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Correlations among survival endpoints are important for exploring surrogate endpoints of the true endpoint. With a valid surrogate endpoint tightly correlated with the true endpoint, the efficacy of a new drug/treatment can be measurable on it. However, the existing methods for measuring correlation between two endpoints impose an invalid assumption: correlation structure is constant across different treatment arms. In this article, we reconsider the definition of Kendall's concordance measure (tau) in the context of individual patient data meta-analyses of randomized controlled trials. According to our new definition of Kendall's tau, its value depends on the treatment arms. We then suggest extending the existing copula (and frailty) models so that their Kendall's tau can vary across treatment arms. Our newly proposed model, a joint frailty-conditional copula model, is the implementation of the new definition of Kendall's tau in meta-analyses. In order to facilitate our approach, we develop an original R function condCox.reg(.) and make it available in the R package joint.Cox ( https://CRAN.R-project.org/package=joint.Cox ). We apply the proposed method to a gastric cancer dataset (3288 patients in 14 randomized trials from the GASTRIC group). This data analysis concludes that Kendall's tau has different values between the surgical treatment arm and the adjuvant chemotherapy arm ( p-value

Background In most studies, the virological response is assessed during the first two years of antiretroviral treatment initiated in HIV-infected infants. However, early initiation of antiretroviral therapy exposes infants to very long-lasting treatment. Moreover, maintaining viral suppression in children is difficult. We aimed to assess the virologic response and mortality in HIV-infected children after five years of early initiated antiretroviral treatment (ART) and identify factors associated with virologic success in Cameroon. Methods In the ANRS-12140 Pediacam cohort study, 2008–2013, Cameroon, we included all the 149 children who were still alive after two years of early ART. Virologic response was assessed after 5 years of treatment. The probability of maintaining virologic success between two and five years of ART was estimated using Kaplan-Meier curve. The immune status and mortality were also studied at five years after ART initiation. Factors associated with a viral load Results The viral load after five years of early ART was suppressed in 66.8% (60.1–73.5) of the 144 children still alive and in care. Among the children with viral suppression after two years of ART, the probability of maintaining viral suppression after five years of ART was 64.0% (54.0–74.0). The only factor associated with viral suppression after five years of ART was achievement of confirmed virological success within the first two years of ART (OR = 2.7 (1.1–6.8); p = 0.033). Conclusions The probability of maintaining viral suppression between two and five years of early initiated ART which was quite low highlights the difficulty of parents to administer drugs daily to their children in sub-Saharan Africa. It also stressed the importance of initial viral suppression for achieving and maintaining virologic success in the long-term. Further studies should focus on identifying strategies that would enhance better retention in care and improved adherence to treatment within the first two years of ART early initiated in Sub-Saharan HIV-infected children.

Background: Vertical (VT) transmission of HIV remains a public health concern in sub-Saharan Africa.Objective: To investigate the VT rate and factors associated with transmission in routine practic...

Only a minority of patients derive long-term clinical benefit from anti-programmed cell death protein 1 (anti-PD-1) or anti-programmed death-ligand 1 (anti-PD-L1) monoclonal antibodies. The presence of tertiary lymphoid structures (TLSs) has been associated with improved survival in several tumor types. Here, using a large-scale retrospective analysis of three independent cohorts of patients with cancer who were treated with anti-PD-1 or anti-PD-L1 antibodies, we show that the presence of mature TLSs was associated with improved objective response rates, progression-free survival and overall survival, independent of PD-L1 expression status and CD8+ T cell density. These results pave the way for using TLS detection to select patients who are more likely to benefit from immune checkpoint blockade. Italiano and colleagues demonstrate the utility of mature tertiary lymphoid structures to predict response to immunotherapy, with pathologic analysis in three independent patient cohorts spanning multiple tumor types.

