Virological failure and antiretroviral resistance among HIV-infected children after five years follow-up in the ANRS 12225-PEDIACAM cohort in Cameroon.

OBJECTIVE: In the present study, we aimed to evaluate the virological failure (VF) and drug resistance among treated HIV-infected children after five years follow-up in the ANRS-Pediacam cohort in Cameroon. METHODS: From November 2007 to October 2011, HIV-infected children born to HIV-infected mothers were included in the ANRS-PEDIACAM study and followed-up for more than 5 years. Plasma viral load (VL) was measured at each visit (every three months until month 24 and every 6 months thereafter). VF was the main outcome and HIV drug resistance test was performed using the ANRS procedures and algorithm. RESULTS: Data from 155 children were analyzed. The median age at combination antiretroviral therapy (cART) initiation was 4.2 months (interquartile range (IQR): 3.2-5.8), with 103 (66.5%) children taking LPV/r-containing regimen and 51 (32.9%) children taking NVP. After five years follow-up, 63 (40.6%; CI: 32.9-48.8) children experienced VF. The median duration between cART initiation and VF was 22.1 months (IQR: 11.9-37.1) with a median VL of 4.8 log10 (IQR: 4.0-5.5). Among the 57 children with HIV drug resistance results, 40 (70.2%) had at least one drug resistance mutation. The highest resistance rates (30.4-66.1%) were obtained with Lamivudine; Efavirenz; Nevirapine and Rilpivirine. CONCLUSIONS: These results show high resistance to NNRTI and emphasize the need of VL and resistance tests for optimal follow-up of HIV-infected people especially children.

A Treatment-Decision Score for HIV-Infected Children With Suspected Tuberculosis.

BACKGROUND: Diagnosis of tuberculosis should be improved in children infected with HIV to reduce mortality. We developed prediction scores to guide antituberculosis treatment decision in HIV-infected children with suspected tuberculosis. METHODS: HIV-infected children with suspected tuberculosis enrolled in Burkina Faso, Cambodia, Cameroon, and Vietnam (ANRS 12229 PAANTHER 01 Study), underwent clinical assessment, chest radiography, Quantiferon Gold In-Tube (QFT), abdominal ultrasonography, and sample collection for microbiology, including Xpert MTB/RIF (Xpert). We developed 4 tuberculosis diagnostic models using logistic regression: (1) all predictors included, (2) QFT excluded, (3) ultrasonography excluded, and (4) QFT and ultrasonography excluded. We internally validated the models using resampling. We built a score on the basis of the model with the best area under the receiver operating characteristic curve and parsimony. RESULTS: A total of 438 children were enrolled in the study; 251 (57.3%) had tuberculosis, including 55 (12.6%) with culture- or Xpert-confirmed tuberculosis. The final 4 models included Xpert, fever lasting >2 weeks, unremitting cough, hemoptysis and weight loss in the past 4 weeks, contact with a patient with smear-positive tuberculosis, tachycardia, miliary tuberculosis, alveolar opacities, and lymph nodes on the chest radiograph, together with abdominal lymph nodes on the ultrasound and QFT results. The areas under the receiver operating characteristic curves were 0.866, 0.861, 0.850, and 0.846, for models 1, 2, 3, and 4, respectively. The score developed on model 2 had a sensitivity of 88.6% and a specificity of 61.2% for a tuberculosis diagnosis. CONCLUSIONS: Our score had a good diagnostic performance. Used in an algorithm, it should enable prompt treatment decision in children with suspected tuberculosis and a high mortality risk, thus contributing to significant public health benefits.

Early treated HIV-infected children remain at risk of growth retardation during the first five years of life: Results from the ANRS-PEDIACAM cohort in Cameroon.

