Effect of isoniazid preventive therapy on risk of death in west African, HIV-infected adults with high CD4 cell counts: long-term follow-up of the Temprano ANRS 12136 trial

Temprano ANRS 12136 was a factorial 2 × 2 trial that assessed the benefits of early antiretroviral therapy (ART; ie, in patients who had not reached the CD4 cell count threshold used to recommend starting ART, as per the WHO guidelines that were the standard during the study period) and 6-month isoniazid preventive therapy (IPT) in HIV-infected adults in Côte d'Ivoire. Early ART and IPT were shown to independently reduce the risk of severe morbidity at 30 months. Here, we present the efficacy of IPT in reducing mortality from the long-term follow-up of Temprano. Methods For Temprano, participants were randomly assigned to four groups (deferred ART, deferred ART plus IPT, early ART, or early ART plus IPT). Participants who completed the trial follow-up were invited to participate in a post-trial phase. The primary post-trial phase endpoint was death, as analysed by the intention-to-treat principle. We used Cox proportional models to compare all-cause mortality between the IPT and no IPT strategies from inclusion in Temprano to the end of the follow-up period. Findings Between March 18, 2008, and Jan 5, 2015, 2056 patients (mean baseline CD4 count 477 cells per μL) were followed up for 9404 patient-years (Temprano 4757; post-trial phase 4647). The median follow-up time was 4·9 years (IQR 3·3–5·8). 86 deaths were recorded (Temprano 47 deaths; post-trial phase 39 deaths), of which 34 were in patients randomly assigned IPT (6-year probability 4·1%, 95% CI 2·9–5·7) and 52 were in those randomly assigned no IPT (6·9%, 5·1–9·2). The hazard ratio of death in patients who had IPT compared with those who did not have IPT was 0·63 (95% CI, 0·41 to 0·97) after adjusting for the ART strategy (early vs deferred), and 0·61 (0·39–0·94) after adjustment for the ART strategy, baseline CD4 cell count, and other key characteristics. There was no evidence for statistical interaction between IPT and ART (pinteraction=0·77) or between IPT and time (pinteraction=0·94) on mortality. Interpretation In Côte d'Ivoire, where the incidence of tuberculosis was last reported as 159 per 100 000 people, 6 months of IPT has a durable protective effect in reducing mortality in HIV-infected people, even in people with high CD4 cell counts and who have started ART

Impact of Drug Stock-Outs on Death and Retention to Care among HIV-Infected Patients on Combination Antiretroviral Therapy in Abidjan, Côte d'Ivoire

To evaluate the type and frequency of antiretroviral drug stock-outs, and their impact on death and interruption in care among HIV-infected patients in Abidjan, Côte d'Ivoire.We conducted a cohort study of patients who initiated combination antiretroviral therapy (cART) in three adult HIV clinics between February 1, 2006 and June 1, 2007. Follow-up ended on February 1, 2008. The primary outcome was cART regimen modification, defined as at least one drug substitution, or discontinuation for at least one month due to drug stock-outs at the clinic pharmacy. The secondary outcome for patients who were on cART for at least six months was interruption in care, or death. A Cox regression model with time-dependent variables was used to assess the impact of antiretroviral drug stock-outs on interruption in care or death. Overall, 1,554 adults initiated cART and were followed for a mean of 13.2 months. During this time, 72 patients discontinued treatment and 98 modified their regimen because of drug stock-outs. Stock-outs involved nevirapine and fixed-dose combination zidovudine/lamivudine in 27% and 51% of cases. Of 1,554 patients, 839 (54%) initiated cART with fixed-dose stavudine/lamivudine/nevirapine and did not face stock-outs during the study period. Among the 975 patients who were on cART for at least six months, stock-out-related cART discontinuations increased the risk of interruption in care or death (adjusted hazard ratio [HR], 2.83; 95%CI, 1.25-6.44) but cART modifications did not (adjusted HR, 1.21; 95%CI, 0.46-3.16).cART stock-outs affected at least 11% of population on treatment. Treatment discontinuations due to stock-outs were frequent and doubled the risk of interruption in care or death. These stock-outs did not involve the most common first-line regimen. As access to cART continues to increase in sub-Saharan Africa, first-line regimens should be standardized to decrease the probability of drug stock-outs

