Community and Home-Based Care HIV Service Delivery Model in the Context of Paediatric HIV Management and Contributing to Health Systems Strengthening in a Resource-Limited Setting (Uganda): Operational Research

This thesis is about the Tukula Fenna Project (TFP) that was set up at the Home Care Department of St. Raphael of St Francis Hospital (Nsambya Hospital) in Kampala, Uganda. In 2003, Associazione Casa Accoglienza alla vita “Padre Angelo” (ACAVPA) or “HOUSE FOR LIFE, Father Angelo” and other Italian partners; in particular, PENTA Foundation and University of Padova, Department of paediatrics collectively signed a memorandum of understanding (MoU) with Nsambya Hospital. The aim of the MoU was to collaborate with the hospital in the fight against HIV particularly in children and adolescents, orphans and vulnerable children (OVC) and their families in Kampala and three surrounding districts (Mukono, Wakiso and Mpigi). Thus, the MoU officially established the children’s HIV programme at Nsambya Hospital, Home Care Department in 2003. The programme was then called the “PCP Project” because the initial intervention was among other things, providing Cotrimoxazole prophylaxis against Pneumocystis Carinii pneumonia (PCP, also known as Jiroveci Pneumonia). As more resources including provision of antiretroviral drugs (ARVs) from external sources and expertise became available over the years, the project evolved into a full-blown HIV programme for infants, children and adolescents as well as their families and caretakers. Additionally, the name “PCP”, was replaced by “Tukula Fenna”, which means “growing up together” in the local language (Luganda). The project was implemented at the Home Care Department within an existing community home-based care (CHBC) model that evolved in response to the HIV epidemic in Uganda, and other high-burden resource-limited settings. The TFP provides comprehensive HIV care, treatment and psychosocial support services (PSS) and apart from operating at the Home Care department of Nsambya Hospital, it also operates at Ggaba Parish Outreach Clinic and 3 other outreach clinics in and around Kampala. This thesis describes the research outcomes of the project that was managed by Dr. Massavon from 2008 to 2013. It reviews the published literature from the key milestones of the HIV epidemic to the post-conflict health reforms in Uganda and their relevance to current health outcomes, the national AIDS response and health systems strengthening. The literature review also examines the human resources for health (HRH) crisis and task shifting in the scaling up of ART in high-burden resource-limited settings. In addition, the review looks at the evolution of complementary HIV service delivery models like community and home-based care as a spontaneous response to the HIV epidemic in many resource-limited settings including Uganda. Finally, the literature documents that, there are relatively few paediatric HIV services in the country, leading to poor geographical access and a low antiretroviral therapy (ART) coverage for children and that, HIV-infected children and in particular, AIDS orphans are an underserved and an understudied population. At the time of this thesis, approximately 2,100 infants, children and adolescents had been enrolled into care in the TFP; about 1140 were active in care, and about 60% were on ART. Approximately, 47% of children and adolescents in the project are orphans. This thesis therefore aims at contributing to improving paediatric HIV management through operational research in the context of a CHBC model in Kampala, Uganda. The findings cover key outcomes such as retention in care, attrition and loss to follow up (LTFU), treatment failure, mortality on antiretroviral therapy (ART) and operationalization of dried blood spots (DBS) for viral load testing among HIV-infected children. The thesis also included a specific study on HIV-Epstein-Barr Virus (EBV) co infections in children and adolescents, considered relevant to the project setting. Except for study 5 (EBV study) which was a cross-sectional study, the studies were generally retrospective cohort studies conducted at the Home Care Department of Nsambya Hospital in Kampala, Uganda. The methodology of the operational research was based on an implementation schema derived from the ART guidelines of the WHO and Uganda (Figure 17). The selection of the outcomes for the operational research was based on the rationale that, they have direct bearings on implementation and potentially could improve the same. The findings and implications from the six studies that constitute the chapters of the thesis are summarized as follows: Study 1: This retrospective observational study compared HIV and TB outcomes from adults and children in the Nsambya CHBC with national averages from 2007-2011. The core findings show that Nsambya CHBC activities enhance and complement national HIV and TB management, and resulted in better outcomes when compared to the national averages. This approach may hold the potential for chronic disease management in resource-limited settings. Scaling up CHBC could have wider positive impacts on the management of not only HIV and TB, but also other chronic diseases as well as the general health system. A