Anna Turkova

Short intensified treatment in children with drug-susceptible tuberculous meningitis.

© 2014 Lippincott Williams & Wilkins www.pidj.com | 993 In Reply: Short Intensified Treatment in Children With Drug-Susceptible Tuberculous Meningitis child effectively on isoniazid monotherapy for most of their treatment. This can be a problem in areas with high prevalence of isoniazid resistance. In addition, the poor CSF penetration of ethambutol renders its inclusion in the regimen questionable. The short intensified treatment regimen used in the Western Cape for nearly 2 decades with higher isoniazid and rifampin dosages, longer administration of pyrazinamide and substitution of ethambutol with ethionamide provides higher CSF concentrations of anti-tuberculosis drugs for the entire duration of treatment. It may also overcome isoniazid-monoresistance and children appear to tolerate combination treatment with pyrazinamide better than adults. Twelve years before the most recent WHO recommendations in 2010, this group published their experience with the same treatment regimen, showing that it was effective and associated with one of the lowest mortality rates reported. It is disappointing that this regimen has not been evaluated further in other centers and that most authorities still recommend only 2 months of intensive treatment. Despite demonstrating good outcomes and a shorter duration of treatment, the study by van Toorn is observational without a randomized control group for comparison; it thus may provide insufficient evidence to change international policy. In addition, the regimen employs a drug usually reserved for second-line treatment, which could have implications for acceptability by tuberculosis programs. Further, recent WHO dosing recommendations may make it difficult to use the higher dosages described in the study, given the shortage of single drug formulations in many settings. However, these operational obstacles should not impede the identification of the best possible treatment regimen. An appropriately powered randomized controlled trial to address this question is long overdue. Onehundred eighty-four children with TBM were enrolled in this study from a single center in 4 years; patient numbers, although limited, should not be an impediment to conducting a multicenter trial. Such a trial should compare the standard WHO-recommended regimen with a shortened regimen using drugs with good CSF penetration for the full duration. Consideration should be given to using a fluoroquinolone (levofloxacin or moxifloxacin) instead of ethionamide, as many pediatricians are hesitant to use ethionamide because of its side-effect profile as well as cross-resistance with isoniazid. Particular attention should be paid to using standardized assessments of neurologic outcome and toxicity and the issue of blinding. Until better evidence is provided, children with TBM will continue to be treated with what is likely to be a suboptimal regimen. Aslınur Ozkaya-Parlakay, MD Ankara Hematology and Oncology Research Hospital

Tuberculosis incidence is high in HIV-infected African children but is reduced by co-trimoxazole and time on antiretroviral therapy

BackgroundThere are few data on tuberculosis (TB) incidence in HIV-infected children on antiretroviral therapy (ART). Observational studies suggest co-trimoxazole prophylaxis may prevent TB, but there are no randomized data supporting this. The ARROW trial, which enrolled HIV-infected children initiating ART in Uganda and Zimbabwe and included randomized cessation of co-trimoxazole prophylaxis, provided an opportunity to estimate the incidence of TB over time, to explore potential risk factors for TB, and to evaluate the effect of stopping co-trimoxazole prophylaxis.MethodsOf 1,206 children enrolled in ARROW, there were 969 children with no previous TB history. After 96xa0weeks on ART, children older than 3xa0years were randomized to stop or continue co-trimoxazole prophylaxis; 622 were eligible and included in the co-trimoxazole analysis. Endpoints, including TB, were adjudicated blind to randomization by an independent endpoint review committee (ERC). Crude incidence rates of TB were estimated and potential risk factors, including age, sex, center, CD4, weight, height, and initial ART strategy, were explored in multivariable Cox proportional hazards models.ResultsAfter a median of 4xa0years follow-up (3,632 child-years), 69 children had an ERC-confirmed TB diagnosis. The overall TB incidence was 1.9/100 child-years (95xa0% CI, 1.5–2.4), and was highest in the first 12xa0weeks following ART initiation (8.8/100 child-years (5.2–13.4) versus 1.2/100 child-years (0.8–1.6) after 52xa0weeks). A higher TB risk was independently associated with younger age (<3xa0years), female sex, lower pre-ART weight-for-age Z-score, and current CD4 percent; fewer TB diagnoses were observed in children on maintenance triple nucleoside reverse transcriptase inhibitor (NRTI) ART compared to standard non-NRTIu2009+u20092NRTI.Over the median 2xa0years of follow-up, there were 20 ERC-adjudicated TB cases among 622 children in the co-trimoxazole analysis: 5 in the continue arm and 15 in the stop arm (hazard ratio (stop: continue)u2009=u20093.0 (95xa0% CI, 1.1–8.3), Pu2009=u20090.028). TB risk was also independently associated with lower current CD4 percent (P <0.001).ConclusionsTB incidence varies over time following ART initiation, and is particularly high during the first 3xa0months post-ART, reinforcing the importance of TB screening prior to starting ART and use of isoniazid preventive therapy once active TB is excluded. HIV-infected children continuing co-trimoxazole prophylaxis after 96xa0weeks of ART were diagnosed with TB less frequently, highlighting a potentially important role of co-trimoxazole in preventing TB.