PLoS One

INTRODUCTION: The Temprano and START trials provided evidence to support early ART initiation recommendations. We projected long-term clinical and economic outcomes of immediate ART initiation in Cote d'Ivoire. METHODS: We used a mathematical model to compare three potential ART initiation criteria: 1) CD4 <350/muL (ART<350/muL); 2) CD4 <500/muL (ART<500/muL); and 3) ART at presentation (Immediate ART). Outcomes from the model included life expectancy, 10-year medical resource use, incremental cost-effectiveness ratios (ICERs) in $/year of life saved (YLS), and 5-year budget impact. We simulated people with HIV (PWH) in care (mean CD4: 259/muL, SD 198/muL) and transmitted cases. Key input parameters to the analysis included first-line ART efficacy (80$90/person-year). We assessed cost-effectiveness relative to Cote d'Ivoire's 2017 per capita annual gross domestic product ($1,600). RESULTS: Immediate ART increased life expectancy by 0.34 years compared to ART<350/muL and 0.17 years compared to ART<500/muL. Immediate ART resulted in 4,500 fewer 10-year transmissions per 170,000 PWH compared to ART<350/muL. In cost-effectiveness analysis, Immediate ART had a 10-year ICER of$680/YLS compared to ART<350/muL, ranging from cost-saving to an ICER of $1,440/YLS as transmission rates varied. ART<500/muL was "dominated" (an inefficient use of resources), compared with Immediate ART. Immediate ART increased the 5-year HIV care budget from$801.9M to $812.6M compared to ART<350/muL. CONCLUSIONS: In Cote d'Ivoire, immediate compared to later ART initiation will increase life expectancy, decrease HIV transmission, and be cost-effective over the long-term, with modest budget impact. Immediate ART initiation is an appropriate, high-value standard of care in Cote d'Ivoire and similar settings

BMJ Open

INTRODUCTION: Acute malnutrition (AM) is a continuum condition, arbitrarily divided into moderate and severe AM (SAM) categories, funded and managed in separate programmes under different protocols. Optimising acute MAlnutrition (OptiMA) treatment aims to simplify and optimise AM management by treating children with mid-upper arm circumference (MUAC) <125 mm or oedema with one product-ready-to-use therapeutic food-at a gradually tapered dose. Our main objective was to compare the OptiMA strategy with the standard nutritional protocol in children 6-59 months presenting with MUAC <125 mm or oedema without additional complications, as well as in children classified as uncomplicated SAM (ie, MUAC <115 mm or weight-for-height Z-score (WHZ) <-3 or with oedema). METHODS AND ANALYSIS: This study was a non-inferiority, individually randomised controlled clinical trial conducted at community level in the Democratic Republic of Congo. Children 6-59 months presenting with MUAC <125 mm or WHZ <-3 or with bipedal oedema and without medical complication were included after signed informed consent in outpatient health facilities. All participants were followed for 6 months. Success in both arms was defined at 6 months post inclusion as being alive, not acutely malnourished per the definition applied at inclusion and without an additional episode of AM throughout the 6-month observation period. Recovery among children with uncomplicated SAM was the main secondary outcome. For the primary objective, 890 participants were needed, and 480 children with SAM were needed for the main secondary objective. We will perform non-inferiority analyses in per-protocol and intention-to-treat basis for both outcomes. ETHICS AND DISSEMINATION: Ethics approvals were obtained from the National Health Ethics Committee of the Democratic Republic of Congo and from the Ethics Evaluation Committee of Inserm, the French National Institute for Health and Medical Research (Paris, France). We will submit results for publication to a peer-reviewed journal and disseminate findings in international and national conferences and meetings. TRIAL REGISTRATION NUMBER: NCT03751475. Registered 19 September 2018, https://clinicaltrials.gov/ct2/show/NCT03751475