long-standing “faith-based solidarity” among international donors and partners has been pivotal to the survival and evolution of the Nsambya CHBC. Study 2: This is a retrospective cohort analysis of attrition and LTFU and their predictors among children and adolescents aged 0-20 years. Over the study period, 5.34% (62) of patients died, 37.61% (437) were LTFU, and thus overall attrition was 42.94% (499). Generally, attrition and LTFU were relatively high among children and adolescents in the TFP. Not receiving ART was the single factor significantly associated with attrition in the cohort, while both baseline BMI z-scores and receipt of ART were protective against LTFU among HIV positive children and adolescents. Efforts should be made to initiate ART among all paediatric patients as soon as possible, and to provide aggressive follow-up for those not yet receiving ART. Orphans need more nutritional support to reduce the burden of malnutrition and improved access to early ART, which could also promote growth responses in this vulnerable and understudied group. Study 3: This retrospective cohort study reviewed records from HIV positive children age 0 to 18 years engaged in a CHBC and a Facility-based, family-centred approach (FBFCA) from 2003 to 2010 focussing on retention in care, loss to follow-up, mortality, use of ART, and clinical characteristics. Irrespective of model of care, children receiving ART had better retention in care and therefore long-term survival. Encouragingly, if children were on ART, then their survival was as good, if not slightly better, in the CHBC compared to the FBFCA. Based on our observations, substantial improvement in child survival can be achieved in either a community-based or a family-care model as long as HIV- infected children are identified early and begun on ART. To ensure this occurs, early identification of HIV infected children requires strong linkages of pregnant HIV- infected women to prevention of mother to child transmission (PMTCT) services; active tracking to ensure all HIV exposed infants receive Polymerase Chain Reaction-based early infant diagnosis. Additionally, rapid early initiation of ART among HIV infected infants and children are essential. Study 4: This is an observational study that included HIV-infected children attending the Beira Central Hospital (Mozambique) and the Nsambya Hospital, Home Care Department (Uganda), and evaluated clinical and immunological failure according to the WHO 2006 guidelines. Two hundred and eighteen of 740 children with at least 24 weeks follow-up experienced treatment failure ((29% 95%CI (26-33)), with crude incidence of 20.0 events per 100 person-years (95%CI 17.5-22.9). Having tuberculosis co-infection or WHO stage 4, or starting a non-triple cART significantly increased the risk of failure. Drug toxicity (18.3%), drug availability (17.3%) and anti-tuberculosis drug interactions (52, 25.7%) were the main reported reasons while only 9 (4%) patients switched cART for clinical or immunological failure. Considerable delay in switching to second line cART may occur despite an observed high rate of treatment failure. Our findings reinforce the need for simplification of more effective clinical and immunological criteria for prompt recognition of cART treatment failure. Children presenting with advanced disease and TB co-infection should be targeted for closer and more sensitive monitoring of treatment response. This should be matched with a constant provision of appropriate antiretroviral drugs with optimization of first line drugs and treatment sequencing. Supply of new paediatric formulations for second line regimens and drug optimization should be considered as critical milestones to allow scaling up of early cART and reduction of treatment failure in children. Study 5: In this cross-sectional study, dried blood spot (DBS) samples from 213 HIV-1 infected children were collected and EBV DNA was extracted and analysed for quantification of EBV types 1 and 2 and for quantification of 16S ribosomial DNA (16S rDNA), a marker of microbial translocation. Ninety-two of 140(66%) children on ART and 57 of 73(78%) ART-naive children had detectable EBV levels. Co-infection with both EBV types was significantly less frequent in ART-treated than in ART-naïve children (OR=0.54, 95%CI 0.30;0.98, p=0.042). HIV-1 inducing microbial translocation and a state of persistent immune activation, may lead to EBV replication and expansion of EBV-infected B-cells, thus increasing the EBV-DNA load. Super-infection by both types of EBV in HIV-1 infected subjects may represent an additional risk for the onset of EBV-related malignancies. ART, by limiting HIV-1 replication, microbial translocation and related immune activation, may prevent super-infection by both EBV types and keep EBV viremia down, thus reducing the risk of EBV-associated lymphomas. Study 6: This was a retrospective study to evaluate viral load (VL) using DBS and to explore the accuracy of clinical and immunological criteria for treatment failure (TF) in a cohort of HIV-1-infected children. In this cohort, immunological and clinical criteria as per WHO 2010 guidelines poorly predicted the presence of a viral load greater than either 1000 cp/ml or 5000 cp/ml (whole blood) from DBS. The