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BMC Pediatrics Oct 2010Important advances in the development and production of quality-certified pediatric antiretroviral (ARV) formulations have recently been made despite significant market... (Comparative Study)
Comparative Study
The global pediatric antiretroviral market: analyses of product availability and utilization reveal challenges for development of pediatric formulations and HIV/AIDS treatment in children.
BACKGROUND
Important advances in the development and production of quality-certified pediatric antiretroviral (ARV) formulations have recently been made despite significant market disincentives for manufacturers. This progress resulted from lobbying and innovative interventions from HIV/AIDS activists, civil society organizations, and international organizations. Research on uptake and dispersion of these improved products across countries and international organizations has not been conducted but is needed to inform next steps towards improving child health.
METHODS
We used information from the World Health Organization Prequalification Programme and the United States Food and Drug Administration to describe trends in quality-certification of pediatric formulations and used 7,989 donor-funded, pediatric ARV purchase transactions from 2002-2009 to measure uptake and dispersion of new pediatric ARV formulations across countries and programs. Prices for new pediatric ARV formulations were compared to alternative dosage forms.
RESULTS
Fewer ARV options exist for HIV/AIDS treatment in children than adults. Before 2005, most pediatric ARVs were produced by innovator companies in single-component solid and liquid forms. Five 2-in1 and four 3-in-1 generic pediatric fixed-dose combinations (FDCs) in solid and dispersible forms have been quality-certified since 2005. Most (67%) of these were produced by one quality-certified manufacturer. Uptake of new pediatric FDCs outside of UNITAID is low. UNITAID accounted for 97-100% of 2008-2009 market volume. In total, 33 and 34 countries reported solid or dispersible FDC purchases in 2008 and 2009, respectively, but most purchases were made through UNITAID. Only three Global Fund country recipients reported purchase of these FDCs in 2008. Prices for pediatric FDCs were considerably lower than liquids but typically higher than half of an adult FDC.
CONCLUSION
Pediatric ARV markets are more fragile than adult markets. Ensuring a long-term supply of quality, well-adapted ARVs for children requires ongoing monitoring and improved understanding of global pediatric markets, including country-based research to explain and address low uptake of new, improved formulations. Continued innovation in pediatric ARV development may be threatened by outdated procurement practices failing to connect clinicians making prescribing decisions, supply chain staff dealing with logistics, donors, international organizations, and pharmaceutical manufacturers. Perceptions of global demand must be better informed by accurate estimates of actual country-level demand.
Topics: Acquired Immunodeficiency Syndrome; Anti-Retroviral Agents; Child; Drug Costs; Drugs, Generic; HIV Infections; Health Services Accessibility; Humans; Marketing; Public Policy; United States; United States Food and Drug Administration; World Health Organization
PubMed: 20950492
DOI: 10.1186/1471-2431-10-74 -
PloS One 2017Patients infected with HIV have a significantly increased risk of developing non-Hodgkin lymphomas despite the widespread use of HAART. To investigate mTOR pathway...
BACKGROUND
Patients infected with HIV have a significantly increased risk of developing non-Hodgkin lymphomas despite the widespread use of HAART. To investigate mTOR pathway activity in acquired immunodeficiency syndrome (AIDS) related diffuse large B-cell lymphoma AR-DLBCL, we used immunohistochemistry to examine the presence of the phosphorylated 70 ribosomal S6 protein-kinase (p70S6K), an extensively studied effector of mTOR Complex 1 (mTORC1) and the phosphorylated phosphatase and tensin homolog (pPTEN), a negative regulator of mTORC1 pathway.