BackgroundAs many longitudinal studies, follow-up in the ANRS-PEDIACAM study is disrupted by repeated absences of participants to scheduled visits. This lead to missing data which influence the quality of results. We describe reasons for participants absence or non-compliance (NC) and assess the influence of phone call reminders (CR) on retention in care.MethodsFrom November 2007 to 2011, 611 infants divided in three groups were included and followed in three referral hospital in Cameroon: HIV-infected children followed from the first week of life or not but diagnosed before seven month of life (n=210), HIV-uninfected children born to HIV-infected (HEU) (n=205) mothers or not (HUU) (n=196). From 2014 to 2017, CR were reinforced to record reasons of missing visits. we used frequency, chi-square or Fisher test for categorical variables; means, median (IQR) and non-parametric Kruskal Wallis test for continuous variables. A multistate transition modelling approach was used to analyse the retention care cascade. The R software was used to perform all statistical analysis.ResultsDuring the study period, 45.1% (246/546) of children were NC at least once of ​​which 16.3% (25/153), 58% (116/200), 54.4% (105/193) respectively among HIV-infected, HEU and HUU-children. Among NC, 69.5% (171/246) has been reachable at least once and 22.2% (38/171) of them returned to follow-up after a median delay of 32 days (IQR: [2.0 – 110]); 44.4% (109/246) were not seen throughout the study period (HIV-infected: 12/153, HEU-children: 57/200, HUU-children: 40/193). A total of 276 reasons have been reported among 54%(115/213) of the NC, mainly related to delocalisation (30.4%), lack of time (23.6%), wish to stop follow-up (11.6%), travelling (9.8%), schooling (9.4%), forgetting (7.2%). Comparing before and after period, CR allowed to divided by three adjusted relative risk ratio to miss one clinical visit (RRR [CI]: 0.35[0.24 – 0.52]), However CR effect was not significant among children who are non-compliant.ConclusionOur finding suggest that maternal HIV and socio-economic status are related to attendance of children in HIV care. Also, the CR are an effective strategy to improve attendance. However, to make this strategy effective for children who are non-compliant, it needs to be strengthened by community monitoring.

Background: In most studies, the virological response is assessed during the first two years of antiretroviral treatment initiated in HIV-infected infants. However, early initiation of antiretroviral therapy exposes infants to very long-lasting treatment. Moreover, maintaining viral suppression in children is difficult. We aimed to assess the virologic response and mortality in HIV-infected children after five years of early initiated antiretroviral treatment (ART) and identify factors associated with virologic success in Cameroon. Methods: In this cohort study, we included 149 children who were still alive after two years of early ART. Virologic response was assessed after 5 years of treatment. The probability of maintaining virologic success between two and five years of ART was estimated using Kaplan-Meier curve. Factors associated with a viral load < 400 copies/mL in children still alive at five years of ART were studied using logistic regressions.Results: The viral load after five years of early ART was suppressed in 66.8% (60.1 - 73.5) of the 144 children still alive and in care. Among the children with viral suppression after two years of ART, the probability of maintaining viral suppression after five years of ART was 64.0% (54.0 - 74.0). The only factor associated with viral suppression after five years of ART was achievement of confirmed virological success within the first two years of ART (OR = 2.7 (1.1-6.8); p = 0.033).Conclusions: This study reported difficulty in maintaining virologic success in sub-Saharan HIV-infected children between two and five years of early initiated ART. It also highlighted the importance of initial viral suppression for achieving and maintaining virologic success in the long-term.