low sensitivity and positive predictive values for immunological and/or clinical failure confirm those reported by the literature. This finding further supports the WHO recommendations that VL monitoring should be implemented and used to identify cases of treatment failure earlier. Policy implications of key findings of thesis Scaling up CHBC could have wider positive impacts on the management of not only HIV and TB, but also other chronic diseases as well as the general health system. In this thesis, and in line with the literature, Early ART initiation was associated with improved survival and retention in both community-based and facility-based approaches. ART is potentially protective against EBV-related lymphoproliferative disorders in HIV-EBV co infected children. This calls for early ART initiation and close monitoring in such children. Operationalization of the use of DBS in viral load monitoring in HIV-infected children in low and middle-income countries is feasible and should be encouraged to improve the quality of paediatric HIV management in such settings. The low ART coverage among children calls for urgent, greater and more effective decentralization of paediatric ART services within primary health care services at the district and sub-district levels in the general health system in Uganda. Children presenting with advanced HIV disease and TB co-infection should be targeted for closer and more sensitive monitoring of treatment response. Orphans need more nutritional support to reduce the burden of malnutrition and improved access to early ART, which in turn could promote growth responses in this vulnerable and understudied grou

Predictors of Treatment Failure in HIV-Positive Children Receiving Combination Antiretroviral Therapy: Cohort Data From Mozambique and Uganda

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Community health workers for ART in sub-Saharan Africa: learning from experience – capitalizing on new opportunities

Low-income countries with high HIV/AIDS burdens in sub-Saharan Africa must deal with severe shortages of qualified human resources for health. This situation has triggered the renewed interest in community health workers, as they may play an important role in scaling-up antiretroviral treatment for HIV/AIDS by taking over a number of tasks from the professional health workers. Currently, a wide variety of community health workers are active in many antiretroviral treatment delivery sites

Community and Home-Based Care HIV Service Delivery Model in the Context of Paediatric HIV Management and Contributing to Health Systems Strengthening in a Resource-Limited Setting (Uganda): Operational Research

This thesis is about the Tukula Fenna Project (TFP) that was set up at the Home Care Department of St. Raphael of St Francis Hospital (Nsambya Hospital) in Kampala, Uganda. In 2003, Associazione Casa Accoglienza alla vita “Padre Angelo” (ACAVPA) or “HOUSE FOR LIFE, Father Angelo” and other Italian partners; in particular, PENTA Foundation and University of Padova, Department of paediatrics collectively signed a memorandum of understanding (MoU) with Nsambya Hospital. The aim of the MoU was to collaborate with the hospital in the fight against HIV particularly in children and adolescents, orphans and vulnerable children (OVC) and their families in Kampala and three surrounding districts (Mukono, Wakiso and Mpigi). Thus, the MoU officially established the children’s HIV programme at Nsambya Hospital, Home Care Department in 2003. The programme was then called the “PCP Project” because the initial intervention was among other things, providing Cotrimoxazole prophylaxis against Pneumocystis Carinii pneumonia (PCP, also known as Jiroveci Pneumonia). As more resources including provision of antiretroviral drugs (ARVs) from external sources and expertise became available over the years, the project evolved into a full-blown HIV programme for infants, children and adolescents as well as their families and caretakers. Additionally, the name “PCP”, was replaced by “Tukula Fenna”, which means “growing up together” in the local language (Luganda). The project was implemented at the Home Care Department within an existing community home-based care (CHBC) model that evolved in response to the HIV epidemic in Uganda, and other high-burden resource-limited settings. The TFP provides comprehensive HIV care, treatment and psychosocial support services (PSS) and apart from operating at the Home Care department of Nsambya Hospital, it also operates at Ggaba Parish Outreach Clinic and 3 other outreach clinics in and around Kampala. This thesis describes the research outcomes of the project that was managed by Dr. Massavon from 2008 to 2013. It reviews the published literature from the key milestones of the HIV epidemic to the post-conflict health reforms in Uganda and their relevance to current health outcomes, the national AIDS response and health systems strengthening. The literature review also examines the human resources for health (HRH) crisis and task shifting in the scaling up of ART in high-burden resource-limited settings. In addition, the review looks at the evolution of complementary HIV service delivery models like community and home-based care as a spontaneous response to