MATERIALS AND METHODS
We evaluated tissue samples from 126 patients with AR-DLBCL. Among them, 98 samples were from tissue microarrays (TMAs) supplied by the Aids and Cancer Specimen Resource (ACSR), the remaining 28 samples were from cases diagnosed and treated at the University of California, San Diego (UCSD). The presence of p70S6K was evaluated with two antibodies directed against the combined epitopes Ser235/236 and Ser240/244, respectively; and additional monoclonal anti-bodies were used to identify pPTEN and phosphorylated proline-rich Akt substrate of 40kDa (pPRAS40). The degree of intensity and percentage of cells positive for p70S6K and pPTEN were assessed in all the samples. In addition, a subgroup of 28 patients from UCSD was studied to assess the presence of pPRAS40, an insulin-regulated activator of the mTORC1. The expression of each of these markers was correlated with clinical and histopathologic features.
RESULTS
The majority of the patients evaluated were males (88%); only two cases (1.6%) were older than 65 years of age. We found high levels of both p70S6K-paired epitopes studied, 48% positivity against Ser235/236 (44% in ACSR and 64% in UCSD group), and 86% positivity against Ser240/244 (82% in ACSR and 100% in UCSD group). We observed more positive cells and stronger intensity with epitope Ser240/244 in comparison to Ser235/236 (p<0.0001). The degree of intensity and percentage of cells positive for pPTEN was positively correlated with p70S6K levels (p = 0.016 for 235/236 and p = 0.007 for 240/244). High levels of pPRAS40 were observed in the majority of the cases evaluated (64.3%), but no correlation was found with either pPTEN (p = 0.9) or p70S6K (p = 0.9) levels.
CONCLUSION
AR-DLBCL frequently contain p70S6K, a main downstream effector of the mTOR pathway. The presence of p70S6K is positively correlated with pPTEN, an inactive form of PTEN, which makes mTORC1 activated. The presence of p70S6K was independent of HIV viral load or CD4 (+) counts. These results suggest that the mTOR pathway is active in the majority of AR-DLBCL, and p70S6K, particularly the Ser240/244 epitope immunohistochemistry is an excellent surrogate biomarker, which could be used to identify cases expected to be responsive to mTOR inhibitors.
Topics: Acquired Immunodeficiency Syndrome; Adaptor Proteins, Signal Transducing; Adult; Aged; California; Female; Gene Expression Profiling; Humans; Immunohistochemistry; Lymphoma, Large B-Cell, Diffuse; Male; Middle Aged; PTEN Phosphohydrolase; Phosphorylation; Ribosomal Protein S6 Kinases, 70-kDa; Serine; Signal Transduction; TOR Serine-Threonine Kinases; Tissue Array Analysis; Young Adult
PubMed: 28192480
DOI: 10.1371/journal.pone.0170771 -
AIDS and Behavior May 2023Eliminating adolescent HIV in high-burden African countries depends on the success of implementing evidence-based interventions to reduce transmission and improve...
Implementation Science for Eliminating HIV Among Adolescents in High-Burden African Countries: Findings and Lessons Learned from the Adolescent HIV Prevention and Treatment Implementation Science Alliance (AHISA).
Eliminating adolescent HIV in high-burden African countries depends on the success of implementing evidence-based interventions to reduce transmission and improve treatment outcomes. The Adolescent HIV Prevention and Treatment Implementation Science Alliance (AHISA) takes a collaborative approach to addressing key challenges and identifying and developing new areas of investigation to advance the adolescent HIV agenda. This special supplement represents the collective learning of the Alliance related to implementation science in the context of the adolescent HIV continuum of care from multiple African countries. Specifically, this series describes the current academic landscape of adolescent HIV and implementation science, such as the methodological use and utility of implementation measures and frameworks; addresses timely topics such as the use of innovative technologies for study adaptations in the context of the global COVID-19 pandemic; and explores opportunities to enhance adolescent-responsive approaches to HIV prevention and treatment using implementation science.
Topics: Adolescent; Humans; HIV Infections; Implementation Science; Pandemics; COVID-19; Acquired Immunodeficiency Syndrome
PubMed: 36964834
DOI: 10.1007/s10461-023-04038-8 -
Transplantation Feb 1990Twenty-five whole-organ recipients treated from 1981 through September 1988 were HIV carriers. Eleven were infected before transplantation, although this was not known...
