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We evaluated Ibalizumab (IBA)-containing standardized optimized salvage regimen (with or without a 4-week foscarnet induction) in individuals harboring multidrug-resistant human immunodeficiency virus type 2 (HIV-2). Nine were included; 2 achieved virological suppression after foscarnet induction with a sustained suppression at Week 24 after IBA initiation, and an additional individual at Week 24 after Ibalizumab initiation.
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Fármacos Anti-VIH , Anticuerpos Monoclonales , Infecciones por VIH , Humanos , Foscarnet/uso terapéutico , VIH-2 , Fármacos Anti-VIH/uso terapéutico , Terapia Recuperativa , Infecciones por VIH/tratamiento farmacológicoRESUMEN
BACKGROUND: Few data are available on the real-world efficacy of receiving tenofovir-lamivudine-dolutegravir (DTG) as HIV treatment, particularly among young people in West Africa. Here, we evaluated pharmaco-virological outcomes and resistance profiles among Togolese children and adolescents. METHODS: A cross-sectional study was conducted in Lomé, Togo, enrolling antiretroviral-treated people with HIV aged from 18 months to 24 years. Plasma HIV-1 viral load and antiretroviral concentrations were measured. Next-Generation Sequencing (NGS) of protease, Reverse Transcriptase (RT) and integrase was performed on all samples with viral load >200 c/mL. Drug resistance mutations (DRMs) were identified and interpreted using the ANRS-MIE algorithm. RESULTS: 264 participants were enrolled (median age=17 years), 226 received a DTG-based regimen for a median of 20.5 months. Among them, virological suppression at the 200 c/mL threshold in 80.0% of the participants. Plasma DTG concentrations were adequate (i.e., >640 ng/mL), suboptimal and below the limit of quantification in 74.1%, 6.7% and 19.2% of participants receiving DTG, respectively. Overall, viruses resistant to any of Nucleoside RT Inhibitors, Non-NRTIs, and protease inhibitors were found in 52%, 66% and 1.6% of participants, respectively. A major integrase inhibitor DRM was observed in 9.4% (n=3/32, R263K, E138A-G140A-Q148R, and N155H) of participants with a viral load >200 c/mL. CONCLUSIONS: These first findings in such a large series of adolescents in a low-income country, showed a good virological response of 80% and the presence of an integrase DRM in 9.4% of the virological failures, supporting the need to monitor DTG drug resistance to reduce the risk of resistance acquisition.
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AIMS: Dolutegravir (DTG) and rilpivirine (RPV) dual therapy is now recommended as a switch option in virologically suppressed HIV patients. Literature suggests that virological failure with dual therapy could possibly relate to subtherapeutic drug concentrations. In this study, we aimed at describing the DTG and RPV trough plasma concentrations (Cmin) and plasma HIV-1 RNA viral load (VL) during maintenance dual therapy. METHODS: We performed a retrospective analysis of DTG and RPV therapeutic drug monitoring in people living with HIV/AIDS (PLWHA) with dual therapy in 9 French centres. DTG and RPV trough plasma concentrations were estimated using a Bayesian approach to predict Cmin. The relationship between the pharmacokinetics of DTG and RPV and VL > 50 copies (cp)/mL was explored using joint nonlinear mixed models. The frequency of subtherapeutic threshold (DTG Cmin below 640 ng/mL and RPV Cmin below 50 ng/mL) were compared between PLWHA presenting VL > 50 cp/mL or not during the study. RESULTS: At baseline, 209 PLWHA were enrolled in the study. At week 48, 19 people living with HIV/AIDS (9.1%) discontinued their treatment and 15 PLWHA (7.1%) exhibited VL > 50 cp/mL. Six PLWHA out of 15 (40.0%) with VL > 50 cp/mL during the follow-up had at least 1 Cmin below the respective thresholds while only 26/194 patients (13.4%) without virological replication had at least 1 concentration below the threshold (P = .015). CONCLUSION: A majority of PLWHA receiving DTG/RPV maintenance dual therapy demonstrated VL < 50 cp/mL but virological replication was more frequent in people living with HIV/AIDS with subtherapeutic Cmin.