International audience; BACKGROUND AND OBJECTIVE:The use of valid surrogate endpoints can accelerate the development of phase III trials. Numerous validation methods have been proposed with the most popular used in a context of meta-analyses, based on a two-step analysis strategy. For two failure time endpoints, two association measures are usually considered, Kendall's τ at individual level and adjusted R2 ([Formula: see text]) at trial level. However, [Formula: see text] is not always available mainly due to model estimation constraints. More recently, we proposed a one-step validation method based on a joint frailty model, with the aim of reducing estimation issues and estimation bias on the surrogacy evaluation criteria. The model was quite robust with satisfactory results obtained in simulation studies. This study seeks to popularize this new surrogate endpoints validation approach by making the method available in a user-friendly R package.METHODS:We provide numerous tools in the frailtypack R package, including more flexible functions, for the validation of candidate surrogate endpoints using data from multiple randomized clinical trials.RESULTS:We implemented the surrogate threshold effect which is used in combination with [Formula: see text] to make decisions concerning the validity of the surrogate endpoints. It is also possible thanks to frailtypack to predict the treatment effect on the true endpoint in a new trial using the treatment effect observed on the surrogate endpoint. The leave-one-out cross-validation is available for assessing the accuracy of the prediction using the joint surrogate model. Other tools include data generation, simulation study and graphic representations. We illustrate the use of the new functions with both real data and simulated data.CONCLUSION:This article proposes new attractive and well developed tools for validating failure time surrogate endpoints.

Introduction Context: Metastatic lung cancer accounts for 40-50% of diagnosed lung cancers, and has a great lethality, with 4% 5-year net survival. Treatment has been recently modified due to the development of immunotherapy. In order to obtain faster results and to overcome the limitations associated with the use of overall survival (OS), the search for surrogate endpoints (SE) has become an area of research. Using the real-life database ESME-AMLC ( NCT03848052 ), we investigated two candidate surrogate endpoints for OS: progression-free survival (PFS) and time to next treatment (TNT) for patients treated with first-line chemotherapy and/or immunotherapy. Methods This is an exploratory analysis assessing investigating surrogate properties for OS of PFS and TNT in patients diagnosed with metastatic non-small cell lung cancer (NSCLC). Using real world data, we estimated the individual-level association between PFS/TNT and OS as well as the center-level association between treatment effect on PFS/TNT and treatment effect on OS. This observational, retrospective and multi-center study uses data from patients treated since 2015 in French cancer care centers for metastatic NSCLC, with first-line chemotherapy and/or immunotherapy. Baseline was the administration of the first treatment. PFS was defined as the time until first progression of disease or death, TNT as the time until initiation of a second line of treatment or death, and OS as the time until death. Associations between OS and surrogate endpoints were estimated at the individual and center level with a meta-analytical approach. A joint frailty model was used with an individual random effect or with copula functions. Estimated parameters were found using penalized likelihood and baseline hazard functions were approximated using splines functions. Effectiveness of models was assessed with predictions using leave-one-out cross validation. Results The study population included 5294 patients: 5055 patients treated with chemotherapy alone, and 239 patients treated with immunotherapy alone or in association with chemotherapy. Median OS was 13 months, and median PFS and TNT were 4 months. These estimates were higher for patients treated with immunotherapy, with 16 months versus 12 months for OS, 5 months versus 4 months for PFS, and 8 months versus 4 months for TNT. With the joint frailty model approach using copula functions, estimated individual-level association was 0.57 (0.54–0.61) between OS and PFS, and 0.57 (0.53–0.60) also between OS and TNT. All estimated coefficients for associations at the center-level were close to 1, with a 95%CI equal to (0.91–1.09) between OS and PFS and equal to (1.00–1.00) between OS and TNT. Conclusion PFS and TNT were moderately correlated with OS at the individual-level. Center-level associations were strong. These results deserve to be confirmed with meta-analyses of clinical trials once published data will become available.

