RESUMEN
We compared the coreceptor tropism-predicting performance of a specific genotypic algorithm for HIV-1 subtype D and that of the geno2pheno algorithm with different cutoffs. The D-specific algorithm and geno2pheno with a false-positivity rate cutoff of 2.5% had the same concordance with the phenotypic determination. The geno2pheno algorithm with a false-positivity rate cutoff of 2.5%, more sensitive but slightly less specific, seems to be an appropriate alternative.
Asunto(s)
Algoritmos , Biología Computacional/métodos , VIH-1/genética , VIH-1/fisiología , Receptores del VIH/metabolismo , Tropismo Viral , Acoplamiento Viral , Genotipo , Humanos , Datos de Secuencia Molecular , ARN Viral/genética , Sensibilidad y Especificidad , Análisis de Secuencia de ADNRESUMEN
BACKGROUND: Surveillance of HIV-1 drug resistance in treated patients with plasma viral load (VL) >50 copies/mL. METHODS: The protease and reverse transcriptase (RT) genes were systematically sequenced in samples from 756 patients with VL >50 copies/mL in 2009. The genotyping results were interpreted for each antiretroviral drug (ARV) by using the ANRS algorithm v21. Weighted analyses were used to derive representative estimates of percentages of patients. Prevalence rates were compared with those obtained in 2004 among patients with VL >1000 copies/mL. RESULTS: Sequences were obtained for 506 patients. Sequencing was successful in 45%, 80% and 96% of samples with VL of 51-500, 501-1000 and >1000 copies/mL, respectively. Resistance or possible resistance to at least one ARV was observed in 59% of samples. Overall, 0.9% of samples contained viruses resistant to all drugs belonging to at least three drug classes. All resistance prevalence rates were significantly lower in 2009 than in 2004. CONCLUSION: In France, where 86% of patients were receiving combination antiretroviral therapy in 2009, only 15.0% of patients had a VL >50 copies/mL, suggesting that only 8.9% of treated patients could potentially transmit resistant viruses. Only 0.08% of patients harboured viruses fully resistant to at least three antiretroviral drug classes. Further studies are needed to determine whether resistance continues to decline over time.
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Infecciones por VIH/epidemiología , Infecciones por VIH/virología , VIH-1 , Anciano , Secuencia de Aminoácidos , Fármacos Anti-VIH/uso terapéutico , Terapia Antirretroviral Altamente Activa , Recolección de Datos , Farmacorresistencia Viral , Femenino , Francia/epidemiología , Genotipo , VIH-1/efectos de los fármacos , VIH-1/genética , Encuestas Epidemiológicas , Humanos , Masculino , Persona de Mediana Edad , Prevalencia , ARN Viral/sangre , Insuficiencia del Tratamiento , Carga ViralRESUMEN
Semen represents the main vector of HIV dissemination worldwide, yet the origin of HIV in semen remains unclear. Viral populations distinct from those found in blood have been observed in semen, indicating local viral replication within the male genital tract. The seminal vesicles, the secretions of which constitute more than 60% of the seminal fluid, could represent a major source of virus in semen. This study is the first to investigate the susceptibility of human seminal vesicles to HIV infection both in vitro and in vivo. We developed and characterized an organotypic culture of human seminal vesicles to test for target cells and HIV infection, and, in parallel, analyzed the seminal vesicle tissues from HIV-infected donors. In vitro, in contrast to HIV-1 X4, HIV-1 R5 exposure induced productive infection. Infected cells consisted primarily of resident CD163(+) macrophages, often located close to the lumen. In vivo, HIV protein and RNA were also detected primarily in seminal vesicle macrophages in seven of nine HIV-infected donors, some of whom were receiving prolonged suppressive highly active antiretroviral therapy. These results demonstrate that human seminal vesicles support HIV infection in vitro and in vivo and, therefore, have the potential to contribute virus to semen. The presence of infected cells in the seminal vesicles of treated men with undetectable viremia suggests that this organ could constitute a reservoir for HIV.
