HIV Treatment For Children Research Articles

Characteristics of children living with HIV in a referral center in Iran: a cross-sectional study

Background. With an estimated 38.4 million people worldwide living with HIV in 2021, including 2.73 million children, there is a pressing need to understand and address HIV transmission and its impact on children’s health. This study aims to describe the demographic characteristics, clinical profiles, and outcomes of Iranian children living with HIV referred to one of the largest center for counseling HIV patients in Iran. Materials and methods. In this descriptive cross-sectional study, we assessed clinical and biological markers in HIV-infected children treated at the counseling center for behavioral diseases in a referral Hospital in Tehran. The study included a total of 60 records of children and adolescents under the age of 18, spanning from 2004 to 2020. We collected detailed clinical and laboratory data, including demographic information, treatment history, comorbidities, opportunistic infections, adherence to treatment, side effects of HIV treatment, and laboratory test results. Additionally, the study investigated any history of COVID-19 infection during the follow-up period, which coincided with the pandemic. Results. Out of the 60 patients included in the study, there were 23 females (38.3%) and 37 males (61.6%), with a mean age of 10.03 years. About 16.7% of patients had at least one comorbidity, including epilepsy, ADHD, autoimmune hepatitis, ITP, allergic asthma, alopecia areata, and cystic fibrosis. Among the mothers of these children, 93.9% were HIV-positive. Out of the 60 mothers, 6.7% were not infected with the virus, 60% were receiving treatment, and 10% had passed away. Treatment adherence was acceptable in 93.3% of patients. Opportunistic infectious diseases were experienced by 36.7% of patients, with oral candidiasis being the most common. Hospitalizations occurred in 21 patients, primarily due to pneumonia, fever, weakness, lethargy, and oral thrush. Conclusions. Investigating the demographic, clinical profile, and long-term outcomes of pediatric HIV is crucial for policymakers to effectively address the ongoing HIV epidemic. Given the significant knowledge gap on pediatric HIV in Iran, further studies in this area are necessary to improve understanding and inform strategies for the prevention, management, and treatment of HIV in children in the country.

Pharmacokinetics and safety of coformulated bictegravir, emtricitabine, and tenofovir alafenamide in children aged 2 years and older with virologically suppressed HIV: a phase 2/3, open-label, single-arm study

Coformulated bictegravir, emtricitabine, and tenofovir alafenamide is a single-tablet regimen and was efficacious and well tolerated in children and adolescents with HIV (aged 6 years to <18 years) in a 48-week phase 2/3 trial. In this study, we report data from children aged at least 2 years and weighing 14 kg to less than 25 kg. We conducted this open-label, multicentre, multicohort, single-arm study in South Africa, Thailand, Uganda, and the USA. Participants were virologically suppressed children with HIV, aged at least 2 years, weighing 14 kg to less than 25 kg. Participants received bictegravir (30 mg), emtricitabine (120 mg), and tenofovir alafenamide (15 mg) once daily, switching to bictegravir (50 mg), emtricitabine (200 mg), and tenofovir alafenamide (25 mg) upon attaining a bodyweight of at least 25 kg. The study included pharmacokinetic evaluation at week 2 to confirm the dose of coformulated bictegravir, emtricitabine, and tenofovir alafenamide for this weight band by comparing with previous adult data. Primary outcomes were bictegravir area under the curve over the dosing interval (AUCtau) and concentration at the end of the dosing interval (Ctau) at week 2, and incidence of treatment-emergent adverse events and laboratory abnormalities until the end of week 24 in all participants who received at least one dose of bictegravir, emtricitabine, and tenofovir alafenamide. This study is registered with ClinicalTrials.gov, NCT02881320. Overall, 22 participants were screened (from Nov 14, 2018, to Jan 11, 2020), completed treatment with bictegravir, emtricitabine, and tenofovir alafenamide (until week 48), and entered an extension phase. The geometric least squares mean (GLSM) ratio for AUCtau for bictegravir was 7·6% higher than adults (GLSM ratio 107·6%, 90% CI 96·7-119·7); Ctau was 34·6% lower than adults (65·4%, 49·1-87·2). Both parameters were within the target exposure range previously found in adults, children, or both". Grade 3-4 laboratory abnormalities occurred in four (18%) participants by the end week 24 and six (27%) by the end of week 48. Drug-related adverse events occurred in three participants (14%) by the end of week 24 and week 48; none were severe. No Grade 3-4 adverse events, serious adverse events, or adverse events leading to discontinuation occurred by the end of week 24 and week 48. Data support the use of single-tablet coformulated bictegravir (30 mg), emtricitabine (120 mg), and tenofovir alafenamide (15 mg) for treatment of HIV in children aged at least 2 years and weighing 14 kg to less than 25 kg. Gilead Sciences.

