BACKGROUND AND OBJECTIVES:Data on HIV drug resistance in Madagascar are rare and outdated. In this study, we assessed the prevalence of HIV drug resistance mutations to antiretrovirals (ARVs) and genetic diversity of circulating strains in treatment-naive people living with HIV (PLHIV) in Madagascar. MATERIALS AND METHODS:We amplified the protease (PR), fragments of the Reverse Transcriptase (RT) and Integrase (IN) genes according to the French ANRS protocol. The amplicons were sequenced using next-generation sequencing technology on an Illumina platform (MiSeq). We determined HIV-1 subtypes through phylogenetic analysis using maximum likelihood in PhyML. Resistance interpretation was performed using the Stanford algorithm (version 9.5.1). RESULTS:We included 239 HIV-infected adults and children, sampled between January 2019 and November 2023, with a median age of 30 years and a mean plasma HIV viral load of 6.3 Log copies/mL. We sequenced at least one genomic fragment (PR or RT or IN) of the 239 samples, but 9 were excluded from analysis (mean depth < 10,000×). Phylogenetic analysis of 230 sequences revealed the presence of subtype C (33.91 %), A1 (11.30 %), B (11.30 %), CRF02_AG (9.56 %), subtype G (3.04 %), subtype D (0.43 %), CRF01_AE (0.43 %), and a significant proportion of unique recombinant forms (URFs) (30.30 %). The prevalence of transmitted drug resistance (TDR) was 4.95 % (10/202) among patients aged 15 years and older. When stratified by ARV class, this prevalence was 4.79 % for non-nucleoside reverse transcriptase inhibitors (NNRTIs), 0.59 % for Nucleoside Reverse Transcriptase inhibitors (NRTIs), and 0.50 % for integrase strand transfer inhibitors (INSTIs). Among children under 15 years old (n = 28), the prevalence of TDR was 14.28 % (4/28), with all mutations conferring resistance to NNRTIs. No mutation conferring resistance to protease inhibitors was found, neither in children nor in adults. CONCLUSION:Our results show a low prevalence of ARV resistance mutations among adult treatment-naive PLHIV in Madagascar. In children under 15 years old, 92 % were infants under two years old, the high resistance rate is likely related to mother-to-child transmission. No resistance mutation to dolutegravir was detected. We also observed high frequencies of subtypes C, B, A1 and a high proportion of URFs, highlighting an ongoing dynamic epidemic.

IRIS is a common complication in HIV-infected patients treated for tuberculosis (TB) and cART. Our aim was to evaluate NK cell reconstitution in HIV-infected patients with TB-IRIS compared to those without IRIS. 147 HIV-infected patients with TB from the CAMELIA trial were enrolled. HIV+TB+ patients were followed for 32 weeks. The NK cell repertoire was assessed in whole blood at different time points. As CAMELIA has two arms (early and late cART initiation), we analysed them separately. At enrolment, individuals had low CD4 cell counts (27 cells/mm3) and high plasma viral loads (5.76 and 5.50 log/mL for IRIS and non-IRIS individuals, respectively). Thirty-seven people developed IRIS (in the early and late arms). In the early and late arms, we observed similar proportions of total NK and NK cell subsets in TB-IRIS and non-IRIS individuals during follow-up, except for the CD56dimCD16pos (both arms) and CD56dimCD16neg (late arm only) subsets, which were higher in TB-IRIS and non-IRIS individuals, respectively, after cART. Regarding the repertoire and markers of NK cells, significant differences (lower expression of NKp30, NKG2A (CD159a), NKG2D (CD314) were observed in TB-IRIS compared to non-IRIS individuals after the start of cART. In the late arm, some changes (increased expression of CD69, NKG2C, CD158i) were observed in TB-IRIS compared to non-IRIS individuals, but only before cART initiation (during TB treatment). KIR expression by NK cells (CD158a and CD158i) was similar in both groups. CD69 expression by NK cells decreased in all groups. Expression of the NCR repertoire (NKp30, NKp44, NKp46) has similar kinetics in TB-IRIS subjects compared to non-IRIS subjects regardless of the arm analysed. NK cell reconstitution appeared to be better in TB-IRIS subjects. Although NK cell reconstitution is impaired in HIV infection after cART, as previously reported, it does not appear to be affected by the development of IRIS in HIV and TB-infected individuals.