Asunto(s)
Infecciones por VIH/virología , VIH-1 , Semen/virología , Vesículas Seminales/virología , Biomarcadores/metabolismo , Células Cultivadas , ADN Viral/metabolismo , Humanos , Inmunohistoquímica , Masculino , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
To identify factors associated with virological response (VR) to an etravirine (ETR)-based regimen, 243 patients previously treated with nonnucleoside reverse transcriptase inhibitors (NNRTIs) were studied. The impact of baseline HIV-1 RNA, CD4 cell count, past NNRTIs used, 57 NNRTI resistance mutations, genotypic sensitivity score (GSS) for nucleoside reverse transcriptase inhibitors (NRTIs) and protease inhibitors (PIs), and the number of new drugs used with ETR for the first time on the VR to an ETR regimen were investigated. Among the 243 patients, the median baseline HIV-1 RNA level was 4.4 log(10) copies/ml (interquartile range [IQR], 3.7 to 4.9) and the median CD4 count was 175 cells/mm(3) (IQR, 69 to 312). Patients had been previously exposed to a median of 6 NRTIs, 1, NNRTI, and 5 PIs. Overall, 82% of patients achieved a VR at month 2, as defined by a decrease of at least 1.5 log(10) copies/ml and/or HIV-1 RNA level of <50 copies/ml. No difference in VR was observed between patients receiving or not a boosted PI in combination with ETR. Factors independently associated with a better VR to ETR were the number of drugs (among enfuvirtide, darunavir, or raltegravir) used for the first time in combination with ETR and the presence of the K103N mutation at baseline. Mutations Y181V and E138A were independently associated with poor VR, whereas no effect of the Y181C on VR was observed. In conclusion, ETR was associated with high response rates in NNRTI-experienced patients in combination with other active drugs regardless of the therapeutic class used.
Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , VIH-1 , Piridazinas/uso terapéutico , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Farmacorresistencia Viral/genética , Femenino , Genotipo , Transcriptasa Inversa del VIH/genética , VIH-1/efectos de los fármacos , VIH-1/genética , Humanos , Masculino , Mutación , Nitrilos , Filogenia , Pirimidinas , ARN Viral/biosíntesis , ARN Viral/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Resultado del TratamientoRESUMEN
Genotypic algorithms for prediction of HIV-1 coreceptor usage need to be evaluated in a clinical setting. We aimed at studying (i) the correlation of genotypic prediction of coreceptor use in comparison with a phenotypic assay and (ii) the relationship between genotypic prediction of coreceptor use at baseline and the virological response (VR) to a therapy including maraviroc (MVC). Antiretroviral-experienced patients were included in the MVC Expanded Access Program if they had an R5 screening result with Trofile (Monogram Biosciences). V3 loop sequences were determined at screening, and coreceptor use was predicted using 13 genotypic algorithms or combinations of algorithms. Genotypic predictions were compared to Trofile; dual or mixed (D/M) variants were considered as X4 variants. Both genotypic and phenotypic results were obtained for 189 patients at screening, with 54 isolates scored as X4 or D/M and 135 scored as R5 with Trofile. The highest sensitivity (59.3%) for detection of X4 was obtained with the Geno2pheno algorithm, with a false-positive rate set up at 10% (Geno2pheno10). In the 112 patients receiving MVC, a plasma viral RNA load of <50 copies/ml was obtained in 68% of cases at month 6. In multivariate analysis, the prediction of the X4 genotype at baseline with the Geno2pheno10 algorithm including baseline viral load and CD4 nadir was independently associated with a worse VR at months 1 and 3. The baseline weighted genotypic sensitivity score was associated with VR at month 6. There were strong arguments in favor of using genotypic coreceptor use assays for determining which patients would respond to CCR5 antagonist.
Asunto(s)
Ciclohexanos/uso terapéutico , Inhibidores de Fusión de VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , VIH-1/metabolismo , Receptores del VIH/genética , Triazoles/uso terapéutico , Tropismo , Adulto , Antagonistas de los Receptores CCR5 , Ciclohexanos/farmacología , Femenino , Genotipo , Proteína gp120 de Envoltorio del VIH , Inhibidores de Fusión de VIH/farmacología , Infecciones por VIH/virología , Proteasa del VIH/genética , Transcriptasa Inversa del VIH/genética , VIH-1/efectos de los fármacos , VIH-1/genética , VIH-1/fisiología , Humanos , Masculino , Maraviroc , Persona de Mediana Edad , Datos de Secuencia Molecular , Fenotipo , Receptores CCR5/genética , Receptores CCR5/metabolismo , Receptores del VIH/metabolismo , Sensibilidad y Especificidad , Análisis de Secuencia de ADN , Resultado del Tratamiento , Triazoles/farmacologíaRESUMEN
BACKGROUND: In order to determine whether human prostate can be productively infected by HIV-1 strains with different tropism, and thus represent a potential source of HIV in semen, an organotypic culture of prostate from men undergoing prostatic adenomectomy for benign prostate hypertrophy (BPH) was developed. The presence of potential HIV target cells in prostate tissues was investigated using immunohistochemistry. The infection of prostate explants following exposures with HIV-1 R5, R5X4 and X4 strains was analyzed through the measure of RT activity in culture supernatants, the quantification of HIV DNA in the explants and the detection of HIV RNA+ cells in situ. RESULTS: The overall prostate characteristics were retained for 21/2 weeks in culture. Numerous potential HIV-1 target cells were detected in the prostate stroma. Whilst HIV-1 R5SF162 strain consistently productively infected prostatic T lymphocytes and macrophages, the prototypic X4IIIB strain and a primary R5X4 strain showed less efficient replication in this organ. CONCLUSION: The BPH prostate is a site of HIV-1 R5 replication that could contribute virus to semen. A limited spreading of HIV-1 X4 and R5X4 in this organ could participate to the preferential sexual transmission of HIV-1 R5 strains.