the HIV epidemic in many resource-limited settings including Uganda. Finally, the literature documents that, there are relatively few paediatric HIV services in the country, leading to poor geographical access and a low antiretroviral therapy (ART) coverage for children and that, HIV-infected children and in particular, AIDS orphans are an underserved and an understudied population. At the time of this thesis, approximately 2,100 infants, children and adolescents had been enrolled into care in the TFP; about 1140 were active in care, and about 60% were on ART. Approximately, 47% of children and adolescents in the project are orphans. This thesis therefore aims at contributing to improving paediatric HIV management through operational research in the context of a CHBC model in Kampala, Uganda. The findings cover key outcomes such as retention in care, attrition and loss to follow up (LTFU), treatment failure, mortality on antiretroviral therapy (ART) and operationalization of dried blood spots (DBS) for viral load testing among HIV-infected children. The thesis also included a specific study on HIV-Epstein-Barr Virus (EBV) co infections in children and adolescents, considered relevant to the project setting. Except for study 5 (EBV study) which was a cross-sectional study, the studies were generally retrospective cohort studies conducted at the Home Care Department of Nsambya Hospital in Kampala, Uganda. The methodology of the operational research was based on an implementation schema derived from the ART guidelines of the WHO and Uganda (Figure 17). The selection of the outcomes for the operational research was based on the rationale that, they have direct bearings on implementation and potentially could improve the same. The findings and implications from the six studies that constitute the chapters of the thesis are summarized as follows: Study 1: This retrospective observational study compared HIV and TB outcomes from adults and children in the Nsambya CHBC with national averages from 2007-2011. The core findings show that Nsambya CHBC activities enhance and complement national HIV and TB management, and resulted in better outcomes when compared to the national averages. This approach may hold the potential for chronic disease management in resource-limited settings. Scaling up CHBC could have wider positive impacts on the management of not only HIV and TB, but also other chronic diseases as well as the general health system. A long-standing “faith-based solidarity” among international donors and partners has been pivotal to the survival and evolution of the Nsambya CHBC. Study 2: This is a retrospective cohort analysis of attrition and LTFU and their predictors among children and adolescents aged 0-20 years. Over the study period, 5.34% (62) of patients died, 37.61% (437) were LTFU, and thus overall attrition was 42.94% (499). Generally, attrition and LTFU were relatively high among children and adolescents in the TFP. Not receiving ART was the single factor significantly associated with attrition in the cohort, while both baseline BMI z-scores and receipt of ART were protective against LTFU among HIV positive children and adolescents. Efforts should be made to initiate ART among all paediatric patients as soon as possible, and to provide aggressive follow-up for those not yet receiving ART. Orphans need more nutritional support to reduce the burden of malnutrition and improved access to early ART, which could also promote growth responses in this vulnerable and understudied group. Study 3: This retrospective cohort study reviewed records from HIV positive children age 0 to 18 years engaged in a CHBC and a Facility-based, family-centred approach (FBFCA) from 2003 to 2010 focussing on retention in care, loss to follow-up, mortality, use of ART, and clinical characteristics. Irrespective of model of care, children receiving ART had better retention in care and therefore long-term survival. Encouragingly, if children were on ART, then their survival was as good, if not slightly better, in the CHBC compared to the FBFCA. Based on our observations, substantial improvement in child survival can be achieved in either a community-based or a family-care model as long as HIV- infected children are identified early and begun on ART. To ensure this occurs, early identification of HIV infected children requires strong linkages of pregnant HIV- infected women to prevention of mother to child transmission (PMTCT) services; active tracking to ensure all HIV exposed infants receive Polymerase Chain Reaction-based early infant diagnosis. Additionally, rapid early initiation of ART among HIV infected infants and children are essential. Study 4: This is an observational study that included HIV-infected children attending the Beira Central Hospital (Mozambique) and the Nsambya Hospital, Home Care Department (Uganda), and evaluated clinical and immunological failure according to the WHO 2006 guidelines. Two hundred and eighteen of 740 children with at least 24 weeks follow-up experienced treatment failure ((29% 95%CI (26-33)), with crude incidence of 20.0 events per 100 person-years (95%CI 17.5-22.9). Having tuberculosis co-infection or WHO stage 4, or starting a non-triple cART significantly increased the risk of