Inflammatory profile of vertically HIV-1 infected adolescents receiving ART in Cameroon: a contribution toward optimal pediatric HIV control strategies.

Antiretroviral therapy (ART) has improved the lifespan of people living with HIV. However, their immune system remains in a state of sustained activation/inflammation, which favors viral replication and depletion of helper T-cells with varying profiles according to ART-response. We herein sought to ascertain the inflammatory profile of adolescents living with perinatal HIV-1 infection (ALPHI) receiving ART in an African context. In this cross-sectional and comparative study among ART-experienced ALPHI in Yaoundé-Cameroon, HIV-1 RNA was measured by Abbott Real-time PCR; CD4 cells were enumerated using flow cytometry; serum cytokines were measured by ELISA; HIV-1 proviral DNA was genotyped by Sanger-sequencing; and archived drug resistance mutations (ADRMs) were interpreted using Stanford HIVdb.v9.0.1. Overall, 73 adolescents were enrolled (60 ALPHI and 13 HIV-1 negative peers) aged 15 (13-18) years; 60.00% were female. ART median duration was 92 (46-123) months; median viral load was 3.99 (3.17-4.66) RNA Log10 (copies)/mL and median CD4 count was 326 (201-654) cells/mm3. As compared to HIV-negative adolescents, TNFα was highly expressed among ALPHI (p<0.01). Following a virological response, inflammatory cytokines (IFNγ and IL-12), anti-inflammatory cytokines (IL-4 and IL-10) and inflammation-related cytokines (IL-6 and IL-1ß) were highly expressed with viral suppression (VS) vs. virological failure (VF), while the chemokine CCL3 was highly expressed with VF (p<0.01). Regarding the immune response, the inflammatory cytokine TNFα was highly expressed in those that are immunocompetent (CD4≥500 cell/mm3) vs. immunocompromised (CD4<500 cell/mm3), p ≤ 0.01; while chemokine CCL2 was highly expressed in the immunocompromised (p<0.05). In the presence of ADRMs, IL-4 and CCL3 were highly expressed (p=0.027 and p=0.043 respectively). Among ART-experienced ALPHI in Cameroon, the TNFα cytokine was found to be an inflammatory marker of HIV infection; IFNγ, IL-1ß, IL-6, and IL-12 are potential immunological markers of VS and targeting these cytokines in addition to antiretroviral drugs may improve management. Moreover, CCL3 and CCL2 are possible predictors of VF and/or being immunocompromised and could serve as surrogates of poor ART response.

Long-term outcomes of early initiated antiretroviral therapy in sub-Saharan children: a Cameroonian cohort study (ANRS-12140 Pediacam study, 2008-2013, Cameroon).

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 < 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: 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.

Low rate of early vertical transmission of HIV supports the feasibility of effective implementation of the national PMTCT guidelines in routine practice of referral hospitals in Cameroon.

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 practice in three referral hospitals in Cameroon. Methods: All HIV-infected mothers who delivered in maternity wards or sought paediatric services during the first postnatal week from November 2007 to October 2010 were invited to participate in the ANRS-Pediacam cohort. Their infants were followed at 6, 10 and 14 weeks of life and HIV status was determined from the 6th week of life using real-time PCR. For those who were breastfed and negative at the first PCR, a second test was performed 6 weeks after breast-feeding was stopped. Logistic regression was performed to identify the independent risk factors of VT. Results: Overall, 2053 HIV-exposed infants were enrolled. Of these, 1827 were tested for HIV including 1777 before the age of 3 months, and 59 were HIV-infected, resulting in an overall early VT rate of 3.3% (CI 2.5-4.3). The VT rate was significantly associated with the type of maternal exposure to ART (0.5%, 2/439, p<0.001, CI 0.0-1.6) in mothers who commenced HAART before pregnancy, 1.9% (6/321, CI 0.7-4.0) in mothers who commenced HAART during pregnancy, 4.1% (34/837, CI 2.8-5.6) in those on short-course ART and 11.1% (17/153, CI 6.6-17.2) in mothers not receiving ART. On multivariate analysis, the type of exposure to ART remained significantly associated with being small for gestational age (aOR 5.0, CI 2.4-10.3, p < 0.001) and female gender (aOR 2.1, CI 1.2-3.8, p = 0.01). Conclusion: The successfully low rate of VT transmission of HIV in mothers who commenced HAART in early pregnancy strongly supports the need to improve access to diagnosis and early treatment of all women of childbearing age with HIV through the national PMTCT programme. Abbreviations: ANRS: French National Agency for Research on AIDS and Viral Hepatitis; ART: antiretroviral therapy; ARV: antiretroviral; AUDIPOG: Association des Utilisateurs de Dossiers Informatisés en Pédiatrie, Obstétrique et Gynécologie; CHM/MCC-CBF: The Central Hospital Maternity/Mother and Child Centre of the Chantal Biya Foundation; EHC: Essos Hospital Centre; EPI: Expanded Programme on Immunization; HAART: highly active antiretroviral therapy; HBV: hepatitis B virus; IQR: interquartile range; LH: Laquintinie Hospital; MTCT: mother-to-child transmission; NVP: nevirapine; Pediacam: Pediatrie Cameroun; PMTCT: prevention of mother-to-child transmission; SGAG: small for gestational age and gender; UNAIDS: Joint United Nations Program on HIV/AIDS; WHO: World Health Organization; ZDV: zidovudine; 3TC: lamivudine.

