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      Traversing the cascade: urgent research priorities for implementing the ‘treat all’ strategy for children and adolescents living with HIV in sub-Saharan Africa

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          Abstract

          Children and adolescents living with HIV (CALHIV) in sub-Saharan Africa experience significant morbidity and alarmingly high mortality rates due to critical gaps in the HIV care cascade, including late diagnosis and initiation of treatment, as well as poor retention in care and adherence to treatment. Interventions to strengthen the adult HIV care cascade may not be as effective in improving the cascade for CALHIV, for whom specific strategies are needed. Particular attention needs to be paid to the contexts of sub-Saharan Africa, where more than 85% of the world's CALHIV live. Implementing the ‘treat all’ strategy in sub-Saharan Africa requires dedicated efforts to address the unique diagnosis and care needs of CALHIV, in order to improve paediatric and adolescent outcomes, prevent viral resistance and reduce the number of new HIV infections. We consider the UNAIDS 90-90-90 targets from the perspective of infants, children and adolescents, and discuss the key challenges, knowledge gaps and urgent research priorities for CALHIV in implementation of the ‘treat all’ strategy in sub-Saharan Africa.

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          Most cited references56

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          Antiretroviral therapy adherence, virologic and immunologic outcomes in adolescents compared with adults in southern Africa.

          To determine adherence to and effectiveness of antiretroviral therapy (ART) in adolescents vs. adults in southern Africa. Observational cohort study. Aid for AIDS, a private sector disease management program in southern Africa. Adolescents (age 11-19 years; n = 154) and adults (n = 7622) initiating ART between 1999 and 2006 and having a viral load measurement within 1 year after ART initiation. Primary: virologic suppression (HIV viral load < or = 400 copies/mL), viral rebound, and CD4 T-cell count at 6, 12, 18, and 24 months after ART initiation. Secondary: adherence assessed by pharmacy refills at 6, 12, and 24 months. Multivariate analyses: loglinear regression and Cox proportional hazards. A significantly smaller proportion of adolescents achieved 100% adherence at each time point (adolescents: 20.7% at 6 months, 14.3% at 12 months, and 6.6% at 24 months; adults: 40.5%, 27.9%, and 20.6% at each time point, respectively; P < 0.01). Patients achieving 100% 12-month adherence were significantly more likely to exhibit virologic suppression at 12 months, regardless of age. However, adolescents achieving virologic suppression had significantly shorter time to viral rebound (adjusted hazard ratio 2.03; 95% confidence interval: 1.31 to 3.13; P < 0.003). Adolescents were less likely to experience long-term immunologic recovery despite initial CD4 T-cell counts comparable to adults. Compared with adults, adolescents in southern Africa are less adherent to ART and have lower rates of virologic suppression and immunologic recovery and a higher rate of virologic rebound after initial suppression. Studies must determine specific barriers to adherence in this population and develop appropriate interventions.
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            High attrition before and after ART initiation among youth (15-24 years of age) enrolled in HIV care.

            To compare pre and post-ART attrition between youth (15-24 years) and other patients in HIV care, and to investigate factors associated with attrition among youth. Cohort study utilizing routinely collected patient-level data from 160 HIV clinics in Kenya, Mozambique, Tanzania, and Rwanda. Patients at least 10 years of age enrolling in HIV care between 01/05 and 09/10 were included. Attrition (loss to follow-up or death 1 year after enrollment or ART initiation) was compared between youth and other patients using multivariate competing risk (pre-ART) and traditional (post-ART) Cox proportional hazards methods accounting for within-clinic correlation. Among youth, patient-level and clinic-level factors associated with attrition were similarly assessed. A total of 312,335 patients at least 10 years of age enrolled in HIV care; 147,936 (47%) initiated ART, 17% enrolling in care and 10% initiating ART were youth. Attrition before and after ART initiation was substantially higher among youth compared with other age groups. Among youth, nonpregnant women experienced lower pre-ART attrition than men [sub-division hazard ratio = 0.90, 95% confidence interval (CI): 0.86-0.94], while both pregnant [adjusted hazard ratio (AHR) = 0.85, 95% CI: 0.74-0.97] and nonpregnant (AHR = 0.79, 95% CI: 0.73-0.86) female youth experienced lower post-ART attrition than men. Youth attending clinics providing sexual and reproductive health services including condoms (AHR = 0.47, 95% CI: 0.32-0.70) and clinics offering adolescent support groups (AHR = 0.73, 95% CI: 0.52-1.0) experienced significantly lower attrition after ART initiation. Youth experienced substantially higher attrition before and after ART initiation compared with younger adolescents and older adults. Adolescent-friendly services were associated with reduced attrition among youth, particularly after ART initiation.
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              Long-acting injectable antiretrovirals for HIV treatment and prevention