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Síndrome de Inmunodeficiencia Adquirida , Fármacos Anti-VIH , Infecciones por VIH , VIH-1 , Humanos , Fármacos Anti-VIH/uso terapéutico , Estudios Retrospectivos , Síndrome de Inmunodeficiencia Adquirida/tratamiento farmacológico , Teorema de Bayes , Monitoreo de Drogas , Rilpivirina/uso terapéutico , Oxazinas , Piridonas/uso terapéutico , Compuestos Heterocíclicos con 3 Anillos/efectos adversos , Carga ViralRESUMEN
BACKGROUND: Treatment of multidrug-resistant (MDR) tuberculosis with linezolid is characterized by high rates of adverse events. Evidence on therapeutic drug monitoring to predict drug toxicity is scarce. This study aimed to evaluate the association of linezolid trough concentrations with severe toxicity. METHODS: We retrospectively assessed consecutive patients started on linezolid for MDR tuberculosis between 2011 and 2017. The primary outcome was severe mitochondrial toxicity (SMT) due to linezolid, defined as neurotoxicity or myelotoxicity leading to drug discontinuation. The impact of plasma linezolid trough concentrations >2 mg/L was assessed in multivariate Cox proportional hazards models including time-varying covariates. RESULTS: SMT occurred in 57 of 146 included patients (39%) at an incidence rate of 0.38 per person-year (95% confidence interval, .30-.49). A maximum linezolid trough concentration >2 mg/L was detected in 52 patients (35.6%), while the mean trough concentration was >2 mg/L in 22 (15%). The adjusted hazard ratio for SMT was 2.35 (95% confidence interval, 1.26-4.38; P = .01) in patients with a mean trough concentration >2 mg/L and 2.63 (1.55-4.47; P < .01) for SMT after the first detection of a trough concentration >2 mg/L. In an exploratory analysis, higher maximum trough concentrations were dose-dependently associated with toxicity, while lowering elevated trough concentrations did not restore baseline risk. CONCLUSIONS: Linezolid trough concentrations >2 mg/L are strongly associated with the development of severe treatment-emergent toxicity in patients treated for MDR tuberculosis. Pending further prospective evidence, an individual risk-benefit assessment on the continuation of linezolid treatment is warranted in any patient with trough concentrations >2 mg/L.
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Antituberculosos , Tuberculosis Resistente a Múltiples Medicamentos , Humanos , Linezolid/efectos adversos , Antituberculosos/efectos adversos , Estudios Retrospectivos , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Monitoreo de DrogasRESUMEN
BACKGROUND: Data on human immunodeficiency virus (HIV) seroconversion among men who have sex with men (MSM) using pre-exposure prophylaxis (PrEP) in West Africa are needed. This study aimed to document HIV seroconversion and associated determinants, PrEP adherence, plasma drug concentrations, and HIV drug resistance in MSM using event-driven or daily PrEP in Burkina Faso, Côte d'Ivoire, Mali, and Togo. METHODS: A prospective cohort study was conducted in 2017-2021 among HIV-seronegative MSM aged 18 or over who were at high risk of HIV infection. Participants could choose between event-driven and daily PrEP, switch regimens, and discontinue or restart PrEP. The determinants of HIV incidence were investigated using a multivariate mixed-effects Poisson regression analysis. RESULTS: A total of 647 participants were followed for a total time of 1229.3 person-years. Of 5371 visits, event-driven PrEP was chosen in 3873 (72.1%), and daily PrEP in 1400 (26.1%). HIV incidence was 2.4 per 100 person-years (95% confidence interval [CI] 1.5-3.6) for event-driven PrEP, and 0.6 per 100 person-years (95% CI .1-2.3) for daily PrEP (adjusted incidence rate ratio 4.40, 95% CI 1.00-19.36, P = .050). Adequate adherence was lower with event-driven than daily PrEP (44.3% vs 74.9%, P < .001). Plasma drug concentrations were undetectable in 92 (97.9%) of the 94 measures taken for 23 participants who seroconverted. Only 1 participant had resistance to PrEP drugs. CONCLUSIONS: HIV seroconversions mainly occurred in participants who chose event-driven PrEP. The study's data highlighted major difficulties with adherence to this regimen. Improving adherence to event-driven PrEP constitutes a major research and public health priority in this context.
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Fármacos Anti-VIH , Infecciones por VIH , Seropositividad para VIH , Profilaxis Pre-Exposición , Minorías Sexuales y de Género , Masculino , Humanos , Infecciones por VIH/epidemiología , Infecciones por VIH/prevención & control , Infecciones por VIH/tratamiento farmacológico , Homosexualidad Masculina , Seropositividad para VIH/epidemiología , Seropositividad para VIH/tratamiento farmacológico , Estudios Prospectivos , Fármacos Anti-VIH/uso terapéutico , Seroconversión , Burkina Faso , VIHRESUMEN
The burden of CMV infection and disease is important in pediatric hematopoietic stem cell transplantation (HSCT), notably in the subgroup of patients with inborn errors of immunity (IEIs). Letermovir (LMV) is now a standard of care for CMV prophylaxis in adult sero-positive (R+) recipients, but is not yet labeled for children. Published pediatric studies are still scarce. We report a monocentric real-life use of LMV in 36 HSCT pediatric recipients with IEIs considered at high-risk of CMV infection including 14 patients between 2 and 12 months of age. A homogenous dosage proportional to the body surface area was used. Pharmacokinetic (PK) was performed in 8 patients with a median of 6 years of age (range 0,6;15). The cumulative incidence of clinically significant CMV infections (CS-CMVi) and the overall survival of patients under LMV were compared to a very similar historical cohort under (val)aciclovir prophylaxis. LMV tolerance was good. As compared to the historical cohort, the incidence of CS-CMVi was significantly lower in LMV group (5 out of 36 transplants (13.9%) versus 28 of the 62 HSCT (45.2%)) (p = 0.002). Plasma LMV exposures did not significantly differ with those reported in adult patients. In this high-risk pediatric HSCT cohort transplanted for IEIs, CMV prophylaxis with LMV at a homogenous dosage was well tolerated and effective in preventing CS-CMVi compared with a historical cohort.