Neurodevelopmental outcomes in HIV-infected and uninfected African children.

OBJECTIVE: HIV infection is associated with cognitive impairments, but outcomes are poorly explored in children starting antiretroviral therapy (ART) early or in those exposed but uninfected. DESIGN: Nested cross-sectional evaluation of the neurocognitive and behavioural outcomes of HIV-infected, HIV-exposed uninfected (HEU) and HIV-unexposed (HUU) Cameroonian children at age 4-9 years prospectively followed. METHODS: Cognitive development was assessed in 127 HIV-infected, 101 HEU, 110 HUU children using the KABC-II, neurologic dysfunction using the Touwen examination and behavioural difficulties using the Strength and Difficulties Questionnaire (SDQ). Analyses were adjusted for children age, sex and primary language. Contextual factors were included in a second step to assess their effects on outcomes. RESULTS: All HIV-infected children were treated before 12 months. There was a negative linear gradient in KABC-II scores from HUU children to HEU and HIV-infected children [gradient: -6.0 (-7.7; -4.3) for nonverbal index, NVI, and -8.8 (-10.7; -6.8) for mental processing index, MPI]. After adjusting for contextual factors, scores of HEU children were not significantly different from those of HUU children (all P > 0.1) and differences between HIV-uninfected and HUU children reduced [NVI: from -11.9 (-15.3; -8.5) to -3.4 (-6.8; -0.01), MPI: from -17.6 (-21.3; -13.8) to -5.5 (-9.3; -1.7)]. Compared with uninfected children, HIV-infected children had more neurological dysfunctions and higher SDQ scores (P = 0.002). CONCLUSION: Despite early ART, perinatal-HIV infection is associated with poorer neurocognitive scores and increased behavioural difficulties during childhood. Contextual factors play an important role in this association, which emphasizes the need for early nutritional and developmental interventions targeting both HIV-affected infants and their relatives.

Predictors of Virologic Failure on First-line Antiretroviral Therapy Among Children in a Referral Pediatric Center in Cameroon.

BACKGROUND: Suboptimal response to antiretroviral therapy (ART) is common among children living with HIV (CLHIV) in resource-limited settings. We sought to assess virologic failure (VF), time for switching to second-line regimens and factors associated with VF in CLHIV receiving first-line ART in Cameroon. METHODS: An observational cohort study was conducted in 375 CLHIV initiating a first-line ART and treated for ≥6 months at the National Social Insurance Fund Hospital in Yaoundé-Cameroon from 2009 to 2013. Using logistic regression, predictors of VF and delayed switch were assessed by univariate and multivariate analysis. P < 0.05 was considered statistically significant. RESULTS: Overall, 17% (64/375) CLHIV experienced VF on first-line ART after a median time of 28 (interquartile range: 22-38) months. After VF, median time to switching from first- to second-line ART was 20 (interquartile range: 8-24) months. In multivariate analysis, VF was associated with male gender (adjusted odds ratio: 0.36; 95% confidence interval: 0.19-0.71; P = 0.003), motherless children (adjusted odds ratio: 2.9; 95% confidence interval: 1.3-6.06; P = 0.005) and treatment with stavudine-containing compared with zidovudine-containing regimens (P = 0.022). Overall, male gender, orphanhood (motherless) and treatment with stavudine-containing regimens predicted VF at a rate of 70% (area under curve =0.70). CONCLUSION: VF on first-line pediatric ART is common, and switching children failing first-line to second-line ART is considerably delayed. These results suggest performance of pediatric ART program can be improved by targeting orphans, adapting counseling for male children, complete phasing-out of stavudine and ensuring timely switch to second-line regimens.

Cytomegalovirus infection in HIV-infected versus non-infected infants and HIV disease progression in Cytomegalovirus infected versus non infected infants early treated with cART in the ANRS 12140-Pediacam study 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 < 0.001). At baseline, median CMV viral load was higher in HIV-infected (3.7 log copies/ml [IQR; 3.1-4.3]) than in HIV-uninfected infants (2.8 log copies [IQR; 2.1-3.4], p < 0.001). cART was initiated in 90% of HIV-infected infants (132/146) at a median age of 4.0 months (IQR; 3.2-5.9); in this sub-group CMV infection was independently associated with being followed from the time of HIV diagnosis rather than from birth (aOR = 3.1, 95%CI [1.2-8.0]), born to a non-single mother (aOR = 3.4[1.4-8.1]), and breastfeeding (aOR = 7.3 [2.7-19.4]). HIV-infected infants were retested after a median of 7.1 months [4.8-9.5]: CMV was undetectable in 37 of the 61 (60.7%) initially CMV-infected cases and became detectable in 8 of the 38 (21.1%) initially CMV-negative cases. After 1 year of cART, the probability of death (0.185 vs 0.203; p = 0.75), the proportion of cases with HIV RNA viral load <400 copies/ml (75.5% vs 61.5%; p = 0.17) and the mean CD4 percentage increase (10.97% vs 6.88%; p = 0.15) did not differ between CMV+ and CMV- infants. CONCLUSIONS: We observed a high prevalence of CMV infection among HIV-infected infants. Early initiation of cART may have limited the negative impact of CMV even in the absence of specific anti-CMV treatment.