Estudio primario

No clasificado

A Phase 3b, Randomized, Open-Label Study to Evaluate the Safety and Efficacy of Switching from Regimens Consisting of Abacavir/Lamivudine (ABC/3TC) plus a Third Antiretroviral Agent to the Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide (E/C/F/TAF) Fixed-Dose Combination (FDC) in Virologically-Suppressed HIV-1 Infected Adult Subjects

Año 2015
Autores Gilead Sciences, Inc.
Registro de estudios EU Clinical Trials Register
Enlaces EUCTR

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INTERVENTION:

Trade Name: Genvoya Product Code: E/C/F/TAF 150mg/150mg/200mg/10mg Pharmaceutical Form: Film‐coated tablet INN or Proposed

INN:

Elvitegravir CAS Number: 697761‐98‐1 Other descriptive name: ELVITEGRAVIR Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 150‐ INN or Proposed

INN:

COBICISTAT CAS Number: 1004316‐88‐4 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 150‐ INN or Proposed

INN:

EMTRICITABINE CAS Number: 143491‐57‐0 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 200‐ INN or Proposed

INN:

Tenofovir alafenamide CAS Number: 379270‐37‐8 Other descriptive name: TENOFOVIR ALAFENAMIDE Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 10‐

CONDITION:

Human Immunodeficiency Virus (HIV‐1) Infection ; MedDRA version: 19.0 Level: LLT Classification code 10068341 Term: HIV‐1 infection System Organ Class: 100000004862 Therapeutic area: Diseases [C] ‐ Virus Diseases [C02]

PRIMARY OUTCOME:

Main Objective: To evaluate the efficacy of switching to E/C/F/TAF FDC relative to continuing on a baseline regimen consisting of ABC/3TC plus a third antiretroviral agent in maintaining HIV‐1 RNA < 50 copies/mL at Week 24 (using FDA snapshot algorithm) in virologically suppressed, HIV‐1 infected adult subjects Primary end point(s): Proportion of subjects with HIV‐1 RNA <50 copies/mL at Week 24 as defined by the FDA snapshot algorithm Secondary Objective: ‐ To evaluate the proportion of subjects maintaining virological response (defined as HIV‐1 RNA < 50 copies/mL, FDA snapshot analysis) at Weeks 12 and 48; ‐ To evaluate changes from baseline in CD4+ cell counts at Weeks 24 and 48; ‐ To evaluate the safety and tolerability of the two treatment groups over 24 and 48 weeks Timepoint(s) of evaluation of this end point: Week 24

SECONDARY OUTCOME:

Secondary end point(s): 1) Proportion of subjects with HIV‐1 RNA <50 copies/mL at Weeks 12 and 48 as defined by the FDA snapshot algorithm ; 2) The change from baseline in CD4+ cell counts at Weeks 24 and 48 Timepoint(s) of evaluation of this end point: 1) Weeks 12 and 48 ; 2) Weeks 24 and 48

INCLUSION CRITERIA:

1) The ability to understand and sign a written informed consent form, which must be obtained prior to initiation of study procedures 2) Age = 18 years 3) Currently receiving ABC/3TC plus a third antiretroviral (ARV) agent for = 6 consecutive months prior to the screening visit. For subjects with 3 or more ART regimens, a regimen history must be provided to the Sponsor for approval. 4) Documented plasma HIV‐1 RNA levels < 50 copies/mL for = 6 months preceding the screening visit (measured at least twice using the same assay). 5) Plasma HIV‐1 RNA level < 50 copies/mL at screening visit 6) All documented historical plasma genotype(s) must not show resistance to TDF or FTC, including, but not limited to the presence of reverse transcriptase resistance mutants K65R, K70E, M184V/I, or thymidine analog‐associated mutations (TAMs) (TAMs are: M41L, D67N, K70R, L210W, T215Y/F, K219Q/E/N/R). If historical plasma genotype prior to first ART is not avai

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Estudio primario

No clasificado

A Phase IIIB, Randomized, Open-Label, Multicenter Study of the Safety and Efficacy of GW433908 700mg BID plus ritonavir 100mg BID Versus Lopinavir/ritonavir 400mg/100mg BID when Administered in Combination with the Abacavir/Lamivudine 600mg/300mg Fixed-Dose Combination Tablet QD in Antiretroviral-Nave HIV-1 Infected Adults Over 48 Weeks

Año 2006
Autores GLAXO SMITHKLINE
Registro de estudios EU Clinical Trials Register
Enlaces EUCTR