To estimate the prevalence of IgG antibodies against six arboviruses in people living with HIV-1 (PLWHIV) in Madagascar, we tested samples collected between January 2018 and June 2021. We used a Luminex-based serological assay to detect IgG antibodies against antigens from Dengue virus serotypes 1–4 (DENV1–4), Zika virus (ZIKV), West Nile virus (WNV), Usutu virus (USUV), Chikungunya virus (CHIKV), and O’nyong nyong virus (ONNV). Of the 1036 samples tested, IgG antibody prevalence was highest for ONNV (28.4%), CHIKV (26.7%), WNV-NS1 (27.1%), DENV1 (12.4%), USUV (9.9%), and DENV3 (8.9%). ZIKV (4.9%), DENV2 (4.6%), WNV-D3 (5.1%), and DENV4 (1.4%) were lower. These rates varied by province of origin, with the highest rates observed in Toamasina, on the eastern coast (50.5% and 56.8%, for CHIKV and ONNV, respectively). The seroprevalence increased with age for DENV1 and 3 (p = 0.006 and 0.038, respectively) and WNV DIII (p = 0.041). The prevalence of IgG antibodies against any given arborvirus varied over the year and significantly correlated with rainfalls in the different areas (r = 0.61, p = 0.036). Finally, we found a significant correlation between the seroprevalence of antibodies against CHIKV and ONNV and the HIV-1 RNA plasma viral load. Thus, PLWHIV in Madagascar are highly exposed to various arboviruses. Further studies are needed to explain some of our findings.

Background:In Madagascar, no study has reported the impact of COVID-19 on people living with HIV (PLHIV). The present work aimed to analyze the seroprevalence of SARS-CoV-2 in Malagasy PLHIV before and during the three waves of COVID-19 pandemic.This is a retrospective study.Materials and Methods:We conducted a retrospective serological survey in PLHIV followed up for HIV viral load (VL) monitoring at the Centre d'Infectiologie Charles Mérieux Madagascar (CICM) between June 2019 and April 2022. The presence of IgM and/or IgG antibodies against SARS-CoV-2 nucleoprotein was detected using a rapid diagnostic test (COVID-PRESTO®).Results:A seroprevalence of 2.5% was found in the 877 patients tested before March 2020, compared to 25.4% (512/2,011) between March 2020 and April 2022. This seroprevalence was 21.7%, 22.3% and 60.1% after the first, second and third waves of COVID-19, respectively. We observed a marginally significant difference (p = 0.043) in SARS-CoV-2 seroprevalence between patients on highly active antiretroviral therapy (HAART) (27.5%) and those who were not (23.7%). No statistically significant difference was observed between PLHIV with undetectable HIV VL (27.4%) and the different detectable VL categories (p>0.05).Conclusions:Our data show the presence of antibodies to SARS-CoV-2 among PLHIV as early as December 2019 in Madagascar. At least 25.4% (512/2,011) of Malagasy PLHIV have been in contact with SARS-CoV-2 since March 2020. There is no significant relation between HIV-1 VL and SARS-CoV-2 seroprevalence. Additional studies with more robust assays in the general population are needed for a detailed knowledge of SARS-CoV-2 impact in Madagascar.