BREATHER (PENTA 16) short-cycle therapy (SCT) (5 days on/2 days off) in young people with chronic human immunodeficiency virus infection: an open, randomised, parallel-group Phase II/III trial

BACKGROUNDnFor human immunodeficiency virus (HIV)-infected adolescents facing lifelong antiretroviral therapy (ART), short-cycle therapy (SCT) with long-acting agents offers the potential for drug-free weekends, less toxicity, better adherence and cost savings.nnnOBJECTIVESnTo determine whether or not efavirenz (EFV)-based ART in short cycles of 5 days on and 2 days off is as efficacious (in maintaining virological suppression) as continuous EFV-based ART (continuous therapy; CT). Secondary objectives included the occurrence of new clinical HIV events or death, changes in immunological status, emergence of HIV drug resistance, drug toxicity and changes in therapy.nnnDESIGNnOpen, randomised, non-inferiority trial.nnnSETTINGnEurope, Thailand, Uganda, Argentina and the USA.nnnPARTICIPANTSnYoung people (aged 8-24 years) on EFV plus two nucleoside reverse transcriptase inhibitors and with a HIV-1 ribonucleic acid level [viral load (VL)] of <u200950u2009copies/ml for >u200912 months.nnnINTERVENTIONSnYoung people were randomised to continue daily ART (CT) or change to SCT (5 days on, 2 days off ART).nnnMAIN OUTCOME MEASURESnFollow-up was for a minimum of 48 weeks (0, 4 and 12 weeks and then 12-weekly visits). The primary outcome was the difference between arms in the proportion with VLu2009>u200950u2009copies/ml (confirmed) by 48 weeks, estimated using the Kaplan-Meier method (12% non-inferiority margin) adjusted for region and age.nnnRESULTSnIn total, 199 young people (11 countries) were randomised (nu2009=u200999 SCT group, nu2009=u2009100 CT group) and followed for a median of 86 weeks. Overall, 53% were male; the median age was 14 years (21% ≥u200918 years); 13% were from the UK, 56% were black, 19% were Asian and 21% were Caucasian; and the median CD4% and CD4 count were 34% and 735 cells/mm(3), respectively. By week 48, only one participant (CT) was lost to follow-up. The SCT arm had a 27% decreased drug exposure as measured by the adherence questionnaire and a MEMSCap(™) Medication Event Monitoring System (MEMSCap Inc., Durham, NC, USA) substudy (median cap openings per week: SCT group, nu2009=u20095; CT group, nu2009=u20097). By 48 weeks, six participants in the SCT group and seven in the CT group had a confirmed VL >u200950u2009copies/ml [difference -1.2%, 90% confidence interval (CI) -7.3% to 4.9%] and two in the SCT group and four in the CT group had a confirmed VL >u2009400u2009copies/ml (difference -2.1%, 90% CI -6.2% to 1.9%). All six participants in the SCT group with a VL >u200950u2009copies/ml resumed daily ART, of whom five were resuppressed, three were on the same regimen and two with a switch; two others on SCT resumed daily ART for other reasons. Overall, three participants in the SCT group and nine in the CT group (pu2009=u20090.1) changed ART regimen, five because of toxicity, four for simplification reasons, two because of compliance issues and one because of VL failure. Seven young people (SCT group, nu2009=u20092; CT group, nu2009=u20095) had major non-nucleoside reverse transcriptase inhibitor mutations at VL failure, of whom two (nu2009=u20091 SCT group, nu2009=u20091 CT group) had the M184V mutation. Two young people had new Centers for Disease Control B events (SCT group, nu2009=u20091; CT group, nu2009=u20091). There were no significant differences between SCT and CT in grade 3/4 adverse events (13 vs. 14) or in serious adverse events (7 vs. 6); there were fewer ART-related adverse events in the SCT arm (2 vs. 14; pu2009=u20090.02). At week 48 there was no evidence that SCT led to increased inflammation using an extensive panel of markers. Young people expressed a strong preference for SCT in a qualitative substudy and in pre- and post-trial questionnaires. In total, 98% of the young people are taking part in a 2-year follow-up extension of the trial.nnnCONCLUSIONSnNon-inferiority of VL suppression in young people on EFV-based first-line ART with a VL of <u200950u2009copies/ml was demonstrated for SCT compared with CT, with similar resistance, safety and inflammatory marker profiles. The SCT group had fewer ART-related adverse events. Further evaluation of the immunological and virological impact of SCT is ongoing. A limitation of the trial is that the results cannot be generalised to settings where VL monitoring is either not available or infrequent, nor to use of low-dose EFV. Two-year extended follow-up of the trial is ongoing to confirm the durability of the SCT strategy. Further trials of SCT in settings with infrequent VL monitoring and with other antiretroviral drugs such as tenofovir alafenamide, which has a long intracellular half-life, and/or dolutegravir, which has a higher barrier to resistance, are planned.nnnTRIAL REGISTRATIONnCurrent Controlled Trials ISRCTN97755073; EUDRACT 2009-012947-40; and CTA 27505/0005/001-0001.nnnFUNDINGnThis project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme (projects 08/53/25 and 11/136/108), the European Commission through EuroCoord (FP7/2007/2015), the Economic and Social Research Council, the PENTA Foundation, the Medical Research Council and INSERM SC10-US19, France, and will be published in full in Health Technology Assessment; Vol. 20, No. 49. See the NIHR Journals Library website for further project information.