Twenty-five whole-organ recipients treated from 1981 through September 1988 were HIV carriers. Eleven were infected before transplantation, although this was not known until later in 8 recipients. The other 14 were infected perioperatively. Ten of the 25 recipients were infants or children. The organs transplanted were the liver (n = 15), and the heart or kidney (n = 5, each). After a mean follow-up of 2.75 years (range, 0.7-6.6 years), 13 recipients are alive. Survival is 7/15, 2/5, and 4/5 of the liver, heart, and kidney recipients, respectively. The best results were in the pediatric group (70% survival) in which only 1 of 10 patients died of AIDS. In contrast, AIDS caused the death of 5 of 15 adult recipients and was the leading cause of death. Transplantation plus immunosuppression appeared to shorten the AIDS-free time in HIV+ patients as compared to nontransplant hemophiliac and transfusion control groups. Accrual of HIV+ transplant recipients has slowed markedly since the systematic screening of donors, recipients, and blood products was begun in 1985.
Topics: Acquired Immunodeficiency Syndrome; Adolescent; Adult; Age Factors; HIV Seropositivity; Heart Transplantation; Humans; Infant; Kidney Transplantation; Liver Transplantation; Middle Aged; Survival Analysis
PubMed: 2305465
DOI: 10.1097/00007890-199002000-00025 -
Current HIV Research Jan 2009Worldwide, the AIDS pandemic continues almost relentlessly. Women are now representing the fastest growing group of newly infected HIV-1 infected patients. The risk of... (Review)
Review
Worldwide, the AIDS pandemic continues almost relentlessly. Women are now representing the fastest growing group of newly infected HIV-1 infected patients. The risk of mother-to-child-transmission (MTCT) of HIV-1 increases proportionally as many of these women are of childbearing age. The screening of pregnant women, the early diagnosis of HIV-1 infection, and the administration of antiretroviral therapy (ART) have helped to reduce MTCT significantly. However, this holds true only for developed countries. In many resource-poor countries, access to ART is limited, and breastfeeding, a major route of HIV-1 transmission, is essential to protect the infant from other infectious diseases preponderant in those geographic regions. HIV-1 infected children, in contrast to adult patients, have higher levels of virus replication that decline only slowly, and a subset progresses to AIDS within the first two years. Thus, it is imperative to understand pediatric HIV-1 pathogenesis to design effective prevention strategies and/or a successful pediatric HIV-1 vaccine. The review summarizes how MTCT of HIV-1 in humans can be modeled in the infant macaque model of SIV infection. Importantly, the infant macaque model of SIV infection provides the opportunity to study early virus-host interactions in multiple anatomic compartments. Furthermore, the review underlines the importance of evaluating SIV/HIV immune responses in the context of the normal developmental changes the immune system undergoes in the newborn. Thus, the pediatric SIV infection model provides a unique resource for preclinical studies of novel intervention therapies and vaccine strategies to stop MTCT of HIV-1.
Topics: Animals; Disease Models, Animal; HIV Infections; Humans; Infant; Infectious Disease Transmission, Vertical; Macaca mulatta; Simian Acquired Immunodeficiency Syndrome
PubMed: 19149549
DOI: 10.2174/157016209787048528 -
HIV Medicine Sep 2021To investigate risk of AIDS and mortality after transition from paediatric to adult care in a UK cohort of young people with perinatally acquired HIV.
OBJECTIVES
To investigate risk of AIDS and mortality after transition from paediatric to adult care in a UK cohort of young people with perinatally acquired HIV.