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INTERVENTION:

Product Name: ABACAVIR/LAMIVUDINE FIX DOSE COMBINATION Product Code: ABC/3TC FDC Pharmaceutical Form: Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 600‐ Product Name: FOSAMPRENAVIR Product Code: GW433908 Pharmaceutical Form: Tablet Current Sponsor code: GW433908 FOSAMPRENAVIR Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 700‐ Trade Name: KALETRA*2FL 90CPS MOLLI Pharmaceutical Form: Capsule, soft INN or Proposed

INN:

Lopinavir Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 166‐

CONDITION:

HIV Infection

PRIMARY OUTCOME:

Main Objective: Primary end point(s): Secondary Objective:

INCLUSION CRITERIA:

Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18‐64 years) yes F.1.2.1 Number of subjects for this age range F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range

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Estudio primario

No clasificado

A Phase 4, Open Label, Randomized, Controlled Study to Assess the Effect on Lipid Profile of Switching a Stable HAART Regimen of fixed dose Abacavir/Lamivudine (Kivexa) Plus Lopinavir/Ritonavir (Kaletra), to Emtricitabine/Tenofovir Disoproxil Fumarate (Truvada) Plus Lopinavir/Ritonavir (Kaletra) in Adult HIV-1 Infected Subjects With Raised Cholesterol - ROCKET II- Randomized Open Label Switch for Cholesterol Elevation on Kivexa+Kaletra Evaluation Trial

Año 2008
Autores [No se listan los autores]
Registro de estudios EU Clinical Trials Register
Enlaces EUCTR

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INTERVENTION:

Trade Name: TRUVADA Pharmaceutical Form: Film‐coated tablet INN or Proposed

INN:

emtricitabine CAS Number: 143491‐57‐0 Current Sponsor code: FTC Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 200‐ INN or Proposed

INN:

tenofovir disoproxil fumarate CAS Number: 52232‐67‐4 Current Sponsor code: TDF Other descriptive name: tenofovir DF Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 300‐ Trade Name: Kivexa Pharmaceutical Form: Film‐coated tablet INN or Proposed

INN:

abacavir CAS Number: 136470‐78‐5 Current Sponsor code: ABC Other descriptive name: abacavir sulfate Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 600‐ INN or Proposed

INN:

lamivudine CAS Number: 134678‐17‐4 Current Sponsor code: 3TC Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 300‐ Trade Name: Kaletra Pharmaceutical Form: Film‐coated tablet INN or Proposed

INN:

Lopinavir CAS Number: 192725‐17‐0 Current Sponsor code: LPV Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 200‐ INN or Proposed

INN:

Ritonavir CAS Number: 155213‐67‐5 Current Sponsor code: RTV Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 50‐

CONDITION:

Adult HIV‐1 infected subjects on a stable HAART regimen of Kivexa + Kaletra, with raised cholesterol ; MedDRA version: 9.1 Level: LLT Classification code 10020192 Term: HIV‐1

PRIMARY OUTCOME:

Main Objective: To determine if switching the NRTI backbone from a Kivexa to Truvada leads to a reduction in fasting total cholesterol at 12 weeks. Primary end point(s): The primary efficacy endpoint is change from baseline in total cholesterol at Week 12. Secondary Objective: • Evaluation of fasting metabolic parameters (e.g., LDL, HDL, non‐HDL cholesterol, triglycerides, and cholesterol ratios).; • Evaluation of efficacy and safety by assessing adverse events, clinical laboratory tests, physical examinations and vital signs at every visit.; • Evaluation of changes in the 10‐year risk factor for coronary heart disease outcomes as measured by total cholesterol, HDL, blood pressure, smoking status, treatment for hypertension, sex and age.

INCLUSION CRITERIA:

Subjects must meet all of the following inclusion criteria to be eligible for participation in this study: • = 18 years old • Plasma HIV 1 RNA < 50 copies/mL at Screening and = 12 weeks prior to Screening • Stable HAART regimen of Kivexa + Kaletra for = 24 weeks prior to Screening • Documented confirmed raised total cholesterol = 5.2 mmol/L (= 200 mg/dL) for the last two consecutive tests (at least 4 weeks apart) with the last result = 4 weeks prior to Screening • Fasted total cholesterol = 5.2 mmol/L (= 200 mg/dL) at Screening • Subject willing to continue current unmodified HAART for 12 weeks if randomized to Group 2 • Subjects requiring concomitant lipid regulating therapy must be established on a stable dose/frequency = 12 weeks prior to Screening and be expected to remain stable in dose and frequency throughout the treatment phase of the study • Adequate renal function by calculated creatinine clearance = 60 mL/min according to the C

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Revisión sistemática

No clasificado

Meta-analysis of randomized controlled trials of simplified versus continued protease inhibitor-based antiretroviral therapy in HIV-1-infected patients.

