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OBJECTIVES: People with HIV and extensive antiretroviral exposure may have limited/exhausted treatment options (LExTO) due to resistance, comorbidities, or antiretroviral-related toxicity. Predictors of LExTO were investigated in the RESPOND cohort. METHODS: Participants on ART for at least 5âyears were defined as having LExTO when switched to at least two anchor agents and one third antiretroviral (any class), a two-drug regimen of two anchor agents (excluding rilpivirine with dolutegravir/cabotegravir), or at least three nucleoside reverse transcriptase inhibitors. Baseline was the latest of January 1, 2012, cohort enrolment or 5âyears after starting antiretrovirals. Poisson regression modeled LExTO rates and clinical events (all-cause mortality, non-AIDS malignancy, cardiovascular disease [CVD], and chronic kidney disease [CKD]). RESULTS: Of 23â827 participants, 2164 progressed to LExTO (9.1%) during 130â061 person-years follow-up (PYFU); incidence 1.66/100 PYFU (95% CI 1.59-1.73). Predictors of LExTO were HIV duration more than 15âyears (vs. 7.5-15; adjusted incidence rate ratio [aIRR] 1.32; 95% CI 1.19-1.46), development of CKD (1.84; 1.59-2.13), CVD (1.64; 1.38-1.94), AIDS (1.18; 1.07-1.30), and current CD4 + cell count of 350âcells/µl or less (vs. 351-500âcells/µl, 1.51; 1.32-1.74). Those followed between 2018 and 2021 had lower rates of LExTO (vs. 2015-2017; 0.52; 0.47-0.59), as did those with baseline viral load of 200âcp/ml or less (0.46; 0.40-0.53) and individuals under 40. Development of LExTO was not significantly associated with clinical events after adjustment for age and current CD4, except CKD (1.74; 1.48-2.05). CONCLUSION: Despite an aging and increasingly comorbid population, we found declining LExTO rates by 2018-2021, reflecting recent developments in contemporary ART options and clinical management. Reassuringly, LExTO was not associated with a significantly increased incidence of serious clinical events apart from CKD.
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Fármacos Anti-HIV , Doenças Cardiovasculares , Infecções por HIV , Insuficiência Renal Crônica , Humanos , Infecções por HIV/complicações , Antirretrovirais/uso terapêutico , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/complicações , Contagem de Linfócito CD4 , Doenças Cardiovasculares/induzido quimicamente , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/complicações , Carga Viral , Fármacos Anti-HIV/uso terapêuticoRESUMO
BACKGROUND: In the primary analysis of the DRIVE-SHIFT trial, switching to doravirine/lamivudine/tenofovir disoproxil fumarate (DOR/3TC/TDF) maintained suppression of HIV-1 through week 48. Here, we present long-term efficacy and safety outcomes through week 144 of the DRIVE-SHIFT trial. METHODS: This phase 3, randomized, open-label trial evaluated switching from a stable antiretroviral regimen to once-daily DOR/3TC/TDF in adults with HIV-1 suppressed for ≥6 months and no previous virologic failure. Participants switched at day 1 [immediate switch group (ISG); n = 447] or week 24 [delayed switch group (DSG); n = 209]. Nine ISG participants who completed week 48 but did not enter extension-1 were excluded from week 144 efficacy analyses. RESULTS: At week 144, HIV-1 RNA <50 copies/mL was maintained in 80.1% of the ISG (351/438) and 83.7% of the DSG (175/209), while 2.7% (12/438) and 4.8% (10/209), respectively, had HIV-1 RNA ≥50 copies/mL (Food and Drug Administration Snapshot approach). Protocol-defined virologic failure after switch occurred in 2.1% of ISG (9/438) and 3.3% of DSG (7/209); no viral resistance to doravirine was detected in 4 participants with samples available. Reductions in fasting lipids were observed at 24 weeks after switch and maintained through week 144. The mean weight change from switch to week 144 was +1.4 kg for ISG and +1.2 kg for DSG. The most common adverse events were nasopharyngitis (16.2%), headache (12.3%), and diarrhea (9.1%). Overall, 4.1% discontinued because of adverse events, and no deaths occurred. CONCLUSIONS: These results confirm that switching to once-daily DOR/3TC/TDF is a generally well-tolerated option for maintaining viral suppression in adults considering a change in therapy. REGISTRATION: ClinicalTrials.gov NCT02397096.
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Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Lamivudina/uso terapêutico , Piridonas/uso terapêutico , Inibidores da Transcriptase Reversa/uso terapêutico , Tenofovir/uso terapêutico , Triazóis/uso terapêutico , Adulto , Fármacos Anti-HIV/efeitos adversos , Terapia Antirretroviral de Alta Atividade/métodos , Quimioterapia Combinada , Feminino , HIV-1/efeitos dos fármacos , Humanos , Lamivudina/efeitos adversos , Masculino , Piridonas/efeitos adversos , Inibidores da Transcriptase Reversa/efeitos adversos , Tenofovir/efeitos adversos , Resultado do Tratamento , Triazóis/efeitos adversos , Aumento de Peso/efeitos dos fármacos , Redução de Peso/efeitos dos fármacosRESUMO
Doravirine is a non-nucleoside reverse transcriptase inhibitor approved for the treatment of HIV-1. In a phase 1 trial, doravirine exposure was transiently decreased when treatment was started immediately after stopping efavirenz. In a post-hoc subgroup analysis of participants who switched from an efavirenz-based regimen to doravirine/lamivudine/tenofovir disoproxil fumarate in the phase 3 DRIVE-SHIFT trial, doravirine plasma levels at week 4 were similar to non-induced levels, and HIV-1 suppression was maintained at weeks 24 and 48.