Asunto(s)
Infecciones por VIH/virología , VIH-1/fisiología , Próstata/virología , Replicación Viral , Infecciones por VIH/inmunología , VIH-1/genética , Humanos , Técnicas In Vitro , Macrófagos/virología , Masculino , Persona de Mediana Edad , Próstata/inmunología , Hiperplasia Prostática/inmunología , Hiperplasia Prostática/virología , Linfocitos T/virologíaRESUMEN
To identify mutations associated with the virological response (VR) to a tipranavir-ritonavir (TPV/r)-based regimen, 143 patients previously treated with protease inhibitor (PI) were studied. VR was defined by a decrease of at least 1 log(10) in, or undetectable, human immunodeficiency virus (HIV) RNA at month 3. The effect of each mutation in the protease, considering all variants at a residue as a single variable, on the VR to TPV/r was investigated. Mutations at six residues were associated with a lower VR (E35D/G/K/N, M36I/L/V, Q58E, Q61D/E/G/H/N/R, H69I/K/N/Q/R/Y, and L89I/M/R/T/V), and one mutation was associated with a higher VR (F53L/W/Y). The genotypic score M36I/L/V-53L/W/Y + Q58E + H69I/K/N/Q/R/Y + L89I/M/R/T/V was selected as providing a strong association with VR. For the seven patients with a genotypic score of -1 (viruses with only mutation at codon 53), the percentage of responders was 100% and the percentages were 79%, 56%, 33%, 21%, and 0% for those with scores of 0, 1, 2, 3, and 4, respectively. The percentage of patients showing a response to TPV/r was lower for patients infected with non-clade B viruses (n = 16, all non-B subtypes considered together) than for those infected with clade B viruses (n = 127) (25% and 59%, respectively; P = 0.015). Most mutations associated with VR to TPV/r had not previously been associated with PI resistance. This is consistent with phenotypic analysis showing that TPV has a unique resistance profile. Mutations at five positions (35, 36, 61, 69, and 89) were observed significantly more frequently in patients infected with a non-B subtype than in those infected with the B subtype, probably explaining the lower VR observed in these patients.
Asunto(s)
Farmacorresistencia Viral/genética , Infecciones por VIH/tratamiento farmacológico , Inhibidores de la Proteasa del VIH/farmacología , Proteasa del VIH/genética , VIH-1/efectos de los fármacos , Piridinas/farmacología , Pironas/farmacología , Ritonavir/farmacología , Fármacos Anti-VIH/uso terapéutico , Quimioterapia Combinada , Femenino , Genotipo , Infecciones por VIH/virología , Proteasa del VIH/efectos de los fármacos , Inhibidores de la Proteasa del VIH/uso terapéutico , VIH-1/clasificación , VIH-1/enzimología , VIH-1/genética , Humanos , Masculino , Mutación , Inhibidores de la Transcriptasa Inversa/uso terapéutico , SulfonamidasRESUMEN
OBJECTIVES: We studied gp41 mutations associated with failing enfuvirtide salvage therapy. METHODS: This multicentre study involved patients with HIV-1 plasma viral load (pVL) > 5000 copies/mL after at least 3 months of uninterrupted enfuvirtide therapy and with plasma samples available at inclusion (T0), at initial enfuvirtide failure (T1) and at last follow-up visit during continued failing enfuvirtide therapy (T2). The HR-1 and HR-2 domains of the gp41 gene were sequenced at T0, T1 and T2. RESULTS: Ninety-nine patients were enrolled. At baseline, the median pVL and CD4 cell count were 5.1 log copies/mL and 72 cells/mm(3), respectively. Based on the ANRS Resistance Group algorithm, the proportion of patients harbouring viruses with enfuvirtide resistance mutations increased significantly between T0 and T1. In the HR-1 domain, the V38A/M, Q40H, N42T, N43D and L45M mutations wereselected (P < 0.02). In the HR-2 domain, no mutations were significantly selected during the follow-up. None of the mutations was associated with a CD4 cell count increment. CONCLUSIONS: Mutations selected during failing enfuvirtide salvage therapy are mainly located in the HR-1 domain of the gp41 gene, between codons 38 and 45. No mutations were associated with an increase in the CD4 cell count.