EBioMedicine

Background High HIV-1 DNA levels in peripheral blood mononuclear cells (PBMC) were associated with a higher risk of severe morbidity and a faster decline in CD4 count in ART-naive patients. We report the association between HIV-1 DNA and mortality in HIV-infected adults in a trial of early ART in West Africa. Methods In the Temprano trial, HIV-infected adults were randomly assigned to start ART immediately or defer ART. After trial termination, HIV-1 DNA was measured in whole blood samples frozen at baseline. We analyzed the association between baseline PBMC HIV-1 DNA and long-term mortality

Simplifying and optimising the management of uncomplicated acute malnutrition in children aged 6–59 months in the Democratic Republic of the Congo (OptiMA-DRC): a non-inferiority, randomised controlled trial

BACKGROUND: Global access to acute malnutrition treatment is low. Different programmes using different nutritional products manage cases of severe acute malnutrition and moderate acute malnutrition separately. We aimed to assess whether integrating severe acute malnutrition and moderate acute malnutrition treatment into one programme, using a single nutritional product and reducing the dose as the child improves, could achieve similar or higher individual efficacy, increase coverage, and minimise costs compared with the current programmes. METHODS: We conducted an open-label, non-inferiority, randomised controlled trial in the Democratic Republic of the Congo. Acutely malnourished children aged 6-59 months with a mid-upper-arm circumference (MUAC) of less than 125 mm or oedema were randomly assigned (1:1), using specially developed software and random blocks (size was kept confidential), to either the current standard strategy (one programme for severe acute malnutrition using ready-to-use therapeutic food [RUTF] at an increasing dose as weight increased, another for moderate acute malnutrition using a fixed dose of ready-to-use supplementary food [RUSF]) or the OptiMA strategy (a single programme for both severe acute malnutrition and moderate acute malnutrition using RUTF at a decreasing dose as MUAC and weight increased). The primary endpoint was a favourable outcome at 6 months, defined as being alive, not acutely malnourished as per the definition applied at inclusion, and with no further episodes of acute malnutrition throughout the 6-month observation period; the endpoint was analysed in the intention-to-treat (all children) and per-protocol populations (participants who had a minimum prescription of 4 weeks' RUTF, received at least 90% of the total amount of RUTF they were supposed to receive as per the protocol, or were prescribed RUSF rations for a minimum of 4 weeks [ie, minimum of 28 RUSF sachets], and had a maximum interval of 6 weeks between any two visits in the 6-month follow-up). The non-inferiority analysis (margin 10%) was to be followed by a superiority analysis (margin 0%) if non-inferiority was concluded. This trial is registered at ClinicalTrials.gov, NCT03751475, and is now closed. FINDINGS: Between July 22 and Dec 6, 2019, 912 children were randomly assigned; after 16 were excluded, 896 were analysed (446 in the standard group and 450 in the OptiMA group). In the intention-to-treat analysis, 282 (63%) of 446 children in the standard group and 325 (72%) of 450 children in the OptiMA group had a favourable outcome (difference -9.0%, 95% CI -15.9 to -2.0). In the per protocol analysis, 161 (61%) of 264 children in the standard group and 291 (74%) of 392 children in the OptiMA group had a favourable outcome (-13.2%, -21.6 to -4.9). INTERPRETATION: In this non-inferiority trial treating children with MUAC of less than 125 mm or oedema, decreasing RUTF dose according to MUAC and weight increase proved to be a superior strategy to the standard protocol in the Democratic Republic of the Congo. These results demonstrate the safety and benefits of an approach that could substantially increase access to treatment for millions of children with acute malnutrition in sub-Saharan Africa. FUNDING: Innocent Foundation and European Civil Protection and Humanitarian Aid Operations. TRANSLATION: For the French translation of the abstract see Supplementary Materials section

Lassa fever outcomes and prognostic factors in Nigeria (LASCOPE): a prospective cohort study