failure. Drug toxicity (18.3%), drug availability (17.3%) and anti-tuberculosis drug interactions (52, 25.7%) were the main reported reasons while only 9 (4%) patients switched cART for clinical or immunological failure. Considerable delay in switching to second line cART may occur despite an observed high rate of treatment failure. Our findings reinforce the need for simplification of more effective clinical and immunological criteria for prompt recognition of cART treatment failure. Children presenting with advanced disease and TB co-infection should be targeted for closer and more sensitive monitoring of treatment response. This should be matched with a constant provision of appropriate antiretroviral drugs with optimization of first line drugs and treatment sequencing. Supply of new paediatric formulations for second line regimens and drug optimization should be considered as critical milestones to allow scaling up of early cART and reduction of treatment failure in children. Study 5: In this cross-sectional study, dried blood spot (DBS) samples from 213 HIV-1 infected children were collected and EBV DNA was extracted and analysed for quantification of EBV types 1 and 2 and for quantification of 16S ribosomial DNA (16S rDNA), a marker of microbial translocation. Ninety-two of 140(66%) children on ART and 57 of 73(78%) ART-naive children had detectable EBV levels. Co-infection with both EBV types was significantly less frequent in ART-treated than in ART-naïve children (OR=0.54, 95%CI 0.30;0.98, p=0.042). HIV-1 inducing microbial translocation and a state of persistent immune activation, may lead to EBV replication and expansion of EBV-infected B-cells, thus increasing the EBV-DNA load. Super-infection by both types of EBV in HIV-1 infected subjects may represent an additional risk for the onset of EBV-related malignancies. ART, by limiting HIV-1 replication, microbial translocation and related immune activation, may prevent super-infection by both EBV types and keep EBV viremia down, thus reducing the risk of EBV-associated lymphomas. Study 6: This was a retrospective study to evaluate viral load (VL) using DBS and to explore the accuracy of clinical and immunological criteria for treatment failure (TF) in a cohort of HIV-1-infected children. In this cohort, immunological and clinical criteria as per WHO 2010 guidelines poorly predicted the presence of a viral load greater than either 1000 cp/ml or 5000 cp/ml (whole blood) from DBS. The low sensitivity and positive predictive values for immunological and/or clinical failure confirm those reported by the literature. This finding further supports the WHO recommendations that VL monitoring should be implemented and used to identify cases of treatment failure earlier. Policy implications of key findings of thesis Scaling up CHBC could have wider positive impacts on the management of not only HIV and TB, but also other chronic diseases as well as the general health system. In this thesis, and in line with the literature, Early ART initiation was associated with improved survival and retention in both community-based and facility-based approaches. ART is potentially protective against EBV-related lymphoproliferative disorders in HIV-EBV co infected children. This calls for early ART initiation and close monitoring in such children. Operationalization of the use of DBS in viral load monitoring in HIV-infected children in low and middle-income countries is feasible and should be encouraged to improve the quality of paediatric HIV management in such settings. The low ART coverage among children calls for urgent, greater and more effective decentralization of paediatric ART services within primary health care services at the district and sub-district levels in the general health system in Uganda. Children presenting with advanced HIV disease and TB co-infection should be targeted for closer and more sensitive monitoring of treatment response. Orphans need more nutritional support to reduce the burden of malnutrition and improved access to early ART, which in turn could promote growth responses in this vulnerable and understudied groupQuesta tesi descrive il Progetto Fenna Tukula (TFP) in corso presso il Home Care Department dell'Ospedale St. Raphael e St. Francis (Nsambya Hospital) a Kampala (Uganda). Nel 2003, l'Associazione Casa Accoglienza alla Vita "Padre Angelo" (ACAVPA) insieme ad altri Partner (in particolare la Fondazione PENTA e l'Università di Padova), hanno firmato una lettera di intenti con il Nsambya Hospital. L'obiettivo di questo documento era di collaborare con l'ospedale nella lotta all'AIDS nei bambini ed adolescenti, orfani (OVC) e le loro famiglie a Kampala e nei distretti circostanti di Mukono, Wakiso e Mpigi. Il progetto è stato chiamato inizialmente "PCP project" in quanto l'intervento consisteva essenzialmente nella profilassi con il Cotrimoxazole per la prevenzione della polmonite da Pneumocystis Carinii (conosciuta anche come Jiroveci Pneumonia). Dopo due anni dall’inizio del progetto grazie ad una aumentata disponibilita’ di risorse e’ stato possibile fornire ai bambini che ne avevano necessita’ la terapia con farmaci antiretrovirali (ARVs) da e quindi il progetto si e’ inidirizzato verso un programma 'tout-court' di lotta all'AIDS pediatrico