor for all deaths, cryptococcal deaths or unknown deaths (Pheterogeneity > 0.3). Conclusions: Relative reductions in cryptococcal disease/death did not depend on CrAg status. Deaths of unknown cause were unlikely to be cryptococcus-related; plausibly azithromycin contributed to their reduction. Findings support including 100 mg fluconazole in an enhanced-prophylaxis package at antiretroviral therapy initiation where CrAg screening is unavailable/impractical.

Background Antiretroviral therapy (ART) adherence is critical for successful HIV treatment outcomes. Once-daily dosing could improve adherence. Plasma concentrations of once-daily vs twice-daily abacavir + lamivudine are bioequivalent in children, but no randomized trial has compared virological outcomes. Methods Children taking abacavir + lamivudine-containing first-line regimens twice daily for more than 36 weeks in the ARROW trial (NCT02028676, ISRCTN24791884) were randomized to continue twice-daily vs move to once-daily abacavir + lamivudine (open-label). Co-primary outcomes were viral load suppression at week 48 (12% noninferiority margin, measured retrospectively) and lamivudine or abacavir-related grade 3/4 adverse events. Results Six hundred and sixty-nine children (median 5 years, range 1-16) were randomized to twice daily (n = 333) vs once daily (n = 336) after median 1.8 years on twice-daily abacavir + lamivudine-containing first-line ART. Children were followed for median 114 weeks. At week 48, 242/331 (73%) twice daily vs 236/330 (72%) once daily had viral load less than 80 copies/ml [difference -1.6% (95% confidence interval -8.4,+5.2%) P = 0.65]; 79% twice daily vs 78% once daily had viral load less than 400 copies/ml (P = 0.76) (week 96 results similar). One grade 3/4 adverse event was judged uncertainly related to abacavir + lamivudine (hepatitis; once daily). At week 48, 9% twice daily vs 10% once daily reported missing one or more ART pills in the last 4 weeks (P = 0.74) and 8 vs 8% at week 96 (P = 0.90). Carers strongly preferred once-daily dosing. There was no difference between randomized groups in postbaseline drug-resistance mutations or drug-susceptibility; WHO 3/4 events; ART-modifying, grade 3/4 or serious adverse events; CD4% or weight-for-age/height-for-age (all P > 0.15). Conclusion Once-daily abacavir + lamivudine was noninferior to twice daily in viral load suppression, with similar resistance, adherence, clinical, immunological and safety outcomes. Abacavir + lamivudine provides the first once-daily nucleoside backbone across childhood that can be used to simplify ART.

OBJECTIVES: To evaluate the effect of early versus deferred antiretroviral therapy (ART) on the neurodevelopment of infants from Cape Town participating in the Children with HIV Early Antiretroviral Therapy (CHER) trial. DESIGN: HIV-infected infants were randomized to early (

BACKGROUND: Cotrimoxazole prophylaxis reduces morbidity and mortality in HIV-1-infected children, but mechanisms for these benefits are unclear. METHODS: CHAP was a randomized trial comparing cotrimoxazole prophylaxis with placebo in HIV-infected children in Zambia where background bacterial resistance to cotrimoxazole is high. We compared causes of mortality and hospital admissions, and antibiotic use between randomized groups. RESULTS: Of 534 children (median age, 4.4 years; 32% 1-2 years), 186 died and 166 had one or more hospital admissions not ending in death. Cotrimoxazole prophylaxis was associated with lower mortality, both outside hospital (P = 0.01) and following hospital admission (P = 0.005). The largest excess of hospital deaths in the placebo group was from respiratory infections [22/56 (39%) placebo versus 10/35 (29%) cotrimoxazole]. By 2 years, the cumulative probability of dying in hospital from a serious bacterial infection (predominantly pneumonia) was 7% on cotrimoxazole and 12% on placebo (P = 0.08). There was a trend towards lower admission rates for serious bacterial infections in the cotrimoxazole group (19.1 per 100 child-years at risk versus 28.5 in the placebo group, P = 0.09). Despite less total follow-up due to higher mortality, more antibiotics (particularly penicillin) were prescribed in the placebo group in year one [6083 compared to 4972 days in the cotrimoxazole group (P = 0.05)]. CONCLUSIONS: Cotrimoxazole prophylaxis appears to mainly reduce death and hospital admissions from respiratory infections, supported further by lower rates of antibiotic prescribing. As such infections occur at high CD4 cell counts and are common in Africa, the role of continuing cotrimoxazole prophylaxis after starting antiretroviral therapy requires investigation.