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Infecciones por Citomegalovirus , Trasplante de Células Madre Hematopoyéticas , Adulto , Humanos , Niño , Receptores de Trasplantes , Acetatos , Infecciones por Citomegalovirus/etiología , Infecciones por Citomegalovirus/prevención & control , Trasplante de Células Madre Hematopoyéticas/efectos adversosRESUMEN
BACKGROUND: Initiating same-day ART for newly HIV-diagnosed individuals reduces secondary HIV transmissions and the risk of them being lost to follow-up between diagnosis and initiation of ART. METHODS: The FAST study was a national, prospective, single-arm study assessing the efficacy, safety and feasibility of bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) in a same-day initiation model. ART had to be started on the first medical appointment, before any laboratory results were available. Participants completed a self-administered questionnaire at each visit including a HIV anxiety 5-point Likert scale. The primary outcome was the proportion of participants in the ITT population with plasma HIV RNA (pVL)â<â50 copies/mL at Week (W) 24 using the FDA Snapshot algorithm. RESULTS: Overall, 112 participants were included in the ITT population. During follow-up, seven participants discontinued the study drug but remained on the study, and seven others discontinued follow-up. According to FDA Snapshot analysis, at W24 and W48, 90/112, (80.4%; 95% CI: 71.8-87.3) and 95/112 (84.8%; 95% CI: 76.8-90.9) of participants achieved pVLâ<â50 copies/mL, respectively. The protocol-defined virological failure (PDVF, 2 consecutive pVLâ≥â50 copies/mL as of W24) was observed in 11/112 (9.8%) at W24 and 14/112 (12.5%) at W48. No emergent resistance-associated mutation was detected in those with PDVF at W24 and W48. BIC/FTC/TAF was well tolerated through to W48, with a low incidence of grade 3-4 adverse events (15/100 person-years). Patient opinion of same-day treatment initiation and continuing BIC/FTC/TAF was very favourable. CONCLUSIONS: These results suggest that BIC/FTC/TAF is safe, effective and well accepted for same-day initiation.
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Fármacos Anti-VIH , Infecciones por VIH , Humanos , Infecciones por VIH/tratamiento farmacológico , Emtricitabina/uso terapéutico , Estudios Prospectivos , Adenina , Alanina/uso terapéutico , Piridonas/uso terapéutico , Combinación de Medicamentos , Compuestos Heterocíclicos de 4 o más Anillos/uso terapéutico , Fármacos Anti-VIH/uso terapéuticoRESUMEN
BACKGROUND: Hypermutated viruses induced by APOBEC3 (apolipoprotein B mRNA-editing, enzyme-catalytic, polypeptide-like 3) proteins comprise some of the defective viruses in the HIV reservoir. Here, we assessed the proportion of APOBEC3-induced defective proviruses in HIV-positive patients before and after receiving dolutegravirâ+âlamivudine dual therapy. METHODS: PBMCs of virologically suppressed patients enrolled in the ANRS 167 LAMIDOL trial, evaluating a switch from triple therapy to dolutegravirâ+âlamivudine, were collected 8â weeks before (W-8) and 48â weeks after (W48) dual-therapy initiation. The Vif and RT regions were subject to next-generation sequencing. Bioinformatic algorithms were developed to identify APOBEC3-defective sequences and APOBEC3-related drug resistance mutations (APOMuts). All hypermutated sequences and those containing at least one stop codon were considered as defective. RESULTS: One hundred and four patients were enrolled (median virological suppression duration: 4.2â years; IQR: 2.0-9.1). Proviral defective reads at W-8 and W48 were detected in Vif in 22% and 29% of patients, respectively, and in RT in 38% and 42% of patients, respectively. At least one APOMut was present in proviruses of 27% and 38% of patients at W-8 and W48, respectively. The ratio of APOMuts/number of potential APOMut sites was significantly higher at W48 (16.5%) than at W-8 (9.8%, Pâ=â0.007). The presence of APOBEC3-defective viruses at W-8 was not associated with HIV total DNA level, nor with the third drug class received prior to switching to dolutegravirâ+âlamivudine, nor with the duration of virological suppression. CONCLUSIONS: Whereas no significant change in the proportion of patients with APOBEC3-defective proviruses was evidenced after 1â year of dolutegravirâ+âlamivudine maintenance, enrichment in APOMuts was observed. Further longer-term studies are needed to assess the other forms of defective viruses with dual-therapy.
