RESUMEN
BACKGROUND: Lymphogranuloma venereum (LGV) is a sexually transmitted infection caused by Chlamydia trachomatis (CT) serovars L1, L2, and L3 and is endemic among men who have sex with men (MSM) in Europe. We evaluated weekly oral azithromycin 1 g for 3 weeks as a treatment for LGV proctitis. METHODS: This is an open clinical trial with convenience allocation according to treating physician preferences. Adults with clinical proctitis received a single dose of 1 g of intramuscular ceftriaxone and were subsequently allocated to receive (i) doxycycline 100 mg twice daily for 21 days (Doxycycline group) or (ii) azithromycin 1 g orally once weekly for 3 weeks (Azithromycin group). LGV cure (primary endpoint) was defined as resolution of symptoms at week 6 (clinical cure, LGV-CC), with an additional supporting negative rectal polymerase chain reaction (PCR) at week 4 (microbiological cure, LGV-MC), if available. RESULTS: One hundred and twenty-five individuals with LGV clinical proctitis were included. All were MSM, and 96% were living with human immunodeficiency virus (HIV). Eighty-two were in the Azithromycin group, and 43 were in the Doxycycline group. LGV cure on a modified intention-to-treat analysis (primary endpoint), occurred in 80 of 82 (98%) in the Azithromycin group versus 41 of 43 (95%) in the Doxycycline group (treatment difference [95% confidence interval {CI}] 2.2% [-3.2, 13.2]). LGV-MC occurred in 70 of 72 (97%) vs 15 of 15 (100%) in the Azithromycin group and Doxycycline group, respectively (treatment difference [95% CI] -2.8% [-9.6; 17.7]). Adverse events were similar in both treatment groups. CONCLUSIONS: Our findings support extended azithromycin dosing as an alternative treatment option for symptomatic LGV proctitis and provides the rationale for future randomized trials.
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Linfogranuloma Venéreo , Proctitis , Minorías Sexuales y de Género , Adulto , Azitromicina/uso terapéutico , Chlamydia trachomatis , Homosexualidad Masculina , Humanos , Linfogranuloma Venéreo/tratamiento farmacológico , Masculino , Proctitis/tratamiento farmacológicoRESUMEN
OBJECTIVES: To construct a classifier that predicts the probability of viral control after analytical treatment interruptions (ATI) in HIV research trials. METHODS: Participants of a dendritic cell-based therapeutic vaccine trial (DCV2) constituted the derivation cohort. One of the primary endpoints of DCV2 was the drop of viral load (VL) set point after 12 weeks of ATI (delta VL12). We classified cases as "controllers" (delta VL12 > 1 log10 copies/mL, n = 12) or "noncontrollers" (delta VL12 < 0.5 log10 copies/mL, n = 10) and compared 190 variables (clinical data, lymphocyte subsets, inflammatory markers, viral reservoir, ELISPOT, and lymphoproliferative responses) between the 2 groups. Naive Bayes classifiers were built from combinations of significant variables. The best model was subsequently validated on an independent cohort. RESULTS: Controllers had significantly higher pre-antiretroviral treatment VL [110,250 (IQR 71,968-275,750) vs. 28,600 (IQR 18737-39365) copies/mL, P = 0.003] and significantly lower proportion of some T-lymphocyte subsets than noncontrollers: prevaccination CD4CD45RA+RO+ (1.72% vs. 7.47%, P = 0.036), CD8CD45RA+RO+ (7.92% vs. 15.69%, P = 0.017), CD4+CCR5+ (4.25% vs. 7.40%, P = 0.011), and CD8+CCR5+ (14.53% vs. 27.30%, P = 0.043), and postvaccination CD4+CXCR4+ (12.44% vs. 22.80%, P = 0.021). The classifier based on pre-antiretroviral treatment VL and prevaccine CD8CD45RA+RO+ T cells was the best predictive model (overall accuracy: 91%). In an independent validation cohort of 107 ATI episodes, the model correctly identified nonresponders (negative predictive value = 94%), while it failed to identify responders (positive predictive value = 20%). CONCLUSIONS: Our simple classifier could correctly classify those patients with low probability of control of VL after ATI. These data could be helpful for HIV research trial design.
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Vacunas contra el SIDA/inmunología , Antirretrovirales/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , Adulto , Teorema de Bayes , Recuento de Linfocito CD4 , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Células Dendríticas/inmunología , Femenino , VIH-1/inmunología , Humanos , Masculino , Persona de Mediana Edad , Receptores CCR5 , Receptores CXCR4 , Resultado del Tratamiento , Vacunación , Carga Viral/efectos de los fármacosRESUMEN
BACKGROUND: The GESIDA/National AIDS Plan expert panel recommended preferred regimens (PR), alternative regimens (AR) and other regimens (OR) for antiretroviral treatment (ART) as initial therapy in HIV-infected patients for 2018. The objective of this study was to evaluate the costs and the efficiency of initiating treatment with PR and AR. METHODS: Economic assessment of costs and efficiency (cost-effectiveness) based on decision tree analyses. Effectiveness was defined as the probability of reporting a viral load <50copies/mL at week 48, in an intention-to-treat analysis. Cost of initiating treatment with an ART regimen was defined as the costs of ART and its consequences (adverse effects, changes of ART regimen, and drug-resistance studies) over the first 48 weeks. The payer perspective (National Health System) was applied considering only differential direct costs: ART (official prices), management of adverse effects, studies of resistance, and HLA B*5701 testing. The setting was Spain and the costs correspond to those of 2018. A deterministic sensitivity analysis was conducted, building three scenarios for each regimen: base case, most favourable and least favourable. RESULTS: In the base-case scenario, the cost of initiating treatment ranges from 6788 euros for TAF/FTC/RPV (AR) to 10,649 euros for TAF/FTC+RAL (PR). The effectiveness varies from 0.82 for TAF/FTC+DRV/r (AR) to 0.91 for TAF/FTC+DTG (PR). The efficiency, in terms of cost-effectiveness, ranges from 7814 to 12,412 euros per responder at 48 weeks, for ABC/3TC/DTG (PR) and TAF/FTC+RAL (PR), respectively. CONCLUSION: Considering ART official prices, the most efficient regimen was ABC/3TC/DTG (PR), followed by TAF/FTC/RPV (AR) and TAF/FTC/EVG/COBI (AR).