METHODS
Records of people aged ≥ 13 years on 31 December 2015 in the UK paediatric HIV cohort (Collaborative HIV Paediatric Study) were linked to those of adults in the UK Collaborative HIV Cohort (CHIC) cohort. We calculated time from transition to a new AIDS event/death, with follow-up censored at the last visit or 31 December 2015, whichever was the earliest. Cumulative incidence of and risk factors for AIDS/mortality were assessed using Kaplan-Meier and Cox regression.
RESULTS
At the final paediatric visit, the 474 participants [51% female, 80% black, 60% born outside the UK, median (interquartile range) age at antiretroviral therapy (ART) initiation = 9 (5-13) years] had a median age of 18 (17-19) years and CD4 count of 471 (280-663) cell/μL; 89% were prescribed ART and 60% overall had a viral load ≤ 400 copies/mL. Over median follow-up in adult care of 3 (2-6) years, 35 (8%) experienced a new AIDS event (n = 25) or death (n = 14) (incidence = 1.8/100 person-years). In multivariable analyses, lower CD4 count at the last paediatric visit [adjusted hazard ratio = 0.8 (95% confidence interval: 0.7-1.0)/100 cells/μL increment] and AIDS diagnosis in paediatric care [2.7 (1.4-5.5)] were associated with a new AIDS event/mortality in adult care.
CONCLUSIONS
Young people with perinatally acquired HIV transitioning to adult care with markers of disease progression in paediatric care experienced poorer outcomes in adult care. Increased investment in multidisciplinary specialized services is required to support this population at high risk of morbidity and mortality.
Topics: Acquired Immunodeficiency Syndrome; Adolescent; Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Child; Female; HIV Infections; Humans; Male; Transition to Adult Care; United Kingdom; Viral Load; Young Adult
PubMed: 33939876
DOI: 10.1111/hiv.13096 -
JMIR MHealth and UHealth Dec 2023Two-thirds of the 2.4 million newborn deaths that occurred in 2020 within the first 28 days of life might have been avoided by implementing existing low-cost...
Development and Pilot Implementation of Neotree, a Digital Quality Improvement Tool Designed to Improve Newborn Care and Survival in 3 Hospitals in Malawi and Zimbabwe: Cost Analysis Study.
BACKGROUND
Two-thirds of the 2.4 million newborn deaths that occurred in 2020 within the first 28 days of life might have been avoided by implementing existing low-cost evidence-based interventions for all sick and small newborns. An open-source digital quality improvement tool (Neotree) combining data capture with education and clinical decision support is a promising solution for this implementation gap.
OBJECTIVE
We present results from a cost analysis of a pilot implementation of Neotree in 3 hospitals in Malawi and Zimbabwe.
METHODS
We combined activity-based costing and expenditure approaches to estimate the development and implementation cost of a Neotree pilot in 1 hospital in Malawi, Kamuzu Central Hospital (KCH), and 2 hospitals in Zimbabwe, Sally Mugabe Central Hospital (SMCH) and Chinhoyi Provincial Hospital (CPH). We estimated the costs from a provider perspective over 12 months. Data were collected through expenditure reports, monthly staff time-use surveys, and project staff interviews. Sensitivity and scenario analyses were conducted to assess the impact of uncertainties on the results or estimate potential costs at scale. A pilot time-motion survey was conducted at KCH and a comparable hospital where Neotree was not implemented.
RESULTS
Total cost of pilot implementation of Neotree at KCH, SMCH, and CPH was US $37,748, US $52,331, and US $41,764, respectively. Average monthly cost per admitted child was US $15, US $15, and US $58, respectively. Staff costs were the main cost component (average 73% of total costs, ranging from 63% to 79%). The results from the sensitivity analysis showed that uncertainty around the number of admissions had a significant impact on the costs in all hospitals. In Malawi, replacing monthly web hosting with a server also had a significant impact on the costs. Under routine (nonresearch) conditions and at scale, total costs are estimated to fall substantially, up to 76%, reducing cost per admitted child to as low as US $5 in KCH, US $4 in SMCH, and US $14 in CPH. Median time to admit a baby was 27 (IQR 20-40) minutes using Neotree (n=250) compared to 26 (IQR 21-30) minutes using paper-based systems (n=34), and the median time to discharge a baby was 9 (IQR 7-13) minutes for Neotree (n=246) compared to 3 (IQR 2-4) minutes for paper-based systems (n=50).