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Fármacos Anti-VIH , Infecciones por VIH , Humanos , Fármacos Anti-VIH/uso terapéutico , Desaminasas APOBEC/genética , ADN/uso terapéutico , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Lamivudine/uso terapéutico , Piridonas/uso terapéutico , Carga ViralRESUMEN
OBJECTIVES: Because NRTIs can have fetal toxicities, we evaluated a perinatal NRTI-sparing strategy to prevent perinatal HIV transmission. Our primary objective was to determine the proportion maintaining a viral load (VL) of <50 copies/mL up to delivery on darunavir/ritonavir monotherapy, without requiring treatment intensification. METHODS: In a one-arm, multicentre Phase 2 clinical trial, eligible patients in the first trimester of pregnancy on ART with plasma VLâ<â50 copies/mL received maintenance monotherapy with darunavir/ritonavir, 600/100 mg twice daily. VL was monitored monthly. ART was intensified in the case of VLâ>â50 copies/mL. Neonates received nevirapine prophylaxis for 14 days. RESULTS: Of 89 patients switching to darunavir/ritonavir monotherapy, 4 miscarried before 22 weeks' gestation, 2 changed treatment for elevated liver enzymes without virological failure, and 83 were evaluable for the main outcome. Six had virological failure confirmed on a repeat sample (median VLâ=â193 copies/mL; range 78-644), including two before switching to monotherapy. In these six cases, ART was intensified with tenofovir disoproxil fumarate/emtricitabine. The success rate was 75/83, 90.4% (95% CI, 81.9%-95.7%) considering two patients with VL missing at delivery as failures, and 77/83, 92.8% (95% CI, 84.9%-97.3%) when considering them as successes since both had undetectable VL on darunavir/ritonavir throughout pregnancy. In ITT, the last available VL before delivery was <50 copies/mL in all of the patients. There was no case of perinatal HIV transmission. CONCLUSIONS: Darunavir/ritonavir maintenance monotherapy required intensification in nearly 10% of cases. This limits its widespread use, thus other regimens should be evaluated in order to limit exposure to antiretrovirals, particularly NRTIs, during pregnancy.
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Fármacos Anti-VIH , Infecciones por VIH , Femenino , Humanos , Recién Nacido , Embarazo , Darunavir , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/prevención & control , Ritonavir , Resultado del Tratamiento , Carga ViralRESUMEN
BACKGROUND: Panzi General Reference Hospital (HGR Panzi) in the Democratic Republic of Congo follows a large number of patients living with HIV-1 (PLWHIV). Although antiretrovirals (ARVs) are available, HIV-1 viral load (HIV-VL) measurement has only been implemented in the hospital since 2018. No data on ARV resistance levels and ARV dosage in plasma have yet been published for this region. We determined the prevalence of virological failure due to ARV resistance amongst patients and assessed the degree of genotypic resistance of the viral strains. METHODS: We performed an HIV-VL test and determined dosage of ARVs on samples collected from 205 PLWHIV at HGR Panzi between 2017 and 2018, including 13 ARV-naive patients. Genotypic resistance testing was performed on all samples with detectable HIV-VLs, and interpreted with the Agence Nationale de Recherches sur le Sida (ANRS) 2018 algorithm. RESULTS: Baseline resistance to NNRTIs was found in 2 of the 13 treatment-naive individuals (15%). ARV dosage was non-optimal for 44/192 of treated patients (22.9%), with an HIV-VL ≥1000 IU/mL for 40/192 (20.8%) of them. In particular, treatment-experienced viruses presented resistance to at least one NRTI (52.5%), to at least one NNRTIs (70%) or to at least one PIs (15%). Finally, two samples contained viruses with resistance polymorphism in the integrase gene. CONCLUSIONS: The high level of resistance to ARVs observed during this study, mainly due to treatment compliance default, fully justifies the implementation of means for closer patient monitoring. The provision of VL tests and therapeutic education management tools in a PLWHIV follow-up remains an absolute necessity to best adapt the current treatment lines in this region.