Prevalence, incidence, and associated risk factors of tuberculosis in children with HIV living in the UK and Ireland (CHIPS): a cohort study

BACKGROUNDnTuberculosis is the most common serious co-infection in people living with HIV worldwide, but little is known about its incidence in HIV-infected children living in high-resource settings with low tuberculosis prevalence. We aimed to assess the incidence and prevalence of tuberculosis in children with HIV living in the UK and Ireland to understand rates, risk factors, and outcomes of the disease in this group.nnnMETHODSnWe did an analysis of children enrolled in CHIPS, an observational multicentre cohort of children receiving HIV care in the UK and Ireland. We assessed characteristics and prevalence of tuberculosis at baseline, measured incidence of disease through the follow-up period using the CHIPS database, and calculated associated risk factors in these children with multivariable logistic and Cox regression models.nnnFINDINGSnBetween Jan 1, 1996, to Sept 18, 2014, data for 1848 children with 14u2008761 years of follow-up were reported to CHIPS. 57 (3%) children were diagnosed with tuberculosis: 29 children had tuberculosis at presentation (prevalent tuberculosis) and 29 had the disease diagnosed during follow-up (incident tuberculosis), including one child with recurrent tuberculosis events. Median age at diagnosis was 9 years (IQR 5-12). 25 (43%) children had pulmonary tuberculosis, 24 (41%) had extrapulmonary tuberculosis with or without pulmonary involvement, and the remainder (n=9; 16%) had unspecified-site tuberculosis. The overall incidence rate for the follow-up period was 196 cases per 100u2008000 person-years (95% CI 137-283). In our multivariable model, tuberculosis at presentation was associated with more severe WHO immunological stage at baseline (odds ratio 0·25, 95% CI 0·08-0·74; p=0·0331; for none vs severe) and being born abroad (odds ratio 0·28, 0·10-0·73; p=0·0036; for UK and Ireland vs abroad). Incident tuberculosis was associated with time-updated more severe WHO immunological stage (hazard ratio 0·15, 95% CI 0·06-0·41; p=0·0056; for none vs severe) and older age at baseline (1·11, 0·47-2·63; p=0·0027; for age >10 years vs 5-9 years).nnnINTERPRETATIONnTuberculosis rates in HIV-infected children in the UK and Ireland were higher than those reported in the general paediatric population. Further study is warranted of tuberculosis screening and preventive treatment for children at high-risk of this disease to avoid morbidity and mortality in this population.nnnFUNDINGnNHS England, PENTA Foundation.