In a meta-analysis framework, the classical approach for the validation of time-to-event surrogate endpoint is based on a two-step analysis. This approach often raises estimation issues. Recently, we proposed a one-step validation approach based on a joint frailty model. This approach was quite time consuming, despite parallel computing, due to individual-level frailties used to take into account heterogeneity in the data at the individual level. We now propose an alternative one-step approach for evaluating surrogacy, using a joint frailty-copula model. The model includes two correlated random effects treatment-by-trial interaction and a shared random effect associated with the baseline risks. At the individual level, the joint survivor functions of time-to-event endpoints are linked using copula functions. We used splines for the baseline hazard functions. We estimated parameters and hazard function using a semiparametric penalized marginal likelihood method, considering various numerical integration methods. Both individual-level and trial-level surrogacy were evaluated using Kendall's tau and coefficient of determination. The performance of the estimators was evaluated using simulation studies. The model was applied to individual patient data meta-analyses in advanced ovarian cancer to assess progression-free survival as a surrogate for overall survival, as part of the evaluation of new therapy. The model showed good performance and was quite robust regarding the integration methods and data variation, regardless of the surrogacy evaluation criteria. Kendall's Tau was better estimated using the Clayton copula model compared to the joint frailty model. The proposed model reduces the convergence and model estimation issues encountered in the two-step approach.

Background: To accelerate access to pediatric HIV care in Cameroon, operational challenges in implementing HIV pediatric care need to be identified. The aim of this study was to assess the knowledge, attitudes, and practices of health care workers regarding pediatric HIV infection in Cameroon. Methods: A descriptive cross-sectional study was conducted over a 4-month period (April to August 2014) in 12 health facilities in 7 regions of Cameroon selected using systematic random sampling. Data were collected from interviews with health care providers and managers using standardized self-administered questionnaires and stored in the ACCESS software. Results: In total, 103 health care providers were included in this study, of which 59 (57.3%) were health workers and 44 (42.7%) community agents. Most of the health workers in charge of HIV pediatric care were nurses, requiring effective medical task shifting that was institutionalized in Cameroon. The knowledge of health care providers in relation to pediatric HIV care was acceptable. Indications for prescription of test for early infant diagnosis were known (96.1%), but their attitudes and practices regarding initiating antiretroviral therapy (ART) in infants less than 2 years (5.2%) and first-line ART protocols (25.4%) were insufficient, due to little information about standard procedures. Conclusion: Capacity building of health care providers and large-scale dissemination of normative national documents are imperative to improve HIV pediatric care in the health care facilities.

A surrogate endpoint can be used instead of the most relevant clinical endpoint to assess the efficiency of a new treatment. Before being used, a surrogate endpoint must be validated based on appropriate methods. Numerous validation approaches have been proposed with the most popular used in a context of meta-analysis, based on a two-step analysis strategy. For two failure-time endpoints, two association measurements are usually used, Kendall's tau at the individual level and the adjusted coefficient of determination ( R t r i a l , a d j 2 ) at the trial level. However, R t r i a l , a d j 2 is not always available due to model estimation constraints. We propose a one-step validation approach based on a joint frailty model, including both individual-level and trial-level random effects. Parameters have been estimated using a semiparametric penalized marginal log-likelihood method, and various numerical integration approaches were considered. Both individual- and trial-level surrogacy were evaluated using a new definition of Kendall's tau and the coefficient of determination. Estimators' performances were evaluated using simulation studies and satisfactory results were found. The model was applied to individual patient data meta-analyses in gastric cancer to assess disease-free survival as a surrogate for overall survival, as part of the evaluation of adjuvant therapy.