Integrase inhibitors in children and adolescents: clinical use and resistance.

Although integrase inhibitor (INI)-based regimens are now the first-line choice for all people living with HIV, experience among children and adolescents is still scarce. We describe the characteristics and outcomes of a paediatric/adolescent cohort on INI-based ART. Retrospective analysis of HIV-infected patients below 18 years of age who started an INI-based regimen from 2007 to 2019, enrolled in the Spanish National Adult (CoRIS) and Paediatric (CoRISpe) cohorts. Resistance mutations were identified by the Stanford HIV Drug Resistance Database. Overall, 318 INI-based regimens were implemented in 288 patients [53.8% female; median age at start of 14.3 years (IQR 12.0-16.3)]. Most were born in Spain (69.1%), vertically infected (87.7%) and treatment-experienced (92.7%). The most frequently prescribed INI was dolutegravir (134; 42.1%), followed by raltegravir (110; 34.6%) and elvitegravir (73; 23.0%). The median exposure was 2.0 years (IQR 1.1-3.0). The main reasons to start an INI-based therapy were treatment simplification (54.4%) and virological failure (34.3%). In total, 103 (32.4%) patients interrupted their regimen: 14.5% for simplification and 8.5% due to virological failure. Most subjects who received dolutegravir (85.8%) and elvitegravir (83.6%) did not interrupt their regimen and maintained undetectable viral load. There were only five virological failures with dolutegravir and three with elvitegravir. There were no interruptions related to adverse events. Seven patients with virological failure presented major resistance mutations to INIs; none of them were on dolutegravir. INI-based regimens were effective and safe for HIV treatment in children and adolescents. Dolutegravir and elvitegravir presented an excellent profile, and most patients achieved and maintained viral suppression.

New diagnosis of mother-to-child transmission of HIV in 8 Latin-American countries during 2018

BackgroundImportant prevention efforts have led to a reduction in mother-to-child transmission of HIV (MTCT) globally. However, new cases of paediatric HIV infections still occur. Early diagnosis of new HIV infections is essential to start an appropriate antiretroviral treatment to avoid childhood morbidity and mortality related to infection. The aim of this study was to describe the new cases of MTCT in Latin-American referral hospitals.MethodsA retrospective, multicentre and descriptive study of the new cases of MTCT diagnosed during 2018 in 13 referral hospitals from 8 Latin-American countries (Costa Rica, Ecuador, El Salvador, Guatemala, Honduras, Mexico, Nicaragua, and Panama) belonging to PLANTAIDS (Paediatric Network for Prevention, Early Detection and Treatment of HIV in Children), was conducted. PLANTAIDS is included in CYTED (Ibero-American Programme of Science and Technology for Development).ResultsEighty-one children (40.7% males) were included, median age at diagnosis of 2.33 years (IQR:0.7–4.7). Less than 3% of women knew their HIV diagnosis before pregnancy. More than 80% of them were diagnosed after delivery, 8.7% during pregnancy, and 2.9% at delivery. Only one patient underwent antiretroviral therapy (ART) prior to pregnancy. At diagnosis, 50.0% of the children presented with an advanced stage of disease (stage C following the current CDC classification for HIV infection), and 34.4% had less than 15% CD4+ cells/mm3. The time elapsed between delivery and the maternal diagnosis was correlated with the age of children at diagnosis, ρ = 0.760, p < 0.001. Younger age at diagnosis (p = 0.03), a smaller number of previous hospitalizations (p < 0.01), and better immunovirological status (p < 0.01) were found in children whose mothers knew their HIV status at delivery, compared to mothers who were not aware of it.ConclusionsAlthough MTCT in Latin America has declined in recent years, our series shows there are still cases that indicate some failures in prevention, being a critical point to improve an earlier diagnosis of pregnant women. Half of the children were diagnosed in an advanced stage of disease and the delay in maternal diagnosis entailed a worse clinical and immunological child’ prognosis.