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BACKGROUND: Doravirine is a novel, nonnucleoside reverse transcriptase inhibitor with demonstrated efficacy in treatment-naive adults with HIV-1. METHODS: In this open-label, active-controlled, noninferiority trial, adults with HIV-1 virologically suppressed for ≥6 months on 2 nucleoside reverse transcriptase inhibitors plus a boosted protease inhibitor, boosted elvitegravir, or a non-nucleoside reverse transcriptase inhibitor were randomized (2:1) to switch to once-daily, single-tablet doravirine 100 mg with lamivudine 300 mg and tenofovir disoproxil fumarate 300 mg (DOR/3TC/TDF) or to continue their current therapy (Baseline Regimen) for 24 weeks. The primary endpoint was the proportion of participants with HIV-1 RNA <50 copies/mL (defined by the FDA Snapshot approach), with the primary comparison between DOR/3TC/TDF at week 48 and Baseline Regimen at week 24 and a secondary comparison between the groups at week 24 (noninferiority margin, -8%). RESULTS: Six hundred seventy participants (447 DOR/3TC/TDF, 223 Baseline Regimen) were treated and included in the analyses. At week 24, 93.7% on DOR/3TC/TDF vs 94.6% on Baseline Regimen had HIV-1 RNA <50 copies/mL [difference -0.9 (-4.7 to 3.0)]. At week 48, 90.8% on DOR/3TC/TDF had HIV-1 RNA <50 copies/mL, demonstrating noninferiority vs Baseline Regimen at week 24 [difference -3.8 (-7.9 to 0.3)]. In participants on ritonavir-boosted protease inhibitor at entry, mean reductions in fasting LDL-C and non-HDL-C at week 24 were significantly greater for DOR/3TC/TDF vs Baseline Regimen (P < 0.0001). Adverse events occurred in 68.9% on DOR/3TC/TDF and 52.5% on Baseline Regimen by week 24, leading to treatment discontinuation in 2.5% and 0.4%, respectively. CONCLUSIONS: Switching to once-daily DOR/3TC/TDF is a generally well-tolerated option for maintaining viral suppression in patients considering a change in therapy. REGISTRATION: ClinicalTrials.gov NCT02397096.
Assuntos
Antirretrovirais/uso terapêutico , HIV-1/efeitos dos fármacos , Lamivudina/uso terapêutico , Piridonas/uso terapêutico , Tenofovir/uso terapêutico , Triazóis/uso terapêutico , Adulto , Idoso , Antirretrovirais/administração & dosagem , Estudos de Equivalência como Asunto , Feminino , Humanos , Lamivudina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Inibidores de Proteases/uso terapêutico , Piridonas/administração & dosagem , Quinolonas/uso terapêutico , Ritonavir/uso terapêutico , Tenofovir/administração & dosagem , Resultado do Tratamento , Triazóis/administração & dosagem , Adulto JovemRESUMO
OBJECTIVE: To evaluate the risk of neural tube defects (NTDs) after exposure to raltegravir during pregnancy. METHODS: Exposures to raltegravir during pregnancy reported cumulatively through May 31, 2018, to the company safety database were reviewed to identify cases of NTDs. This database includes all reports of pregnancy from Merck-sponsored clinical trials, spontaneous postmarketing reports, and non-interventional data sources, including the Antiretroviral Pregnancy Registry (APR). Reports were classified as prospective (before knowledge of pregnancy outcome) or retrospective (after knowledge of pregnancy outcome). We also reviewed data from 2 ongoing pregnancy cohorts. RESULTS: A total of 2426 pregnancies with reported outcomes were identified among women exposed to raltegravir: 1238 from the Merck database and 1188 from United Kingdom/Ireland and French pregnancy cohorts. Among all 2426 reports, 1991 were prospective. No cases of NTDs were identified among the prospective pregnancy reports, of which 767 were first trimester, including 456 in the periconception period (at or within 28 days after conception). Among the 435 retrospective reports, 3 NTD cases per APR criteria were identified (anencephaly, and 2 meningomyelocele), of which only one (meningomyelocele) was among exposures in the periconception period. Given the inherent limitations and bias of retrospective reports, it is not appropriate to calculate an incidence rate. CONCLUSIONS: Prospectively collected pregnancy outcome data do not suggest an association between raltegravir exposure in the periconception period and NTDs. The current data support the updated DHHS and EACS treatment guidelines for use of raltegravir as a preferred integrase inhibitor in all stages of pregnancy.
Assuntos
Fármacos Anti-HIV/toxicidade , Infecções por HIV/complicações , Defeitos do Tubo Neural/induzido quimicamente , Complicações Infecciosas na Gravidez/tratamento farmacológico , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Raltegravir Potássico/toxicidade , Feminino , Infecções por HIV/tratamento farmacológico , Humanos , Gravidez , Estudos Prospectivos , Estudos RetrospectivosRESUMO
BACKGROUND: Raltegravir 1200mg (2×600mg tablets) once daily (QD) demonstrated noninferior efficacy and similar safety to raltegravir 400mg twice daily (BID) at week 48 of the ONCEMRK trial. Here, we report the week 96 results from this study. METHODS: ONCEMRK is a phase 3, multicenter, double-blind, noninferiority trial comparing raltegravir 1200mg QD with raltegravir 400mg BID in treatment-naive HIV-1-infected adults. Participants were assigned (2:1) to raltegravir 2×600mg QD or 400mg BID, both with emtricitabine and tenofovir disoproxil fumarate (FTC/TDF) for 96 weeks. Randomization was stratified by screening HIV-1 RNA and hepatitis B/C status. Efficacy was assessed as the proportion of participants with HIV-1 RNA <40 copies per milliliter (Food and Drug Administration Snapshot approach); the noninferiority margin was 10 percentage points. RESULTS: Of the 797 participants who received study therapy (84.6% were men, 59.3% were white, and mean age was 35.9 years), 694 completed 96 weeks of treatment (87.6% QD; 84.4% BID), with few discontinuations because of lack of efficacy (1.1% for both groups) or adverse events (1.3% QD; 2.3% BID). At week 96, 81.5% (433/531) of QD recipients and 80.1% (213/266) of BID recipients achieved HIV-1 RNA <40 copies per milliliter (difference 1.4%, 95% confidence interval: -4.4 to 7.3). CD4 T-cell counts increased >260 cells/mm from baseline in both groups. Resistance to raltegravir was infrequent, occurring in 0.8% of each treatment group through week 96. Adverse event rates were similar for the 2 regimens. CONCLUSIONS: In HIV-1-infected treatment-naive adults receiving FTC/TDF, raltegravir 1200mg QD demonstrated noninferior efficacy to raltegravir 400mg BID that was durable to week 96, with a safety profile similar to raltegravir 400mg BID.