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Síndrome de Inmunodeficiencia Adquirida/tratamiento farmacológico , Síndrome de Inmunodeficiencia Adquirida/economía , Antirretrovirales/economía , Antirretrovirales/uso terapéutico , Análisis Costo-Beneficio , Adhesión a Directriz/economía , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/economía , Humanos , Modelos Económicos , EspañaRESUMEN
OBJECTIVE: The efficacy of therapeutic vaccines against HIV-1 infection has been modest. New inerts to redirect responses to vulnerable sites are urgently needed to improve these results. DESIGN: We performed the first-in-human clinical trial with naked mRNA (iHIVARNA) combining a dendritic cell activation strategy (TriMix:CD40L+CD70+caTLR4 RNA) with a novel HIV immunogen sequences (HTI immunogen). METHODS: A dose escalation, phase I clinical trial was performed in 21 chronic HIV-1-infected patients under ART who received three intranodal doses of mRNA (weeks 0, 2 and 4) as follow: TriMix-100âg, TriMix-300âg, TriMix-300âg with HTI-300âg, TriMix-300âg with HTI-600âg, TriMix-300âg with HTI-900âg. Primary end-point was safety and secondary-exploratory end-points were immunogenicity, changes in viral reservoir and transcriptome. RESULTS: Overall, the vaccine was secure and well tolerated. There were 31 grade 1/2 and 1 grade 3 adverse events, mostly unrelated to the vaccination. Patients who received the highest dose showed a moderate increase in T-cell responses spanning HTI sequence at week 8. In addition, the proportion of responders receiving any dose of HTI increased from 31% at w0 to 80% postvaccination. The intervention had no impact on caHIV-DNA levels, however, caHIV-RNA expression and usVL were transiently increased at weeks 5 and 6 in the highest dose of iHIVARNA, and these changes were positively correlated with HIV-1-specific-induced immune responses. CONCLUSION: This phase I dose-escalating trial showed that iHIVARNA administration was safe and well tolerated, induced moderate HIV-specific T-cell responses and transiently increased different viral replication readouts. These data support further exploration of iHIVARNA in a phase II study. CLINICALTRIALS. GOV IDENTIFIER: NCT02413645.
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Vacunas contra el SIDA/administración & dosificación , Células Dendríticas/inmunología , Infecciones por VIH/terapia , ARN Mensajero/administración & dosificación , Adulto , Antirretrovirales/administración & dosificación , Terapia Combinada/métodos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
OBJECTIVE: To evaluate the efficiency of single-tablet regimens (STR) and multiple-tablet regimens (MTR) with exactly the same or different components. METHODS: A study was conducted on HIV-1-infected antiretroviral-naïve patients from 6 Spanish or French centers, who were started on treatment with STR-Atripla®, or the same components separately (MTR-SC), or a different MTR (MTR-Other). Effectiveness was measured as percentage of HIV-RNA <50copies/mL at 48 weeks (ITT). Efficiency was the ratio between costs (direct cost of antiretrovirals plus outpatient visits, hospital admissions, and resistance tests) and effectiveness. RESULTS: The study included a total of 2773 patients (759 STR-Atripla®, 483 MTR-SC, and 1531 MTR-Other). Median age was 37 years, 15% were HCV co-infected, 27% had a CD4+ count <200cells/µL, and 30% had viral load ≥100.000copies/mL. The duration of the assigned treatment was longer for STR-Atripla® (P<.0001). Response rates (adjusted for CD4+ count, viral load, and clustered on hospitals) at 48 weeks were 76%, 74%, and 62%, respectively (P<.0001). Virological failure was more common in MTR patients (P=.0025), and interruptions due to intolerance with MTR-Other (P<.0001). Cost per responder at 48 weeks (efficiency) was 12,406 with STR-Atripla®, 11,034 with MTR-SC (0.89 [0.82, 0.99] times lower), and 18,353 (1.48 [1.38, 1.61] times higher) with MTR-Other. CONCLUSIONS: STR-Atripla® and MTR-SC regimens showed similar effectiveness, but virological failure rate was lower with STR-Atripla. MTR-SC, considered less convenient, had a marginally better efficiency, mainly due to lower direct costs. MTR-Other regimens had both a worse effectiveness and efficiency. Similar efficiency analyses adjusting for baseline characteristics should be recommended for new STRs.