Año 2003
Revista AIDS (London, England)
Enlaces Pubmed , DOI

Este artículo está incluido en 1 Resumen estructurado de revisiones sistemáticas 5 Resúmenes estructurados de revisiones sistemáticas (1 referencia)

Este artículo incluye 5 Estudios primarios 5 Estudios primarios (5 referencias)

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OBJECTIVE:

To evaluate the efficacy and safety of simplified maintenance therapy (SMT) compared with continued protease inhibitor (PI) therapy.

DESIGN:

Meta-analysis of nine randomized controlled trials in which 833 patients were switched to SMT (abacavir, efavirenz or nevirapine) and 616 continued PI, assessing virologic failure (primary outcome), discontinuation of therapy for reasons other than virologic failure, CD4 cell count, total plasma cholesterol and triglycerides.

RESULTS:

The risk ratio for virologic failure for SMT compared to continued PI was 1.06 [95% confidence interval (CI) 0.58-1.92; test for homogeneity P = 0.01] for SMT, 2.56, (95% CI, 1.17-5.64) for abacavir, 0.83 (95% CI, 0.36-1.91) for efavirenz and 0.54 (95% CI, 0.29-1.02) for nevirapine. The risk ratio for premature discontinuation of therapy with SMT was 0.61 (95% CI, 0.48-0.77; test for homogeneity P < 0.10). The difference in absolute mean cholesterol for SMT compared to continued PI was -0.15 mmol/l, (95% CI, -0.40 to 0.09; test for homogeneity P < 0.01) for SMT, -0.51 mmol/l (95% CI, -0.70 to -0.33) for abacavir, 0.22 mmol/l (95% CI, 0 to 0.43) for efavirenz and -0.19 mmol/l (95% CI, -0.48 to 0.09) for nevirapine.

CONCLUSIONS:

Current evidence suggests that SMT with abacavir rather than continued PI increases the risk of virologic failure, this increased risk may be confined to patients with prior mono or dual therapy with reverse transcriptase inhibitors. There is not enough evidence on whether SMT with efavirenz and nevirapine influences the risk of virologic failure. SMT with any of the three drugs reduces the risk of discontinuation of therapy, and SMT with abacavir reduces plasma cholesterol.

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Estudio primario

No clasificado

Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients enrolled in the D:A:D study: a multi-cohort collaboration.

Año 2008
Revista Lancet
Enlaces Pubmed , DOI , PMC

Este artículo está incluido en 1 Revisión sistemática Revisiones sistemáticas (1 referencia) 1 Síntesis amplia Síntesis amplias (1 referencia)

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BACKGROUND:

Whether nucleoside reverse transcriptase inhibitors increase the risk of myocardial infarction in HIV-infected individuals is unclear. Our aim was to explore whether exposure to such drugs was associated with an excess risk of myocardial infarction in a large, prospective observational cohort of HIV-infected patients.

METHODS:

We used Poisson regression models to quantify the relation between cumulative, recent (currently or within the preceding 6 months), and past use of zidovudine, didanosine, stavudine, lamivudine, and abacavir and development of myocardial infarction in 33 347 patients enrolled in the D:A:D study. We adjusted for cardiovascular risk factors that are unlikely to be affected by antiretroviral therapy, cohort, calendar year, and use of other antiretrovirals.

FINDINGS:

Over 157,912 person-years, 517 patients had a myocardial infarction. We found no associations between the rate of myocardial infarction and cumulative or recent use of zidovudine, stavudine, or lamivudine. By contrast, recent-but not cumulative-use of abacavir or didanosine was associated with an increased rate of myocardial infarction (compared with those with no recent use of the drugs, relative rate 1.90, 95% CI 1.47-2.45 [p=0.0001] with abacavir and 1.49, 1.14-1.95 [p=0.003] with didanosine); rates were not significantly increased in those who stopped these drugs more than 6 months previously compared with those who had never received these drugs. After adjustment for predicted 10-year risk of coronary heart disease, recent use of both didanosine and abacavir remained associated with increased rates of myocardial infarction (1.49, 1.14-1.95 [p=0.004] with didanosine; 1.89, 1.47-2.45 [p=0.0001] with abacavir).