Assuntos
Adenina/análogos & derivados , Fármacos Anti-HIV/uso terapêutico , Emtricitabina/uso terapêutico , Infecções por HIV/tratamento farmacológico , Ácidos Fosforosos/uso terapêutico , Raltegravir Potássico/uso terapêutico , Adenina/administração & dosagem , Adenina/uso terapêutico , Adulto , Fármacos Anti-HIV/administração & dosagem , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Quimioterapia Combinada , Emtricitabina/administração & dosagem , Feminino , HIV-1/genética , HIV-1/isolamento & purificação , Humanos , Masculino , Ácidos Fosforosos/administração & dosagem , Placebos , RNA Viral/sangue , Raltegravir Potássico/administração & dosagemRESUMO
BACKGROUND: In the C-SURFER study, therapy with the all-oral elbasvir plus grazoprevir regimen for 12 weeks in patients with chronic hepatitis C virus (HCV) infection and stage 4-5 chronic kidney disease resulted in a high rate of virological cure compared with placebo. Here, we report sustained virological response (SVR), safety data, health-related quality-of-life (HRQOL), and virological resistance analyses in patients in C-SURFER who received immediate antiviral therapy or who received placebo before therapy. METHODS: In this phase 3, multicentre, randomised, placebo-controlled study, we randomly assigned adults with HCV genotype 1 infection and stage 4-5 chronic kidney disease enrolled at 68 centres worldwide to either elbasvir 50 mg plus grazoprevir 100 mg once per day for 12 weeks (immediate treatment group) or placebo for 12 weeks followed by elbasvir 50 mg plus grazoprevir 100 mg once per day for 12 weeks beginning at week 16 (deferred treatment group). The primary safety and efficacy endpoints for the immediate treatment group and placebo phase of the deferred treatment group have been reported previously. Here, we report safety and efficacy data for the treatment phase of the deferred treatment group, as well as HRQOL assessed using the 36-Item Short Form Health Survey for all groups, and baseline and treatment-emergent resistance-associated substitutions (RASs). SVR at 12 weeks (SVR12) was assessed in the modified full analysis set (FAS), defined as all patients excluding those who did not receive at least one dose of study drug, who died, or who discontinued the study before the end of treatment for reasons determined to be unrelated to HCV treatment. This trial is registered with ClinicalTrials.gov, Number NCT02092350. FINDINGS: Between March 30 and Nov 28, 2014, 235 patients were enrolled and received at least one dose of study drug. The modified FAS included 116 patients assigned to immediate treatment and 99 assigned to deferred treatment. 115 (99·1%; 95% CI 95·3-100·0) of 116 assigned to immediate treatment achieved SVR12 compared with 97 (98·0%; 92·9-99·7) of 99 assigned to deferred treatment. In patients with genotype 1a infections, SVR12 was achieved by 11 (84·6%) of 13 patients with detectable baseline NS5A RASs and in 98 (100%) of 98 without. HRQOL did not differ at week 12 between immediate treatment and the placebo phase of deferred treatment. Safety was generally similar between patients receiving immediate treatment and those receiving placebo in the deferred treatment group. One serious adverse event during deferred treatment (interstitial nephritis) and one during the placebo phase of deferred treatment (raised lipase concentration) were deemed related to study drug. Four patients died, one who received immediate treatment (cardiac arrest) and three who received deferred treatment (aortic aneurysm, pneumonia, and unknown cause); all four deaths were considered unrelated to study drugs. Of the three deaths in the deferred treatment group, one occurred during placebo treatment and two occurred before starting active treatment. There were no notable differences in aminotransferase elevations in the deferred treatment group compared with the immediate treatment group, and no patients in the deferred treatment group had total bilirubin elevations. INTERPRETATION: These data add to the growing body of clinical evidence for the fixed-dose combination regimen of elbasvir plus grazoprevir for 12 weeks and support use of this therapy in patients with HCV genotype 1 infection and stage 4-5 chronic kidney disease. FUNDING: Merck Sharp & Dohme.