Canine rabies is endemic in Cameroon, but human rabies exposures and cases are likely underreported because of inadequate surveillance. In 2014, the surveillance network in the West region of Cameroon was reinforced by introducing a new anti-rabies center, a framework for data collection and evaluation, provisions for sample collecting and laboratory confirmation, and training for health professionals. The objective of this observational cohort study was to describe the incidence and characteristics of reported exposures and human and animal rabies cases following this reinforcement of the existing rabies surveillance system. The surveillance network consisted of local, regional, and national health and veterinary authorities in 11 of the 20 West region districts, and was completely integrated within the existing national rabies surveillance network. Animal exposures and suspected rabies exposures, the suspected rabid animals involved, and laboratory confirmation of human and animal rabies cases were recorded in a centralized information database. Between January 2014 and June 2016, the network recorded 1340 animal exposure cases for an overall incidence rate of 38.2 animal exposures per 100,000 people, four confirmed rabies-positive animals, and one confirmed human rabies case out of four clinically suspected cases. In contrast, 62 animal exposures and an overall incidence rate of 6.1 exposures per 100,000 people were reported for the West region districts not participating in the reinforced surveillance. Of the 925 animal exposure victims for whom a detailed case report form was completed, 703 were considered to be at risk of rabies and only 428 (61%) of these received any post-exposure prophylaxis in the form of rabies vaccine. Obstacles encountered within the network included low rates of animal sample submission and animal follow-up by veterinarians. Reinforced rabies surveillance in the West region of Cameroon has provided the most accurate estimate of the region's disease and exposure burdens to date, and indicates that animal exposures are substantially underreported. The reinforced network also signaled that greater access to post-exposure prophylaxis is needed. Integration of regions not covered by the surveillance network and efforts to improve engagement of veterinary services will be needed to reveal the true burden of rabies in Cameroon.

Background The outcome of CMV/HIV co-infection in infants treated early with combined antiretroviral therapy (cART) in resource-limited settings has not been described. We aimed to estimate the prevalence and identify factors associated with early CMV infection in HIV-infected and non-infected infants included in a study in Cameroon, and to compare HIV disease progression and survival after 1 year of early cART, following infants’ CMV status. Methods HIV-infected infants followed from birth or from HIV diagnosis before 7 months old and HIV-uninfected infants born to HIV-infected or uninfected mothers were tested for CMV at a median age of 4.0 months [Interquartile range (IQR): 3.4–4.9]. Multivariable logistic regression was performed to identify factors associated with CMV infection. Early cART was offered to HIV-infected infants: mortality, immunological and virological outcomes were assessed. Results Three hundred and sixty-nine infants were tested. The proportion of infants infected with CMV at baseline was significantly higher in HIV-infected than in HIV-uninfected groups (58.9% (86/146) vs 30.0% (67/223), p

Introduction Little is known about the long-term outcome of growth in early treated infants in resources limited countries. Here, we compared growth parameters over the first 5 years of life of early treated HIV-infected and uninfected children and identified factors associated with growth retardation, taking into account informative censorship. Methods Data used in this study were obtained from the ANRS-Pediacam cohort based in three referral hospitals in Cameroon (The Maternity of the Central hospital/Mother and Child Center of the Chantal Biya Foundation in Yaounde, the Essos Hospital Center in Yaounde and the Laquintinie Hospital in Douala). Anthropometric indices [weight-for-age (WAZ), weight-for-length (WLZ), and length-for-age (LAZ) Z-scores] were calculated using data from this observational study. Of the four groups included, three were followed from the first week of life: HIV-infected (HI, n = 69), HIV-exposed uninfected (HEU, n = 205) and HIV-unexposed uninfected (HUU, n = 196), and the last group constituted of HIV-infected infants not followed from first week of life but diagnosed before 7 months of age (HIL, n = 141). We performed under the Missing At Random hypothesis a multiple imputation by a conditional approach of missing data on different covariates, except the anthropometric parameters. To take account of informative censorship, recurrent events and interval censoring, we used markov multi-state model for panel data to describe the incidence of growth retardation (defined as WAZ or WLZ or LAZ Results During the first 5 years, 27.5% of children experienced underweight (WAZ P P = 0.01 respectively) and stunting for HIL (aHR = 8.4 (95%CI: 2.4–29.7). HEU and HUU infants were not different according to stunting and wasting. However, the risk of underweight was higher in HEU compared to HUU children (aHR = 5.0 (CI: 1.4–10.0), P = 0.001). Others associated factors were younger age, chronic pathologies, small size at birth, diarrhea, CD4 Conclusions Despite early antiretroviral treatment HIV-infected children are at high risk of wasting and stunting within the first 5 years period of follow up. Nutritional status of HIV infected children should be closely monitored even in the context of early treatment.

