Persistent difficulties in switching to second-line ART in sub-saharan Africa--a systematic review and meta-analysis.

OBJECTIVES: Switching to second-line antiretroviral therapy (ART) largely depends on careful clinical assessment and access to biological measurements. We performed a systematic review and meta-analysis to estimate the incidence of switching to second-line ART in sub-Saharan Africa and its main programmatic determinants. METHODS: We searched 2 databases for studies reporting the incidence rate of switching to second-line ART in adults living in sub-Saharan Africa. Data on the incidence rate of switching were pooled, and random-effect models were used to evaluate the effect of factors measured at the programme level on this incidence rate. RESULTS: Nine studies (157,340 patients) in 21 countries were included in the meta-analysis. All studies considered patients under first-line ART and conditions to initiate ART were similar across studies. Overall, 3,736 (2.4%) patients switched to second-line ART. Incidence rate of switch was in mean 2.65 per 100 person-years (PY) (95% confidence interval: 2.01-3.30); it ranged from 0.42 to 4.88 per 100 PY and from 0 to 4.80 per 100 PY in programmes with and without viral load monitoring, respectively. No factors measured at the programme level were associated with the incidence rate of switching to second-line ART. CONCLUSION: The low incidence rate of switching to second-line ART suggests that the monitoring of patients under ART is challenging and that access to second-line ART is ineffective; efforts should be made to increase access to second-line ART to those in need by providing monitoring tools, education and training, as well as a more convenient regimen.

Hepatitis B virus exposure during childhood in Cameroon, Central African Republic and Senegal after the integration of HBV vaccine in the expanded program on immunization.

BACKGROUND: More than 2 billion people worldwide have been exposed to hepatitis B virus (HBV). To prevent these infections, Senegal and Cameroon integrated the HBV vaccine into their Expanded Program on Immunization (EPI) in 2005, as did the Central African Republic (CAR) in 2008. We evaluated the prevalence of HBV exposure and infection after the integration of the HBV vaccine in the EPI. METHODS: An observational cross-sectional study was conducted among the hospitalized children 3 months to 6 years of age in Cameroon, CAR and Senegal. Plasma was collected for the detection of anti-HBc, anti-HBs and hepatitis B surface antigen in children with anti-HBc and anti-HBs. RESULTS: Between April 2009 and May 2010, 1783 children were enrolled, 19.4% of whom were anti-HBc positive. The percentage of children with anti-HBc was 44.4% among the children younger than 6 months, decreasing after 6 months to reach 18.8% at 12 months. This decline was followed by a rapid increase in anti-HBc positivity rate in CAR observed as early as 12 months of age compared with Cameroon and Senegal, where the anti-HBc increased between 18 and 36 months of age, respectively. The prevalence of hepatitis B surface antigen-positive children was significantly higher in CAR than that in Cameroon and Senegal (5.1% versus 0.7% and 0.2%; P < 0.001). Socioeconomic level, age and country were factors associated with the presence of anti-HBc. CONCLUSIONS: Passive transfer of anti-HBc maternal antibodies versus HBV exposure could be differentiated as early as 12 months of age. The low prevalence of anti-HBc and hepatitis B surface antigen among children born after the integration of HBV vaccine in the EPI in Cameroon and Senegal suggests a positive impact of HBV vaccination.

Acute plasma biomarkers of T cell activation set-point levels and of disease progression in HIV-1 infection.