Assuntos
Antivirais/uso terapêutico , Benzofuranos/uso terapêutico , Hepatite C Crônica/complicações , Hepatite C Crônica/tratamento farmacológico , Imidazóis/uso terapêutico , Qualidade de Vida , Quinoxalinas/uso terapêutico , Insuficiência Renal Crônica/complicações , Adulto , Amidas , Antivirais/efeitos adversos , Benzofuranos/efeitos adversos , Carbamatos , Ciclopropanos , Método Duplo-Cego , Esquema de Medicação , Farmacorresistência Viral , Quimioterapia Combinada , Feminino , Genótipo , Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/genética , Hepatite C Crônica/virologia , Humanos , Imidazóis/efeitos adversos , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados da Assistência ao Paciente , Quinoxalinas/efeitos adversos , Sulfonamidas , Resposta Viral SustentadaRESUMO
AIM: Treatment options have been limited for patients with hepatitis C virus (HCV) infection and chronic kidney disease stage 4/5 (CKD 4/5). The aim of this analysis was to evaluate the impact of elbasvir/grazoprevir (EBR/GZR) on estimated glomerular filtration rate (eGFR) in patients with CKD stage 3 enrolled in phase II/III clinical trials. METHODS: We undertook a retrospective integrated analysis of patients with CKD 3 enrolled in the EBR/GZR phase II/III clinical trials. All patients were required to have chronic HCV infection and have received EBR 50 mg/GZR 100 mg, with or without ribavirin, for 8-18 weeks. Patients with CKD 3 (eGFR <60 to ≥30 mL/min/1.73 m2 ) at baseline plus ≥1 eGFR assessment postbaseline were included. In all studies, the primary endpoint was sustained virologic response 12 weeks after completion of therapy. RESULTS: Thirty-two patients with CKD 3 were identified from a pooled dataset of 1689 patients enrolled in the EBR/GZR clinical trial program. Thirty-one (97%) patients achieved SVR12 and one patient relapsed. In these 32 patients, there was no decline in median eGFR at the end of treatment or at follow-up week 12 compared with baseline. Median eGFR values were 56 mL/min/1.73 m2 (range, 45-59) at baseline, 58 mL/min/1.73 m2 (range, 41-78) at the end of treatment and 59 mL/min/1.73 m2 (range, 38-78) 12 weeks after completing treatment. DISCUSSION: Elbasvir/grazoprevir is a safe and effective treatment option for patients with compromised renal function, irrespective of baseline eGFR.
RESUMO
AIM: To evaluate efficacy/safety of hepatitis C virus (HCV) protease inhibitor boceprevir with pegylated interferon (PEG-IFN) alfa and weight-based ribavirin (RBV) in a phase 3 trial. METHODS: A prospective, multicenter, phase 3, open-label, single-arm study of PEG-IFN alfa, weight-based RBV, and boceprevir, with a PEG-IFN/RBV lead-in phase was performed. The HCV/human immunodeficiency virus coinfected study population included treatment naïve (TN) and treatment experienced (TE) patients. Treatment duration ranged from 28 to 48 wk dependent upon response-guided criteria. All patients had HCV Genotype 1 with a viral load > 10000 IU/mL. Compensated cirrhosis was allowed. Sample size was determined to establish superiority to historical (PEG-IFN plus RBV) rates in sustained viral response (SVR). RESULTS: A total of 257 enrolled participants were analyzed (135 TN and 122 TE). In the TN group, 81.5% were male and 54.1% were black. In the TE group, 76.2% were male and 47.5% were white. Overall SVR12 rates (HCV RNA < lower limit of quantification, target not detected, target not detected) were 35.6% in TN and 30.3% in TE. Response rates at SVR24 were 28% in TN and 10% in TE, and exceeded those in historical controls. The highest rate was observed in TN non-cirrhotic participants (36.8% and the lowest in TE cirrhotics (26.3%). Cirrhotic TN participants had a 27.8% SVR12 rate and 32.1% of TE non-cirrhotics achieved SVR12. Significantly lower response rates were observed among black participants; in the TE, SVR12 was 39.7% in white participants but only 13.2% of black subjects (P = 0.002). Among the TN, SVR12 was 42.1% among whites and 27.4% among blacks (P = 0.09). CONCLUSION: The trial met its hypothesis of improved SVR compared to historical controls but overall SVR rates were low. All-oral HCV treatments will mitigate these difficulties.
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BACKGROUND: Chronic hepatitis C virus (HCV) infection in patients with stage 4-5 chronic kidney disease increases the risk of death and renal graft failure, yet patients with hepatitis C and chronic kidney disease have few treatment options. This study assesses an all-oral, ribavirin-free regimen in patients with HCV genotype 1 infection and stage 4-5 chronic kidney disease. METHODS: In this phase 3 randomised study of safety and observational study of efficacy, patients with HCV genotype 1 infection and chronic kidney disease (stage 4-5 with or without haemodialysis dependence) were randomly assigned to receive grazoprevir (100 mg, NS3/4A protease inhibitor) and elbasvir (50 mg, NS5A inhibitor; immediate treatment group) or placebo (deferred treatment group) once daily for 12 weeks. Randomisation was done centrally with an interactive voice response system. An additional cohort of patients who were not randomised received the same regimen open-label and underwent intensive pharmacokinetic sampling. The primary efficacy outcome was a non-randomised comparison of sustained virological response at 12 weeks (SVR12) after the end of therapy for the combined immediate treatment group and the pharmacokinetic population with a historical control. The primary safety outcome was a randomised comparison between the immediate treatment group and the deferred treatment group. After 4 weeks of follow-up (study week 16), unmasking occurred and patients in the deferred treatment group received grazoprevir and elbasvir. The primary efficacy hypothesis was tested at a two-sided significance level (type I error) of 0·05 using an exact test for a binomial proportion. Safety event rates were compared between immediate treatment and deferred treatment groups using the stratified Miettinen and Nurminen method with baseline dialysis status as the strata. The study is registered at ClinicalTrials.gov, number NCT02092350. FINDINGS: 224 patients were randomly assigned to the immediate treatment group with grazoprevir and elbasvir (n=111) or the deferred treatment group (n=113), and 11 were assigned to the intensive pharmacokinetic population. Overall, 179 (76%) were haemodialysis-dependent, 122 (52%) had HCV genotype 1a infection, 189 (80%) were HCV treatment-naive, 14 (6%) were cirrhotic, and 108 (46%) were African American. Of the 122 patients receiving grazoprevir and elbasvir, six were excluded from the primary efficacy analysis for non-virological reasons (death, lost-to-follow-up [n=2], non-compliance, patient withdrawal, and withdrawal by physician for violent behaviour). No patients in the combined immediate treatment group and intensive pharmacokinetic population and five (4%) in the deferred treatment group discontinued because of an adverse event. Most common adverse events were headache, nausea, and fatigue, occurring at similar frequencies in patients receiving active and placebo drugs. SVR12 in the combined immediate treatment group and intensive pharmacokinetic population was 99% (95% CI 95·3-100·0; 115/116), with one relapse 12 weeks after end of treatment when compared with a historical control of 45%, based on meta-analyses of interferon-based regimens used in clinical trials of patients infected with HCV who are on haemodialysis. INTERPRETATION: Once-daily grazoprevir and elbasvir for 12 weeks had a low rate of adverse events and was effective in patients infected with HCV genotype 1 and stage 4-5 chronic kidney disease. FUNDING: Merck Sharp & Dohme Corp.