BACKGROUND: Long-term growth in HIV-infected infants treated early in resource-limited settings is poorly documented. Incidence of growth retardation, instantaneous risk of death related to malnutrition and growth parameters evolution during the first five years of life of uninfected and early treated HIV-infected children were compared and associated factors with growth retardation were identified. METHODS: Weight-for-age (WAZ), weight-for-length (WLZ), and length-for-age (LAZ) Z-scores were calculated. The ANRS-PEDIACAM cohort includes four groups of infants with three enrolled during the first week of life: HIV-infected (HI, n = 69), HIV-exposed uninfected (HEU, n = 205) and HIV-unexposed uninfected (HUU, n = 196). The last group included HIV-infected infants diagnosed before 7 months of age (HIL, n = 141). The multi-state Markov model was used to describe the incidence of growth retardation and identified associated factors. RESULTS: During the first 5 years, 27.5% of children experienced underweight (WAZ<-2), 60.4% stunting (LAZ<-2) and 41.1% wasting (WLZ<-2) at least once. The instantaneous risk of death observed from underweight state (35.3 [14.1-88.2], 84.0 [25.5-276.3], and 6.0 [1.5-24.1] per 1000 person-months for 0-6 months, 6-12 months, and 12-60 months respectively) was higher than from non-underweight state (9.6 [5.7-16.1], 20.1 [10.3-39.4] and 0.3 [0.1-0.9] per 1000 person-months). Compared to HEU, HIL and HI children were most at risk of wasting (adjusted HR (aHR) = 4.3 (95%CI: 1.9-9.8), P<0.001 and aHR = 3.3 (95%CI: 1.4-7.9), P = 0.01 respectively) and stunting for HIL (aHR = 8.4 (95%CI: 2.4-29.7). 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 to growth retardation were chronic pathologies, small size at birth, diarrhea and CD4< 25%. CONCLUSIONS: HIV-infected children remained at high risk of wasting and stunting within the first 5 years period of follow-up. There is a need of identifying suitable nutritional support and best ways to integrate it with cART in pediatric HIV infection global care.

Virologic Response to Early Antiretroviral Therapy in HIV-infected Infants: Evaluation After 2 Years of Treatment in the Pediacam Study, Cameroon.

INTRODUCTION: Little is known about virologic responses to early antiretroviral therapy (ART) in HIV-infected infants in resource-limited settings. We estimated the probability of achieving viral suppression within 2 years of ART initiation and investigated the factors associated with success. METHODS: We analyzed all 190 infants from the Cameroon Pediacam who initiated ART by 12 months of age. The main outcome measure was viral suppression (<1000 copies/mL) on at least 1 occasion; the other outcome measures considered were viral suppression (<400 copies/mL) on at least 1 occasion and confirmed viral suppression (both thresholds) on 2 consecutive occasions. We used competing-risks regression for a time-to-event analysis to estimate the cumulative incidence of outcomes and univariate and multivariate models to identify risk factors. RESULTS: During the first 24 months of ART, 20.0% (38) of the infants died, giving a mortality rate of 11.9 deaths per 100 infant-years (95% confidence interval: 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 virologic suppression (with these 2 thresholds) on 2 consecutive occasions was 67.0% (56.0-70.0) and 60.0% (49.0-64.0), respectively. Virologic success was associated with not having missed any doses of treatment before the visit, but not with socioeconomic and living conditions. CONCLUSION: Many early treated children failed to achieve virologic suppression, likely due to a combination of adherence difficulties, drug dosing and viral resistance, which highlights the need for routine viral load monitoring. The high infant mortality despite early ART initiation needs to be addressed in sub-Saharan countries.

Mortality and its determinants in antiretroviral treatment-naive HIV-infected children with suspected tuberculosis: an observational cohort study.