T cell activation levels, viral load and CD4(+) T cell counts at early stages of HIV-1 infection are predictive of the rate of progression towards AIDS. We evaluated whether the inflammatory profile during primary HIV-1 infection is predictive of the virological and immunological set-points and of disease progression. We quantified 28 plasma proteins during acute and post-acute HIV-1 infection in individuals with known disease progression profiles. Forty-six untreated patients, enrolled during primary HIV-1 infection, were categorized into rapid progressors, progressors and slow progressors according to their spontaneous progression profile over 42 months of follow-up. Already during primary infection, rapid progressors showed a higher number of increased plasma proteins than progressors or slow progressors. The plasma levels of TGF-ß1 and IL-18 in primary HIV-1 infection were both positively associated with T cell activation level at set-point (6 months after acute infection) and together able to predict 74% of the T cell activation variation at set-point. Plasma IP-10 was positively and negatively associated with, respectively, T cell activation and CD4(+) T cell counts at set-point and capable to predict 30% of the CD4(+) T cell count variation at set-point. Moreover, plasma IP-10 levels during primary infection were predictive of rapid progression. In primary infection, IP-10 was an even better predictor of rapid disease progression than viremia or CD4(+) T cell levels at this time point. The superior predictive capacity of IP-10 was confirmed in an independent group of 88 HIV-1 infected individuals. Altogether, this study shows that the inflammatory profile in primary HIV-1 infection is associated with T cell activation levels and CD4(+) T cell counts at set-point. Plasma IP-10 levels were of strong predictive value for rapid disease progression. The data suggest IP-10 being an earlier marker of disease progression than CD4(+) T cell counts or viremia levels.

Low immune response to hepatitis B vaccine among children in Dakar, Senegal.

HBV vaccine was introduced into the Expanded Programme on Immunization (EPI) in Senegal and Cameroon in 2005. We conducted a cross-sectional study in both countries to assess the HBV immune protection among children. All consecutive children under 4 years old, hospitalized for any reason between May 2009 and May 2010, with an immunisation card and a complete HBV vaccination, were tested for anti-HBs and anti-HBc. A total of 242 anti-HBc-negative children (128 in Cameroon and 114 in Senegal) were considered in the analysis. The prevalence of children with anti-HBs ≥ 10 IU/L was higher in Cameroon with 92% (95% CI: 87%-97%) compared to Senegal with 58% (95% CI: 49%-67%), (p<0.001). The response to vaccination in Senegal was lower in 2006-2007 (43%) than in 2008-2009 (65%), (p = 0.028). Our results, although not based on a representative sample of Senegalese or Cameroonian child populations, reveal a significant problem in vaccine response in Senegal. This response problem extends well beyond hepatitis B: the same children who have not developed an immune response to the HBV vaccine are also at risk for diphtheria, tetanus, pertussis (DTwP) and Haemophilus influenzae type b (Hib). Field biological monitoring should be carried out regularly in resource-poor countries to check quality of the vaccine administered.

Dynamic shift from CD85j/ILT-2 to NKG2D NK receptor expression pattern on human decidual NK during the first trimester of pregnancy.

During the first trimester of human pregnancy, Natural Killer (NK) cells of the maternal uterine mucosa (e.g. decidua) have a unique phenotype and are involved in crucial physiological processes during pregnancy. We investigated whether modifications of the NK receptor repertoire occur during the first trimester of pregnancy. We found significantly decreased expression of KIR2DL1/S1 and KIR2DL2/L3/S2 receptors, NKp30 and NKp44 activatory receptors, and the CD85j (ILT-2) inhibitory receptor. We also observed significantly increased expression of the NKG2D activatory receptor at the decidual NK cell surface. By flow cytometry, we further highlighted an evolution of NK subsets between 8 and 12 weeks of gestation, with a shift from the KIR2DL1/S1⁺/KIR2DL2/L3/S2⁺ subset towards the double negative subset, coupled with a decrease of the CD85j⁺/NKG2D⁻ subset in favour of the CD85j⁻/NKG2D⁺ subset. Furthermore, cell surface expression of NK receptor ligands, including CD85j and NKG2D ligands, has been characterized by flow cytometry on decidual immune CD14⁺ and CD3⁺ cells. HLA-G, the high affinity ligand of CD85j, was detected on both cell types. In contrast, NKG2D ligands ULBP-2 ULBP-3 and MICA/B were not expressed on CD14⁺ and CD3⁺ cells, however a variable expression of ULBP-1 was observed. The ligand expression of KIR2DL1/S1 and KIR2DL2/L3/S2 was also analyzed: the HLA-C molecule was expressed at a low level on some CD14⁺ cells whereas it was not detected on CD3⁺ cell surface. NK receptor ligands are known to be also expressed on the invading placental trophoblast cells. Thus, the phenotypic evolutions of decidual NK cells described in this present study may preserve their activation/inhibition balance during the first trimester of pregnancy.