Assuntos
Benzofuranos/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Imidazóis/uso terapêutico , Inibidores de Proteases/uso terapêutico , Quinoxalinas/uso terapêutico , Insuficiência Renal Crônica/tratamento farmacológico , Idoso , Amidas , Carbamatos , Ciclopropanos , Quimioterapia Combinada , Feminino , Hepacivirus/genética , Hepatite C Crônica/complicações , Humanos , Masculino , Pessoa de Meia-Idade , RNA Viral , Insuficiência Renal Crônica/complicações , Sulfonamidas , Resultado do TratamentoRESUMO
BACKGROUND: Rates of sustained virological response (SVR) to peginterferon-ribavirin are low in patients with hepatitis C virus (HCV) genotype 1 and HIV. We aimed to assess efficacy and safety of triple therapy with boceprevir plus pegylated interferon alfa-2b (peginterferon) and ribavirin, which increases rates of SVR in patients with HCV alone. METHODS: In our double-blind, randomised controlled phase 2 trial, we enrolled adults (18-65 years) with untreated HCV genotype 1 infection and controlled HIV (HIV RNA <50 copies per mL) at 30 academic and non-academic study sites. We randomly allocated patients (1:2) according to a computer generated sequence, stratified by Metavir score and baseline HCV RNA level, to receive peginterferon 1·5 µg/kg per week with weight-based ribavirin (600-1400 mg per day) for 4 weeks, followed by peginterferon-ribavirin plus either placebo (control group) or 800 mg boceprevir three times per day (boceprevir group) for 44 weeks. Non-nucleoside reverse-transcriptase inhibitors, zidovudine, and didanosine were not permitted. The primary efficacy endpoint was SVR (defined as undetectable plasma HCV RNA) at follow-up week 24 after end of treatment. We assessed efficacy and safety in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT00959699. FINDINGS: From Jan 15, 2010, to Dec 29, 2010, we enrolled 99 patients, 98 of whom received at least one treatment dose. 40 (63%) of 64 patients in the boceprevir group had an SVR at follow-up week 24, compared with ten (29%) of 34 control patients (difference 33·1%, 95% CI 13·7-52·5; p=0·0008). Adverse events were more common in patients who received boceprevir than in control patients: 26 (41%) versus nine (26%) had anaemia, 23 (36%) versus seven (21%) pyrexia, 22 (34%) versus six (18%) decreased appetite, 18 (28%) versus five (15%) dysgeusia, 18 (28%) versus five (15%) vomiting, and 12 (19%) versus two (6%) neutropenia. Three patients who received boceprevir plus peginterferon-ribavirin and four controls had HIV virological breakthrough. INTERPRETATION: Boceprevir in combination with peginterferon-ribavirin could be an important therapeutic option for patients with HCV and HIV. FUNDING: Merck.
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Antivirais/administração & dosagem , Infecções por HIV/complicações , Hepatite C Crônica/complicações , Hepatite C Crônica/tratamento farmacológico , Interferon-alfa/administração & dosagem , Polietilenoglicóis/administração & dosagem , Prolina/análogos & derivados , Ribavirina/administração & dosagem , Adolescente , Adulto , Idoso , Antivirais/efeitos adversos , Método Duplo-Cego , Quimioterapia Combinada/efeitos adversos , Quimioterapia Combinada/métodos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Genótipo , Infecções por HIV/virologia , HIV-1/isolamento & purificação , Hepacivirus/classificação , Hepacivirus/genética , Hepacivirus/isolamento & purificação , Humanos , Interferon alfa-2 , Interferon-alfa/efeitos adversos , Masculino , Pessoa de Meia-Idade , Placebos/administração & dosagem , Placebos/efeitos adversos , Polietilenoglicóis/efeitos adversos , Prolina/administração & dosagem , RNA Viral/sangue , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Ribavirina/efeitos adversos , Resultado do Tratamento , Carga Viral , Adulto JovemRESUMO
BACKGROUND: Vicriviroc (VCV), a small-molecule antagonist of the C-C chemokine receptor 5 (CCR5), blocks HIV's entry into CD4+ cells. Small studies have suggested that resistance to CCR5 antagonists is slow to develop. OBJECTIVES: To examine resistance to VCV in isolates from treatment experienced patients who experienced virologic failure in two phase 3 trials. STUDY DESIGN: Genotypic and phenotypic susceptibility to VCV, and other antiretroviral drugs were evaluated at baseline and at defined intervals during the study. In a post hoc analysis, viral tropism at baseline was evaluated using the Trofile-ES assay. Only subjects with R5-tropic virus were included in the analysis. Viral envelope sequencing was performed on samples from subjects with emergent VCV resistance defined using a relative MPI cutoff. RESULTS: 71/486 subjects treated with VCV for 48 weeks met the protocol-defined virologic failure criteria. 7/71 (10%) had DM/X4 virus at the time of virologic failure; VCV resistance was identified in 4/486 treated subjects (1%). No control subject had detectable DM/X4 virus or VCV resistance at virologic failure. Clonal analysis of envelope sequences from VCV-resistant virus identified 2-5 amino acid substitutions at or near the crown of the V3 loop; however, no signature V3 mutations were identified. Changes outside the V3 loop were also observed in resistant clones; no consistent variant pattern was observed. CONCLUSIONS: In these trials, use of a sensitive tropism assay and potent antiretroviral drug combinations contributed to the infrequent detection of X4-tropic virus and VCV resistance. Substitutions in the V3 loop were associated with VCV resistance, however, no specific pattern of amino acid changes were sufficient to reliably predict VCV susceptibility.