con un approccio globale, che includeva anche le famiglie e non solamente i bambini. Di conseguenza, il nome "PCP" è stato rimpiazzato da "Tukula Fenna", che significa "crescere insieme" nella lingua locale (luganda). Il progetto si e’ caratterizzato con l’implementazione di un modello di cure domiciliari (CHBC) adattato alla realta’ dell’ Uganda andando quindi oltre i confini dello NHC fino a comprendere delle strutture periferiche tra cui la Clinica della Parrocchia di Ggaba ed altre 3 cliniche nei dintorni di Kampala. Questa tesi descrive i risultati dell’ attivita’ di ricerca svolta nell’ ambito del progetto che è stato coordinato dal Dr. Massavon tra il 2008 e il 2013. La tesi si articola in una prima parte di revisione della letteratura con particolare riferimento alla realta’ ugandese sia da un punto di vista dell’ epidemiologia dell’ HIV che dell’ organizzazione sanitaria nel paese con particolare riferimento all'evoluzione dei modelli sanitari finalizzati alla lotta all'AIDS, come modelli di cura comunitaria o domiciliari. L’ analisi della letteratura ha documentato che, in Uganda vi sono relativamente pochi servizi specialistici sull’ HIV pediatrico. Tale aspetto ha come conseguenza una disparita’ tra le varie regioni del paese e un limitato accesso alla terapia antiretrovirale per i bambini soprattutto coloro che sono senza genitori naturali. A dicembre 2013 circa 2.100 bambini ed adolescenti sono stati arruolati nel TFP. 1.140 sono seguiti regolarmente e il 60% di loro sono in terapia con ART. Il 47% dei bambini è orfano. La finalita’ ultima della tesi e’ quello di contribuire al miglioramento delle cure nei bambini HIV positivi in Uganda attraverso la valutazione di un modello di assistenza domiciliare. In quest’ ottica l’ attivita’ di ricerca si e’ articolata nella valutazione delle caratteristiche dei pazienti persi al follow-up, dell’ outcome della terapia antiretrovirale e, in un ambito piu’ prettamente clinico, nello studio dell’ impatto della infezione da EBV sulla progressione della malattia da HIV. L’ attivita’ si e’ sviluppata attorno diverse linee di ricerca i cui risultati sono stati pubblicati (o in corso di pubblicazione) nei lavori i cui elementi fondamentali sono riassunti di seguito: Studio 1: Studio osservazionale retrospettivo che analizza i risultati del follow-up dei pazienti con HIV e TB (adulti e bambini) seguiti presso lo Nsambya Hospital confrontandoli con i dati nazionali tra il 2007 e il 2011. I risultati mostrano che il modello seguito allo Nsambya ha prodotto migliori risultati in termini di morbilita’ e mortalita’ rispetto alle medie nazionali. Il modello descritto basato sull’ assistenza domiciliare potrebbe essere utilizzato anche in altri contesti nei paesi in via di sviluppo. Studio 2: Analisi di coorte retrospettiva per la valutazione delle caratteristiche dei pazienti persi al follow up (LTFU) e dei fattori di rischio associati, nei bambini ed adolescenti tra 0 e 20 anni. Nel corso del periodo di follow up considerato, il 5,3% dei pazienti è deceduto, il 37,6% e’ stato perso al follow-up con un “attritio” globale del 42,9%. In generale, LTFU sono stati relativamente alti tra i bambini e gli adolescenti nel TFP. La terapia con ARV e la crescita regolare sono stati fattori associati con la permanenza in follow up e con la sopravvivenza. Tali osservazioni suggeriscono come gli sforzi dovrebbero essere indirizzati ad iniziare la ART nei pazienti pediatrici il prima possibile, e a fornire un follow-up regolare a coloro che non sono ancora in terapia. Particolare attenzione va data agli orfani che necessitano di un supporto alimentare particolarmente attento e di un follow up regolare per definire il momento migliore quando iniziare la ART. Studio 3: Studio di coorte retrospettivo che ha studiato i bambini HIV positivi tra 0 e 18 anni inseriti in un programma di assistenza domiciliare con un approccio centrato sulla famiglia (FBFCA) dal 2003 al 2010, focalizzandosi sulla perdita al follow-up, la mortalità, l'uso di ART e le caratteristiche cliniche. A prescindere dal modello di cura, i bambini che ricevevano l'ART sono seguiti piu’ regolarmente e di conseguenza hanno una sopravvivenza a lungo termine maggiore. Basandosi sulle nostre osservazioni, un miglioramento sostanziale nella sopravvivenza dei bambini può essere raggiunto sia con un modello basato sulla assistenza domiciliare che sul coinvolgimento attivo della comunita’. Studio 4: Studio osservazionale prospettico che ha incluso bambini HIV positivi assistiti presso il Beira Central Hospital, in Mozambico e lo Nsambya Hospital, che ha valutato il rischio di fallimento immunologico e clinico secondo le linee guida del WHO del 2006. 