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Antirretrovirales/administración & dosificación , Antirretrovirales/economía , Análisis Costo-Beneficio , Infecciones por VIH/tratamiento farmacológico , Adulto , Combinación de Medicamentos , Femenino , Humanos , Masculino , Estudios Prospectivos , ComprimidosRESUMEN
INTRODUCTION: GESIDA and the Spanish National AIDS Plan panel of experts have recommended preferred (PR), alternative (AR) and other regimens (OR) for antiretroviral therapy (ART) as initial therapy in HIV-infected patients for 2017. The objective of this study was to evaluate the costs and the efficiency of initiating treatment with PR and AR. METHODS: Economic assessment of costs and efficiency (cost-efficacy) based on decision tree analyses. Efficacy was defined as the probability of reporting a viral load <50copies/mL at week 48, in an intention-to-treat analysis. Cost of initiating treatment with an ART regimen was defined as the costs of ART and its consequences (adverse effects, changes of ART regimen and drug resistance studies) during the first 48 weeks. The payer perspective (National Health System) was applied considering only differential direct costs: ART (official prices), management of adverse effects, resistance studies and HLA B*5701 screening. The setting was Spain and the costs correspond to those of 2017. A deterministic sensitivity analysis was conducted, building three scenarios for each regimen: base case, most favourable and least favourable. RESULTS: In the base case scenario, the cost of initiating treatment ranged from 6882 euro for TFV/FTC/RPV (AR) to 10,904 euros for TFV/FTC+RAL (PR). The efficacy varied from 0.82 for TFV/FTC+DRV/p (AR) to 0.92 for TAF/FTC/EVG/COBI (PR). The efficiency, in terms of cost-efficacy, ranged from 7923 to 12,765 euros per responder at 48 weeks, for ABC/3TC/DTG (PR) and TFV/FTC+RAL (PR), respectively. CONCLUSION: Considering ART official prices, the most efficient regimen was ABC/3TC/DTG (PR), followed by TFV/FTC/RPV (AR) and TAF/FTC/EVG/COBI (PR).
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Antirretrovirales/economía , Antirretrovirales/uso terapéutico , Análisis Costo-Beneficio , Infecciones por VIH/tratamiento farmacológico , Adulto , Humanos , Guías de Práctica Clínica como Asunto , EspañaRESUMEN
Background: HIV infection and HAART trigger genetic and functional mitochondrial alterations leading to cell death and adverse clinical manifestations. Mitochondrial dynamics enable mitochondrial turnover and degradation of damaged mitochondria, which may lead to apoptosis. Objectives: To evaluate markers of mitochondrial dynamics and apoptosis in pregnancies among HIV-infected women on HAART and determine their potential association with obstetric complications. Methods: This controlled, single-site, observational study without intervention included 26 HIV-infected pregnant women on HAART and 18 control pregnancies and their newborns. Maternal PBMCs and neonatal cord blood mononuclear cells (CBMCs) were isolated at the first trimester of gestation and at delivery. The placenta was homogenized at 5% w/v. Mitochondrial dynamics, fusion events [mitofusin 2 (Mfn2)/ß-actin] and fission events [dynamin-related protein 1 (Drp1/ß-actin)] and apoptosis (caspase 3/ß-actin) were assessed by western blot analysis. Results: Obstetric complications were significantly more frequent in pregnancies among HIV-infected women [OR 5.00 (95% CI 1.21-20.70)]. Mfn2/ß-actin levels in PBMCs from controls significantly decreased during pregnancy (202.13⯱â¯57.45%), whereas cases maintained reduced levels from the first trimester of pregnancy and no differences were observed in CBMCs. Mfn2/ß-actin and Drp1/ß-actin contents significantly decreased in the placenta of cases. Caspase 3/ß-actin levels significantly increased during pregnancy in PBMCs of cases (50.00⯱â¯7.89%), remaining significantly higher than in controls. No significant differences in caspase 3/ß-actin content of neonatal CBMCs were observed, but there was a slight increased trend in placenta from cases. Conclusions: HIV- and HAART-mediated mitochondrial damage may be enhanced by decreased mitochondrial dynamics and increased apoptosis in maternal and placental compartments but not in the uninfected fetus. However, direct effects on mitochondrial dynamics and implication of apoptosis were not demonstrated in adverse obstetric outcomes.
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Fármacos Anti-VIH/efectos adversos , Terapia Antirretroviral Altamente Activa/efectos adversos , Apoptosis/efectos de los fármacos , Infecciones por VIH/tratamiento farmacológico , Dinámicas Mitocondriales/efectos de los fármacos , Complicaciones Infecciosas del Embarazo/tratamiento farmacológico , Resultado del Embarazo , Adulto , Fármacos Anti-VIH/uso terapéutico , Caspasa 3/genética , Femenino , GTP Fosfohidrolasas/genética , Infecciones por VIH/virología , Humanos , Recién Nacido , Leucocitos Mononucleares , Mitocondrias/efectos de los fármacos , Proteínas Mitocondriales/genética , Placenta/fisiología , Embarazo , Complicaciones Infecciosas del Embarazo/virologíaRESUMEN
: We assessed if the increase on viral reservoir after long-term antiretroviral therapy (ART) interruption (ATI) is reversible upon ART resumption in chronic HIV-1 infected patients. Total HIV-1 DNA increased to pre-ART levels after 48 weeks of ATI to return to pre-ATI levels after 104 weeks of ART resumption. Conversely, integrated HIV-1 DNA remained elevated after ART reinitiation. These data suggest that the increase in reservoir after long-term ART discontinuation might not be reversible at midterm.