OBJECTIVE: To assess the feasibility and impact of highly active antiretroviral therapy (HAART) started in vertically HIV-1-infected infants less than 3 months of age. DESIGN: A multicentre, phase I/II, non-randomized, open-label study (PENTA 7). METHODS: Adverse events, plasma HIV-1 RNA, CD4 cell counts, CD4 cell percentage (CD4%) and clinical progression were recorded at baseline and prospectively to 72 weeks in order to assess the toxicity, tolerability and efficacy of a combination of stavudine, didanosine and nelfinavir. Selection of genotypic resistance was also investigated. RESULTS: Twenty infants, of whom only three had Centers for Disease Control and Prevention stage B, initiated HAART at median age 2.5 months (range, 0.9-4.7) with median HIV-1 RNA concentration 5.5 log10 copies/ml (range, 3.2-6.8) and CD4% 33% (range, 11-66). Median follow-up was 96 weeks (range, 60-144). At week 72, 11 infants were still taking the original treatment. Few adverse events were reported related to treatment, all minor and causing treatment interruption in only three infants. No AIDS-defining events occurred; one child died of non-HIV-related causes (prematurity). All but two had CD4% > 25% at 72 weeks; however, 14 infants had virological failure and six acquired resistance mutations. CONCLUSIONS: Early treatment with stavudine, didanosine and nelfinavir was well tolerated and associated with good clinical and immunological outcomes at week 72. However, a high rate of virological failure with emergence of genotypic resistance is of great concern. More palatable drug combinations for infants and closer drug monitoring are required.

Objectives: The outcome of Pneumocystis carinii pneumonia (PCP) in HIV-infected infants is poor, and the role of cytomegalovirus (CMV) co-infection in the course and outcome of PCP is unclear. This study describes the prevalence, clinical characteristics, management and changes in survival over time of vertically HIV-infected infants developing PCP and/or CMV infection.Methods: Data on children with HIV, born in the UK and ireland and reported to the National Study of HIV in Pregnancy and Childhood, with PCP and/or CMV were combined with clinical information collected from reporting paediatricians.Results: By April 1998, 340 vertically HIV-infected children had been reported, of whom 93 had PCP and/or CMV, as their first AIDS indicator disease; 85 (91%) were infants. Among infants with PCP, 79% were born to mothers not diagnosed as HIV infected, and there was an independent and statistically significant association with breast-feeding, being black African, and developing CMV disease. Median survival after PCP and/or CMV was significantly better in those born between 1993 and 1998 compared with those born before 1993 (P = 0.009), and worse than after other AIDS diagnoses (P = 0.01). Infants with dual infection were more likely to be ventilated (P = 0.003) and receive corticosteroids (P = 0.002) than those with PCP alone.Conclusion: Although survival from PCP and CMV has improved over time, these remain serious and potentially fatal infections among infants in whom maternal HIV status is not recognized in pregnancy. Breast-feeding increases the risk of combined PCP and CMV infection, which is associated with severe disease. (C) 2001 Lippincott Williams & Wilkins.

OBJECTIVE To assess the health service costs and benefits for the woman of an earlier HIV diagnosis as a result of antenatal HIV testing. DESIGN A model of maternal disease progression was developed based on the rate of decline in CD4 cell counts and applied to two matched simulated cohorts of women with identical initial CD4 cell levels and decline rates but whose HIV diagnosis occurred at different times as a result of antenatal HIV testing. UK data on CD4 cell count at HIV diagnosis and annual health service costs of care excluding antiretroviral therapy (ART) incurred at defined states of CD4 cell count were taken from published UK data. Costs of triple ART were added and effectiveness modelled by retarding the rate of CD4 cell count decline. Discounting costs at 6% and life-years at 2% per year, the additional costs per life-year gained by screening were calculated. Uncertainty was explored using sensitivity analysis. RESULTS Costs per life-year gained by antenatal diagnosis of women were pound sterling 51258 ($76887) assuming untested women were diagnosed a median of 20.4 months later than tested women, ART was initiated at a CD4 cell count of 350x10(6) cells/l and ART efficacy retarded decline in CD4 cell counts by 40% for life. Sensitivity analyses showed results were most sensitive to the assumed efficacy of lifetime ART and time assumed to HIV diagnosis for women not tested in pregnancy. CONCLUSION This model provides a way of estimating the additional costs and benefits of future care for the woman resulting from an earlier HIV diagnosis through antenatal testing. These should be included with the paediatric costs averted and life-years gained from interventions to reduce mother-to-child transmission in order to evaluate the cost-effectiveness of antenatal screening in different populations and settings.

Patient adherence to combination therapy is a critical component of successful treatment outcomes. While combination therapy is known to be effective in slowing disease progression, the long-term benefit of these therapies can only be sustained if resistant strains of HIV do not emerge. Among factors that can result in the emergence of resistance, non-adherence is perhaps the most amenable to intervention. To maximize intervention efforts, a program of research on adherence is needed. A prerequisite for progress in adherence research is a focused effort on developing reliable and valid methods for measuring adherence that are feasible for patients living with HIV/AIDS. If new adherence assessment procedures cannot be developed, it would be helpful if a consensus on measurement approaches could be achieved. This consensus might propose strategies for matching measurement approaches with research questions and recommendations for the use of multiple measures where appropriate. It is important that research continue to identify psychological, physiological, socio-cultural and environmental factors that are associated with non-adherence in various populations both in the developed and the developing world. Intervention programs that address these risk factors and promote adherence need to be developed and evaluated in controlled clinical trials. These programs will need to be tailored to different populations and cultural groups, and tested in both developed and developing countries where HIV therapies are being prescribed. The results of this research would significantly contribute to efforts to prevent virus breakthrough and, by doing so, assist persons living with HIV/AIDS in achieving the health benefits that the combination therapies offer.