218 su 740 bambini con almeno 24 settimane di follow-up ha avuto un fallimento della terapia ((29% 95% CI (26-33)), con una incidenza di 20.0 eventi su 100 anni-persona (95%CI 17.5-22.9). La coinfezione con la TB, la presenza di AIDS (WHO stadio 4), o l’inizio della ART con uno o due farmaci aumenta significativamente il rischio di fallimento terapeutico. Un ritardo considerevole nel passaggio alla seconda linea di cART si e’ osservato nonostante un alto tasso di fallimento terapeutico. Tali osservazioni sottolineano ancora una volta l’importanza di garantire un efficace monitoraggio clinico e immunolgico per poter modificare la terapia prima che insorgano ceppi virali resistenti. Insieme alla necessita’ di un corretto monitoraggio va sottolineata l’importanza di garantire una fornitura di farmaco regolare senza interruzioni e le formulazioni pediatriche per i bambini piu’ piccoli Studio 5: Studio trasversale, effettuato su campioni raccolti in cartoncini assorbenti (DBS) prelevati da 243 bambini affetti da HIV-1 da cui e’ stato estratto il DNA del EBV per analisi e quantificazione dei tipi 1 e 2, e per la quantificazione di 16s DNA ribosomiale (16S rDNA), un marker di traslocazione microbica. 92 su 140 (66%) dei bambini in terapia con ART e 57 su 73 (78%) di bambini non trattati sono risultati positivi all’ EBV. La coinfezione con entrambi i tipi di EBV è stata significativamente meno frequente in coloro in terapia con ART (OR=0.54, 95%CI 0.30; 0.98, p=0.042). Tale osservazione e’ compatibile con il fatto che ' HIV-1, che induce una traslocazione microbica e uno stato di persistente attivazione immunitaria, può portare a una replicazione di EBV ed ad una espansione di cellule B infette, aumentando di conseguenza il DNA dell'EBV. La co-infezione da EBV in soggetti affetti da HIV-1 può rappresentare un rischio addizionale per lo scatenarsi di tumori (linfomi) associati al EBV. Il trattamento con ART, riducendo la replicazione dell’ HIV-1, la traslocazione microbica e la relativa attivazione immunitaria, può prevenire la super infezione da EBV e mantenere la viremia EBV bassa, riducendo il rischio di linfomi ad esso associata. Studio 6: Studio retrospettivo per valutare la carica virale dell’HIV (VL) su campioni raccolti in DBS e per esplorare l'accuratezza dei criteri clinici ed immunologici per la definizione del fallimento terapeutico. La bassa sensibilità e valore predittivo del fallimento clinico e/o immunologico, da noi osservate, confermano quanto riportato in letteratura. Questa osservazione supporta ulteriormente la raccomandazione del WHO che il monitoraggio della carica virale debba essere implementato ed utilizzato per identificare precocemente casi di fallimento del trattamento. Implicazioni dei risultati della tesi e messaggi chiave Il modello assistenziale centrato sull’ assistenza domiciliare e’ risultato molto efficace per ridurre il rischio di perdita al follow up. Tale modello potrebbe quindi essere considerato anche per l’assistenza dei malati di TB o con altre malattie croniche. Le nostre osservazioni supportano quanto gia’ riportato in letteratura che l’inizio precoce dell’ ART e’ era associato non solo aduna migliore sopravvivenza ma anche ad un minor rischio di perdita al follow up. Il trattamento ART è potenzialmente protettivo contro patologie linfoproliferative correlate al EBV nei bambini con coinfezione da HIV ed EBV. L’uso del DBS per il monitoraggio della carica virale nei bambini HIV positivi si e’ rivelato fattibile sia da un punto di vista organizzativo che della qualita’ dei campioni da testare. Tale metodica dovrebbe quindi essere incoraggiata per migliorare la qualità della gestione pediatrica dell'HIV soprattutto nei paesi in via di sviluppo La bassa copertura di ART

Nsambya Community Home-Based Care Complements National HIV and TB Management Efforts and Contributes to Health Systems Strengthening in Uganda: An Observational Study

Community Home-Based Care (CHBC) has evolved in resource-limited settings to fill the unmet needs of people living with HIV/AIDS (PLHA). We compare HIV and tuberculosis (TB) outcomes from the Nsambya CHBC with national averages in Kampala, Uganda. This retrospective observational study compared HIV and TB outcomes from adults and children in the Nsambya CHBC to national averages from 2007 to 2011. Outcomes included numbers of HIV and TB patients enrolled into care, retention, loss to follow-up (LTFU), and mortality among patients on antiretroviral therapy (ART) at 12 months from initiation; new smear-positive TB cure and defaulter rates; and proportion of TB patients tested for HIV. Chi-square test and trends analyses were used to compare outcomes from Nsambya CHBC with national averages. By 2011, approximately 14,000 PLHA had been enrolled in the Nsambya CHBC, and about 4,000 new cases of TB were detected and managed over the study period. Overall, retention and LTFU of ART patients 12 months after initiation, proportion of TB patients tested for HIV, and cure rates for new smear-positive TB scored higher in the Nsambya CHBC compared to national averages. The findings show that Nsambya CHBC complements national HIV and TB management and results in more positive outcomes

Effects of demand-side incentives in improving the utilisation of delivery services in Oyam District in northern Uganda: a quasi-experimental study