Survival of HIV-1 vertically infected children.

Purpose of reviewIt is 20 years since the start of the combination antiretroviral therapy (cART) era and more than 10 years since cART scale-up began in resource-limited settings. We examined survival of vertically HIV-infected infants and children in the cART era. Recent findingsGood survival has been achieved on cART in all settings with up to 10-fold mortality reductions compared with before cART availability. Although mortality risk remains high in the first few months after cART initiation in young children with severe disease, it drops rapidly thereafter even for those who started with advanced disease, and longer term mortality risk is low. However, suboptimal retention on cART in routine programs threatens good survival outcomes and even on treatment children continue to experience high comorbidity risk; infections remain the major cause of death. Interventions to address infection risk include a cotrimoxazole prophylaxis, isoniazid preventive therapy, routine childhood and influenza immunization, and improving maternal survival. SummaryPediatric survival has improved substantially with cART and HIV-infected children are aging into adulthood. It is important to ensure access to diagnosis and early cART, good program retention as well as optimal comorbidity prophylaxis and treatment to achieve the best possible long-term survival and health outcomes for vertically infected children.

Causes and Timing of Mortality and Morbidity Among Late Presenters Starting Antiretroviral Therapy in the REALITY Trial

Abstract Background 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. Methods 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. Results 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). Conclusions 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. Clinical Trials Registration ISRCTN43622374.

Multidrug-resistant tuberculosis in children in northwest Russia: an observational cohort study

Russia has the third highest absolute number of multidrug-resistant (MDR) tuberculosis (TB) cases in the world [1], yet little is known about the scale of childhood MDR-TB in the country; available publications are limited to small case series in older children [2, 3]. Successful treatment outcomes for children with MDR-TB vary widely in other settings, ranging from 53% to 97% [4]. High proportion of children with MDR-TB had favourable outcome (90%) with early diagnosis and treatment initiation http://ow.ly/2eq5302gWmr

Shorter treatment for minimal tuberculosis (TB) in children (SHINE) : a study protocol for a randomised controlled trial

BackgroundTuberculosis (TB) in children is frequently paucibacillary and non-severe forms of pulmonary TB are common. Evidence for tuberculosis treatment in children is largely extrapolated from adult studies. Trials in adults with smear-negative tuberculosis suggest that treatment can be effectively shortened from 6 to 4xa0months. New paediatric, fixed-dose combination anti-tuberculosis treatments have recently been introduced in many countries, making the implementation of World Health Organisation (WHO)-revised dosing recommendations feasible. The safety and efficacy of these higher drug doses has not been systematically assessed in large studies in children, and the pharmacokinetics across children representing the range of weights and ages should be confirmed.Methods/designSHINE is a multicentre, open-label, parallel-group, non-inferiority, randomised controlled, two-arm trial comparing a 4-month vs the standard 6-month regimen using revised WHO paediatric anti-tuberculosis drug doses. We aim to recruit 1200 African and Indian children aged below 16xa0years with non-severe TB, with or without HIV infection. The primary efficacy and safety endpoints are TB disease-free survival 72xa0weeks post randomisation and grade 3 or 4 adverse events. Nested pharmacokinetic studies will evaluate anti-tuberculosis drug concentrations, providing model-based predictions for optimal dosing, and measure antiretroviral exposures in order to describe the drug-drug interactions in a subset of HIV-infected children. Socioeconomic analyses will evaluate the cost-effectiveness of the intervention and social science studies will further explore the acceptability and palatability of these new paediatric drug formulations.DiscussionAlthough recent trials of TB treatment-shortening in adults with sputum-positivity have not been successful, the question has never been addressed in children, who have mainly paucibacillary, non-severe smear-negative disease. SHINE should inform whether treatment-shortening of drug-susceptible TB in children, regardless of HIV status, is efficacious and safe. The trial will also fill existing gaps in knowledge on dosing and acceptability of new anti-tuberculosis formulations and commonly used HIV drugs in settings with a high burden of TB. A positive result from this trial could simplify and shorten treatment, improve adherence and be cost-saving for many children with TB.Recruitment to the SHINE trial begun in July 2016; results are expected in 2020.Trial registrationInternational Standard Randomised Controlled Trials Number: ISRCTN63579542, 14 October 2014.Pan African Clinical Trials Registry Number: PACTR201505001141379, 14 May 2015.Clinical Trial Registry-India, registration number: CTRI/2017/07/009119, 27 July 2017.