Assuntos
Fármacos Anti-HIV/administração & dosagem , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , HIV-1/fisiologia , Piperazinas/administração & dosagem , Pirimidinas/administração & dosagem , Tropismo Viral , Ensaios Clínicos Fase III como Assunto , Genótipo , HIV-1/isolamento & purificação , Humanos , Testes de Sensibilidade Microbiana , Fenótipo , RNA Viral/genética , Análise de Sequência de DNA , Falha de Tratamento , Produtos do Gene env do Vírus da Imunodeficiência Humana/genéticaRESUMO
BACKGROUND: Vicriviroc, a novel HIV CCR5 antagonist, demonstrated significant efficacy and favorable tolerability in phase II trials in treatment-experienced subjects, supporting further evaluation in phase III studies. METHODS: Two identical double-blind, placebo (PBO)-controlled trials in CCR5-tropic HIV-infected subjects with documented resistance to two antiretroviral classes were conducted. Subjects were randomized to vicriviroc 30 mg QD (N = 571) or PBO (N = 286) with open-label optimized background therapy (OBT) containing ≥2 fully active antiretroviral drugs. The primary endpoint was percentage of subjects with <50 copies/mL HIV RNA at 48 weeks. It was analyzed in a logistic regression with treatment (vicriviroc + OBT/PBO + OBT), use of enfuvirtide in baseline OBT (yes/no), and baseline HIV RNA (≤100,000/>100,000 copies/mL) as covariates. In addition, a pre-planned analysis to examine other efficacy and safety endpoints was conducted. RESULTS: Baseline characteristics of the pooled mITT population (vicriviroc, n = 486; PBO, n = 235) included mean HIV RNA of 4.6 log(10) copies/mL and mean CD4 count of 257 cells/µL. Approximately 60% of subjects received ≥3 active drugs in the OBT. The percentage of subjects with <50 copies/mL HIV RNA was not significantly different between vicriviroc and PBO at week 48 (64% vs 62%, p = 0.6). However, in subjects receiving ≤2 active drugs in their OBT, the proportion achieving <50 copies/mL HIV RNA was higher in those receiving vicriviroc compared with PBO (70% vs 55%, p = 0.02). CONCLUSIONS: The studies failed to show significant efficacy gains when vicriviroc was added to OBT. However, given the efficacy results of earlier vicriviroc trials and other CCR5 antagonist, studies are needed to define the role of this class of drugs in the treatment of HIV. Clinical trial identifier: http://www.clinicaltrial.gov/: VICTOR-E3 (NCT00523211) and VICTOR-E4 (NCT00474370).
Assuntos
Fármacos Anti-HIV/administração & dosagem , Infecções por HIV/tratamento farmacológico , HIV-1/genética , Piperazinas/administração & dosagem , Pirimidinas/administração & dosagem , Receptores CCR5/metabolismo , Receptores de HIV/metabolismo , Adulto , Método Duplo-Cego , Feminino , Infecções por HIV/virologia , HIV-1/isolamento & purificação , HIV-1/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Placebos/administração & dosagem , RNA Viral/sangue , Resultado do Tratamento , Carga Viral , Viremia/virologiaRESUMO
HIV CCR5 antagonists select for env gene mutations that enable virus entry via drug-bound coreceptor. To investigate the mechanisms responsible for viral adaptation to drug-bound coreceptor-mediated entry, we studied viral isolates from three participants who developed CCR5 antagonist resistance during treatment with vicriviroc (VCV), an investigational small-molecule CCR5 antagonist. VCV-sensitive and -resistant viruses were isolated from one HIV subtype C- and two subtype B-infected participants; VCV-resistant isolates had mutations in the V3 loop of gp120 and were cross-resistant to TAK-779, an investigational antagonist, and maraviroc (MVC). All three resistant isolates contained a 306P mutation but had variable mutations elsewhere in the V3 stem. We used a virus-cell ß-lactamase (BlaM) fusion assay to determine the entry kinetics of recombinant viruses that incorporated full-length VCV-sensitive and -resistant envelopes. VCV-resistant isolates exhibited delayed entry rates in the absence of drug, relative to pretherapy VCV-sensitive isolates. The addition of drug corrected these delays. These findings were generalizable across target cell types with a range of CD4 and CCR5 surface densities and were observed when either population-derived or clonal envelopes were used to construct recombinant viruses. V3 loop mutations alone were sufficient to restore virus entry in the presence of drug, and the accumulation of V3 mutations during VCV therapy led to progressively higher rates of viral entry. We propose that the restoration of pre-CCR5 antagonist therapy HIV entry kinetics drives the selection of V3 loop mutations and may represent a common mechanism that underlies the emergence of CCR5 antagonist resistance.