Abstract Background We evaluated the effects and financial costs of two interventions with respect to utilisation of institutional deliveries and other maternal health services in Oyam District in Uganda. Methods We conducted a quasi-experimental study involving intervention and comparable/control sub-counties in Oyam District for 12 months (January–December 2014). Participants were women receiving antenatal care, delivery and postnatal care services. We evaluated two interventions: the provision of (1) transport vouchers to women receiving antenatal care and delivering at two health centres (level II) in Acaba sub-county, and (2) baby kits to women who delivered at Ngai Health Centre (level III) in Ngai sub-county. The study outcomes included service coverage of institutional deliveries, four antenatal care visits, postnatal care, and the percentage of women ‘bypassing’ maternal health services inside their resident sub-counties. We calculated the effect of each intervention on study outcomes using the difference in differences analysis. We calculated the cost per institutional delivery and the cost per unit increment in institutional deliveries for each intervention. Results Overall, transport vouchers had greater effects on all four outcomes, whereas baby kits mainly influenced institutional deliveries. The absolute increase in institutional deliveries attributable to vouchers was 42.9%; the equivalent for baby kits was 30.0%. Additionally, transport vouchers increased the coverage of four antenatal care visits and postnatal care service coverage by 60.0% and 49.2%, respectively. ‘Bypassing’ was mainly related to transport vouchers and ranged from 7.2% for postnatal care to 11.9% for deliveries. The financial cost of institutional delivery was US$9.4 per transport voucher provided, and US$10.5 per baby kit. The incremental cost per unit increment in institutional deliveries in the transport-voucher system was US$15.9; the equivalent for the baby kit was US$30.6. Conclusion The transport voucher scheme effectively increased utilisation of maternal health services whereas the baby-kit scheme was only effective in increasing institutional deliveries. The transport vouchers were less costly than the baby kits in the promotion of institutional deliveries. Such incentives can be sustainable if the Ministry of Health integrates them in the health system

Thermal effect of a woolen cap in low birth weight infants during kangaroo care

BACKGROUND AND OBJECTIVES: World Health Organization guidelines recommend covering the head during kangaroo mother care (KMC), but the effect of a cap on neonatal thermal control during KMC remains to be defined. Our objective was to assess the effectiveness and safety of a woolen cap in maintaining low birth weight infants (LBWIs) in normal thermal range during KMC. METHODS: Three hundred LBWI candidates for KMC in 3 African hospitals were randomly assigned to KMC with (CAP group) or without (NOCAP group) a woolen cap in a 1:1 ratio during the first week after birth. Axillary temperature was measured every 6 hours. Maternal and room temperature and adherence to skin-to-skin contact were registered at the same time points. RESULTS: A total number of 5064 measurements were recorded (median 19 measurements per subject; interquartile range: 10\u201325). Mean time spent in normal temperature range was 55% (SD 24) in CAP and 56% (SD 24) in NOCAP groups. Multivariable analysis estimated a rate ratio of 0.92 (95% confidence interval: 0.84 to 1.00; P = .06) for the effect of the cap versus no cap on time spent in the normal temperature range. CONCLUSIONS: In these 3 African, low-resource settings and so many days post birth, the use of a woolen cap was safe but provided no advantages in maintaining LBWI in the normal thermal range while being in a KMC ward. LBWIs spent only half of the time in the normal temperature range despite warm rooms and skin-to-skin contact. Maintaining normothermia in LBWIs remains an unfinished challenge in low-resource settings

Epstein-Barr virus load in children infected with human immunodeficiency virus type 1 in Uganda.

BACKGROUND: Epstein-Barr Virus (EBV) is involved in a wide range of malignancies, particularly in immunocompromised subjects. In Africa, EBV primary infection occurs during early childhood, but little is known about the EBV load in Human Immunodeficiency Virus type 1 (HIV-1)-infected children. METHODS: Blood samples from 213 HIV-1-infected children, 140 of whom were receiving antiretroviral therapy (ART), were collected at the Nsambya Hospital in Kampala, Uganda, and obtained for dried blood spot analysis. Nucleic acids were extracted and analyzed for quantification of EBV types 1 and 2; 16S ribosomal DNA (rDNA), a marker of microbial translocation; and HIV-1 RNA. RESULTS: Ninety-two of 140 children (66%) receiving ART and 57 of 73 ART-naive children (78%) had detectable EBV DNA levels. Coinfection with both EBV types was less frequent in ART-treated children than in ART-naive children (odds ratio, 0.54 [95% confidence interval {CI}, .30-.98]; P = .042). Mean EBV DNA levels (±standard deviation) were lower in the former (3.99 ± 0.59 vs 4.22 ± 0.54 log10 copies/mL; P = .006) and tended to be inversely associated with ART duration. EBV DNA levels were higher in children with an HIV-1 RNA load of > 3 log10 copies/mL of blood (regression coefficient, 0.32 [95% CI, .05-.59]; P = .020) and correlated with circulating 16S rDNA levels (rs = 0.25 [95% CI, .02-.46]; P = .031). CONCLUSIONS: These findings suggest that ART, by limiting HIV-1 replication, microbial translocation, and related immune activation, prevents superinfection with both EBV types and keeps EBV viremia down, thus potentially reducing the risk of EBV-associated lymphomas