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Antirretrovirales/administración & dosificación , Terapia Antirretroviral Altamente Activa/métodos , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , VIH-1/aislamiento & purificación , Privación de Tratamiento , ADN Viral/análisis , VIH-1/genética , VIH-1/fisiología , Humanos , Carga Viral , Integración ViralRESUMEN
INTRODUCTION: There is a growing interest in developing curative strategies for HIV infection. Therapeutic vaccines are one of the most promising approaches. We will review the current knowledge and the new challenges in this research field. Areas covered: PubMed and ClinicalTrial.gov databases were searched to review the progress and prospects for clinical development of immunotherapies aimed to cure HIV infection. Dendritic cells (DC)-based vaccines have yielded the best results in the field. However, major immune-virologic barriers may hamper current vaccine strategies. We will focus on some new challenges as the antigen presentation by DCs, CTL escape mutations, B cell follicle sanctuary, host immune environment (inflammation, immune activation, tolerance), latent reservoir and the lack of surrogate markers of response. Finally, we will review the rationale for designing new therapeutic vaccine candidates to be used alone or in combination with other strategies to improve their effectiveness. Expert commentary: In the next future, the combination of DCs targeting candidates, inserts to redirect responses to unmutated parts of the virus, adjuvants to redirect responses to sanctuaries or improve the balance between activation/tolerance (IL-15, anti-PD1 antibodies) and latency reversing agents could be necessary to finally achieve the remission of HIV-1 infection.
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Vacunas contra el SIDA/uso terapéutico , Infecciones por VIH/terapia , Inmunoterapia/métodos , Humanos , Inmunoterapia/tendenciasRESUMEN
BACKGROUND: The objective of this study was to determine the impact of tenofovir or abacavir discontinuation on low-density lipoprotein (LDL) phenotype and lipoprotein-associated phospholipase A2 (Lp-PLA2) activity in HIV-infected patients treated with lopinavir/ritonavir plus 2 nucleos(t)ide reverse transcriptase inhibitors (NRTI). METHODS: Multicenter, open-label study. Patients were randomized to continue with lopinavir/ritonavir plus 2 NRTI (triple therapy) or to switch to lopinavir/ritonavir plus lamivudine (dual therapy). LDL phenotype (by gradient gel electrophoresis) and Lp-PLA2 (by 2-thio-PAF) were determined at baseline and week 48. RESULTS: Forty-four patients included (triple therapy n = 19, dual therapy n = 25): men 63.6%, age 41.5 years (25-61), Framingham score 4.9% (0.2-22). Tenofovir was part of the regimen in 28 (63.6%) patients. Dual therapy patients were younger (p = 0.013) and had lower baseline apolipoprotein A1 (p = 0.029). At week 48, there were no changes in standard lipid measurements, except ApoA1/Apo B, which increased in dual therapy (p = 0.038) with no differences between arms. At week 48, no change in LDL phenotype was found in either arm. No changes in total Lp-PLA2 activity or the relative distribution of LDL and HDL particles were found at week 48 in either arm. CONCLUSIONS: Discontinuing the third nucleos(t)ide, mainly tenofovir and abacavir, in a lopinavir/ritonavir-containing regimen was not associated with a deleterious effect on LDL phenotype nor in Lp-PLA2 activity.
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Didesoxinucleósidos/efectos adversos , Infecciones por VIH/metabolismo , Lamivudine/efectos adversos , Lipoproteínas LDL/metabolismo , Lopinavir/efectos adversos , 1-Alquil-2-acetilglicerofosfocolina Esterasa/sangre , 1-Alquil-2-acetilglicerofosfocolina Esterasa/metabolismo , Fármacos Anti-VIH , Terapia Antirretroviral Altamente Activa/efectos adversos , Biomarcadores , Recuento de Linfocito CD4 , Didesoxinucleósidos/administración & dosificación , Combinación de Medicamentos , Sustitución de Medicamentos , Femenino , Infecciones por VIH/sangre , Infecciones por VIH/diagnóstico , Infecciones por VIH/tratamiento farmacológico , Humanos , Lamivudine/administración & dosificación , Metabolismo de los Lípidos/efectos de los fármacos , Lípidos/sangre , Lipoproteínas LDL/sangre , Lopinavir/administración & dosificación , Masculino , Carga ViralRESUMEN
INTRODUCTION: GESIDA and the AIDS National Plan panel of experts suggest preferred (PR), alternative (AR), and other regimens (OR) for antiretroviral treatment (ART) as initial therapy in HIV-infected patients for the year 2016. The objective of this study is to evaluate the costs and the efficacy of initiating treatment with these regimens. METHODS: Economic assessment of costs and efficiency (cost/efficacy) based on decision tree analyses. Efficacy was defined as the probability of reporting a viral load <50copies/mL at week 48 in an intention-to-treat analysis. Cost of initiating treatment with an ART regimen was defined as the costs of ART and its consequences (adverse effects, changes of ART regimen, and drug resistance studies) during the first 48 weeks. The payer perspective (National Health System) was applied, only taking into account differential direct costs: ART (official prices), management of adverse effects, studies of resistance, and HLA B*5701 testing. The setting is Spain and the costs correspond to those of 2016. A sensitivity deterministic analysis was conducted, building three scenarios for each regimen: base case, most favourable, and least favourable. RESULTS: In the base case scenario, the cost of initiating treatment ranges from 4663 Euros for 3TC+LPV/r (OR) to 10,894 Euros for TDF/FTC+RAL (PR). The efficacy varies from 0.66 for ABC/3TC+ATV/r (AR) and ABC/3TC+LPV/r (OR), to 0.89 for TDF/FTC+DTG (PR) and TDF/FTC/EVG/COBI (AR). The efficiency, in terms of cost/efficacy, ranges from 5280 to 12,836 Euros per responder at 48 weeks, for 3TC+LPV/r (OR), and RAL+DRV/r (OR), respectively. CONCLUSION: Despite the overall most efficient regimen being 3TC+LPV/r (OR), among the PR and AR, the most efficient regimen was ABC/3TC/DTG (PR). Among the AR regimes, the most efficient was TDF/FTC/RPV.