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Fármacos Anti-VIH , Infecciones por VIH , Seropositividad para VIH , VIH-1 , Humanos , VIH-1/genética , República Democrática del Congo/epidemiología , Farmacorresistencia Viral/genética , Antirretrovirales/farmacología , Antirretrovirales/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/epidemiología , Seropositividad para VIH/tratamiento farmacológico , Carga Viral , Fármacos Anti-VIH/farmacología , Fármacos Anti-VIH/uso terapéuticoRESUMEN
No data about antiretroviral (ARV) treatment coverage and virological response are available among key populations (female sex workers [FSW] and Men having Sex with Men [MSM]) in Togo. This study aimed to both describe Human Immunodeficiency Virus (HIV) immunovirological status and evaluate the pertinence of an original algorithm combining pharmacology (PK) and viral load (VL) to identify subjects at risk of ARV drug resistance. A cross-sectional multicentric study was conducted in 2017 in Togo. Our PK-virological algorithm (PK-VA) defines subjects at risk of resistance when exhibiting both detectable plasma drug concentrations and VL > 200 c/mL. Among the 123 FSW and 136 MSM included, 50% and 66% were receiving ARV, with 69% and 80% of them successfully-treated, respectively. Genotypes showed drug-resistance mutation in 58% and 63% of nonvirologically controlled (VL > 200 c/mL) ARV-treated FSW and MSM, respectively. PK-VA would have enabled to save 75% and 72% of genotypic tests, for FSW and MSM, respectively. We reported first data about HIV care cascade among key populations in Togo, highlighting they are tested for HIV but linkage to care remains a concern. Furthermore, 70%-80% of ARV-treated participants experienced virological success. In limited resources settings, where genotyping tests are beyond reach, PK-VA might be an easiest solution to sort out patients needing ARV adaptation due to resistance.
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Fármacos Anti-VIH , Infecciones por VIH , Trabajadores Sexuales , Minorías Sexuales y de Género , Masculino , Humanos , Femenino , Homosexualidad Masculina , Togo/epidemiología , Estudios Transversales , Antirretrovirales/uso terapéutico , Carga Viral , Farmacorresistencia Viral/genética , Fármacos Anti-VIH/uso terapéuticoRESUMEN
We compared the proportion of participants achieving first undetectable HIV-1 RNA (VL) in seminal plasma (SP) and blood plasma (BP) in 19 men starting dolutegravir-based regimen at primary HIV infection. At baseline, median VL was 6.5 (interquartile range [IQR], 5.6-7.9) and 4.5 (IQR, 3.5-5.0) log10 copies/mL in BP and SP, respectively. Between baseline and week 48, significantly higher proportion of participants achieved first VL below limit of quantification in SP (93.0%) than in BP (84.2%; P = .008). Time to first undetectable VL was 8 weeks in SP (95% confidence interval [CI], 5.6-10.4) and 24 weeks in BP (95% CI, 14.1-33.9).
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Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , VIH-1/genética , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Oxazinas/uso terapéutico , Piperazinas/uso terapéutico , Piridonas/uso terapéutico , Semen/virología , Adulto , Infecciones por VIH/genética , Humanos , Cinética , Masculino , Persona de Mediana Edad , ARN Viral/genética , Carga ViralRESUMEN
BACKGROUND: Nearly half of HIV-infected children worldwide are born in West and Central African countries where access to prevention of mother-to-child transmission of HIV (PMTCT) programmes is still limited. WHO recommends reinforced antiretroviral prophylaxis for infants at high risk of mother-to-child transmission of HIV (MTCT) but its implementation needs further investigation in the field. METHODS: The prospective ANRS 12344-DIAVINA study evaluated the feasibility of a strategy combining early infant diagnosis (EID) and reinforced antiretroviral prophylaxis in high-risk infants as identified by interviews with mothers at Ignace Deen Hospital, Conakry, Guinea. RESULTS: 6493 women were admitted for delivery, 6141 (94.6%) accepted HIV testing and 114 (1.9%) were HIV positive. Among these, 51 high-risk women and their 56 infants were included. At birth, a blood sample was collected for infant EID and reinforced antiretroviral prophylaxis was initiated in 48/56 infants (86%, 95% CI 77%-95%). Iron supplementation was given to 35% of infants for non-severe anaemia. Retrospective measurement of maternal plasma viral load (pVL) at delivery revealed that 52% of women had pVLâ<â400â copies/mL attributable to undisclosed HIV status and/or antiretroviral intake. Undisclosed HIV status was associated with self-stigmatization (85% versus 44%, Pâ=â0.02). Based on the results of maternal pVL at delivery, 'real' high-risk infants were more frequently lost to follow-up (44% versus 8%, Pâ<â0.01) in comparison with low-risk infants, and this was associated with mothers' stigmatization (69% versus 31%, Pâ<â0.01). CONCLUSIONS: Reinforced antiretroviral prophylaxis and EID at birth are widely feasible. However, mothers' self-disclosure of HIV status and antiretroviral intake do not allow adequate evaluation of MTCT risk, which argues for maternal pVL measurement near delivery. Furthermore, actions against stigmatization are crucial to improve PMTCT.