Asunto(s)
Síndrome de Inmunodeficiencia Adquirida/tratamiento farmacológico , Síndrome de Inmunodeficiencia Adquirida/virología , Proteína gp41 de Envoltorio del VIH/uso terapéutico , Inhibidores de Fusión de VIH/uso terapéutico , VIH-1/efectos de los fármacos , Fragmentos de Péptidos/uso terapéutico , ARN Viral/genética , Síndrome de Inmunodeficiencia Adquirida/inmunología , Adulto , Sustitución de Aminoácidos/genética , Recuento de Linfocito CD4 , Enfuvirtida , Femenino , Francia , Proteína gp41 de Envoltorio del VIH/genética , VIH-1/genética , Humanos , Masculino , Persona de Mediana Edad , Mutación Missense , Terapia Recuperativa , Análisis de Secuencia de ADN , Resultado del Tratamiento , Carga ViralRESUMEN
The appearance of primary HIV infection ranges from an asymptomatic presentation to a symptomatic illness resembling infectious mononucleosis. Severe unusual presentations include acute myopericarditis, renal failure, and opportunistic infections such as esophageal candidiasis, cytomegalovirus infection, and Pneumocystis jirovecii pneumonia. We report a case of multiple organ failure during primary HIV infection.
Asunto(s)
Infecciones por VIH/complicaciones , VIH/patogenicidad , Insuficiencia Multiorgánica/virología , Viremia/tratamiento farmacológico , Adolescente , Linfocitos T CD4-Positivos/efectos de los fármacos , Femenino , Infecciones por VIH/diagnóstico , Infecciones por VIH/tratamiento farmacológico , Humanos , Carga ViralRESUMEN
BACKGROUND: Different approaches using genotypic, pharmacokinetic parameters or combination of both have been recently developed to monitor antiretroviral treatment in HIV-1-infected individuals. Their uses in clinical practice may improve the benefit of protease inhibitor-based salvage therapy while reducing treatment toxicity and emergence of viral resistance. OBJECTIVES: To assess the prediction of genotypic inhibitory quotient (GIQ) using different genotypic drug resistance interpretation's algorithms and lopinavir plasma concentration in PI-experienced patients treated by lopinavir/ritonavir (LPV/r). Genotypic susceptibility score (GSS) was also evaluated. STUDY DESIGN: Forty-seven HIV-1 PI-experienced, but LPV naïve patients were included in a retrospective cohort study. Plasma HIV-1 viral load (VL), CD4 cell count and LPV plasma concentrations were assessed at weeks (W) 12 and 24. Interpretation of baseline resistance genotype was achieved according to four different algorithms and GSS calculated using two expert systems. GIQ was defined as the ratio of LPV concentration to the number of LPV resistance mutations at day 0 (D0) and patients classified by units of GIQ. The end point of the study was the virological response expressed in HIV VL median decrease from D0 to W24. RESULTS: The overall median VL decrease from D0 to W24 was -2.42 log(10)copies/mL and 60% of patients had VL below 400 copies/mL. The LPV mutation score was predictive of response for all algorithms whereas plasma concentrations of LPV were not. Mean VL decrease was greater for higher GIQ classes and difference reached statistical significance at W24. When considering virological response at W24, GSS calculated with ANRS and Stanford system were good predictor scores as areas under the receiver operating characteristics (ROC) curves were 0.76 for both. CONCLUSION: GIQ was found to be a useful drug-monitoring tool which could be helpful in targeting LPV concentrations in order to achieve long-term undetectable viral load, particularly in genotypic resistant patients.