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Fármacos Anti-VIH/economía , Fármacos Anti-VIH/uso terapéutico , Análisis Costo-Beneficio , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/economía , Humanos , Guías de Práctica Clínica como Asunto , EspañaRESUMEN
BACKGROUND: It has been suggested that routine CD4 cell count monitoring in human immunodeficiency virus (HIV)-monoinfected patients with suppressed viral loads and CD4 cell counts >300 cell/µL could be reduced to annual. HIV/hepatitis C virus (HCV) coinfection is frequent, but evidence supporting similar reductions in CD4 cell count monitoring is lacking for this population. We determined whether CD4 cell count monitoring could be reduced in monoinfected and coinfected patients by estimating the probability of maintaining CD4 cell counts ≥200 cells/µL during continuous HIV suppression. METHODS: The PISCIS Cohort study included data from 14 539 patients aged ≥16 years from 10 hospitals in Catalonia and 2 in the Balearic Islands (Spain) since January 1998. All patients who had at least one period of 6 months of continuous HIV suppression were included in this analysis. Cumulative probabilities with 95% confidence intervals were calculated using the Kaplan-Meier estimator stratified by the initial CD4 cell count at the period of continuous suppression initiation. RESULTS: A total of 8695 patients were included. CD4 cell counts fell to <200 cells/µL in 7.4% patients, and the proportion was lower in patients with an initial count >350 cells/µL (1.8%) and higher in those with an initial count of 200-249 cells/µL (23.1%). CD4 cell counts fell to <200 cells/µL in 5.7% of monoinfected and 11.1% of coinfected patients. Of monoinfected patients with an initial CD4 cell count of 300-349 cells/µL, 95.6% maintained counts ≥200 cells/µL. In the coinfected group with the same initial count, this rate was lower, but 97.6% of coinfected patients with initial counts >350 cells/µL maintained counts ≥200 cells/µL. CONCLUSIONS: From our data, it can be inferred that CD4 cell count monitoring can be safely performed annually in HIV-monoinfected patients with CD4 cell counts >300 cells/µL and HIV/HCV-coinfected patients with counts >350 cells/µL.
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Linfocitos T CD4-Positivos/inmunología , Infecciones por VIH/epidemiología , Infecciones por VIH/inmunología , Hepatitis C/epidemiología , Hepatitis C/inmunología , Adolescente , Adulto , Estudios de Cohortes , Coinfección/epidemiología , Coinfección/inmunología , Coinfección/virología , Femenino , Infecciones por VIH/complicaciones , Infecciones por VIH/virología , VIH-1 , Hepacivirus , Hepatitis C/complicaciones , Hepatitis C/virología , Humanos , Masculino , Persona de Mediana Edad , Carga Viral , Adulto JovenRESUMEN
OBJECTIVES: The objective of this study was to assess post-exposure prophylaxis (PEP) non-completion at day 28, comparing two regimens. METHODS: A prospective, open, randomized clinical trial was conducted at a tertiary hospital in Barcelona, Spain. Individuals attending the emergency room because of potential sexual exposure to HIV were randomized to tenofovir disoproxil/emtricitabine (245/200 mg) plus either ritonavir-boosted lopinavir (400/100 mg) or raltegravir (400 mg). The primary endpoint was PEP non-completion at day 28. Secondary endpoints were adherence, adverse events and rate of seroconversions. This study was registered in ClinicalTrials.gov: NCT01576731. RESULTS: One-hundred-and-twenty-one individuals were randomized to receive ritonavir-boosted lopinavir and 122 to raltegravir (nâ=â243). PEP non-completion at day 28 was 43% with no significant difference between arms. We performed a modified ITT analysis including only those patients who attended on day 1 (nâ=â191). PEP non-completion in this subgroup was higher in the ritonavir-boosted lopinavir arm than in the raltegravir arm (34.6% versus 20.4%, Pâ=â0.04), as was the number of patients lost to follow-up at day 28 (32.6% versus 21.6%, Pâ=â0.08) and the proportion of patients with low adherence (49.2% versus 30.8%, Pâ=â0.03). Adverse events were significantly more common in the ritonavir-boosted lopinavir arm (73.4% versus 60.2%, Pâ=â0.007). There was an HIV seroconversion at day 90 in the raltegravir arm in a patient who had multiple potential sexual risk exposures before and after receiving PEP. CONCLUSIONS: Although we found no differences between arms regarding PEP non-completion, poor adherence and adverse events were significantly higher in patients allocated to tenofovir disoproxil/emtricitabine plus ritonavir-boosted lopinavir. These data support the use of raltegravir as the preferred third drug in current PEP recommendations.