              Purpose of review Long-acting antiretroviral (ARV) drugs may improve adherence to therapy and extend opportunities for therapeutic or prophylactic intervention to underserved patient populations. This review focuses on recent advances in the development of small molecule long-acting injectable ARV agents. Recent findings The need for combination ART and physicochemical and dosing limitations of current ARV drugs impede attempts to redevelop them as long-acting injectable formulations. However, the intrinsic properties of rilpivirine, a nonnucleoside reverse transcriptase inhibitor, and GSK1265744, an HIV-1 integrase strand transfer inhibitor, have enabled crystalline nanoparticle formulations to progress to clinical trials. Summary Investigational long-acting injectable nanoformulations of rilpivirine and GSK1265744 are clinical-stage development candidates. Complementary pharmacologic properties of both agents – different mechanisms of action, resistance profiles, metabolic pathways, lack of drug interactions and low daily oral doses – offer the potential for combination use. Phase I studies of the pharmacokinetics and safety of each long-acting formulation alone and in combination indicate that a monthly dosing regimen is possible for HIV treatment. An ongoing phase IIb trial of oral GSK1265744 and oral rilpivirine is evaluating this two-drug regimen for maintenance of virologic suppression; results will inform future studies using the injectable formulations. Additional preclinical and clinical studies indicate a potential use of each agent for HIV pre-exposure prophylaxis.
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                Author and article information

                Journal
                J Virus Erad
                J Virus Erad
                JOURNAL OF VIRUS ERADICATION
                Journal of Virus Eradication
                Mediscript Ltd
                2055-6640
                2055-6659
                November 2018
                15 November 2018
                : 4
                : Suppl 2
                : 40-46
                Affiliations
                [ 1 ] Ryan White Center for Pediatric Infectious Disease and Global Health, Department of Pediatrics, Indiana University School of Medicine , Indianapolis, IN, USA
                [ 2 ] Center for Infectious Disease Epidemiology and Research, University of Cape Town , South Africa
                [ 3 ] Inserm (French Institute of Health and Medical Research), UMR 1027, Université Toulouse 3 , France
                [ 4 ] Department of Epidemiology, University of North Carolina at Chapel Hill , NC, USA
                [ 5 ] Moi Teaching and Referral Hospital , Eldoret, Kenya
                [ 6 ] Department of Epidemiology and Population Health, Albert Einstein College of Medicine , Bronx, NY, USA
                Author notes
                [* ]Corresponding author:  Leslie Enane, 1044 W Walnut Street, Room 402A, Indianapolis, Indiana, 46202, USA Email:  lenane@ 123456iu.edu
                Article
                10.1016/S2055-6640(20)30344-7
                6248846
                30515313
                c3c5e9e8-b352-4974-a144-70bd8c5cce52
                © 2018 The Authors.  Journal of Virus Eradication published by Mediscript Ltd

                This is an open access article published under the terms of a Creative Commons License.

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                Categories
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                children, adolescents, hiv/aids, sub-saharan africa, hiv care cascade, hiv care continuum, antiretroviral therapy

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