Asunto(s)
Algoritmos , Farmacorresistencia Viral , Infecciones por VIH/tratamiento farmacológico , Inhibidores de la Proteasa del VIH/uso terapéutico , VIH-1/genética , Pirimidinonas/uso terapéutico , Ritonavir/uso terapéutico , Adulto , Anciano , Estudios de Cohortes , Femenino , Genotipo , Infecciones por VIH/sangre , Infecciones por VIH/virología , Inhibidores de la Proteasa del VIH/sangre , VIH-1/enzimología , Humanos , Lopinavir , Masculino , Persona de Mediana Edad , Pirimidinonas/sangre , Estudios Retrospectivos , Ritonavir/sangre , Sensibilidad y Especificidad , Carga ViralRESUMEN
OBJECTIVE: To develop a stepwise methodology for the development and validation of clinically relevant genotypic score for resistance to antiretroviral drugs and to apply this approach to the genotypic resistance to abacavir. METHODS: All patients having received abacavir during the Narval trial were included in this study. The impact of each nucleoside analogue resistance mutation on the virologic response to abacavir was studied in a univariate analysis. Mutations with a P value < 0.20 and those selected by abacavir were retained. According to the number of mutations three levels of resistance were defined. A multivariate analysis accounting for confonding variables assessed whether the genotypic score was an independent predictor of the response. The robustness of the score was analysed using the bootstrap resampling method. RESULTS: In the 175 patients exposed to abacavir, the strongest association between the decrease in viral load and the number of mutations was observed with a set of six mutations at codons 41, 67, 210, 215, 74 and 184 of the reverse transcriptase gene. In patients with fewer than four mutations (no evidence of resistance) the median decrease in viral load was -1.64 log(10) copies/ml while it was -0.69 log(10) and -0.19 log(10) in those with four (possible resistance) and five or six (resistance) mutations respectively. In the multivariate analysis this score was an independent predictor of the response. The bootstrap analysis showed the robustness of the score. CONCLUSIONS: We developed a new strategy for the analysis of correlation between genotype profile at baseline and virologic response.
Asunto(s)
Algoritmos , Didesoxinucleósidos/uso terapéutico , Farmacorresistencia Viral/genética , Infecciones por VIH/tratamiento farmacológico , VIH-1/genética , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Genotipo , Infecciones por VIH/virología , Humanos , Análisis Multivariante , Mutación , ARN Viral/sangre , Estadísticas no ParamétricasRESUMEN
OBJECTIVE: To evaluate the frequency of drug-resistant HIV-1 viral strains from patients presenting with primary infection in 1999-2000 and to survey the molecular epidemiology of these viruses circulating in France. METHODS: Resistance mutations were detected by sequencing the reverse transcriptase and the protease genes in plasma samples from 249 individuals. Phylogenetic analysis was performed on the reverse transcriptase genes. RESULTS: Ten per cent of patients [26/249; 95% confidence interval (CI) 7-15%] presented with virus mutations associated with resistance to at least one antiretroviral drug. The distribution of the resistance mutations was as follows: to nucleoside reverse transcriptase inhibitors in 19 (8%; 95% CI 5-12%) and to non-nucleoside reverse transcriptase inhibitors in 10 (4%; 95% CI 2-7%). Primary resistance mutations to protease inhibitors were detected in 14 (6%; 95% CI 3-9%). Twelve patients (5%; 95% CI 3-8%) presented with virus harbouring mutations associated with resistance to two or three classes of antiretroviral drugs. The median HIV RNA in plasma at enrollment was lower in patients with one or more drug resistance mutations than in patients with no mutations (5.05 log versus 5.47 log, P = 0.05). Phylogenetic analysis revealed that 19% (14-24%) of patients harboured HIV-1 non-B subtype strains; this proportion remained high when Caucasian patients only were considered (14%). CONCLUSION: This study, performed within the French network on HIV-1 primary infection survey, revealed no change in the frequency of resistant viral strains over time, but showed an increasing prevalence of non-B subtypes overall and among Caucasian individuals.
Asunto(s)
Infecciones por VIH/epidemiología , VIH-1/genética , Farmacorresistencia Viral/genética , Quimioterapia Combinada , Femenino , Francia/epidemiología , Genotipo , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/genética , Inhibidores de la Proteasa del VIH/uso terapéutico , Humanos , Masculino , Mutación/genética , Filogenia , Polimorfismo Genético , Prevalencia , ARN Viral/sangre , Inhibidores de la Transcriptasa Inversa/uso terapéuticoRESUMEN
Several viruses infect the testis, inducing inflammation, which may lead to infertility. In this study we investigated the production in rat and human testicular cells exposed to the Sendai virus of several chemokines that play a major role in inflammatory processes. Exposure of rat testicular macrophages and Sertoli, Leydig, and peritubular cells to the Sendai virus led to the production of mRNA and protein for monocyte chemotactic protein-1 (MCP-1), regulated on activation normal T cell expressed and secreted protein, growth-related oncogene-alpha, and interferon-gamma-inducible protein-10. In rat peritubular cells exposed to the Sendai virus, MCP-1 production was time and dose dependent. In contrast, rat germ cells did not produce these chemokines. Chemokine synthesis was detected in human Leydig cells exposed to the Sendai virus, but not in human total germ cells, suggesting that rats and humans display similar responses in terms of chemokine production. MCP-1, regulated on activation normal T cell expressed and secreted protein, growth-related oncogene-alpha, and interferon-gamma-inducible protein-10 have been reported to be chemoattractants for a large variety of leukocytes. The ability of the Sendai virus to induce chemokine production in somatic cells (mostly peritubular and Leydig cells) may therefore increase the recruitment of leukocytes to sites of infection.