INTERPRETATION:

There exists an increased risk of myocardial infarction in patients exposed to abacavir and didanosine within the preceding 6 months. The excess risk does not seem to be explained by underlying established cardiovascular risk factors and was not present beyond 6 months after drug cessation.

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Estudio primario

No clasificado

Three-year follow-up of protease inhibitor-based regimen simplification in HIV-infected patients.

Año 2007
Revista AIDS (London, England)
Enlaces Pubmed , DOI

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Patients with sustained virological suppression on protease inhibitor (PI)-based therapy were randomly assigned to switch the PI to nevirapine (n = 155), efavirenz (n = 156), or abacavir (n = 149) and were followed for at least 3 years regardless of the discontinuation of assigned therapy. There was a higher probability of maintaining virological suppression after 3 years of follow-up with nevirapine or efavirenz than with abacavir. In contrast, abacavir showed a lower incidence of adverse effects leading to drug discontinuation.

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Revisión sistemática

No clasificado

Risk of cardiovascular disease from antiretroviral therapy for HIV: a systematic review.

Año 2013
Revista PloS one
Enlaces Pubmed , DOI , PMC

Este artículo incluye 27 Estudios primarios 27 Estudios primarios (27 referencias)

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BACKGROUND:

Recent studies suggest certain antiretroviral therapy (ART) drugs are associated with increases in cardiovascular disease.

PURPOSE:

We performed a systematic review and meta-analysis to summarize the available evidence, with the goal of elucidating whether specific ART drugs are associated with an increased risk of myocardial infarction (MI).

DATA SOURCES:

We searched Medline, Web of Science, the Cochrane Library, and abstract archives from the Conference on Retroviruses and Opportunistic Infections and International AIDS Society up to June 2011 to identify published articles and abstracts.

STUDY SELECTION:

Eligible studies were comparative and included MI, strokes, or other cardiovascular events as outcomes.

DATA EXTRACTION:

Eligibility screening, data extraction, and quality assessment were performed independently by two investigators.

DATA SYNTHESIS:

Random effects methods and Fisher's combined probability test were used to summarize evidence.

FINDINGS:

Twenty-seven studies met inclusion criteria, with 8 contributing to a formal meta-analysis. Findings based on two observational studies indicated an increase in risk of MI for patients recently exposed (usually defined as within last 6 months) to abacavir (RR 1.92, 95% CI 1.51-2.42) and protease inhibitors (PI) (RR 2.13, 95% CI 1.06-4.28). Our analysis also suggested an increased risk associated with each additional year of exposure to indinavir (RR 1.11, 95% CI 1.05-1.17) and lopinavir (RR 1.22, 95% CI 1.01-1.47). Our findings of increased cardiovascular risk from abacavir and PIs were in contrast to four published meta-analyses based on secondary analyses of randomized controlled trials, which found no increased risk from cardiovascular disease.

CONCLUSION:

Although observational studies implicated specific drugs, the evidence is mixed. Further, meta-analyses of randomized trials did not find increased risk from abacavir and PIs. Our findings that implicate specific ARTs in the observational setting provide sufficient evidence to warrant further investigation of this relationship in studies designed for that purpose.

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Estudio primario

No clasificado

Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients

Año 2008
Revista AIDS (London, England)
Enlaces Pubmed , DOI , PMC

Este artículo está incluido en 1 Revisión sistemática Revisiones sistemáticas (1 referencia) 1 Síntesis amplia Síntesis amplias (1 referencia)

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BACKGROUND:

Two nucleos(t)ide reverse transcriptase inhibitors (NRTIs) - abacavir and didanosine - may each be associated with excess risk of myocardial infarction. The reproducibility of this finding in an independent dataset was explored and plausible biological mechanisms were sought.

METHODS:

Biomarkers, ischemic changes on the electrocardiogram, and rates of various predefined types of cardiovascular disease (CVD) events according to NRTIs used were explored in the Strategies for Management of Anti-Retroviral Therapy (SMART) study. Patients receiving abacavir and not didanosine were compared with those receiving didanosine, and to those receiving NRTIs other than abacavir or didanosine (other NRTIs). Patients randomly assigned to the continuous antiretroviral therapy arm of SMART were included in all analyses (N ≤ 2752); for the study of biomarkers, patients from the antiretroviral therapy interruption arm were also included.