Pour le suivi biologique du traitement antirétroviral, les recommandations nationales ivoiriennes préconisent la mesure de charge virale plasmatique ARN (CV) du VIH qui dans la pratique demeurait inaccessible jusqu’en 2013. A partir de 2014, la réalisation de ce paramètre a été offerte en routine grâce à l’appui financier d’UNITAID. L’objectif de l’étude était d’analyser la CV ARN VIH-1 et le taux de lymphocytes TCD4 (CD4) dans ce suivi. Ainsi, les patients infectés par le VIH sous antirétroviraux depuis au moins 6 mois ont bénéficié des mesures de CV et de CD4. Ont été inclus 8410 patients d’un âge médian de 41 ans (1- 91 ans), avec un sex-ratio de 0,46 et 91% sous première ligne d’antirétroviraux. Le taux médian de CD4 était de 399 cellules/µL (1-17185 /µL) et 80,3% des cas présentaient un taux de CD4>200 cellules/µL. La CV médiane était de 4,61 log10/mL (2,5-7,60 log10/mL) et la réplication virale était sous contrôle de l’organisme (< 3 log10/mL) dans 73,8% des cas. Il a été observé 50,1% de discordance immuno-virologique dont 44,5% de succès virologique malgré un échec immunologique (I-/V+) évitant un changement inutile de ligne thérapeutique et 5,6% de dépistage précoce d’échec virologique malgré un succès immunologique (I+/V-). Finalement, l’ARN VIH-1 permettait un meilleur suivi biologique du traitement antirétroviral et la dynamique de son évolution devrait être étudiée.Mots clés: ARN VIH, numération des CD4, ARV, OPP-ERA, routine. English Title: HIV-1 plasma RNA mesearment and lymphocytes TCD4 count in the monitoring of antiretroviral treatment of HIV infected patients in Côte d’Ivoire Côte d'Ivoire national recommendations for biological monitoring of antiretroviral therapy (ART) include measurement of HIV RNA viral load (VL), but this assay remained inaccessible until 2013. Since 2014, VL was made routinely available with the financial support of UNITAID. The objective of the current study was to analyze the relevance of HIV1 RNA VL versus CD4 count (CD4 ) in this follow-up. Thus, people living with HIV (PLWH) receiving ART for at least 6 months had VL and CD4 measurements. A total number of 8410 patients were included with a median age of 41 years (1-91). Sex ratio was 0.46 and 91% of PLWH were on first-line treatment. Median CD4 count was 399 cells/μL (1-17185 /μL) and 80.3% of the patients had CD4 count higher than 200 cells/μL. The Median of VL was 4.61 log10/mL (2.5-7.60 log10/mL) and 73.8% of the cases had viral replication under control (<3 log10/mL). There were 50.1% cases of immuno-virological discordance of which 44.5% were virological success with immunological failure (I-/V+) avoiding an unnecessary change of therapeutic line and 5.6% of early screening of virological failure despite an immunological success (I+/V-). Finally, HIV-1 RNA allowed a better biological monitoring of antiretroviral therapy and its evolution must be monitored.Keywords: HIV RNA, CD4 count, ART, OPP-ERA, routine.

BACKGROUND:Assessment of virological outcomes among HIV-infected patients receiving protease (PR) inhibitor-based second-line regimen are uncommon in Cambodia. The objective of this study is to assess the virological effectiveness of this regimen as well as impact of adherence boosting for patients experiencing virological failure. METHODS:The 2PICAM study (Clinicaltrial: NCT01801618) is a cross-sectional study of HIV-infected adults on PR inhibitor-based second-line regimen since at least 6 months, conducted in 13 representative sites, comprising more than 90% of the target population. Adults with HIV RNA above 250 copies/mL (threshold of the assay) at inclusion received boosted adherence counseling during 3 months followed by HIV RNA control. For confirmed virological failure, genotype resistance test was performed and expert committee used results for therapeutic decision. RESULTS:Among the 1,317 adults enrolled, the median duration of second-line regimen was 5 years. At inclusion, 1,182 (89.7%) patients achieved virological success (<250 copies/mL) and 135 (10.3%) experienced a virological failure (>250 copies/mL). In multivariable analysis, factors associated with virological success were: CD4 cell count between 201 and 350/mm3 (OR: 4.66, 95% CI: 2.57-8.47, p < 0.0001) and >350/mm3 (OR: 6.67, 95% CI: 4.02-11.06, p < 0.0001), duration of PI-based regimen >2 years (OR: 1.64, 95% CI: 1.03-2.62, p = 0.037), ATV-containing regimen (0R: 1.65, 95% CI: 1.04-2.63, p = 0.034) and high level of adherence (OR: 2.41, 95% CI: 1.07-5.41, p = 0.033). After adherence counseling, 63 (46.7%) patients were rescued while 72 (53.3%) were not. For the 54 patients with genotype resistance tests available, high or intermediate levels of resistance to lopinavir, atazanavir, and darunavir were reported for 13 (24%), 12 (22.2%), and 2 (3.7%) patients, respectively. Change to an alternative PR inhibitor-based regimen was recommended for 17 patients and to third-line regimen, including integrase inhibitors for 12. CONCLUSION:This study reports high rate of virological suppression of second-line regimen and importance of adherence boosting prior to deciding any change of ART regimen. Genotype resistance tests appear necessary to guide decisions. Such information was of great importance for National HIV Program to adapt guidelines and program needs for third-line regimen.