Asunto(s)
Quimiocina CCL2/biosíntesis , Quimiocina CCL5/biosíntesis , Quimiocinas CXC/biosíntesis , Infecciones por Respirovirus/genética , Virus Sendai , Testículo/metabolismo , Testículo/virología , Animales , Northern Blotting , Quimiocina CCL2/genética , Quimiocina CCL5/genética , Quimiocina CXCL10 , ADN/biosíntesis , ADN/genética , Ensayo de Inmunoadsorción Enzimática , Células Germinativas/metabolismo , Células Germinativas/virología , Humanos , Células Intersticiales del Testículo/metabolismo , Células Intersticiales del Testículo/virología , Macrófagos/metabolismo , Macrófagos/virología , Masculino , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Ratas , Ratas Sprague-Dawley , Células de Sertoli/metabolismo , Células de Sertoli/virología , Espermatocitos/metabolismo , Espermatocitos/virología , Espermatogonias/metabolismo , Espermatogonias/virologíaRESUMEN
OBJECTIVE: To assess the genotypic determinants of the virological response to tenofovir disoproxil fumarate (TDF) in a multicentre cohort of antiretroviral (ARV)-experienced patients receiving TDF as a part of a salvage therapy. METHODS: HIV-1 genotype was assessed at baseline in a subgroup of 161 patients of the French expanded access program receiving a stable TDF-including regimen for 3 months or more. Reverse transcriptase mutations associated with the viral load decrease at month 3 with a P-value <0.15 were retained for the construction of a mutation score. The score was then validated using a multivariate analysis and bootstrap resampling method. RESULTS: The strongest association with decrease in viral load was observed with a set of seven mutations (TDF mutation score) that consisted of M41L, E44D, D67N, T69D/N/S, L74V, L210W and T215Y/F RT mutations. The RT K65R mutation and the insertions at codon 69 were not included in the analysis due to low prevalences. A TDF mutation score of < or = 2 predicted the absence of resistance to TDF and > or = 6 mutations predicted resistance to TDF with corresponding reductions in viral load of -1.3 +/- 1.1, and +0.1 +/- 0.7 log10 copies/ml, respectively. In patients with a TDF mutation score of 3-5, the decrease in viral load was -0.8 +/- 1.0 log10 copies/ml and was considered possibly resistant. In the multivariate analysis, a TDF mutation score > or = 6, previous use of amprenavir, indinavir and lopinavir, and co-prescription of didanosine were associated with a worse virological response. The bootstrap analysis showed the robustness of the TDF mutation score. CONCLUSION: In ARV-experienced patients receiving TDF-containing regimens, a score derived from seven reverse transcriptase mutations was shown to be independently predictive of the virological response.
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Adenina/análogos & derivados , Adenina/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , VIH-1/efectos de los fármacos , Organofosfonatos/uso terapéutico , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Adenina/sangre , Codón , Estudios de Cohortes , Francia , Genotipo , Infecciones por VIH/sangre , Infecciones por VIH/virología , Transcriptasa Inversa del VIH/antagonistas & inhibidores , Transcriptasa Inversa del VIH/genética , VIH-1/genética , VIH-1/aislamiento & purificación , Humanos , Análisis Multivariante , Organofosfonatos/sangre , Mutación Puntual/efectos de los fármacos , ARN Viral/sangre , TenofovirRESUMEN
We report an in vitro analysis of the spatial pattern of production of three antiviral proteins (2'5'oligoadenylate synthetase, 2'5'AS; double-stranded RNA-activated protein kinase, PKR; and Mx protein, Mx) in the rat testis, in basal conditions and following stimulation with interferon (IFN) or Sendai virus. The two major constituents of interstitial tissue--Leydig cells and macrophages--constitutively produce 2'5' oligoadenylate synthetase (2'5'AS), PKR and Mx. Production of an isoform of 2'5'AS was induced following Leydig cells stimulation by the Sendai virus. The most immature germ cells, spermatogonia, were devoid of 2'5'AS whatever the type of stimulation, whereas IFN treatment induced Mx production and increased PKR production in this cell type. IFN stimulation strongly increased PKR production in all three cell types. This new set of data extends our previous investigations and demonstrates that the testis possesses an anti-viral defense system involving IFNs and IFN-induced anti-viral proteins.