BACKGROUND: Lassa fever is a viral haemorrhagic fever endemic in parts of west Africa. New treatments are needed to decrease mortality, but pretrial reference data on the disease characteristics are scarce. We aimed to document baseline characteristics and outcomes for patients hospitalised with Lassa fever in Nigeria. METHODS: We did a prospective cohort study (LASCOPE) at the Federal Medical Centre in Owo, Nigeria. All patients admitted with confirmed Lassa fever were invited to participate and asked to give informed consent. Patients of all ages, including newborn infants, were eligible for inclusion, as were pregnant women. All participants received standard supportive care and intravenous ribavirin according to Nigeria Centre for Disease Control guidelines and underwent systematic biological monitoring for 30 days. Patients' characteristics, care received, mortality, and associated factors were recorded using standard WHO forms. We used univariable and multivariable logistic regression models to investigate an association between baseline characteristics and mortality at day 30. FINDINGS: Between April 5, 2018, and March 15, 2020, 534 patients with confirmed Lassa fever were admitted to hospital, of whom 510 (96%) gave consent and were included in the analysis. The cohort included 258 (51%) male patients, 252 (49%) female patients, 426 (84%) adults, and 84 (16%) children (younger than 18 years). The median time between first symptoms and hospital admission was 8 days (IQR 7-13). At baseline, 176 (38%) of 466 patients had a Lassa fever RT-PCR cycle threshold (Ct) lower than 30. From admission to end of follow-up, 120 (25%) of 484 reached a National Early Warning Score (second version; NEWS2) of 7 or higher, 67 (14%) of 495 reached a Kidney Disease-Improving Global Outcome (KDIGO) stage of 2 or higher, and 41 (8%) of 510 underwent dialysis. All patients received ribavirin for a median of 10 days (IQR 9-13). 62 (12%) patients died (57 [13%] adults and five [6%] children). The median time to death was 3 days (1-6). The baseline factors independently associated with mortality were the following: age 45 years or older (adjusted odds ratio 16·30, 95% CI 5·31-50·30), NEWS2 of 7 or higher (4·79, 1·75-13·10), KDIGO grade 2 or higher (7·52, 2·66-21·20), plasma alanine aminotransferase 3 or more times the upper limit of normal (4·96, 1·69-14·60), and Lassa fever RT-PCR Ct value lower than 30 (4·65, 1·50-14·50). INTERPRETATION: Our findings comprehensively document clinical and biological characteristics of patients with Lassa fever and their relationship with mortality, providing prospective estimates that could be useful for designing future therapeutic trials. Such trials comparing new Lassa fever treatments to a standard of care should take no more than 15% as the reference mortality rate and consider adopting a combination of mortality and need for dialysis as the primary endpoint. FUNDING: Institut National de la Santé et de la Recherche Médicale, University of Oxford, EU, UK Department for International Development, Wellcome Trust, French Ministry of Foreign Affairs, Agence Nationale de Recherches sur le SIDA et les hépatites virales, French National Research Institute for Sustainable Development

Fighting factors associated with poor prognosis among HIV-infected adults on antiretroviral therapy in sub-Saharan Africa