Weekends-off efavirenz-based antiretroviral therapy in HIV-infected children, adolescents and young adults (BREATHER): Extended follow-up results of a randomised, open-label, non-inferiority trial.

Background Weekends off antiretroviral therapy (ART) may help engage HIV-1-infected young people facing lifelong treatment. BREATHER showed short cycle therapy (SCT; 5 days on, 2 days off ART) was non-inferior to continuous therapy (CT) over 48 weeks. Planned follow-up was extended to 144 weeks, maintaining original randomisation. Methods BREATHER was an open-label, non-inferiority trial. Participants aged 8-24yrs with virological suppression on efavirenz-based first-line ART were randomised 1:1, stratified by age and African/non-African sites, to remain on CT or change to SCT. The Kaplan-Meier method was used to estimate the proportion of participants with viral rebound (confirmed VL≥50 copies/mL) under intent-to-treat at 48 weeks (primary outcome), and in extended follow-up at 96, 144, and 192 weeks. SCT participants returned to CT following viral rebound, 3 VL blips or discontinuation of efavirenz. Findings Of 199 participants (99 SCT, 100 CT), 97 per arm consented to extended follow-up. Median follow-up was 185.3 weeks (IQR 160.9–216.1). 69 (70%) SCT participants remained on SCT at last follow-up. 105 (53%) were male, baseline median age 14 years (IQR 12–18), median CD4 count 735 cells/μL (IQR 576–968). 16 SCT and 16 CT participants had confirmed VL≥50 copies/mL by the end of extended follow-up (HR 1.00, 95% CI 0.50–2.00). Estimated difference in percentage with viral rebound (SCT minus CT) by week 144 was 1.9% (90% CI -6.6–10.4; p = 0.72) and was similar in a per-protocol analysis. There were no significant differences between arms in proportions of participants with grade 3/4 adverse events (18 SCT vs 16 CT participants; p = 0.71) or ART-related adverse events (10 vs 12; p = 0.82). 20 versus 8 serious adverse events (SAEs) were reported in 16 SCT versus 4 CT participants, respectively (p = 0.005 comparing proportions between groups; incidence rate ratio 2.49, 95%CI 0.71–8.66, p = 0.15). 75% of SAEs (15 SCT, 6 CT) were hospitalisations for a wide range of conditions. 3 SCT and 6 CT participants switched to second-line ART following viral failure (p = 0.50). Conclusions Sustainable non-inferiority of virological suppression in young people was shown for SCT versus CT over median 3.6 years. Standard-dose efavirenz-based SCT is a viable option for virologically suppressed HIV-1 infected young people on first-line ART with 3-monthly VL monitoring. Trial registration EudraCT 2009-012947-40 ISRCTN 97755073 ClinicalTrials.gov NCT01641016

Cancer in adolescents and young adults living with HIV.

Purpose of review Adults living with HIV have an increased risk of malignancy yet there is little data for adolescents and young adults. We reviewed recently published cancer epidemiology, treatment, and outcome data for adolescents and young adults living with HIV (AYALHIV) aged 10 to less than 25 years between 2016 and 2017. Recent findings AYALHIV are at increased risk of developing cancer compared to their uninfected peers. Kaposi sarcoma and non-Hodgkin lymphoma occur most frequently with variation by geographical region. Increased cancer risk is associated with HIV-related immunosuppression and coinfection with oncogenic viruses. Published data, particularly on posttreatment outcomes, remain limited and analyses are hampered by lack of data disaggregation by age and route of HIV transmission. Summary Although data are sparse, the increased cancer risk for AYALHIV is the cause for concern and must be modified by improving global access and uptake of antiretroviral therapy, human papilloma virus (HPV) and hepatitis B virus (HBV) vaccination, screening for hepatitis B and C infection, and optimized cancer screening programs. Education aimed at reducing traditional modifiable cancer risk factors should be embedded within multidisciplinary services for AYALHIV.