HIV Drug Efavirenz Inhibits CYP21A2 Activity with Possible Clinical Implications

Background: The HIV drugs lopinavir and ritonavir have recently been reported to cause transient adrenal insufficiency in preterm newborns. We, therefore, considered HIV drugs as a cause of transiently elevated 17-hydroxyprogesterone (17OHP) levels in a neonatal screening test for congenital adrenal hyperplasia in a preterm girl exposed to zidovudine, efavirenz, tenofovir, and emtricitabine. Objective: So far, HIV drugs have not been tested for their effect on steroidogenesis and the steroidogenic enzyme activity of CYP21A2 specifically in an in vitro system. Methods: We tested the effect of efavirenz, tenofovir, emtricitabine, and zidovudine on steroidogenesis of human adrenal H295R cells. Cells were treated with the drugs at different concentrations including concentrations in therapeutic use. The effect on CYP21A2 activity was assessed by testing the conversion of radiolabeled 17OHP to 11-deoxycortisol. Cell viability was tested by an MTT assay. In addition, recombinant human CYP21A2 protein was used to assess direct drug effects on CYP21A2 activity. Results: We observed significantly decreased CYP21A2 activity in both in vitro testing systems after treatment with efavirenz at therapeutic concentrations. Moreover, efavirenz affected cell viability. By contrast, the other test drugs did not affect steroidogenesis. Follow-up of our patient revealed elevated 17OHP and androgen levels during the first weeks of life, but values normalized spontaneously. Genetic testing for CYP21A2 mutations was negative. Thus, it remains unsettled whether the transient 17OHP elevation in this baby was due to a drug effect. Conclusion: The HIV drug efavirenz inhibits CYP21A2 activity in vitro through direct interaction with enzyme catalysis at therapeutic concentrations. This may have clinical implications for HIV treatment in children and adults. However, so far, clinical data are scarce, and further studies are needed to be able to draw clinical conclusions.

An evaluation of elvitegravir plus cobicistat plus tenofovir alafenamide plus emtricitabine as a single-tablet regimen for the treatment of HIV in children and adolescents

ABSTRACTIntroduction: Approximately 2.1 million of the estimated 36 million infected with HIV are children or adolescents. International guidelines for HIV-1 Infection suggest starting antiretrovirals (ARV) at the moment of diagnosis. Many factors limit the optimization of antiretroviral therapy in children and adolescents: lack of pediatric formulations, poor adherence, metabolic and pharmacokinetic changes associated withnormal child development and puberty.Areas covered: Three integrase inhibitors are approved by the US Food and Drug Administration and by European Medical Agency for children and adolescents with HIV-1 infection. Raltegravir is approved for children aged 4 weeks to 18 years, while dolutegravir and elvitegravir co-formulated with cobicistat, emtricitabine, and tenofovir alafenamide (E/C/FTC/TAF) are approved for children from 6 years of age. This article evaluates E/C/FTC/TAF as a treatment option.Expert opinion: E/C/FTC/TAF was well tolerated, and the antiretroviral activity and tolerability data of this combination support the use in children and adolescents. However, the studies regarding E/C/FTC/TAF in children and adolescents are scant. Consequently, additional studies investigating its safety and efficacy in children are paramount.

\u201cI will not stop visiting!\u201d a qualitative study of community health workers\u2019 reluctance to withdraw household support following the end of a community-based intervention in Zimbabwe

BackgroundCommunity Health Worker (CHW) programmes are increasingly important in HIV service delivery. CHWs’ familiarity with the local context can improve intervention acceptability and sustainability but concerns have been raised about potential exploitation and “burnout” of CHWs as they become emotionally involved in clients’ lives. Little attention has been paid to what happens at the end of time-limited CHW interventions. This study aimed to examine the experience of CHWs’ withdrawal from clients and their families.MethodsWe conducted a qualitative study of CHWs’ experiences of “exiting” from households during the ZENITH (Zimbabwe Study for Enhancing Testing and Improving Treatment of HIV in Children) intervention, which provided 12 structured home visits over 72 weeks to families with children recently diagnosed with HIV. We conducted semi-structured interviews at 12 and 18 months with all 19 CHWs delivering the intervention and 36 purposively selected caregivers who received home visits. Analysis focused on perceptions of the end of the trial, when CHWs completed the scheduled home-based visits and there was no guarantee of programme continuation beyond the study.ResultsTermination of scheduled home visits caused significant distress to both CHWs and the households they visited. We identify 3 thematic “lessons learned” for CHW programmes. First, CHWs derived pride and self-worth from emotional labour as they became integral to families’ improved ability to cope, motivating them to go beyond formal job requirements. Second, clients’ growing dependence on CHWs led to “exit” being interpreted as abandonment by both CHWs and households, causing distress on both sides. Finally, in response to anxiety about “abandoning” families, CHWs maintained contact with families long after scheduled withdrawal of services.ConclusionsCHWs can forge genuine bonds with households, creating expectations of long-term engagement. On the positive side, CHW derive pride from their work, attach social responsibility to their roles, and feel personal fulfilment in supporting families. If CHWs do not disengage from interventions as planned, or become demoralised by “exits”, interventions will prove less sustainable. CHWs are often lauded for their ability to develop trust with peers, yet this willingness and ability to create enduring emotional bonds could threaten programme delivery.