Asunto(s)
2',5'-Oligoadenilato Sintetasa/metabolismo , Proteínas de Unión al GTP/metabolismo , Células Intersticiales del Testículo/metabolismo , Espermatogonias/metabolismo , eIF-2 Quinasa/metabolismo , Animales , Línea Celular , Células Cultivadas , Humanos , Interferón-alfa/farmacología , Interferón gamma/farmacología , Células Intersticiales del Testículo/efectos de los fármacos , Células Intersticiales del Testículo/enzimología , Células Intersticiales del Testículo/virología , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Macrófagos/virología , Masculino , Proteínas de Resistencia a Mixovirus , Ratas , Virus Sendai/fisiología , Espermatogonias/efectos de los fármacos , Espermatogonias/enzimología , Espermatogonias/virologíaRESUMEN
OBJECTIVE: To evaluate the safety profile and efficacy of salvage regimens containing amprenavir (APV) 600 mg twice daily and ritonavir (RTV) 200 mg twice daily. DESIGN: Prospective, single-center study. METHOD: The patient database of the department of infectious diseases was screened for patients who had failed at least two successive three-drug combinations. These patients were proposed to take APV and RTV in association with two to four other drugs. They were followed monthly for 6 months. RESULTS: Seventeen patients were included. They had been previously treated for 70 +/- 23 months. At baseline, viral load (VL) was 4.86 +/- 0.98 log10 copies/mL and CD4 187 +/- 145 10(6)/L. On week 24, using intent-to-treat analysis, VL decreased to 2.95 +/- 1.59 log10 copies/mL and CD4 increased to 365 +/- 210 10(6)/L. Nine patients (53%) had a VL < 2.3 log10 copies/mL. The most common adverse events were grade 1 or 2 diarrhea and an increase of cholesterol and triglyceride levels. Mean APV trough concentration was 1727 +/- 1749 ng/mL on week 24. CONCLUSION: These data show that the combination of low-dose RTV and reduced doses of APV is safe. This combination can be added to nonnucleoside analogs.
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Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Inhibidores de la Proteasa del VIH/uso terapéutico , VIH-1 , Ritonavir/uso terapéutico , Terapia Recuperativa , Sulfonamidas/uso terapéutico , Adulto , Fármacos Anti-VIH/efectos adversos , Recuento de Linfocito CD4 , Carbamatos , Farmacorresistencia Viral/genética , Quimioterapia Combinada , Femenino , Furanos , Genotipo , Inhibidores de la Proteasa del VIH/efectos adversos , VIH-1/efectos de los fármacos , VIH-1/genética , VIH-1/inmunología , Humanos , Masculino , Persona de Mediana Edad , Cooperación del Paciente , Fenotipo , Estudios Prospectivos , Ritonavir/efectos adversos , Sulfonamidas/efectos adversos , Resultado del Tratamiento , Carga ViralRESUMEN
BACKGROUND: The aim of this study was to characterize the mutations selected upon failure on etravirine (ETR)-containing regimen in non-nucleoside reverse transcriptase inhibitors (NNRTIs)-experienced HIV-infected patients and the associated factors. METHODS: Forty-two patients displaying virological failure after a 6 months ETR-containing regimen were studied. For each patient the reverse transcriptase (RT) sequence at failure was compared with all the RT sequences available before introduction of ETR. The effect of baseline and failure HIV-1 RNA, HIV-1 subtype, baseline number of NNRTI resistance mutations, protease inhibitor and nucleoside RT inhibitor genotypic sensitivity scores, number of new drugs used in the treatment, and previous use of efavirenz or nevirapine on the selection of NNRTI resistance mutations were investigated. RESULTS: At failure, 12/42 (29%) patients showed development of at least 1 new NNRTI mutation (7 patients selected 1 mutation and 5 patients 2 mutations). NNRTI mutations selected were V179I (5 patients), V179L (1), V179F (2), L100I (1), K103N (2), Y181C (3), K101E (1), K101R (1) and H221Y (1). Univariate analysis showed that HIV-1 RNA level at failure (P=0.033) and past exposure to efavirenz (P<0.001) were associated with the occurrence of at least one NNRTI mutation. The multivariate model retained only past exposure to efavirenz. Among the 36 viruses classified as susceptible to ETR at baseline, 3 were classified as possibly resistant at failure. CONCLUSION: In this study, 29% of viruses from patients experiencing ETR failure selected new NNRTI resistance mutations (at position V179 in 2/3 of cases) in a context of multiple NNRTI resistance mutations.