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Fármacos Anti-VIH/administración & dosificación , Quimioprevención/métodos , Infecciones por VIH/prevención & control , Cumplimiento de la Medicación , Profilaxis Posexposición/métodos , Adolescente , Adulto , Anciano , Fármacos Anti-VIH/efectos adversos , Quimioprevención/efectos adversos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , España , Adulto JovenRESUMEN
OBJECTIVES: The objective of this study was to assess post-exposure prophylaxis (PEP) non-completion at day 28, comparing ritonavir-boosted lopinavir versus maraviroc, both with tenofovir disoproxil/emtricitabine as the backbone. METHODS: We conducted a prospective, open, randomized clinical trial. Individuals attending the emergency room because of potential sexual exposure to HIV and who met criteria for receiving PEP were randomized to one of two groups: tenofovir disoproxil/emtricitabine (245/200 mg) once daily plus either ritonavir-boosted lopinavir (400/100 mg) or maraviroc (300 mg) twice daily. Five follow-up visits were scheduled for days 1, 10, 28, 90 and 180. The primary endpoint was PEP non-completion at day 28. Secondary endpoints were adherence, adverse events and rate of seroconversions. This study was registered in ClinicalTrials.gov: NCT01533272. RESULTS: One-hundred-and-seventeen individuals were randomized to receive ritonavir-boosted lopinavir and 120 to maraviroc (nâ=â237). PEP non-completion at day 28 was 38% (nâ=â89), with significant differences between arms [ritonavir-boosted lopinavir 44% (nâ=â51) versus maraviroc 32% (nâ=â38), Pâ=â0.05]. We performed a modified ITT analysis including only those patients who attended on day 1 (nâ=â182). PEP non-completion in this subgroup was also significantly higher in the ritonavir-boosted lopinavir arm (27% versus 13%, Pâ=â0.004). The proportion of patients with low adherence was similar between arms (52% versus 47%, Pâ=â0.56). Adverse events were reported by 111 patients and were significantly more common in the ritonavir-boosted lopinavir arm (72% versus 51%, Pâ=â0.003). No seroconversions were observed during the study. CONCLUSIONS: PEP non-completion and adverse events were both significantly higher in patients allocated to ritonavir-boosted lopinavir. These data suggest that maraviroc is a well-tolerated antiretroviral that can be used in this setting.
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Fármacos Anti-VIH/administración & dosificación , Quimioprevención/métodos , Infecciones por VIH/prevención & control , Cumplimiento de la Medicación , Profilaxis Posexposición/métodos , Adulto , Fármacos Anti-VIH/efectos adversos , Quimioprevención/efectos adversos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Femenino , Humanos , Masculino , Estudios ProspectivosRESUMEN
The advances seen in ART during the last 30 years have been outstanding. Treatment has evolved from the initial use of single agents as monotherapy. The ability to use HIV RNA as a surrogate marker for clinical outcomes allowed the more rapid evaluation of new therapies. This led to the understanding that triple-drug regimens, including a core agent (an NNRTI or a boosted PI) and two NRTIs, are optimal. These combinations have demonstrated continued improvements in their efficacy and toxicity as initial therapy. However, the need for pharmacokinetic boosting, with potential drug-drug interactions, or residual issues of efficacy or toxicity have persisted for some agents. Most recently, integrase strand transfer inhibitors, particularly dolutegravir, have shown unparalleled safety and efficacy and are currently the core agents of choice. Regimens that included only core agents or only backbone agents have not been as successful as combined therapy in antiretroviral-naive patients. It appears that at least one NRTI is needed for optimal performance and lamivudine and emtricitabine may be the ideal candidates. Several studies are ongoing of agents with longer dosing intervals, lower cost and new NRTI-saving strategies to address unmet needs.
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Fármacos Anti-VIH/uso terapéutico , Terapia Antirretroviral Altamente Activa/métodos , Infecciones por VIH/tratamiento farmacológico , Fármacos Anti-VIH/efectos adversos , Terapia Antirretroviral Altamente Activa/efectos adversos , Interacciones Farmacológicas , Quimioterapia Combinada , Humanos , Seguridad del PacienteRESUMEN
INTRODUCTION: GESIDA and the AIDS National Plan panel of experts suggest a preferred (PR), alternative (AR) and other regimens (OR) for antiretroviral treatment (ART) as initial therapy in HIV-infected patients for 2015. The objective of this study is to evaluate the costs and the effectiveness of initiating treatment with these regimens. METHODS: Economic assessment of costs and effectiveness (cost/effectiveness) based on decision tree analyses. Effectiveness was defined as the probability of reporting a viral load <50 copies/mL at week 48, in an intention-to-treat analysis. Cost of initiating treatment with an ART regimen was defined as the costs of ART and its consequences (adverse effects, changes of ART regimen, and drug resistance studies) during the first 48 weeks. The payer perspective (National Health System) was applied, only taking into account differential direct costs: ART (official prices), management of adverse effects, studies of resistance, and HLA B*5701 testing. The setting is Spain and the costs correspond to those of 2015. A deterministic sensitivity analysis was conducted, building three scenarios for each regimen: base case, most favourable and least favourable. RESULTS: In the base case scenario, the cost of initiating treatment ranges from 4663 Euros for 3TC+LPV/r (OR) to 10,902 Euros for TDF/FTC+RAL (PR). The effectiveness varies from 0.66 for ABC/3TC+ATV/r (AR) and ABC/3TC+LPV/r (OR), to 0.89 for TDF/FTC+DTG (PR) and TDF/FTC/EVG/COBI (AR). The efficiency, in terms of cost/effectiveness, ranges from 5280 to 12,836 Euros per responder at 48 weeks, for 3TC+LPV/r (OR) and RAL+DRV/r (OR), respectively. CONCLUSION: The most efficient regimen was 3TC+LPV/r (OR). Among the PR and AR, the most efficient regimen was TDF/FTC/RPV (AR). Among the PR regimes, the most efficient was ABC/3TC+DTG.