Le traitement antirétroviral (ARV) a révolutionné le pronostic de la maladie à VIH. Avec un traitement ARV bien conduit on peut maintenant retrouver un niveau de risque de morbi-mortalité proche de celui de la population générale. Une grande partie des événements morbides et des décès survenant chez les personnes sous ARV peuvent donc maintenant être qualifiés "d'évitables". Pour éviter ces événements, il faut connaître les facteurs qui les favorisent. Avoir une vue d'ensemble de ces facteurs pronostiques ne va pas de soi. Les facteurs eux-mêmes, les méthodes utilisées pour les qualifier de facteur de mauvais pronostic et les niveaux de preuve pour arriver à cette conclusion sont de natures potentiellement très différentes. Dans cette thèse, nous analysons la littérature consacrée aux facteurs associés à la mortalité des adultes infectés par le VIH en Afrique sub-Saharienne et nous en discutons les enseignements. Nous avons retrouvé 59 articles, dont 14 comportaient uniquement un résultat d'analyse univariable et 45 un résultat d'analyse multivariable. Les périodes concernées par l'étude s'échelonnaient de 1986 à 2018. Le nombre de participants variait de 100 à 40657. La durée de suivi moyenne s'échelonnait de 2 mois à 6 ans et le pourcentage de décès observés s'étendait de de 2.1% à 37%. Les problèmes de qualité des données et de censure informative sont réels et fréquents. Les patients exclus des analyses ne sont pas exclus ou sortis prématurément de l'étude par hasard. Un grand nombre de participants n’implique pas systématiquement une grande robustesse. La qualité de type "recherche clinique" qu’on trouve dans les essais et cohortes dotés d'un dispositif d'ingénierie scientifique ne se retrouve pas forcément dans les bases de données issues de programmes de soins de routine. La "morbidité sévère" est souvent plus utilisée que la "mortalité" comme critère de jugement standard dans les essais d'intervention. Lorsque la preuve d'association d'une nouvelle intervention avec la mortalité est établie, elle l'est souvent secondairement à la faveur d'un suivi prolongé au-delà du suivi dans l'étude tel qu'il était initialement prévu. Si ce suivi prolongé n'est pas fait, des analyses de mortalité dotées de faible puissance ne doivent pas amener à jeter à tort un doute sur une intervention qui a été démontrée efficace pour réduire la morbidité sévère. Pour diminuer la mortalité liée au VIH en Afrique sub-Saharienne il faut débuter le traitement ARV le plus tôt possible, pratiquer systématiquement (même à l'ère des ARV) une prophylaxie par le cotrimoxazole et une prophylaxie antituberculeuse, s'attacher à prévenir la non-observance et le cas échéant la corriger rapidement. Il s'agit de grands messages qui paraissent simples et bien connus mais sont encore incomplètement exploités. Si ces interventions étaient pratiquées partout, il est probable que le gain en survie serait spectaculaire. Le repérage de certains facteurs de risque de mortalité ne donne pas de piste d'amélioration immédiate, mais indique des sujets à travailler. Par exemple, le traitement ARV ne corrige pas totalement par la perte de chance que représente une infection par le VHB active avant la mise sous ARV. Ceci invite donc à développer des programmes ambitieux pour lutter contre l'hépatite B, et à ne pas compter sur le seul traitement ARV sous l'argument qu'il contient des molécules actives contre le VHB. L'utilisation des marqueurs d'inflammation ou d'activation pourrait être intéressante dans une approche de médecine individualisée pour monitorer la réplication virale à bas bruit et orienter le traitement ARV en conséquence.Antiretroviral therapy (ARV) has revolutionized the prognosis of HIV disease. With a well-conducted ARV treatment, the risk of morbidity and mortality is now close to that of the general population. A large proportion of morbidity events and deaths occurring in people on ARV therapy can now be described as "avoidable". To avoid these events, it is necessary to know the factors that contribute to them. Having an overview of these prognostic factors is not self-evident. The factors themselves, the methods used to qualify them as poor prognostic factors and the levels of evidence to reach this conclusion are potentially very different. In this document, we review the literature on factors associated with mortality of HIV-infected adults in sub-Saharan Africa and discuss the findings. We found 59 articles, 14 of which had only a univariate analysis result and 45 had a multivariate analysis result. The time periods covered by the study ranged from 1986 to 2018. The number of participants ranged from 100 to 40657. The average follow-up time ranged from 2 months to 6 years and the percentage of observed deaths ranged from 2.1% to 37%. Problems with data quality and informative censoring are real and frequent. Patients excluded from the analyses were not excluded or prematurely dropped out of the study by chance. A large number of participants does not systematically imply high robustness. The "clinical research" quality found in scientifically engineered trials and cohorts is not necessarily found in databases from routine care programs. "Severe morbidity" is often used more than "mortality" as a standard endpoint in intervention trials. When evidence of an association of a new intervention with mortality is established, it is often established secondarily through extended follow-up beyond the study follow-up as originally planned. If this extended follow-up is not done, low-powered mortality analyses should not be used to cast undue doubt on an intervention that has been shown to reduce severe morbidity. To reduce HIV-related mortality in sub-Saharan Africa, ARV treatment must be started as early as possible, cotrimoxazole and TB prophylaxis must be routinely provided (even in the ARV era), and efforts must be made to prevent non-adherence and, whenever necessary, to correct it rapidly. These are key messages that seem simple and well known but are still incompletely implemented. If these interventions were practiced everywhere, it is likely that the gain in survival would be dramatic. The identification of certain risk factors for mortality does not provide an immediate avenue for improvement, but it does indicate areas to work on. For example, ARV treatment does not totally correct for the loss of chance that active HBV infection represents before being put on ARV. This invites to develop ambitious programs to fight hepatitis B, and not to rely on ARV treatment alone under the argument that it contains active molecules against HBV. The use of inflammation or activation markers could be interesting in an individualized medicine approach to monitor low-level viral replication and orient ARV treatment accordingly