BACKGROUND: Tuberculosis is a major cause of morbidity and mortality in HIV-infected children, but is difficult to diagnose. We studied mortality and its determinants in antiretroviral treatment (ART)-naive HIV-infected children presenting with suspected tuberculosis. METHODS: In this observational cohort study, HIV-infected children aged 13 years or younger with suspected tuberculosis were followed up for 6 months as part of the ANRS 12229 PAANTHER 01 cohort in eight hospitals in four countries (Burkina Faso, Cambodia, Cameroon, and Vietnam). Children started ART and antituberculosis treatment at the clinician's discretion and were retrospectively classified into one of three groups by tuberculosis documentation: confirmed by culture or Xpert MTB/RIF, unconfirmed, and unlikely. We assessed mortality and associated factors using Kaplan-Meier methods and Cox proportional hazard models. The ANRS 12229 PAANTHER 01 study is registered at ClinicalTrials.gov, number NCT01331811. FINDINGS: 266 (61%) of 438 children enrolled in the study between April 27, 2011, and May 31, 2014, were ART-naive and included in the analysis (40 had confirmed tuberculosis, 119 unconfirmed tuberculosis, and 107 unlikely tuberculosis). 112·5 person-years of follow-up were available. 154 children (58%) started antituberculosis treatment and 212 (80%) started ART. 50 children (19%) died. Mortality by 6 months was higher in children with confirmed tuberculosis (14 deaths; 2 month survival probability 65·0% [95% CI 50·2-79·8]) compared with unconfirmed tuberculosis (19 deaths; 83·5% [76·8-90·3]) and unlikely tuberculosis (17 deaths; 83·5% [76·3-90·7]; log-rank p=0·0141) and was lower in children with confirmed or unconfirmed tuberculosis who started antituberculosis treatment (p<0·0001 for both). In a multivariate analysis, ART started during the first month of follow-up (hazard ratio 0·08; 95% CI 0·01-0·67), confirmed tuberculosis (6·33; 2·15-18·64), young age (5·90; 2·02-17·19), CD4 less than 10% (2·63; 1·25-5·53), miliary features (4·08; 1·56-10·66), and elevated serum transaminases (4·40; 1·82-10·65) were all independently associated with mortality. INTERPRETATION: In our cohort, mortality was high in the first 6 months after suspicion of tuberculosis in ART-naive children. ART should be started early, particularly in children with factors associated with high mortality. Documented or empirical tuberculosis treatment decision should be accelerated to reduce mortality and allow early ART initiation. FUNDING: ANRS and Fondation Total.

Immuno-virological response and associated factors amongst HIV-1 vertically infected adolescents in Yaoundé-Cameroon.

INTRODUCTION: Limited studies have reported the outcomes of lifelong antiretroviral therapy (ART) amongst adolescents living with HIV (ALWHIV) in resource-limited settings (RLS), thus classifying this population as underserved. We therefore aimed to ascertain the immunological and virological responses, and associated factors amongst Cameroonian ALWHIV. METHOD: A cross-sectional and observational study was conducted from January through May 2016 at the National Social Insurance Fund Health Centre in Yaoundé-Cameroon. Immunological and virological responses were evaluated using CD4 cell count and viral load respectively, with viral suppression (VS) defined as <50 copies/ml. Adherence was evaluated using self-reported missing doses during the past 14 days. Data were analyzed using R v.3.3.0, with p<0.05 considered statistically significant. RESULTS: Of the 145 ALWHIV on ART enrolled in the study, 52% were female, median age [interquartile (IQR)] was 13 [11-16] years, median [IQR] time-on-ART was 7 [5-10] years, 48% were orphans, 92% were on first-line ART and 36% were adherent to ART. Following ART response, 79% (114/145) had CD4 ≥500/mm3, 71.0% (103/145) were on VS of whom 52.4% (76/145) had a sustained VS. Duration of ART was associated with immune restoration (Odd Ratio 3.73 [1.26-12.21]) but not with virological response. Risks of poor adherence were greater in orphans of both parents (p = 0.078). CONCLUSION: In this urban setting of Cameroon, ALWHIV receiving ART show favorable immunological and virological response in a medium run. For long-term ART success, implementing a close monitoring of adherence and risks of viral rebound would be highly relevant, especially for orphans of both parents.

Could caregiver reporting adherence help detect virological failure in Cameroonian early treated HIV-infected infants?

BACKGROUND: Viral 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. METHODS: PEDIACAM 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. RESULTS: cART 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%). CONCLUSIONS: The 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.

Feasibility of Routinely Offering Early Combined Antiretroviral Therapy to HIV-infected Infants in a Resource-limited Country: The ANRS-PediaCAM Study in Cameroon.