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Fármacos Anti-VIH/economía , Infecciones por VIH/tratamiento farmacológico , Síndrome de Inmunodeficiencia Adquirida/tratamiento farmacológico , Adulto , Fármacos Anti-VIH/uso terapéutico , Análisis Costo-Beneficio , Árboles de Decisión , Infecciones por VIH/virología , Humanos , España , Carga ViralRESUMEN
INTRODUCTION: Antiretroviral therapy has led to a decrease in HIV-related mortality and to the emergence of non-AIDS defining diseases as competing causes of death. This study estimates the HIV mortality rate and their risk factors with regard to different causes in a large city from January 2001 to June 2013. MATERIALS AND METHODS: We followed-up 3137 newly diagnosed HIV non-AIDS cases. Causes of death were classified as HIV-related, non-HIV-related and external. We examined the effect of risk factors on survival using mortality rates, Kaplan-Meier plots and Cox models. Finally, we estimated survival for each main cause of death groups through Fine and Gray models. MORTALITY RESULTS: 182 deaths were found [14.0/1000 person-years of follow-up (py); 95% confidence interval (CI):12.0-16.1/1000 py], 81.3% of them had a known cause of death. Mortality rate by HIV-related causes and non-HIV-related causes was the same (4.9/1000 py; CI:3.7-6.1/1000 py), external was lower [1.7/1000 py; (1.0-2.4/1000 py)]. SURVIVAL RESULTS: Kaplan-Meier estimate showed worse survival in intravenous drug user (IDU) and heterosexuals than in men having sex with men (MSM). Factors associated with HIV-related causes of death include: IDU male (subHazard Ratio (sHR):3.2; CI:1.5-7.0) and <200 CD4 at diagnosis (sHR:2.7; CI:1.3-5.7) versus ≥500 CD4. Factors associated with non-HIV-related causes of death include: ageing (sHR:1.5; CI:1.4-1.7) and heterosexual female (sHR:2.8; CI:1.1-7.3) versus MSM. Factors associated with external causes of death were IDU male (sHR:28.7; CI:6.7-123.2) and heterosexual male (sHR:11.8; CI:2.5-56.4) versus MSM. CONCLUSION AND RECOMMENDATION: There are important differences in survival among transmission groups. Improved treatment is especially necessary in IDUs and heterosexual males.
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Síndrome de Inmunodeficiencia Adquirida/mortalidad , Causas de Muerte , Infecciones por VIH/mortalidad , Adulto , Fármacos Anti-VIH/uso terapéutico , Terapia Antirretroviral Altamente Activa/métodos , Estudios de Cohortes , Consumidores de Drogas/psicología , Femenino , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/etiología , Heterosexualidad/psicología , Homosexualidad Masculina/psicología , Humanos , Estimación de Kaplan-Meier , Masculino , Factores de Riesgo , Abuso de Sustancias por Vía Intravenosa/complicacionesRESUMEN
UNLABELLED: HIV-1-specific immune responses induced by a dendritic cell (DC)-based therapeutic vaccine might have some effect on the viral reservoir. Patients on combination antiretroviral therapy (cART) were randomized to receive DCs pulsed with autologous HIV-1 (n = 24) (DC-HIV-1) or nonpulsed DCs (n = 12) (DC-control). We measured the levels of total and integrated HIV-1 DNA in CD4 T cells isolated from these patients at 6 time points: before any cART; before the first cART interruption, which was at 56 weeks before the first immunization to isolate virus for pulsing DCs; before and after vaccinations (VAC1 and VAC2); and at weeks 12 and 48 after the second cART interruption. The vaccinations did not influence HIV-1 DNA levels in vaccinated subjects. After the cART interruption at week 12 postvaccination, while total HIV-1 DNA increased significantly in both arms, integrated HIV-1 DNA did not change in vaccinees (mean of 1.8 log10 to 1.9 copies/10(6) CD4 T cells, P = 0.22) and did increase in controls (mean of 1.8 log10 to 2.1 copies/10(6) CD4 T cells, P = 0.02) (P = 0.03 for the difference between groups). However, this lack of increase of integrated HIV-1 DNA observed in the DC-HIV-1 group was transient, and at week 48 after cART interruption, no differences were observed between the groups. The HIV-1-specific T cell responses at the VAC2 time point were inversely correlated with the total and integrated HIV-1 DNA levels after cART interruption in vaccinees (r [Pearson's correlation coefficient] = -0.69, P = 0.002, and r = -0.82, P < 0.0001, respectively). No correlations were found in controls. HIV-1-specific T cell immune responses elicited by DC therapeutic vaccines drive changes in HIV-1 DNA after vaccination and cART interruption. (This study has been registered at ClinicalTrials.gov under registration no. NCT00402142.) IMPORTANCE: There is an intense interest in developing strategies to target HIV-1 reservoirs as they create barriers to curing the disease. The development of therapeutic vaccines aimed at enhancing immune-mediated clearance of virus-producing cells is of high priority. Few therapeutic vaccine clinical trials have investigated the role of therapeutic vaccines as a strategy to safely eliminate or control viral reservoirs. We recently reported that a dendritic cell-based therapeutic vaccine was able to significantly decrease the viral set point in vaccinated patients, with a concomitant increase in HIV-1-specific T cell responses. The HIV-1-specific T cell immune responses elicited by this therapeutic dendritic cell vaccine drove changes in the viral reservoir after vaccinations and significantly delayed the replenishment of integrated HIV-1 DNA after cART interruption. These data help in understanding how an immunization could shift the virus-host balance and are instrumental for better design of strategies to reach a functional cure of HIV-1 infection.