To investigate whether adherence to antiretroviral treatment (ART) can be explained not only by individual factors but also by health care facilities' characteristics, among a sample of people living with HIV (PLWH) treated with PI‐based regimens in Cambodia.

Molecular screening of 300 at-risk people from Central Africa identified 2 human T-lymphotropic virus (HTLV)-4-infected individuals. A zoonotic origin of infection was suggested, as both individuals reported being severely bitten by a gorilla during hunting activities. One strain was highly divergent and was designated as the HTLV-4 subtype-b prototype.

The primate T Lymphotropic viruses, which include HTLV-1/STLV-1, HTLV-2/STLV-2, HTLV-3/STLV-3 and HTLV-4/STLV-4 constitute a group of related human and simian retroviruses which share some common epidemiological, biological and molecular features. While HTLV-1 and HTLV-2 are relatively widespread, HTLV-3 has only been observed in few African individuals living in close contact with infected non-human primates (NHPs) and HTLV-4 has been identified in only one hunter living in South Cameroon. Recently, a molecular study conducted in Cameroon on 1107 NHPs of 21 different species detected and characterized STLV-4 infection in 6 gorillas. Therefore HTLV-4 could have emerged from a gorilla reservoir. In the context of our current ongoing studies on PTLV in Cameroon, we decided to look for PTLV-4 in a large series of blood DNA originating from persons at risk for such infection (hunters of NHPs), living in the same region than the index case, and also from several gorillas. HTLV WB serology was available for all the persons. We searched for HTLV-4/STLV-4 infection in humans and gorillas using two different nested PCR, one targeting the pol gene, the other one targeting the LTR. These methods were able to detect 1 copy in a background of 250 ng of DNA. We included in the first preliminary study: 1) 228 individuals from Cameroon that had reported a contact (mostly bite) with a NHP (80 of them specifically with a gorilla); 2) 21 gorillas (16 from Cameroon, 2 from Gabon and 3 from European zoos). Out of the 21 gorillas, one originating from Cameroon was found positive for both STLV-4 pol and LTR PCR. The screening of the human samples is still in progress and will be presented.

African green monkeys (AGMs) represent the most widely distributed non-human primates species in Africa. SIVagm naturally infects four of the 6 AGMs species at high prevalence in a species-specific manner. To date, only limited information is available on molecular characteristics of SIVagm infecting Chlorocebus tantalus.Here, we characterized the full-length genome of a virus infecting a naturally infected captive C. tantalus from Cameroon by amplifying and sequencing sub-genomic PCR fragments. The isolate (SIVagmTAN-CM545) is 9923bp long and contained all canonical genes of a functional SIV. SIVagmTAN-CM545 showed a mosaic structure, with gag, pol, nef and accessory genes closely related to SIVagmSAB infecting Chlorocebus sabaeus monkeys from west Africa, and the env gene, closely related to SIVagmTAN infecting tantalus monkeys from Central Africa. Thus SIVagmTAN-CM545 is SIVagmSAB/SIVagmTAN recombinant.These unexpected findings suggest that the evolution of SIVagm is more complex than previously thought and warrant further studies.

