EBioMedicine

Background High HIV-1 DNA levels in peripheral blood mononuclear cells (PBMC) were associated with a higher risk of severe morbidity and a faster decline in CD4 count in ART-naive patients. We report the association between HIV-1 DNA and mortality in HIV-infected adults in a trial of early ART in West Africa. Methods In the Temprano trial, HIV-infected adults were randomly assigned to start ART immediately or defer ART. After trial termination, HIV-1 DNA was measured in whole blood samples frozen at baseline. We analyzed the association between baseline PBMC HIV-1 DNA and long-term mortality

Etude de la variabilité génétique du VIH-1 en Côte d'Ivoire et relation avec la résistance aux antiviraux

Le VIH-1 est caractérisé par une grande variabilité génétique. Dans les pays en développement où circulent la majorité des sous-types non B, la résistance naturelle aux antirétroviraux (ARV) due à la diversité génétique ou la résistance primaire liée à la transmission de virus résistants sont peu documentées. Nous avonscaractérisé la diversité génétique de variants VIH retrouvés dans une population de patients naifs de traitement antirétroviral à Abidjan, Côte d'Ivoire. Dans cette population virale appartenant majoritairement au recombinant CRF02_AG, nous avons montré que la prévalence des mutations de résistance augmentait régulièrement entre 1997 et 2004. Nous avons également caractérisé le génome entier de certains virus et décrit des recombinants secondaires impliquant dans leur structure génomique le CRF09_cpx et d'autres recombinants déjà décrits. L'ensemble de ces données constitue une base pour la poursuite d'un suivi longitudinal de la résistance et de la diversité génétique du VIH-1 en Côte d'Ivoire.One of the major characteristics of HIV is its high genetic diversity. In developing countries where HIV-1 non-B subtypes are predominant, few data concerning HIV-1 natural or primary resistance to antiretroviral drug are available. We characterized the genetic diversity of HIV-1 variants infecting drug-naive patients from Abidjan, Côte d'Ivoire. Most HIV-1 viruses were recombinant CRF02_AG. In this population, we showed an increasing frequency of key resistance mutations from 1997 to 2004. Moreover, a number of HIV-1 genomes were entirely sequenced. We characterized second-generation HIV-1 recombinants with genomic structure involving CRF09_cpx and other previously described recombinants. A continued monitoring of HIV-1 resistance and genetic diversity is necessary in Côte d'Ivoire.BORDEAUX2-BU Santé (330632101) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

Nucleoside and Nucleotide Analogs Select in Culture for Different Patterns of Drug Resistance in Human Immunodeficiency Virus Types 1 and 2 ▿ †

Recent findings suggest bidirectional antagonisms between the K65R mutation and thymidine analogue mutations in human immunodeficiency virus type 1 (HIV-1)-infected, treatment-experienced patients, yet little is known about HIV-2 in this regard. This study addressed the effects of innate polymorphisms in HIV-2 on emergent resistance to nucleoside/nucleotide analogues. Emergent drug resistance profiles in HIV-2 subtypes A (n = 3) and B (n = 1) were compared to those of HIV-1 subtypes B and C. Drug resistance was evaluated with cord blood mononuclear cells (CBMCs) and MT2 cells, using selective pressure with tenofovir (TFV), zidovudine (ZDV), stavudine (d4T), didanosine (ddI), abacavir (ABC), lamivudine (3TC), emtricitabine (FTC), or various dual-drug combinations. Resistance was evaluated using conventional and ultrasensitive sequencing approaches. In agreement with our previous findings, dual-drug combinations of TFV, ddI, ABC, d4T, ZDV, and 3TC preferentially selected for K65R in HIV-1 subtype C isolates. In HIV-1 subtype B, TFV-3TC and ZDV-3TC selected for M184I and D67N, respectively. In contrast, selections with all four HIV-2 cultures favored the development of M184I in dual-drug combinations that included either 3TC or FTC. Since HIV-2 cultures did not develop K65R, an ultrasensitive allele-specific real-time PCR assay was developed to distinguish the presence of 65R from wild-type K65 after 16 cycles with a discriminatory ability of 0.1% against a population of wild-type virus. These results underscore potential differences in emergent drug resistance pathways in HIV-1 and HIV-2 and show that polymorphisms may influence the development of the resistance pathways that are likely to emerge

Model-based cost-effectiveness estimates of testing strategies for diagnosing hepatitis C virus infection in people who use injecting drugs in Senegal

International audienceBackground: Scaling-up the access to hepatitis C virus (HCV) diagnostics for people who use injecting drugs (PWID) is essential to reduce the HCV incidence in low and middle-income countries. Methods: A decision tree model was developed to compare the cost-effectiveness of 12 strategies for diagnosing HCV in Senegal with a health sector perspective. Strategies included HCV-Ab screening and confirmation of viraemia (based on HCV-RNA or HCV core antigen detection) or only the latter step. Laboratory assays and decentralized tools (point-of-care (POC) tests and dried blood spot (DBS) samples) were included. The base-case assumed a 38.9% seroprevalence, as reported in the PWID population of Dakar. Results: Compared to the cheapest strategy (POC HCV-Ab followed by POC HCV-RNA (S5)), one strategy remained un-dominated in the base-case: POC HCV-Ab followed by venepuncture-based laboratory HCV-RNA (S3). Above a lost to follow-up testing rate of 2.3%, combining POC HCV-Ab with HCV-RNA on DBS (S4) became more cost-effective than S3. Above this threshold, a single-step POC HCV-RNA (S12) was also found un-dominated (ICER to S5=€3,297.50). S5, S12 and S4 cost €14.21, €17.03 and €36.55/screened individual. Incremental cost-effectiveness ratios (€/additional true positive case) were 2,164.82 (S12 versus S5) and 3,297.50 (S4 versus S12). Whenever HCV seroprevalence reached 55.5%, S12 became more cost-effective than S5. Moreover, S4 required a budget 2 to 2.5 times higher than S5 or S12 for diagnosing 90% of HCV-infected PWID in Dakar.Conclusion: A two-step POC-based strategy (S5) would be the most cost-effective option among those proposed in this study for diagnosing HCV in PWID in Senegal. This study illustrates how the lack of secure financing and of data on PWID in LMICs, render difficult to identify the most sustainable strategy in those countries, as well as its implementation