Fighting factors associated with poor prognosis among HIV-infected adults on antiretroviral therapy in sub-Saharan Africa

Le traitement antirétroviral (ARV) a révolutionné le pronostic de la maladie à VIH. Avec un traitement ARV bien conduit on peut maintenant retrouver un niveau de risque de morbi-mortalité proche de celui de la population générale. Une grande partie des événements morbides et des décès survenant chez les personnes sous ARV peuvent donc maintenant être qualifiés "d'évitables". Pour éviter ces événements, il faut connaître les facteurs qui les favorisent. Avoir une vue d'ensemble de ces facteurs pronostiques ne va pas de soi. Les facteurs eux-mêmes, les méthodes utilisées pour les qualifier de facteur de mauvais pronostic et les niveaux de preuve pour arriver à cette conclusion sont de natures potentiellement très différentes. Dans cette thèse, nous analysons la littérature consacrée aux facteurs associés à la mortalité des adultes infectés par le VIH en Afrique sub-Saharienne et nous en discutons les enseignements. Nous avons retrouvé 59 articles, dont 14 comportaient uniquement un résultat d'analyse univariable et 45 un résultat d'analyse multivariable. Les périodes concernées par l'étude s'échelonnaient de 1986 à 2018. Le nombre de participants variait de 100 à 40657. La durée de suivi moyenne s'échelonnait de 2 mois à 6 ans et le pourcentage de décès observés s'étendait de de 2.1% à 37%. Les problèmes de qualité des données et de censure informative sont réels et fréquents. Les patients exclus des analyses ne sont pas exclus ou sortis prématurément de l'étude par hasard. Un grand nombre de participants n’implique pas systématiquement une grande robustesse. La qualité de type "recherche clinique" qu’on trouve dans les essais et cohortes dotés d'un dispositif d'ingénierie scientifique ne se retrouve pas forcément dans les bases de données issues de programmes de soins de routine. La "morbidité sévère" est souvent plus utilisée que la "mortalité" comme critère de jugement standard dans les essais d'intervention. Lorsque la preuve d'association d'une nouvelle intervention avec la mortalité est établie, elle l'est souvent secondairement à la faveur d'un suivi prolongé au-delà du suivi dans l'étude tel qu'il était initialement prévu. Si ce suivi prolongé n'est pas fait, des analyses de mortalité dotées de faible puissance ne doivent pas amener à jeter à tort un doute sur une intervention qui a été démontrée efficace pour réduire la morbidité sévère. Pour diminuer la mortalité liée au VIH en Afrique sub-Saharienne il faut débuter le traitement ARV le plus tôt possible, pratiquer systématiquement (même à l'ère des ARV) une prophylaxie par le cotrimoxazole et une prophylaxie antituberculeuse, s'attacher à prévenir la non-observance et le cas échéant la corriger rapidement. Il s'agit de grands messages qui paraissent simples et bien connus mais sont encore incomplètement exploités. Si ces interventions étaient pratiquées partout, il est probable que le gain en survie serait spectaculaire. Le repérage de certains facteurs de risque de mortalité ne donne pas de piste d'amélioration immédiate, mais indique des sujets à travailler. Par exemple, le traitement ARV ne corrige pas totalement par la perte de chance que représente une infection par le VHB active avant la mise sous ARV. Ceci invite donc à développer des programmes ambitieux pour lutter contre l'hépatite B, et à ne pas compter sur le seul traitement ARV sous l'argument qu'il contient des molécules actives contre le VHB. L'utilisation des marqueurs d'inflammation ou d'activation pourrait être intéressante dans une approche de médecine individualisée pour monitorer la réplication virale à bas bruit et orienter le traitement ARV en conséquence.Antiretroviral therapy (ARV) has revolutionized the prognosis of HIV disease. With a well-conducted ARV treatment, the risk of morbidity and mortality is now close to that of the general population. A large proportion of morbidity events and deaths occurring in people on ARV therapy can now be described as "avoidable". To avoid these events, it is necessary to know the factors that contribute to them. Having an overview of these prognostic factors is not self-evident. The factors themselves, the methods used to qualify them as poor prognostic factors and the levels of evidence to reach this conclusion are potentially very different. In this document, we review the literature on factors associated with mortality of HIV-infected adults in sub-Saharan Africa and discuss the findings. We found 59 articles, 14 of which had only a univariate analysis result and 45 had a multivariate analysis result. The time periods covered by the study ranged from 1986 to 2018. The number of participants ranged from 100 to 40657. The average follow-up time ranged from 2 months to 6 years and the percentage of observed deaths ranged from 2.1% to 37%. Problems with data quality and informative censoring are real and frequent. Patients excluded from the analyses were not excluded or prematurely dropped out of the study by chance. A large number of participants does not systematically imply high robustness. The "clinical research" quality found in scientifically engineered trials and cohorts is not necessarily found in databases from routine care programs. "Severe morbidity" is often used more than "mortality" as a standard endpoint in intervention trials. When evidence of an association of a new intervention with mortality is established, it is often established secondarily through extended follow-up beyond the study follow-up as originally planned. If this extended follow-up is not done, low-powered mortality analyses should not be used to cast undue doubt on an intervention that has been shown to reduce severe morbidity. To reduce HIV-related mortality in sub-Saharan Africa, ARV treatment must be started as early as possible, cotrimoxazole and TB prophylaxis must be routinely provided (even in the ARV era), and efforts must be made to prevent non-adherence and, whenever necessary, to correct it rapidly. These are key messages that seem simple and well known but are still incompletely implemented. If these interventions were practiced everywhere, it is likely that the gain in survival would be dramatic. The identification of certain risk factors for mortality does not provide an immediate avenue for improvement, but it does indicate areas to work on. For example, ARV treatment does not totally correct for the loss of chance that active HBV infection represents before being put on ARV. This invites to develop ambitious programs to fight hepatitis B, and not to rely on ARV treatment alone under the argument that it contains active molecules against HBV. The use of inflammation or activation markers could be interesting in an individualized medicine approach to monitor low-level viral replication and orient ARV treatment accordingly