BACKGROUND: Early diagnosis of HIV is increasingly available for infants in resource-limited settings. We assessed the timing of events until combined antiretroviral therapy (cART) initiation in infants diagnosed before 7 months of age in Cameroon. METHODS: The ANRS-PediaCAM cohort included HIV-infected infants followed from birth associated with prevention of mother-to-child transmission activities (group 1) or diagnosed for any other reason before 7 months of age (group 2). All infants were offered free cART early after diagnosis. Frequency and factors associated with no or delayed cART initiation, were studied using univariable and multivariable logistic regressions. RESULTS: Between 2007 and 2011, 210 HIV-infected infants (group 1: 69; group 2: 141) were included. Fewer group 1 (14.3%) than group 2 (59.1%) infants were symptomatic (World Health Organization stage 3 or 4). Overall, 5.7% (n = 12) died before receiving any cART. Of the remaining 198 infants, 3.0% (n = 6) were not treated. The median age at initiating cART was 4.1 months [interquartile range (IQR): 3.2-5.6]. The median time until cART initiation after HIV testing was 6.2 weeks (IQR: 4.4-9.4) in group 1 and 5.1 weeks (IQR: 2.9-9.4) in group 2. No or delayed cART, observed for 37.9% (75 of 198) of the infants, was associated with clinical site [adjusted odds ratio (aOR): 4.8; 95% confidence interval: (2.1-11.2)], late diagnosis [aOR: 2.0 (0.9-4.1)], and delayed pretherapeutic biological assessment [aOR: 3.7 (1.4-10.0)]. CONCLUSIONS: Although most children included were treated before age 7 months, the initiation of therapy was delayed for more than 1 in 3. The period around HIV diagnosis is critical and should be better managed to reduce delays before cART initiation.

Low birth weight in perinatally HIV-exposed uninfected infants: observations in urban settings in Cameroon.

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<.001) and lower among HIV-unexposed uninfected infants (3.5% vs. 6.3%; p<.001) than among HIV-exposed uninfected infants. Similarly, SGAG was significantly more frequent among HIV-infected infants (aOR: 4.1; 2.0-8.1) and less frequent among HIV-unexposed uninfected infants (aOR: 0.5; 0.4-0.8) than among HIV-exposed uninfected infants. Primiparity (aOR: 1.9; 1.3-2.7) and the presence of any disease during pregnancy (aOR: 1.4; 1.0-2.0) were identified as other contributors to SGAG. CONCLUSION: Maternal HIV infection was independently associated with SGAG for HIV-exposed uninfected infants. This provides further evidence of the need for adapted monitoring of pregnancy in HIV-infected women, especially if they are symptomatic, to minimize additional risk factors for SGAG.

Preventing HIV-1 transmission in breastfed infants in low resource settings: early HIV infection and late postnatal transmission in a routine prevention of mother-to-child transmission program in Yaounde, Cameroon.

OBJECTIVE: To report on overall HIV-transmission rates [early and late postnatal transmission (LPNT)] in breastfed infants born to HIV-positive women. METHODS: Mother-baby pairs in a routine prevention of mother-to-child transmission program. Promotion of exclusive breastfeeding (EBF) coupled with access to antiretroviral treatment (ART) or prevention using antiretroviral (pARV). Early infant diagnosis using HIV-RNA/PCR or HIV-DNA/PCR >6 weeks. LPNT assessed 6 weeks after weaning in infant earlier tested negative. MAIN MEASUREMENT: early HIV infection and LPNT. RESULTS: We included 285 infants for analysis; 89.5 % of mothers were receiving ART or pARV; 86% babies took daily pARV (median duration, 6 weeks). Exclusive breastfeeding (EBF) rate: 96% (median duration, 4 months). The cumulative transmission of HIV-1 was 2.8% at 8 weeks (95% confidence interval: 1.9-3.7). After weaning (abrupt 44%), 3 of 212 infants were HIV infected (1.4%). Nine-month cumulative HIV-transmission rate was 4.2% (1.5-6.9). Incidence of late postnatal HIV infection stood at 1.5/100 child-years of breastfeeding (BF). Cumulative risk of HIV transmission (8 weeks-9 months) was 1%. CONCLUSION: Both promotion of EBF and access to antiretroviral therapy contribute to lower HIV transmission in breastfed infants in low resource settings.