RESULTS:

Current use of abacavir was associated with an excess risk of CVD compared with other NRTIs. Adjusted hazard ratios for clinical myocardial infarction (n ≤ 19), major CVD (myocardial infarction, stroke, surgery for coronary artery disease, and CVD death; n ≤ 70), expanded CVD (major CVD plus congestive heart failure, peripheral vascular disease, coronary artery disease requiring drug treatment, and unwitnessed deaths; n ≤ 112) were 4.3 [95% confidence interval (CI): 1.4-13.0], 1.8 (1.0-3.1), and 1.9 (1.3-2.9). At baseline in a subset of patients with biomarker data, high sensitivity-C-reactive protein and interleukin-6 were 27% (P ≤ 0.02) and 16% (P ≤ 0.02) higher for patients receiving abacavir (N ≤ 175) compared with those receiving other NRTIs (N ≤ 500). Didanosine was associated neither with altered risk of CVD nor with altered levels of biomarkers.

CONCLUSION:

Abacavir was associated with an increased risk of CVD. The drug may cause vascular inflammation, which may precipitate a CVD event. © 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins.

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Estudio primario

No clasificado

Outcome of 2 simplification strategies for the treatment of human immunodeficiency virus type 1 infection.

Año 2003
Revista Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
Enlaces Pubmed , DOI

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In a prospective, open-label, 104-week study, patients who were infected with human immunodeficiency virus type 1 (virus load, <50 copies/mL) and who were receiving protease inhibitor-based therapy were randomly assigned to continue treatment with a protease inhibitor or to replace it with abacavir or efavirenz. Treatment failure, defined as virological failure (virus load, >500 copies/microL) or any clinical or biochemical adverse event with a grade of >or=3 (on the basis of the World Health Organization [WHO] or American Heart Association [AHA] scales), was the primary outcome measurement. Failure rates were more frequent in the group treated with protease inhibitors (P<.01), and there were no significant differences in the rate of treatment failure between the group treated with efavirenz and the group treated with abacavir. Tolerability was better in the groups treated with abacavir or with efavirenz versus those treated with protease inhibitors. Fewer patients who received efavirenz experienced viral rebound. Among all groups, the mean increase in the CD4 cell count was 131 cells/microL (P<.001), with no significant difference between groups. This switching strategy maintains optimal levels of virological suppression and may improve lipid profiles in most patients.

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Estudio primario

No clasificado

Effects of combination antiretroviral therapies on the risk of myocardial infarction among HIV patients.

Año 2014
Revista Epidemiology (Cambridge, Mass.)
Enlaces Pubmed , DOI , PMC

Este artículo está incluido en 1 Revisión sistemática Revisiones sistemáticas (1 referencia)

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BACKGROUND:

Cohort studies have demonstrated greater risk of myocardial infarction (MI) associated with specific antiretroviral use, while meta-analyses of randomized controlled trials (RCTs) have not. These differences may be due to inherent biases in the observational study design or to the limited duration of randomized trials. We conducted a new-user, active-comparator cohort study emulating an RCT comparing the initiation of several antiretrovirals as part of combination antiretroviral therapy (cART) and MI.

METHODS:

We included North Carolina (NC) Medicaid beneficiaries infected with human immunodeficiency virus between 2002 and 2008 who were previously untreated with cART. We compared hazard ratios (HRs) and 95% confidence intervals (CIs) of MI between abacavir and tenofovir recipients, and lopinavir-ritonavir or atazanavir recipients and nonnucleoside reverse transcriptase inhibitor (NNRTI) recipients. We adjusted for confounding through inverse probability weighting methods.

RESULTS:

There were 3481 NC Medicaid new cART recipients who contributed 6399 person-years and experienced 38 MI events. Receiving abacavir compared with tenofovir as part of cART was associated with an increased rate of MI (unadjusted HR = 2.70 [95% CI = 1.24-5.91]; adjusted HR = 2.05 [0.72-5.86]). Point estimates also suggest a relationship between receipt of atazanavir or lopinavir-ritonavir compared with an NNRTI and MI, although estimates were imprecise.

CONCLUSIONS:

We found an increased rate of MI among patients initiating abacavir compared with tenofovir, although the association was decreased after confounding adjustment. Without a very large prospective comparative clinical trial, a much larger observational study of patients initiating cART would be needed to better define this apparent association.

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