The caveolin-1 binding domain of HIV-1 glycoprotein gp41 (CBD1) contains several overlapping neutralizing epitopes.

The CBD1 peptide (SLEQIWNNMTWMQWDK), corresponding to the consensus caveolin-1 binding domain in HIV-1 envelope glycoprotein gp41 (CBD1), elicits the production of antibodies that inhibit infection of primary CD4(+) T lymphocytes by various primary HIV-1 isolates. Here we show that HIV-neutralizing antibodies against CBD1 react with multiple conformational epitopes that overlap the highly conserved caveolin-1 binding motif (CBM) with the N-terminal conserved isoleucine residue. The CBM-based peptides IWNNMTWMQW and IWNNMTW when fused to a T helper epitope are immunogenic by inducing high titer CBM-specific antibodies capable of neutralizing HIV-1 infection in primary T lymphocyte cultures. Interestingly, neutralizing immune sera raised against a given peptide do not cross-react with related CBM-derived peptides, thus suggesting the existence of distinct neutralizing epitopes that probably reflect the dynamic conformational features of CBD1. In accord with this, the mixture of neutralizing immune sera raised against several CBM-derived peptides exerts a synergistic neutralizing activity against HIV-1 infection. Finally, the existence of several distinct overlapping epitopes in CBD1 is confirmed by murine monoclonal antibodies that we generated against the CBM-derived chimeric peptides. Our results indicate that CBD1- and CBM-based peptides mimic distinct dynamic conformations of CBD1, and thus such peptides could provide specific immunogens for an efficient vaccine preparation against HIV/AIDS infection.

HIV-1 neutralizing antibodies elicited by the candidate CBD1 epitope vaccine react with the conserved caveolin-1 binding motif of viral glycoprotein gp41.

To date, candidate HIV-1 vaccines that have been tested in clinical trials have failed to induce broadly neutralizing activities and/or antibodies that inhibit infection by primary isolates of HIV-1. We recently identified a conserved caveolin-1 binding motif, WNNMTWMQW, in the ectodomain of HIV-1 transmembrane envelope glycoprotein gp41. We designed the synthetic CBD1 peptide SLEQIWNNMTWMQWDK, corresponding to the consensus caveolin-1 binding domain (CBD) in gp41, and showed that it elicits in rabbits the production of antibodies that inhibit infection of primary CD4(+) T lymphocytes by various primary HIV-1 isolates. Although a conserved and highly homologous caveolin-1 binding motif is present in the transmembrane envelope glycoprotein of different HIV-2 isolates, anti-CBD1 immune sera do not inhibit HIV-2 infection. Here we show that anti-CBD1 antibodies are directed against the conserved caveolin-1 binding motif WNNMTWMQW in the CBD1 epitope. In spite of this, anti-CBD1 antibodies do not react with the CBD2 peptide SLTPDWNNMTWQEWER, corresponding to the potential consensus caveolin-1 binding domain in HIV-2. The presence of a conserved proline residue upstream of the caveolin-1 binding motif in CBD2 might affect the presentation of this motif, and thus account for the lack of reactivity of the immune sera. Anti-CBD1 antibodies therefore appear to be directed against a conformational epitope mimicked by the synthetic CBD1 peptide. In accordance with this, anti-CBD1 immune sera react with the native but not denatured gp41. The reactivity of anti-CBD1 immune sera with a highly conserved conformational epitope could explain the broad inhibitory activity of such antipeptide antibodies against HIV-1 isolates of various clades.