Assuntos
Fármacos Anti-HIV/uso terapêutico , Antagonistas dos Receptores CCR5 , Farmacorresistência Viral , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Internalização do Vírus/efeitos dos fármacos , Amidas/farmacologia , Fármacos Anti-HIV/farmacologia , Proteína gp120 do Envelope de HIV/genética , Infecções por HIV/virologia , HIV-1/genética , HIV-1/isolamento & purificação , HIV-1/fisiologia , Humanos , Cinética , Dados de Sequência Molecular , Mutação , Piperazinas/uso terapêutico , Pirimidinas/uso terapêutico , Compostos de Amônio Quaternário/farmacologiaRESUMO
BACKGROUND: Vicriviroc, an investigational CCR5 antagonist, demonstrated short-term safety and antiretroviral activity. METHODS: Phase 2, double-blind, randomized study of vicriviroc in treatment-experienced subjects with CCR5-using HIV-1. Vicriviroc (5, 10, or 15 mg) or placebo was added to a failing regimen with optimization of background antiretroviral medications at day 14. Subjects experiencing virologic failure and subjects completing 48 weeks were offered open-label vicriviroc. RESULTS: One hundred eighteen subjects were randomized. Virologic failure (<1 log10 decline in HIV-1 RNA > or =16 weeks postrandomization) occurred by week 48 in 24 of 28 (86%), 12 of 30 (40%), 8 of 30 (27%), 10 of 30 (33%) of subjects randomized to placebo, 5, 10, and 15 mg, respectively. Overall, 113 subjects received vicriviroc at randomization or after virologic failure, and 52 (46%) achieved HIV-1 RNA <50 copies per milliliter within 24 weeks. Through 3 years, 49% of those achieving suppression did not experience confirmed viral rebound. Dual or mixed-tropic HIV-1 was detected in 33 (29%). Vicriviroc resistance (progressive decrease in maximal percentage inhibition on phenotypic testing) was detected in 6 subjects. Nine subjects discontinued vicriviroc due to adverse events. CONCLUSIONS: Vicriviroc seems safe and demonstrates sustained virologic suppression through 3 years of follow-up. Further trials of vicriviroc will establish its clinical utility for the treatment of HIV-1 infection.
Assuntos
Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/efeitos adversos , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Piperazinas/administração & dosagem , Piperazinas/efeitos adversos , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Placebos/administração & dosagem , Resultado do Tratamento , Carga ViralRESUMO
BACKGROUND: Vicriviroc is a C-C motif chemokine receptor 5 (CCR5) antagonist that is in clinical development for the treatment of human immunodeficiency virus type 1 (HIV-1) infection. This study explored the molecular basis for the development of phenotypically resistant virus. METHOD: HIV-1 RNA from treatment-naive subjects who experienced virological failure in a phase 2 dose-finding trial was evaluated for coreceptor usage and susceptibility. For viruses that exhibited reduced susceptibility to vicriviroc, envelope clones were phenotypically and genotypically characterized. RESULTS: Twenty-six vicriviroc-treated subjects experienced virological failure; for 24 the virus remained CCR5-tropic, and 2 had dual/X4 virus. Reduced susceptibility to vicriviroc, manifested as decreases in the maximum percent inhibition value (no increase in median inhibitory concentration), was detected in 4 of the 26 subjects who experienced virological failure. Clonal analysis of envelopes in samples from these 4 subjects revealed multiple sequence changes in gp160, principally within the variable domain 1/variable domain 2, variable domain 3, and variable domain 4 loops. However, no consistent pattern of mutations was observed across subjects. CONCLUSIONS: In this study, only a small proportion of treatment failures were associated with tropism changes or reduced susceptibility to vicriviroc. Genotypic analysis of cloned env sequences revealed no specific mutational pattern associated with reduced susceptibility to vicriviroc, although numerous changes were observed in the variable domain 3 loop and in other regions of gp160.
Assuntos
Fármacos Anti-HIV/farmacologia , Farmacorresistência Viral/genética , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Piperazinas/farmacologia , Pirimidinas/farmacologia , Relação Dose-Resposta a Droga , Esquema de Medicação , Proteína gp160 do Envelope de HIV/genética , HIV-1/classificação , Humanos , Piperazinas/farmacocinética , Pirimidinas/farmacocinética , RNA Viral/genética , Carga ViralRESUMO
OBJECTIVE: This substudy of AIDS Clinical Trials Group (ACTG) Protocol 5211 explored the relationship between antiretroviral effect and plasma concentrations of vicriviroc, an investigational CCR5 antagonist for HIV infection. METHODS: Eighty-six treatment-experienced subjects failing their current antiretroviral regimens were randomized to add vicriviroc 5, 10, or 15 mg once daily or placebo for 2 weeks. Beyond week 2, subjects were changed to optimized background antiretroviral treatment while continuing vicriviroc or placebo. Plasma samples collected at weeks 2 and 8 were assayed for vicriviroc concentrations and combined with vicriviroc concentration data from 110 seronegatives enrolled in 5 phase 1 studies. An inhibitory Emax model was used to assess pharmacokinetic (PK)/pharmacodynamic relationships and recursive partitioning was applied to determine the breakpoint in vicriviroc PK parameters associated with virologic suppression. RESULTS: A 2-compartment model was fitted to the drug concentration data. At week 2, a higher vicriviroc Cmin was associated with a greater mean drop in HIV RNA (viral load) and a higher percentage of subjects experiencing a >1 log10 copies/mL drop in viral load. In subjects with Cmin > 54 ng/mL, the mean viral load decrease was 1.35 log10 copies/mL vs. 0.76 log10 with Cmin < 54 ng/mL (P = 0.003, Student t test). At this Cmin breakpoint, 70% of subjects with the higher Cmin had a >1 log drop in HIV RNA, compared with 44% with a lower Cmin (P = 0.048, Fisher exact test). Similar results were seen with an area under the curve breakpoint of 1460 ng h/mL. At weeks 16 and 24, all vicriviroc-treated subjects experienced better viral load responses than placebo recipients, but there was no apparent relationship between PK and change in viral load among these vicriviroc-treated subjects. CONCLUSIONS: There was a positive correlation between vicriviroc Cmin, area under the curve, and viral load changes at week 2 in treatment-experienced HIV-infected subjects receiving no other new active antiretroviral drugs. This correlation did not persist beyond week 16, probably because treatment response at that point also depended on having other active drugs in the regimen.