Simulation Modeling and Metamodeling to Inform National and International HIV Policies for Children and Adolescents.

Objective and Approach:Computer-based simulation models serve an important purpose in informing HIV care for children and adolescents. We review current model-based approaches to informing pediatric and adolescent HIV estimates and guidelines.Findings:Clinical disease simulation models and epidemiologic models are used to inform global and regional estimates of numbers of children and adolescents living with HIV and in need of antiretroviral therapy, to develop normative guidelines addressing strategies for diagnosis and treatment of HIV in children, and to forecast future need for pediatric and adolescent antiretroviral therapy formulations and commodities. To improve current model-generated estimates and policy recommendations, better country-level and regional-level data are needed about children living with HIV, as are improved data about survival and treatment outcomes for children with perinatal HIV infection as they age into adolescence and adulthood. In addition, novel metamodeling and value of information methods are being developed to improve the transparency of model methods and results, as well as to allow users to more easily tailor model-based analyses to their own settings.Conclusions:Substantial progress has been made in using models to estimate the size of the pediatric and adolescent HIV epidemic, to inform the development of guidelines for children and adolescents affected by HIV, and to support targeted implementation of policy recommendations to maximize impact. Ongoing work will address key limitations and further improve these model-based projections.

The role of community health workers in improving HIV treatment outcomes in children: lessons learned from the ZENITH trial in Zimbabwe.

Reliance on community health workers (CHWs) for HIV care continues to increase, particularly in resource-limited settings. CHWs can improve HIV service use and adherence to treatment, but effectiveness of these programmes relies on providing an enabling work environment for CHWs, including reasonable workload, supportive supervision and adequate training and supplies. Although criteria for effective CHW programmes have been identified, these have rarely been prospectively applied to design and evaluation of new interventions. For the Zimbabwe study for Enhancing Testing and Improving Treatment of HIV in Children (ZENITH) randomized controlled trial, we based our intervention on an existing evidence-based framework for successful CHW programmes. To assess CHWs’ experiences delivering the intervention, we conducted longitudinal, qualitative semi-structured interviews with all 19 CHWs at three times during implementation. The study aimed to explore CHWs’ perceptions of how the intervention’s structure and management affected their performance, and consider implications for the programme’s future scale-up and adoption in other settings. CHWs expressed strong motivation, commitment and job satisfaction. They considered the intervention acceptable and feasible to deliver, and levels of satisfaction rose over interview rounds. Intensive supervision and mentoring emerged as critical to ensuring CHWs’ long-term satisfaction. Provision of job aids, standardized manuals and refresher training were also important, as were formalized links between clinics and CHWs. Concerns raised by CHWs included poor remuneration, their reluctance to stop providing support to individual families following the requisite number of home visits, and disappointment at the lack of programme sustainability following completion of the trial. Furthermore, intensive supervision and integration with clinical services may be difficult to replicate outside a trial setting. This study shows that existing criteria for designing successful CHW programmes are useful for maximizing effectiveness, but challenges remain for ensuring long-term sustainability of ‘task shifting’ strategies.

Genetic variants in CYP2B6 and CYP2A6 explain interindividual variation in efavirenz plasma concentrations of HIV-infected children with diverse ethnic origin.