ObjectiveTo assess efavirenz plasma concentrations and their association with treatment efficacy and tolerance of efavirenz 600 mg daily in HIV-tuberculosis co-infected patients.MethodsHIV-infected adults with CD4+ T cell count ≤ 200/mm(3) received standard 6-month tuberculosis treatment and antiretroviral therapy including a daily-dose of 600 mg of efavirenz, irrespective of their body weight. Mid-dose blood samples were drawn both on tuberculosis treatment (week +2 and week +6 after antiretroviral therapy initiation, and week 22 of follow-up) and off tuberculosis treatment (week 50 of follow-up). Considered therapeutic range was 1,000 to 4,000 ng/mL. Multivariate analysis was performed to evaluate the association between efavirenz concentration below 1,000 ng/mL and virological failure. Linear regression was used to test the association between efavirenz exposure and CD4+ T cell gain. Severe side effects potentially related to efavirenz were described and their association with efavirenz exposure was tested by multivariate analysis.ResultsEfavirenz plasma concentrations were available in 540 patients. Median [interquartile range] efavirenz concentrations were 2,674 ng/mL [1,690-4,533], 2,667 ng/mL [1,753-4,494] and 2,799 ng/mL [1,804-4,744] at week +2, week +6, week 22, respectively, and 2,766 ng/mL [1,941-3,976] at week 50. Efavirenz concentrations were lower at week 50 (off rifampicin) compared to week 22 (on rifampicin) (p<0.001). Late attendance to study visit and low hemoglobinemia were the only factors associated with an increased risk of efavirenz concentration below 1,000 ng/mL. Efavirenz concentration below 1,000 ng/mL was not associated with treatment failure. Efavirenz concentration above 4,000 ng/mL was associated with higher risk of central nervous system side effects (p<0.001) and of hepatotoxicity (p<0.001).ConclusionBody weight and tuberculosis treatment were not associated with low efavirenz concentrations or treatment failure, supporting the 600 mg daily-dose of efavirenz in HIV-tuberculosis co-infected patients. High efavirenz concentrations were related to a higher risk of central nervous system side effects and hepatotoxicity.Trial registrationClinicalTrials.gov NCT01300481.

ABSTRACT Primates are naturally infected with herpesviruses. During the last 15 years, the search for homologues of human herpesviruses in nonhuman primates allowed the identification of numerous viruses belonging to the different herpesvirus subfamilies and genera. No simian homologue of human herpesvirus 7 (HHV7) has been reported to date. To investigate the putative existence of HHV7-like viruses in African great apes, we applied the consensus-degenerate hybrid oligonucleotide primers (CODEHOP) program-mediated PCR strategy to blood DNA samples from the four common chimpanzee subspecies ( Pan troglodytes verus , P. t. ellioti , P. t. troglodytes , and P. t. schweinfurthii ), pygmy chimpanzees ( Pan paniscus ), as well as lowland gorillas ( Gorilla gorilla gorilla ). This study led to the discovery of a novel roseolovirus close to HHV7 in each of these nonhuman primate species and subspecies. Generation of the partial glycoprotein B (1,111-bp) and full-length DNA polymerase (3,036/3,042-bp) gene sequences allowed the deciphering of their evolutionary relationships. Phylogenetic analyses revealed that HHV7 and its African great ape homologues formed well-supported monophyletic lineages whose topological resemblance to the host phylogeny is suggestive of virus-host codivergence. Notably, the evolutionary branching points that separate HHV7 from African great ape herpesvirus 7 are remarkably congruent with the dates of divergence of their hosts. Our study shows that African great apes are hosts of human herpesvirus homologues, including HHV7 homologues, and that the latter, like other DNA viruses that establish persistent infections, have cospeciated with their hosts. IMPORTANCE Human herpesviruses are known to possess simian homologues. However, surprisingly, none has been identified to date for human herpesvirus 7 (HHV7). This study is the first to describe simian homologues of HHV7. The extensive search performed on almost all African great ape species and subspecies, i.e., common chimpanzees of the four subspecies, bonobos, and lowland gorillas, has allowed characterization of a specific virus in each. Genetic characterization of the partial glycoprotein B and full-length DNA polymerase gene sequences, followed by their phylogenetic analysis and estimation of divergence times, has shed light on the evolutionary relationships of these viruses. In this respect, we conclusively demonstrate the cospeciation between these new viruses and their hosts and report cases of cross-species transmission between two common chimpanzee subspecies in both directions.

Tuberculosis is a major cause of death among adults infected by HIV. The CAMELIA (ANRS 1295/CIPRA KH001) randomized clinical trial aimed to determine the optimal timing of ARV initiation after tuberculosis treatment onset to reduce mortality. Here, we describe the trial implementation in five hospitals in Cambodia under the coordination of the Institut Pasteur in Cambodia, its conduct, the challenges and public health benefits in Cambodia and beyond.