International audience; AbstractBackgroundViral load is still the marker of choice for monitoring adherence to combined antiretroviral therapy (cART) and confirming the success of HIV treatment. Unfortunately it is difficult to access in many resource-poor settings. We aimed to measure the performance of caregiver reporting adherence for detecting virological failure in routine practice during the first 2 years after cART initiation in infants.MethodsPEDIACAM is an ongoing prospective cohort study including HIV1-infected infants diagnosed before 7 months of age between November 2007 and October 2011 in Cameroon. Adherence was assessed using a questionnaire administered every 3 months from cART initiation; the HIV-RNA viral load was determined at the same visits. Virological failure was defined as having a viral load ≥ 1000 cp/mL at 3 and 12 months after cART initiation or having a viral load ≥ 400 cp/mL at 24 months after cART initiation. The performance of each current missed and cumulative missed dose defined according to adherence as reported by caregiver was assessed using the viral load as the gold standard.ResultscART was initiated at a median age of 4 months (IQR: 3–6) in the 167 infants included. The cumulative missed dose showed the best overall performance for detecting virological failure after 12 months of cART (AUC test, p = 0.005, LR + =4.4 and LR− = 0.4). Whatever the adherence reporting criterion, the negative predictive value was high (NPV ≥ 75 %) 12 and 24 months after cART initiation, whereas the positive predictive value was low (PPV ≤ 50 %).ConclusionsThe adherence questionnaire administered by the health care provider to the infants’ caregivers is not reliable for detecting virological failure in routine practice: its positive predictive value is low. However, the cumulative missed dose measurement may be a reliable predictor of virological success, particularly after 12 months of cART, given its high negative predictive value.

Background Little is known about virological responses to early combined antiretroviral therapy (cART) in HIV-infected infants in limited-resource settings. We estimated the probability of achieving viral suppression within two years of cART initiation, and investigated the factors associated with success. Methods We analysed all 190 infants from the Cameroon PediaCAM study who began free cART before the age of 12 months. The main outcome measure was viral suppression ( Results During the first 24 months of cART, 20.0% (38) of the infants died, giving a mortality rate of 11.9 deaths per 100 infant-years [95% CI: 8.1–15.7]. The probability of achieving a viral load below 1000 or 400 copies/mL was 80.0% [69.0–81.0] and 78.0% [66.0–79.0], respectively. The probability of virological suppression (with these two thresholds) on two consecutive occasions was 67.0% [56.0–70.0] and 60.0% [49.0–64.0], respectively. Virological success was associated with not having missed any doses of treatment before the visit, but not with socioeconomic and living conditions. Conclusions The long-term daily administration of drugs to babies seems to be difficult. Mortality remained high despite early cART initiation. Future studies should focus on longer-term treatment outcomes in children still alive after two years of treatment.

Background The consequences of maternal HIV infection for fetal growth are controversial. Here, we estimated the frequency of small for gestational age and gender (SGAG) among neonates born to HIV-infected or uninfected mothers and assessed the contribution, if any, of maternal HIV to the risk of SGAG. Methods The data used were obtained from the ANRS-Pediacam cohort in Cameroon. Pairs of newborns, one to a HIV-infected mother and the other to an uninfected mother, were identified during the first week of life, and matched on gender and recruitment site from 2007–2010. SGAG was defined in line with international recommendations as a birth weight Z-score adjusted for gestational age at delivery and gender more than two standard deviations below the mean (−2SD). Considering the matched design, logistic regression modeling was adjusted on site and gender to explore the effect of perinatal HIV exposure on SGAG. Results Among the 4104 mother-infant pairs originally enrolled, no data on birth weight and/or gestational age were available for 108; also, 259 were twins and were excluded. Of the remaining 3737 mother-infant pairs, the frequency of SGAG was 5.3% (95%CI: 4.6–6.0), and was significantly higher among HIV-infected infants (22.4% vs. 6.3%; p