Combattre les facteurs associés à un mauvais pronostic chez les adultes infectés par le VIH sous traitement antirétroviral en Afrique sub-Saharienne

Antiretroviral therapy (ARV) has revolutionized the prognosis of HIV disease. With a well-conducted ARV treatment, the risk of morbidity and mortality is now close to that of the general population. A large proportion of morbidity events and deaths occurring in people on ARV therapy can now be described as "avoidable". To avoid these events, it is necessary to know the factors that contribute to them. Having an overview of these prognostic factors is not self-evident. The factors themselves, the methods used to qualify them as poor prognostic factors and the levels of evidence to reach this conclusion are potentially very different. In this document, we review the literature on factors associated with mortality of HIV-infected adults in sub-Saharan Africa and discuss the findings. We found 59 articles, 14 of which had only a univariate analysis result and 45 had a multivariate analysis result. The time periods covered by the study ranged from 1986 to 2018. The number of participants ranged from 100 to 40657. The average follow-up time ranged from 2 months to 6 years and the percentage of observed deaths ranged from 2.1% to 37%. Problems with data quality and informative censoring are real and frequent. Patients excluded from the analyses were not excluded or prematurely dropped out of the study by chance. A large number of participants does not systematically imply high robustness. The "clinical research" quality found in scientifically engineered trials and cohorts is not necessarily found in databases from routine care programs. "Severe morbidity" is often used more than "mortality" as a standard endpoint in intervention trials. When evidence of an association of a new intervention with mortality is established, it is often established secondarily through extended follow-up beyond the study follow-up as originally planned. If this extended follow-up is not done, low-powered mortality analyses should not be used to cast undue doubt on an intervention that has been shown to reduce severe morbidity. To reduce HIV-related mortality in sub-Saharan Africa, ARV treatment must be started as early as possible, cotrimoxazole and TB prophylaxis must be routinely provided (even in the ARV era), and efforts must be made to prevent non-adherence and, whenever necessary, to correct it rapidly. These are key messages that seem simple and well known but are still incompletely implemented. If these interventions were practiced everywhere, it is likely that the gain in survival would be dramatic. The identification of certain risk factors for mortality does not provide an immediate avenue for improvement, but it does indicate areas to work on. For example, ARV treatment does not totally correct for the loss of chance that active HBV infection represents before being put on ARV. This invites to develop ambitious programs to fight hepatitis B, and not to rely on ARV treatment alone under the argument that it contains active molecules against HBV. The use of inflammation or activation markers could be interesting in an individualized medicine approach to monitor low-level viral replication and orient ARV treatment accordingly.Le traitement antirétroviral (ARV) a révolutionné le pronostic de la maladie à VIH. Avec un traitement ARV bien conduit on peut maintenant retrouver un niveau de risque