HIV-1 DNA in peripheral blood mononuclear cells is strongly associated with HIV-1 disease progression in recently infected West African adults.

International audienceOBJECTIVE: To analyze the association between the HIV-1 DNA level in peripheral blood mononuclear cells (PBMCs) and disease progression in recently infected West African adults. METHODS: HIV-1 DNA levels were measured in the PBMCs of 200 adults in the French National Agency for Research on AIDS and viral Hepatitis (ANRS) 1220 cohort who had recently been infected with HIV-1. The association between baseline HIV-1 DNA levels and disease progression was analyzed using multivariate Cox regression. Disease progression was defined as the occurrence of any of the following outcomes: death, first World Health Organization stage 3-4 event, or CD4 count3.0 log10 copies/10 PBMCs compared with other patients (95% CI: 1.24 to 3.80, P=0.007). The only other factor associated with progression was follow-up CD4 count (hazard ratio=1.23 per 100 cells/mm decrease; 95% CI: 1.07 to 1.41, P=0.003). DISCUSSION: PBMC HIV-1 DNA level was strongly associated with HIV-1 disease progression, even after adjusting for HIV-1 RNA and CD4 T-cell count. Further studies should assess whether patients with high HIV-1 DNA levels should start antiretroviral therapy earlier than other patients

Association of cellular HIV-1 DNA and virological success of antiretroviral treatment in HIV-infected sub-Saharan African adults

BACKGROUND: HIV-1 DNA persists in infected cells, forming viral reservoirs. Pre-antiretroviral treatment (ART) HIV-1 DNA load was reported to predict ART success in European severely immunocompromised patients. The aim of this study was to determine whether HIV-1 DNA levels are associated with virological success in less severely immunocompromised patients who receive early ART in sub-Saharan Africa. METHODS: The association between pre-ART HIV-1 DNA and the virological response after 30 months on ART was studied in multivariate logistic regression in patients randomised to immediate ART groups in the Temprano trial, which assessed the benefits of early ART in HIV-infected adults in Côte d'Ivoire. HIV-1 DNA was quantified in peripheral blood mononuclear cell (PBMC) using real-time PCR. RESULTS: HIV-1 DNA levels were measured in 1013 patients. Their medians [IQR] of pre-ART CD4 count, HIV-1 RNA and HIV-1 DNA levels were 465 [379-578]/mm(3), 4.7 [4.0-5.3] log(10) copies/ml and 2.9 [2.5-3.2] log(10) copies/million PBMC, respectively. Pre-ART HIV-1 DNA was significantly correlated with pre-ART HIV-1 RNA (R = 0.59, p < 0.0001). In multivariate analysis, HIV-1 DNA < 3 log(10) copies/million PBMC was significantly associated with virological success at M30 after adjustment for other key variables (ART regimen, IPT, sex, age, WHO clinical stage, CD4 and HIV-1 RNA; aOR 1.57; 95% CI 1.08-2.30; p = 0.02). CONCLUSION: Low HIV-1 DNA was statistically associated with virological success in this population of sub-Saharan African adults who started treatment with a median pre-ART CD4 count at 465/mm(3). HIV-1 DNA could become a useful tool for guiding some therapeutic decisions in the test-and-treat era. Trial registration TEMPRANO ANRS 12136 ClinicalTrials.gov, number NCT00495651, date of registration 03/07/2007

Virological failure and drug resistance in West African HIV-infected adults who started ART immediately or deferred ART initiation

BACKGROUND: Asymptomatic HIV-infected people who start ART early may feel less motivated and neglect compliance. This might promote the emergence of resistance. METHODS: In the Temprano trial, ART-naive HIV-infected adults with high CD4 counts were randomly assigned to start ART immediately (immediate group) or defer ART until the WHO criteria were met (deferred group). All participants were monitored for 30 months. Those in the deferred group who started ART were monitored for longer, until they had completed 30 months on ART. We compared the rate of virological failure and drug resistance between the immediate and deferred groups 30 months after ART initiation. RESULTS: Of the 2056 participants in Temprano, 1033 were assigned to start ART immediately and 1023 to defer ART. Of the latter, 488 started ART during trial follow-up. Patients in the deferred group who started ART had a lower median CD4 count (280 versus 465 cells/mm3) and a higher median plasma HIV-1 RNA (5.1 versus 4.7 log10 copies/mL) at baseline. During follow-up, participants in both groups had similar antiretroviral drug exposure. Thirty months after ART initiation, patients in the deferred group had a higher rate of virological failure (35.3% versus 29.9%, P = 0.04) and a lower genotypic susceptibility score (P = 0.04). CONCLUSIONS: Starting ART early decreases the risk of virological failure and drug resistance in the medium term. This benefit is of particular importance in countries where access to viral load monitoring and the number of antiretroviral drug lines is limited