CONCLUSIONS
Neotree is a time- and cost-efficient tool, comparable with the results from limited similar mHealth decision-support tools in low- and middle-income countries. Implementation costs of Neotree varied substantially between the hospitals, mainly due to hospital size. The implementation costs could be substantially reduced at scale due to economies of scale because of integration to the health systems and reductions in cost items such as staff and overhead. More studies assessing the impact and cost-effectiveness of large-scale mHealth decision-support tools are needed.
Topics: Humans; Infant, Newborn; Costs and Cost Analysis; Hospitals; Malawi; Quality Improvement; Zimbabwe; Neonatology
PubMed: 38153802
DOI: 10.2196/50467 -
Epidemiology and Health 2022The Asenze cohort is set in South Africa, a middle-income country impacted by one of the highest global rates of people living with HIV/AIDS and high levels of...
The Asenze cohort is set in South Africa, a middle-income country impacted by one of the highest global rates of people living with HIV/AIDS and high levels of socioeconomic inequality. This longitudinal population-based cohort of children and their primary caregivers assesses household and caregiver functioning, child health, social well-being, and neuro-development from childhood through adolescence. Almost 1,600 children born at the peak of the human immunodeficiency virus epidemic (2003-2005) were followed (with their primary caregivers) in 3 waves, between 2008 and 2021, at average ages of 5, 7, and 16. Wave 3 is currently underway, having assessed over 1,100 of the original wave 1 children. Wave 4 begins in 2022. The study, with a dyadic structure, uses a broad range of measures, validated in South Africa or recommended for global use, that address physical, social and neuro-development in childhood and adolescence, and the social, health, and psychological status of children's primary caregivers. The Asenze study deepens our understanding of childhood physical, cognitive, and social abilities and/or disabilities, including risk-taking behaviors, and biological, environmental, and social determinants of health. We anticipate the findings will contribute to the development of community-informed interventions to promote well-being in this South African population and elsewhere.
Topics: Acquired Immunodeficiency Syndrome; Adolescent; Caregivers; Child; Cohort Studies; HIV Infections; Humans; South Africa
PubMed: 35413165
DOI: 10.4178/epih.e2022037 -
PLoS Medicine Jan 2018Published estimates of mortality and progression to AIDS as children with HIV approach adulthood are limited. We describe rates and risk factors for death and...
Long-term trends in mortality and AIDS-defining events after combination ART initiation among children and adolescents with perinatal HIV infection in 17 middle- and high-income countries in Europe and Thailand: A cohort study.
BACKGROUND
Published estimates of mortality and progression to AIDS as children with HIV approach adulthood are limited. We describe rates and risk factors for death and AIDS-defining events in children and adolescents after initiation of combination antiretroviral therapy (cART) in 17 middle- and high-income countries, including some in Western and Central Europe (W&CE), Eastern Europe (Russia and Ukraine), and Thailand.