de morbi-mortalité proche de celui de la population générale. Une grande partie des événements morbides et des décès survenant chez les personnes sous ARV peuvent donc maintenant être qualifiés "d'évitables". Pour éviter ces événements, il faut connaître les facteurs qui les favorisent. Avoir une vue d'ensemble de ces facteurs pronostiques ne va pas de soi. Les facteurs eux-mêmes, les méthodes utilisées pour les qualifier de facteur de mauvais pronostic et les niveaux de preuve pour arriver à cette conclusion sont de natures potentiellement très différentes. Dans cette thèse, nous analysons la littérature consacrée aux facteurs associés à la mortalité des adultes infectés par le VIH en Afrique sub-Saharienne et nous en discutons les enseignements. Nous avons retrouvé 59 articles, dont 14 comportaient uniquement un résultat d'analyse univariable et 45 un résultat d'analyse multivariable. Les périodes concernées par l'étude s'échelonnaient de 1986 à 2018. Le nombre de participants variait de 100 à 40657. La durée de suivi moyenne s'échelonnait de 2 mois à 6 ans et le pourcentage de décès observés s'étendait de de 2.1% à 37%. Les problèmes de qualité des données et de censure informative sont réels et fréquents. Les patients exclus des analyses ne sont pas exclus ou sortis prématurément de l'étude par hasard. Un grand nombre de participants n’implique pas systématiquement une grande robustesse. La qualité de type "recherche clinique" qu’on trouve dans les essais et cohortes dotés d'un dispositif d'ingénierie scientifique ne se retrouve pas forcément dans les bases de données issues de programmes de soins de routine. La "morbidité sévère" est souvent plus utilisée que la "mortalité" comme critère de jugement standard dans les essais d'intervention. Lorsque la preuve d'association d'une nouvelle intervention avec la mortalité est établie, elle l'est souvent secondairement à la faveur d'un suivi prolongé au-delà du suivi dans l'étude tel qu'il était initialement prévu. Si ce suivi prolongé n'est pas fait, des analyses de mortalité dotées de faible puissance ne doivent pas amener à jeter à tort un doute sur une intervention qui a été démontrée efficace pour réduire la morbidité sévère. Pour diminuer la mortalité liée au VIH en Afrique sub-Saharienne il faut débuter le traitement ARV le plus tôt possible, pratiquer systématiquement (même à l'ère des ARV) une prophylaxie par le cotrimoxazole et une prophylaxie antituberculeuse, s'attacher à prévenir la non-observance et le cas échéant la corriger rapidement. Il s'agit de grands messages qui paraissent simples et bien connus mais sont encore incomplètement exploités. Si ces interventions étaient pratiquées partout, il est probable que le gain en survie serait spectaculaire. Le repérage de certains facteurs de risque de mortalité ne donne pas de piste d'amélioration immédiate, mais indique des sujets à travailler. Par exemple, le traitement ARV ne corrige pas totalement par la perte de chance que représente une infection par le VHB active avant la mise sous ARV. Ceci invite donc à développer des programmes ambitieux pour lutter contre l'hépatite B, et à ne pas compter sur le seul traitement ARV sous l'argument qu'il contient des molécules actives contre le VHB. L'utilisation des marqueurs d'inflammation ou d'activation pourrait être intéressante dans une approche de médecine individualisée pour monitorer la réplication virale à bas bruit et orienter le traitement ARV en conséquence