Objective: To describe the ARV resistance profiles of patients experiencing virological failure after at least 6 months on LPV/r-based 2nd line regimen in Cambodia. Design: Retrospective analysis of resistance testing of 89 patients with detectable viral load under LPV/r-based 2nd line regimen. Methods: Bulk sequencing of HIV-1 protease, reverse transcriptase and integrase PCR products. Results: Protease gene amplification was successful for 71/89 patients (80%). All were infected by CRF01_AE viruses. Among them, 42 did not present any resistance to PIs. A high level of resistance to PIs was observed for the 29 remaining patients. Twenty-six were resistant to LPV/r (8 possibly resistant). Twenty-eight, 21 and 20 were also found resistant to IDV, ATV/r and FPV/r, respectively. Twenty-six were resistant to NFV (11 possibly) and 22 to SQV/r (9 possibly). Finally, 22/29 (75.8%) were resistant to at least 3 PIs. Interestingly, 78.6% (22/29) were found sensitive to DRV/r. In this group, a high frequency of resistance to RTIs including ETV was also reported. No resistance to raltegravir (RAL) or elvitegravir (EVG) was observed (n=24). Detailed ARV histories documented for 15 patients revealed past exposition to multiple RTIs and PIs. Conclusion: Almost 2/3 of patients (60/89) with virological failure on LPV/r-based 2nd line in our study were not in urgent need for treatment change. In contrast, switching treatment was clearly required for 1/3 (29/89) presenting high level of resistance to PIs and RTIs. For those patients, DRV, RAL/EVG, and potentially ETV, could be good candidates for 3rd line ARV regimen if available.

Antiretroviral therapy in resource-limited settings is monitored clinically and immunologically according to WHO guidelines. Frequent misclassification of virologic failure is reported, mostly in adults, leading to early therapy switch or late failure diagnosis. Pediatric treatment monitoring and resistance data upon first-line failure are limited, particularly when the 2010-WHO pediatric guidelines are used without routine viral load monitoring. We previously reported high treatment failure misclassification rates by pediatric 2010 guidelines in Cambodian children on first-line therapy. Here we determine the extent and patterns of resistance, with yearly viral load and 6-monthly CD4. Drug resistance mutations were determined using the IAS-USA 2011 list. Predicted resistance interpretation was determined with Stanford Database tools. Fifty-one children with available genotypes met inclusion criteria. All but one (subtype B) were CRF01_AE. The most common regimen was stavudine, lamivudine, and nevirapine (96%), taken for a median of 2.2 years. Resistance was seen in 98%; 96% to nucleoside and nonnucleoside reverse transcriptase inhibitors (NRTIs and NNRTIs); 51% with ≥4 mutations. The most common NRTI mutations were 184V/I and 67N and the most common NNRTI mutations were 181C/Y/I/V and 190A/S. A total of 22% had multiresistant mutations and 18% had predicted high-level resistance to subsequent therapy options didanosine, abacavir, etravirine, and tenofovir. In 98% of Cambodian children misclassified as nonfailing first-line therapy by 2010 guidelines, 51% had extensive drug resistance to current and 18% to subsequent antiretroviral therapy. Affordable routine viral load monitoring allowing for early and more accurate treatment failure diagnosis is desperately needed in resource-limited settings.

Objective:To analyze cases of paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) in the CAMbodian Early versus Late Introduction of Antiretrovirals (CAMELIA) randomized trial designed to compare early (2 weeks) versus late (8 weeks) antiretroviral therapy (ART) initiation after tuberculosis treatment onset in Cambodia (NCT00226434).Methods:ART-naive adults with CD4(+) cell count of 200cells/l or less, newly diagnosed tuberculosis, and at least one follow-up visit after ART initiation were included in this analysis. Each case of suspected TB-IRIS was systematically validated by two physicians not involved in patients' management. Factors associated with occurrence of TB-IRIS were identified using the Cox proportional hazard model.Results:Among 597 patients, 26% experienced TB-IRIS with an incidence rate of 37.9 cases per 100 person-years [95% confidence interval (CI) 32.4-44.4]. Main clinical manifestations included new or worsening lymphadenopathy (77.4%) and fever (68.4%). Chest radiograph revealed new or worsening abnormalities in 53.4%. Symptoms resolved in 95.5% of patients. Six deaths were directly related to TB-IRIS. Initiating ART early increased the risk of TB-IRIS by 2.61 (95% CI 1.84-3.70). Extrapulmonary or disseminated tuberculosis, CD4(+) cell count of 100cells/l or less, and HIV RNA concentration more than 6 log(10)copies/ml were also significantly associated with higher risk of TB-IRIS.Conclusion:Shortening the delay between tuberculosis treatment onset and ART initiation to 2 weeks was associated with an increased risk of developing TB-IRIS. However, TB-IRIS was generally easily manageable. Given the marked reported survival advantage of early ART initiation after tuberculosis treatment onset, these data indicate that fear of TB-IRIS should not be an impediment to early ART in adults with advanced immunodeficiency in resource-limited, high burden settings. (C) 2013 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins

BackgroundMulti-nucleos(t)ide resistance (MNR) mutations including Q151M, K65R mutations, and insertion at codon 69 of HIV-1 reverse transcriptase coding region may confer resistance to all molecules of nucleos(t)ide reverse transcriptase inhibitors (NRTI). The presence of these mutations is an emerging problem compromising non-nucleoside reverse transcriptase inhibitors and protease inhibitors-based therapies. Furthermore, factors associated with selection of these mutations are still not well defined. The current study aimed to evaluate the frequency and to characterize factors associated with the occurrence of multi-nucleos(t)ide resistance mutations among HIV-1 infected patients failing recommended first-line antiretroviral regimens in Cambodia.Methodology/principal findingThis is a retrospective analysis of HIV-1 drug resistance genotyping of 520 HIV-1 infected patients in virological failure (viral load > 250 copies/mL) while on first-line antiretroviral therapy in Cambodia with at least one reverse transcriptase inhibitor resistance associated mutation. Among these 520 patients, a total of 66 subjects (66/520, 12.7%) presented ≥ 1 MNR mutation, including Q151M, K65R, and Insert69 for 59 (11.3%), 29 (5.6%), and 2 (0.4%) patients, respectively. In multivariate analysis, both Q151M (p = 0.039) and K65R (p = 0.029) mutations were independently associated with current stavudine- compared to zidovudine-use.ConclusionSuch selection of mutations by stavudine drastically limits the choice of antiretroviral molecules available for second-line therapy in resource-limited settings. This finding supports the World Health Organization's recommendation for stavudine phase-out.

The study of the genetic and selective landscape of immunity genes across primates can provide insight into the existing differences in susceptibility to infection observed between human and non-human primates. Here, we explored how selection has driven the evolution of a key family of innate immunity receptors, the Toll-like receptors (TLRs), in African great ape species. We sequenced the 10 TLRs in various populations of chimpanzees and gorillas, and analysed these data jointly with a human data set. We found that purifying selection has been more pervasive in great apes than in humans. Furthermore, in chimpanzees and gorillas, purifying selection has targeted TLRs irrespectively of whether they are endosomal or cell surface, in contrast to humans where strong selective constraints are restricted to endosomal TLRs. These observations suggest important differences in the relative importance of TLR-mediated pathogen sensing, such as that of recognition of flagellated bacteria by TLR5, between humans and great apes. Lastly, we used a population genetics-phylogenetics method that jointly analyses polymorphism and divergence data to detect fine-scale variation in selection pressures at specific codons within TLR genes. We identified different codons at different TLRs as being under positive selection in each species, highlighting that functional variation at these genes has conferred a selective advantage in immunity to infection to specific primate species. Overall, this study showed that the degree of selection driving the evolution of TLRs has largely differed between human and non-human primates, increasing our knowledge on their respective biological contribution to host defence in the natural setting.

La tuberculose est une des principales causes de mortalité chez les adultes infectés par le VIH (virus de l’immunodéficience humaine). L’essai clinique randomisé CAMELIA (ANRS 1295/CIPRA KH001) visait à déterminer le moment optimal de l’initiation du traitement antirétroviral après le début du traitement antituberculeux afin de réduire la mortalité. Nous décrivons ici sa mise en œuvre dans cinq hôpitaux cambodgiens sous la coordination de l’Institut Pasteur du Cambodge, sa conduite dans les établissements de santé, les défis liés à cette thérapie, ainsi que les bénéfices en termes de santé publique au Cambodge et au-delà.