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Vacunas contra el SIDA/administración & dosificación , Antirretrovirales/administración & dosificación , Células Dendríticas , Infecciones por VIH/terapia , VIH-1/inmunología , Vacunación , Vacunas de ADN/administración & dosificación , Vacunas contra el SIDA/genética , Vacunas contra el SIDA/inmunología , Adulto , Autoinjertos , Recuento de Linfocito CD4 , Linfocitos T CD4-Positivos/inmunología , Células Dendríticas/inmunología , Células Dendríticas/trasplante , Femenino , Infecciones por VIH/inmunología , VIH-1/genética , Humanos , Masculino , Persona de Mediana Edad , Vacunas de ADN/genética , Vacunas de ADN/inmunologíaRESUMEN
BACKGROUND: A proportion of patients who spontaneously control viral load (controllers) experienced clinical progression. We hypothesized that microbial translocation would independently determine the rate of disease progression in controllers. METHODS: sCD14, lipopolysaccharide-binding protein (LBP) and EndoCab levels were assessed in 114 antiretroviral-naive patients with CD4(+) T cells above 500 cells/µl (including 63 controllers and 51 noncontrollers). The independent predictive value of these markers on time to progression to the combined endpoint of AIDS, non-AIDS event, initiation of combination antiretroviral therapy (cART) or CD4(+) cell count less than 500 cells/µl was assessed using a Cox regression model. RESULTS: Most of the patients progressed to a combined endpoint (60%). Clinical progression in controllers was significantly lower than in noncontrollers (P = 0.02). Controllers with lower than the median baseline CD4(+) T-cell count and higher than the median baseline viral load, sCD14 and EndoCab levels had a worse prognosis (P < 0.0001, P = 0.007, P = 0.05 and P = 0.012), while noncontrollers with higher than the median baseline LBP level also had a worse prognosis (P = 0.019). sCD14 and LBP increased and EndoCab decreased over time [from baseline (median values: 1486, 17604 ng/ml and 68 MMU/ml, respectively, to the date of event or the last determination (median values: 1663, 20230 ng/ml and 49 MMU/ml), respectively] in controllers (P = 0.04, 0.08 and 0.0006, respectively). CONCLUSION: Microbial translocation seems to be an important determinant of clinical progression in HIV-infected controllers independently of viremia. Measures to improve the intestinal mucosa damage or decrease translocation could influence the outcome in these patients.
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Traslocación Bacteriana , Biomarcadores/análisis , Progresión de la Enfermedad , Enfermedades Gastrointestinales/patología , Infecciones por VIH/inmunología , Infecciones por VIH/patología , Sobrevivientes de VIH a Largo Plazo , Adulto , Estudios de Cohortes , Femenino , Enfermedades Gastrointestinales/complicaciones , Infecciones por VIH/complicaciones , Humanos , Masculino , Persona de Mediana Edad , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: The virological efficacy of switching from a ritonavir-boosted protease inhibitor (PI/r)- to a raltegravir (RAL)-containing regimen remains controversial according to the results of SWITCHMRK and SPIRAL studies. The aim of this analysis is to assess the impact of prior resistance mutations to nucleos(t)ides and other potential factors on the virological outcome. METHODS: This was a substudy of the prospective, open-label, multicentre SPIRAL study. Demographic, virological variables, prior episodes of virological failures (VF) and archived resistance mutations to nucleos(t)ides were identified from databases and its impact measured by genotypic sensitive scores (GSS) according to the genotypic resistance interpretation algorithm from the Stanford HIV Drug Resistance Database on outcome was analysed. RESULTS: Of 250 patients (128 RAL and 122 PI/r) included in the main SPIRAL study, 74 (30%) had previous VF with prior genotypic resistance tests (GRT). Median time of virological suppression prior to inclusion in SPIRAL study was 63.5 months. GSS for backbone nucleos(t)ides was <1 in 15/38 (39%) in the RAL arm and in 9/36 (25%) in the PI/r arm (P=0.13). Among those with nucleos(t)ides GSS <1, 0/15 (0%) in the RAL versus 2/9 (22%) in the PI/r arm developed VF (P=0.13). Moreover 0/11 subjects with null or residual (GSS≤0.5) backbone activity developed VF in the RAL arm. CONCLUSIONS: The 48-week virological efficacy of switching from a PI/r to RAL in subjects with long-term virological suppression was not compromised by a reduction of the nucleos(t)ide backbone activity.