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Fármacos Anti-VIH/administración & dosificación , Infecciones por VIH/tratamiento farmacológico , VIH-1/genética , Piridazinas/administración & dosificación , Inhibidores de la Transcriptasa Inversa/administración & dosificación , Alquinos , Fármacos Anti-VIH/uso terapéutico , Benzoxazinas/administración & dosificación , Benzoxazinas/uso terapéutico , Ciclopropanos , Farmacorresistencia Viral , Quimioterapia Combinada , Femenino , Infecciones por VIH/virología , Transcriptasa Inversa del VIH/antagonistas & inhibidores , VIH-1/efectos de los fármacos , Humanos , Masculino , Tipificación Molecular , Mutación , Nevirapina/administración & dosificación , Nevirapina/uso terapéutico , Nitrilos , Piridazinas/uso terapéutico , Pirimidinas , ARN Viral/análisis , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Insuficiencia del Tratamiento , Carga Viral/efectos de los fármacosAsunto(s)
Infecciones por VIH/complicaciones , VIH-1 , Complicaciones Infecciosas del Embarazo/sangre , Sobreinfección/complicaciones , Femenino , Infecciones por VIH/sangre , Infecciones por VIH/transmisión , Humanos , Masculino , Embarazo , ARN Viral/sangre , Parejas Sexuales , Sobreinfección/sangre , Carga ViralRESUMEN
BACKGROUND: Atazanavir (ATV) is a potent and safe protease inhibitor (PI) initially approved in adult HIV-1 infected patients in combination with other antiretroviral drugs with once daily administration. In combination with nucleoside reverse transcriptase inhibitors (NRTIs) and boosted with ritonavir, it has been established as the preferred initial regimen in published guidelines. OBJECTIVE: This article reviews relevant pharmacodynamic, pharmacokinetic, efficacy and safety data of ATV, administered boosted with ritonavir or unboosted, in comparison with other PIs and/or non-NRTIs, with special focus on recent studies. METHODS: Review articles, recent primary literature and scientific meeting reports were analyzed. RESULTS: Compared to most PIs with similar efficacy, the advantages of ATV are a once daily administration with only 100 mg ritonavir when boosted, a good gastrointestinal tolerance with limited diarrhea, a neutral effect on cholesterol and triglycerides, and a favorable resistance profile. However, highly frequent hyperbilirubinemia is observed resulting in some cases in clinical jaundice. Unboosted ATV must be cautiously used because increased resistances have been described. CONCLUSION: The combination of a similar efficacy, a better tolerance and a low pill burden, as compared to other PIs, makes boosted ATV one of the best options, in combination with NRTIs, in PI-naive HIV-1 infected patients.
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Infecciones por VIH/tratamiento farmacológico , Inhibidores de la Proteasa del VIH/efectos adversos , Inhibidores de la Proteasa del VIH/uso terapéutico , Oligopéptidos/efectos adversos , Oligopéptidos/uso terapéutico , Piridinas/efectos adversos , Piridinas/uso terapéutico , Adulto , Animales , Sulfato de Atazanavir , Ensayos Clínicos Fase II como Asunto , Ensayos Clínicos Fase III como Asunto , Interacciones Farmacológicas , Farmacorresistencia Viral , Inhibidores de la Proteasa del VIH/farmacología , Humanos , Oligopéptidos/farmacología , Piridinas/farmacologíaRESUMEN
OBJECTIVE: The objectives of this study were to determine whether peripheral blood mononuclear cell (PBMC)-associated HIV-1 DNA level in patients on long-term suppressive antiretroviral therapy (ART) was associated with plasma HIV-1 RNA level, CD4 cell count, and therapeutic factors throughout patient history. DESIGN: Patients receiving triple or dual therapy with plasma HIV-1 RNA below detection limit for more than 3 years were recruited in a multicentric, cross-sectional study within the eight virology laboratories of the Agence Nationale de Recherche sur le SIDA et les Hépatites virales HIV quantification working group, each one in relation with a clinical center. METHODS: PBMC-associated HIV-1 DNA was quantified using a standardized real-time PCR method in all laboratories. RESULTS: A total of 236 patients was included. Median HIV-1 DNA was 2.8 log10 copies/10 PBMCs (interquartile range 2.4-3.0). Univariate analysis showed PBMC HIV-1 DNA level to be related to pre-ART immuno-virologic status (plasma HIV-1 RNA zenith and CD4 cell count nadir) and to current CD4 T-cell count. HIV-1 DNA was lower in patients receiving ART with inferior virologic efficacy, as they also had a higher CD4 nadir and a lower HIV-1 RNA zenith than other patients. PBMC HIV-1 DNA level was not related to therapy duration, to time spent with undetectable HIV-1 RNA or to occurrence of a blip. Plasma HIV-1 RNA zenith and CD4 cell count nadir remained predictive of HIV-1 DNA level in the multivariate model which was associated with 22% of its variability. CONCLUSION: Whatever the duration of treatment, HIV-1 DNA level during ART gives a picture of the intensity of viral replication and immune deficiency reached before starting therapy.