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Infecciones por VIH , Complicaciones Infecciosas del Embarazo , Lactante , Recién Nacido , Femenino , Humanos , Embarazo , Transmisión Vertical de Enfermedad Infecciosa/prevención & control , Estudios Retrospectivos , Estudios Prospectivos , Guinea , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/prevención & control , Antirretrovirales/uso terapéutico , Complicaciones Infecciosas del Embarazo/tratamiento farmacológicoRESUMEN
BACKGROUND: HIV-2 resistance to integrase strand-transfer inhibitors (INSTIs) is characterized by two main pathways: (i) mutations at codons 143, 148 and155; and (ii) amino acid insertion after integrase codon 231 (231ins). OBJECTIVES: To complete INSTI resistance data on HIV-2 by determining the viral replicative capacity and INSTI phenotypic susceptibility of integrase mutants obtained through site-directed mutagenesis. METHODS: Site-directed mutants (SDMs) were constructed and viral stocks produced. Viral replicative capacity was assessed by measuring HIV-2 viral load at days 3, 7 and 14. In vitro phenotypic susceptibility was measured using the ANRS PBMC assay. RESULTS: Viruses bearing 231ins did not present impaired replicative capacity, except the 231ins GIRGK mutant. A 231ins GK SDM was resistant to raltegravir and cabotegravir, but remained susceptible to dolutegravir and bictegravir. SDMs harbouring a 5 amino acid insertion (GYKGK or SREGK) were both resistant to all INSTIs. The SDM with T97A+N155H, with or without E92Q, was resistant to all INSTIs, except bictegravir. CONCLUSIONS: These first data on the newly described resistance pathway 231ins, using site-directed mutagenesis, showed no measurable impact on viral fitness and confirmed the decreased susceptibility to a first-generation INSTI (raltegravir) and cabotegravir. Resistance to second-generation INSTIs (dolutegravir and bictegravir) occurred for mutants with a 5 amino acid 231ins.
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Infecciones por VIH , Inhibidores de Integrasa VIH , Integrasa de VIH , VIH-1 , Farmacorresistencia Viral/genética , Infecciones por VIH/tratamiento farmacológico , Integrasa de VIH/metabolismo , Inhibidores de Integrasa VIH/farmacología , Inhibidores de Integrasa VIH/uso terapéutico , VIH-1/genética , VIH-2/genética , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Humanos , Leucocitos Mononucleares/metabolismo , Piridonas/farmacología , Piridonas/uso terapéutico , Raltegravir Potásico/uso terapéuticoRESUMEN
BACKGROUND: The antiviral efficacy of remdesivir in COVID-19 hospitalized patients remains controversial. OBJECTIVES: To estimate the effect of remdesivir in blocking viral replication. METHODS: We analysed nasopharyngeal normalized viral loads from 665 hospitalized patients included in the DisCoVeRy trial (NCT04315948; EudraCT 2020-000936-23), randomized to either standard of care (SoC) or SoC + remdesivir. We used a mathematical model to reconstruct viral kinetic profiles and estimate the antiviral efficacy of remdesivir in blocking viral replication. Additional analyses were conducted stratified on time of treatment initiation (≤7 or >7â days since symptom onset) or viral load at randomization (< or ≥3.5 log10 copies/104 cells). RESULTS: In our model, remdesivir reduced viral production by infected cells by 2-fold on average (95% CI: 1.5-3.2-fold). Model-based simulations predict that remdesivir reduced time to viral clearance by 0.7â days compared with SoC, with large inter-individual variabilities (IQR: 0.0-1.3â days). Remdesivir had a larger impact in patients with high viral load at randomization, reducing viral production by 5-fold on average (95% CI: 2.8-25-fold) and the median time to viral clearance by 2.4â days (IQR: 0.9-4.5â days). CONCLUSIONS: Remdesivir halved viral production, leading to a median reduction of 0.7â days in the time to viral clearance compared with SoC. The efficacy was larger in patients with high viral load at randomization.
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Tratamiento Farmacológico de COVID-19 , Adenosina Monofosfato/análogos & derivados , Alanina/análogos & derivados , Alanina/uso terapéutico , Antivirales/uso terapéutico , Humanos , SARS-CoV-2RESUMEN
BACKGROUND: The recent HIV-1 NNRTI doravirine is likely to be used in pregnant women despite the complete lack of data on safety and exposure in the fetus. The objective of this study was to determine its placental transfer. METHODS: Maternal-to-fetal transfer was investigated using the open-circuit ex vivo dually perfused human cotyledon model. Doravirine was added to a maternal perfusate (theoretical doravirine concentration of 250 ng/mL) containing 2 g/L human albumin and 20 g/L antipyrine, a marker to validate the cotyledon's viability, and cotyledons were dually perfused for up to 90 min. RESULTS: In five experiments, the median (IQR) doravirine concentrations in the maternal and fetal compartments were, respectively, 303 (178-420) and 40 (30-54) ng/mL, the fetal-to-maternal ratio was 16% (12%-18%) and the clearance index (in comparison with antipyrine transfer) was 48% (35%-64%). The median accumulation index in cotyledon tissue was 39% (range 10%-66%). CONCLUSIONS: Doravirine both crosses and accumulates in the placenta. This may be useful as pre/post-exposure prophylaxis to reduce the risk of vertical HIV transmission but carries the potential for fetal toxicities. Further investigation is required to determine the safety and efficacy of this new antiretroviral agent in pregnancy.