Assuntos
Fármacos Anti-HIV/farmacologia , Antagonistas dos Receptores CCR5 , Infecções por HIV/tratamento farmacológico , HIV/imunologia , Piperazinas/farmacologia , Pirimidinas/farmacologia , Adolescente , Adulto , Idoso , Fármacos Anti-HIV/sangue , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/uso terapêutico , Área Sob a Curva , Método Duplo-Cego , Feminino , Infecções por HIV/sangue , Infecções por HIV/imunologia , Infecções por HIV/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Dinâmica não Linear , Piperazinas/sangue , Piperazinas/farmacocinética , Piperazinas/uso terapêutico , Pirimidinas/sangue , Pirimidinas/farmacocinética , Pirimidinas/uso terapêutico , RNA Viral/sangue , Adulto JovemRESUMO
OBJECTIVE: The primary objectives of this study were to evaluate the safety, tolerability, and antiviral activity of pegylated interferon-alpha (PegIntron) in HIV-1 treatment-experienced patients failing their current antiretroviral regimen. DESIGN: This was a phase II, multicenter, randomized, double-blind, placebo-controlled study. METHODS: Patients were randomized to receive either weekly subcutaneous PegIntron 0.5, 1.0, 1.5, or 3 microg/kg or placebo added to their failing antiretroviral regimen for the first 4 weeks of study. Individuals who achieved more than 0.5 log10 reduction in HIV RNA at week 4 were allowed to continue study medication with optimization of their antiretroviral therapy for an additional 24 weeks. RESULTS: In the 259 patients included in the intent-to-treat analysis, changes in plasma HIV RNA from baseline to week 4 were -0.25 (P > 0.5), -0.46 (P = 0.024), -0.39 (P = 0.008), -0.53 (P < 0.001), and -0.17 (P > 0.5) log10 copies/ml in the 0.5, 1.0, 1.5, and 3.0 microg/kg and placebo arms, respectively. No significant changes were seen in CD4 T-cell parameters in any of the treatment or control arms. Adverse events (most commonly fever, flu-like symptoms, other constitutional symptoms, and psychiatric symptoms) resulted in discontinuation of study medication in 13, 17, 16, 28, and 2% of patients in the 0.5, 1.0, 1.5, 3.0 microg/kg, and placebo group, respectively. CONCLUSION: The demonstration of significant antiviral activity in a heavily pretreated patient population with acceptable toxicity and only weekly dosing makes PegIntron a potentially valuable therapy for patients with HIV infection that warrants further investigation in a broader population of patients.
Assuntos
Antivirais/uso terapêutico , Infecções por HIV/tratamento farmacológico , HIV-1 , Interferon-alfa/uso terapêutico , Polietilenoglicóis/uso terapêutico , Adulto , Análise de Variância , Contagem de Linfócito CD4 , Método Duplo-Cego , Feminino , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1/genética , Humanos , Interferon alfa-2 , Masculino , RNA Viral/sangue , Proteínas Recombinantes , Estados UnidosRESUMO
The enhanced-sensitivity Trofile assay (Monogram Biosciences) was used to retest coreceptor use at both study screening and study entry for 118 treatment-experienced subjects in AIDS Clinical Trials Group A5211 who had CCR5-tropic (R5) virus detected by the original Trofile assay at study screening. Among 90 recipients of vicriviroc, a significantly (P< .001) greater mean reduction in HIV-1 RNA was observed in 72 subjects with R5 virus versus 15 subjects reclassified as having dual/mixed-tropic viruses at screening: -1.11 versus -0.09 log(10) copies/mL at day 14 and -1.91 versus -0.57 log(10) copies/mL at week 24, respectively. Results suggest that the enhanced-sensitivity assay is a better screening tool for determining patient eligibility for CCR5 antagonist therapy.
Assuntos
Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Fármacos Anti-HIV/uso terapêutico , Antagonistas dos Receptores CCR5 , HIV-1/fisiologia , Piperazinas/uso terapêutico , Pirimidinas/uso terapêutico , Contagem de Linfócito CD4 , Método Duplo-Cego , HIV-1/efeitos dos fármacos , HIV-1/genética , HIV-1/metabolismo , Humanos , RNA Viral/metabolismo , Sensibilidade e Especificidade , Estatísticas não Paramétricas , Tropismo Viral/efeitos dos fármacos , Tropismo Viral/fisiologiaRESUMO
Detection of CXCR4-using human immunodeficiency virus by the Trofile assay was compared to that by assays using virus isolates or replication-competent recombinants. Concordance with the Trofile assay was good, but assays using replicating viruses did not increase substantially the ability to detect the presence of CXCR4-using virus.