BackgroundApproximately 2.6 million children live with HIV globally, and efavirenz (EFV) is one of the most widely used antiretroviral agents for HIV treatment in children and adults. There are concerns about the appropriateness of current EFV dosing and it has been discussed whether EFV dosing should be adapted according to genotype in children as suggested for adults.AimTo investigate if pediatric EFV dosing should be guided by genetic variation in drug metabolizing enzymes rather than by body weight.MethodEFV plasma concentrations measured for clinical purposes from all children less than 18 years old at Karolinska University Hospital, Stockholm, Sweden, treated with EFV were collected retrospectively. They were genotyped for eleven polymorphisms in genes coding for drug-metabolizing enzymes and P-glycoprotein, of potential importance for EFV disposition. Data on country of origin, sex, age, weight, HIV RNA, viral resistance patterns, CD4 cells, adherence to treatment, subjective health status and adverse events were collected from their medical records.ResultsThirty-six patients and 182 (mean 5 samples/patient) EFV plasma concentration measurements from children of African, Asian and Latin American origin were included. EFV plasma concentration varied 21-fold between measurements (n = 182) (0.85–19.3 mg/L) and 9-fold measured as mean EFV plasma concentration across the subjects (1.55–13.4 mg/L). A multivariate mixed-effects restricted maximum likelihood regression model, including multiple gene polymorphisms, identified CYP2B6*6 T/T (p < 0.0005), CYP2B6*11 G/G (p < 0.0005), CYP2A6*9 A/C (p = 0.001) genotypes, age at treatment initiation (p = 0.002) and time from treatment initiation (p < 0.0005) as independent factors significantly related to loge concentration/(dose/weight). The contribution of the model to the intra- and interindividual variation were 6 and 75%, respectively (Bryk/Raudenbush R-squared level).ConclusionGenetic polymorphisms in CYP2B6 and CYP2A6 explained a significant proportion of variability in EFV plasma concentration in HIV-infected children in a multi-ethnic outpatient clinic. Knowledge about individual variants in key drug metabolizing enzyme genes could improve clinical safety and genotype directed dosing could achieve more predictable EFV plasma concentrations in HIV-infected children.

Starting treatment in pediatric HIV infection: try to clarify a gray area.

The introduction of combination antiretroviral therapy (ART) in HIV-infected children led to a dramatic reduction in HIV-related morbidity and mortality. The decision about which ART regimen to use on children and when to start the treatment needs to focus on assuring normal growth and neuropsychological development. According to the available treatment guidelines, all infants under 1 year of age with HIV should be started on an ART at diagnosis. It is difficult to balance between the benefits of providing treatment to asymptomatic children >1 year and the concerns about long-term resistance and antiretroviral drug side effects if the treatment is started too early. Current guidelines agree that the need for antiretroviral treatment among asymptomatic children >12 months depends on age-specific CD4+ T-cell count thresholds and viral loads. Recent studies showed that the introduction of combination ART during the first year of life preserves a good function of B-cell and T-cell compartments. Starting treatment earlier might have fundamental roles both in preserving the not yet depleted immune function and in preventing the progressive HIV encephalopathy. The comparison of the international guidelines available for starting HIV treatment in children in developed countries highlights a gray area. New randomized controlled studies are needed to clarify the appropriate approach in asymptomatic children between 2 and 5 years of age.

The glory of guidelines and the twilight of reality: controversies and challenges in the prevention and treatment of HIV in children

Since the discovery of HIV 30 years ago, we have learned much about HIV in children and adolescents. Dramatic declines have occurred in mother-to-child transmission of HIV in resource-rich countries. Resource-poor countries struggle with improving prevention of mother-to-child transmission due to the lack of universal antiretroviral treatment for pregnant and nursing mothers. In children infected with HIV, pharmacokinetic, safety and efficacy data have been determined for many of the older drugs. Data are lacking for the newer, safer and more effective currently available drugs, resulting in the pediatric guidelines lagging behind adult recommendations. Although guidelines for prevention and treatment are helpful, the way they are created causes them to lag behind new scientific evidence, and in some situations they will be confusing or only based on expert opinion. Improving prevention of HIV infection in adolescents and young adults and in treating those who become HIV infected is crucially important. The next 10 years hold tremendous opportunities for improvements in prevention and treatment of HIV in children, adolescents and young adults.

Treatment of pediatric HIV infection

HIV-infected children require a peculiar management when compared to infected adults. Antiretroviral therapy has been quite well adapted to children, but new studies are needed to answer many unsolved questions, such as when to start therapy in asymptomatic infected children. Recently, several guidelines have been updated. In this review, we compare these recommendations together with the latest studies concerning the treatment of HIV in children. A triple-drug combination therapy based either on nonnucleoside reverse transcriptase inhibitors or protease inhibitors is the recommended initial therapy. After treatment failure, a second-line therapy should be based on switching between these two regimens. Antiretroviral therapy should be managed by an expert in pediatric and adolescent HIV infection. The importance of children's adherence to therapy is a crucial point, particularly in adolescents.