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VIH-1 , Placenta , Cotiledón , Humanos , Intercambio Materno-Fetal , Perfusión , Embarazo , Piridonas , TriazolesRESUMEN
OBJECTIVES: Despite the effectiveness of antiretroviral (ARV) therapy to control HIV infection, HIV-associated neurocognitive disorders (HAND) remain frequent. The Neuro+3 study assessed the cognitive improvement associated with ARV intensification based on increased CNS penetration effectiveness (CPE) scoring ≥+3 and total CPE score ≥9. METHODS: Thirty-one patients, aged 18-65 years, with confirmed diagnosis of HAND and effective ARV therapy were included. The cognitive improvement was measured using Frascati three-stage classification and global deficit score (GDS) after 48 and 96 weeks of ARV intensification. Ultrasensitive HIV-RNA, neopterin, soluble CD14, CCL2, CXCL10, IL6, IL8 and NF-L were measured in plasma and cerebrospinal fluid at Day 0 (baseline), Week 48 (W48) and W96. RESULTS: The intensified ARV was associated with a median (IQR) CPE score increase from 6 (4-7) at baseline to 10 (9-11). From baseline to W96, the median (IQR) GDS decreased from 1.4 (0.8-2.2) to 1.0 (0.6-2.0) (Pâ=â0.009); HAND classification improved from 2 to 1 HIV-associated dementia, 22 to 8 mild neurocognitive disorders, 7 to 17 asymptomatic neurocognitive impairment and 0 to 5 patients without any neurocognitive alterations (Pâ=â0.001). In multivariable linear regression analysis, GDS improvement at W96 was significantly associated with CPE score ≥9 after intensification (Pâ=â0.014), CD4 lymphocyte increase at W48 (Pâ<â0.001) and plasma CXCL10 decrease at W96 (Pâ=â0.001). CONCLUSIONS: In patients with HAND, a significant cognitive improvement was observed after the ARV intensification strategy, with a higher CPE score. Cognitive improvement was more often observed in the case of a switch of two drug classes, arguing for better control of CNS HIV immune activation.
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Complejo SIDA Demencia , Infecciones por VIH , Complejo SIDA Demencia/tratamiento farmacológico , Terapia Antirretroviral Altamente Activa , Recuento de Linfocito CD4 , Linfocitos T CD4-Positivos , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Humanos , Trastornos Neurocognitivos/tratamiento farmacológico , Trastornos Neurocognitivos/etiología , Pruebas NeuropsicológicasRESUMEN
OBJECTIVES: To assess in real life whether two-drug regimens (2-DRs) given 4-5 days a week in virally suppressed patients can maintain viral suppression over 48 and 96 weeks. METHODS: This observational single-centre study enrolled all patients who initiated an intermittent 2-DR between 01/01/2016 and 30/06/2019. The primary outcome was the rate of virological failure (VF), defined as confirmed plasma viral load (pVL) ≥50 copies/mL or single pVL ≥50 copies/mL followed by ART change at week 48 (W48) and W96. Secondary outcomes were the 2-DR intermittent strategy success rate (pVL <50 copies/mL with no ART change), change in CD4 count, CD4/CD8 ratio and rate of residual viraemia. RESULTS: Eighty-five patients were included; 67/85 (79%) were men, median age = 57 years (IQR = 50-63), CD4 nadir = 233 cells/mm3 (110-327), ART duration = 21 years (13-24), duration of virological suppression = 6.5 years (3.7-10.8) and CD4 count = 658 cells/mm3 (519-867). Intermittent 2-DRs consisted of integrase strand transfer inhibitor (INSTI)/NNRTI (58%), INSTI/NRTI (13%), two NRTIs (11%), PI/NRTI (7%) and other combinations (11%). The median follow-up was 90 weeks (IQR = 64-111). Overall, four VFs occurred, leading to a virological success rate of 98.8% (95% CI = 93.6-100) at W48 and 95.3% (95% CI = 88.4-98.7) at W96. Resuming the same 2-DR 7 days a week led to viral resuppression in three patients, whereas the M184V mutation emerged in one patient, leading to ART modification. There was no significant change in the CD4 count or residual viraemia rate, but a small increase in the CD4/CD8 ratio (P = 0.009) occurred over the study period. CONCLUSIONS: This observational study shows the potential for intermittent 2-DRs to maintain a high virological success rate, which should be assessed in larger prospective randomized studies.