METHODS AND FINDINGS
Children with perinatal HIV aged <18 years initiating cART were followed until their 21st birthday, transfer to adult care, death, loss to follow-up, or last visit up until 31 December 2013. Rates of death and first AIDS-defining events were calculated. Baseline and time-updated risk factors for early/late (≤/>6 months of cART) death and progression to AIDS were assessed. Of 3,526 children included, 32% were from the United Kingdom or Ireland, 30% from elsewhere in W&CE, 18% from Russia or Ukraine, and 20% from Thailand. At cART initiation, median age was 5.2 (IQR 1.4-9.3) years; 35% of children aged <5 years had a CD4 lymphocyte percentage <15% in 1997-2003, which fell to 15% of children in 2011 onwards (p < 0.001). Similarly, 53% and 18% of children ≥5 years had a CD4 count <200 cells/mm3 in 1997-2003 and in 2011 onwards, respectively (p < 0.001). Median follow-up was 5.6 (2.9-8.7) years. Of 94 deaths and 237 first AIDS-defining events, 43 (46%) and 100 (42%) were within 6 months of initiating cART, respectively. Multivariable predictors of early death were: being in the first year of life; residence in Russia, Ukraine, or Thailand; AIDS at cART start; initiating cART on a nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimen; severe immune suppression; and low BMI-for-age z-score. Current severe immune suppression, low current BMI-for-age z-score, and current viral load >400 c/mL predicted late death. Predictors of early and late progression to AIDS were similar. Study limitations include incomplete recording of US Centers for Disease Control (CDC) disease stage B events and serious adverse events in some countries; events that were distributed over a long time period, and that we lacked power to analyse trends in patterns and causes of death over time.
CONCLUSIONS
In our study, 3,526 children and adolescents with perinatal HIV infection initiated antiretroviral therapy (ART) in countries in Europe and Thailand. We observed that over 40% of deaths occurred ≤6 months after cART initiation. Greater early mortality risk in infants, as compared to older children, and in Russia, Ukraine, or Thailand as compared to W&CE, raises concern. Current severe immune suppression, being underweight, and unsuppressed viral load were associated with a higher risk of death at >6 months after initiation of cART.
Topics: Acquired Immunodeficiency Syndrome; Adolescent; Anti-Retroviral Agents; Child; Child, Preschool; Cohort Studies; Disease Progression; Drug Therapy, Combination; Europe; HIV Infections; Humans; Infant; Infant, Newborn; Risk Factors; Thailand
PubMed: 29381702
DOI: 10.1371/journal.pmed.1002491 -
Journal of the International AIDS... Feb 2018This commentary by authors from the Adolescent HIV Treatment Coalition calls for action to improve advocacy and service delivery for young people by leveraging the...
INTRODUCTION
This commentary by authors from the Adolescent HIV Treatment Coalition calls for action to improve advocacy and service delivery for young people by leveraging the interlinkages between HIV and the broader development agenda. The 2030 Agenda for Sustainable Development includes target 3.3 on ending the AIDS epidemic by 2030, and along with the 2016 Political Declaration on HIV and AIDS, this has led to a global renewal of political commitment to the HIV response. However, young people are still being left behind, and to provide an equitable and sustainable response to HIV we must ensure that we are meeting the needs of the 3.9 million young people living with HIV, and the millions more at risk.
DISCUSSION
While HIV has its own target within the 2030 Agenda, efforts to end AIDS are inextricable from other goals and targets, such as on poverty eradication, education, gender equality and peace. To tackle HIV we must work beyond target 3.3 and provide a comprehensive response that addresses the underlying structural inequalities that impact adolescents and young people, ensuring that we enable the meaningful engagement of youth and adolescents as partners and leaders of sustainable development and the HIV response. Finally, it is necessary to collect better disaggregated data and evidence on the HIV epidemic among adolescents, as well as on best practices for supporting them.
CONCLUSIONS
Ending the AIDS epidemic among adolescents and young people (aged 10 to 24) by 2030 is possible. However, it requires an integrated, multi-sectoral response to HIV which pays attention to the social determinants that put adolescents at risk and fuel the epidemic. Positioning efforts to end AIDS among young people within the broader 2030 Agenda and building youth leadership will contribute to building a more healthy, equitable and sustainable society for all.
Topics: Acquired Immunodeficiency Syndrome; Adolescent; Adult; Child; Epidemics; Female; Humans; Leadership; Male; Poverty; Sexual Behavior; Socioeconomic Factors; Sustainable Development; Young Adult
PubMed: 29485749
DOI: 10.1002/jia2.25061