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Fármacos Anti-VIH , Infecciones por VIH , Preparaciones Farmacéuticas , Fármacos Anti-VIH/uso terapéutico , Terapia Antirretroviral Altamente Activa , Recuento de Linfocito CD4 , Infecciones por VIH/tratamiento farmacológico , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Carga ViralRESUMEN
BACKGROUND: Etravirine/raltegravir dual therapy has been shown to be highly effective as a twice-daily (q12h) regimen in suppressed HIV-infected patients enrolled in the ANRS-163 study. OBJECTIVES: As a once-daily (q24h) regimen is easier for daily life, we aimed to evaluate the capacity of etravirine/raltegravir (400/800 mg) q24h to maintain viral suppression in patients on etravirine/raltegravir q12h. METHODS: Patients on a suppressive etravirine/raltegravir q12h regimen for at least 96 weeks were switched to etravirine/raltegravir q24h in this prospective, multicentre, open-label, single-arm study. Primary outcome was the rate of virological failure (VF: confirmed pVL >50 copies/mL, single pVL >400 copies/mL or single pVL >50 copies/mL with ART change) at Week 48 (W48). Secondary outcomes included treatment strategy success rate (no VF and no treatment discontinuation), regimen tolerability, plasma drug concentrations and resistance profile in the case of VF. RESULTS: A total of 111 patients were enrolled, with a median (IQR) age of 57 years (52-62), CD4 count of 710 cells/mm3 (501-919) and viral suppression for 7.9 years (5.9-10.7). Two patients experienced viral rebound at W24 and W48, leading to a VF rate of 2.0% (95% CI 0.5-7.8) at W48, associated with INSTI resistance in one case. Both had past NNRTI mutations. Ten patients discontinued treatment for adverse events (n = 2), investigator or patient decisions (n = 3), lost to follow-up (n = 3), death (n = 1) or pregnancy (n = 1). Overall, the strategy success rate was 89% (95% CI 81.5-93.6) at W48. In a subgroup of 64 patients, median (IQR) plasma C24h concentrations were 401 ng/mL (280-603) for etravirine and 62 ng/mL (31-140) for raltegravir. CONCLUSIONS: Switching patients virally suppressed on etravirine/raltegravir q12h to the same regimen but given q24h was highly effective in maintaining virological suppression in HIV-infected patients.
Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , VIH-1 , Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Humanos , Persona de Mediana Edad , Nitrilos , Estudios Prospectivos , Pirimidinas , Raltegravir Potásico/uso terapéutico , Resultado del Tratamiento , Carga ViralRESUMEN
Background: Patients diagnosed with advanced HIV infection have a poor prognosis despite initiation of combined antiretroviral therapy (c-ART). Objective: To assess the benefit of adding maraviroc, an antiretroviral drug with immunologic effects, to standard c-ART for patients with advanced disease at HIV diagnosis. Design: Randomized controlled trial. (ClinicalTrials.gov: NCT01348308). Setting: Clinical sites in France (n = 25), Italy (n = 5), and Spain (n = 20). Participants: 416 HIV-positive, antiretroviral-naive adults with CD4 counts less than 0.200 × 109 cells/L and/or a previous AIDS-defining event (ADE). Intervention: C-ART plus placebo or maraviroc (300 mg twice daily with dose modification) for 72 weeks. Measurements: The primary end point was first occurrence of severe morbidity (new ADE, selected serious infections, serious non-ADE, immune reconstitution inflammatory syndrome, or death). Prespecified secondary outcomes included primary outcome components, biological and pharmacokinetic measures, and adverse events graded 2 or higher. Results: 409 randomly assigned participants (207 in the placebo group and 202 in the maraviroc group) who received more than 1 dose were included in the analysis. During 72 weeks of follow-up, incidence of severe morbidity was 11.1 per 100 person-years in the maraviroc group and 11.2 per 100 person-years in the placebo group (hazard ratio, 0.97 [95% CI, 0.57 to 1.67]). Incidence of adverse events graded 2 or higher was 36.1 versus 41.5 per 100 person-years (incidence rate ratio, 0.87 [CI, 0.65 to 1.15]). Limitations: Sixty-four participants discontinued therapy during follow-up. The study was not designed to evaluate time-dependent outcomes or effect modification. Conclusion: Addition of maraviroc to standard c-ART does not improve clinical outcomes of patients initiating therapy for advanced HIV infection. Primary Funding Source: INSERM-ANRS (French National Agency for Research on AIDS).