VENICE Study Nevirapine Full Dose/Dose Escalation

NCT ID: NCT00704249

Last Updated: 2009-02-11

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 80 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2006-07-31
• Study Completion Date: 2009-02-28

Brief Summary

This study aims to compare the trough plasma concentrations of nevirapine after 7 days of treatment at the full dose from baseline with dose escalation in patients taking efavirenz who switch to nevirapine due to neuropsychiatric adverse reactions.

Detailed Description

The prognosis for HIV infection changed radically after 1996 thanks to the arrival of protease inhibitors (PI), which, when combined with 2 nucleoside analogue reverse transcriptase inhibitors (NRTI) formed the so-called highly active antiretroviral therapy (HAART). HAART led to a considerable decrease in the incidence and mortality of opportunistic infections and made HIV infection a chronic condition and not necessarily the progressive, irreversible, and fatal disease it was before 1996. The initial euphoria led people to believe that HAART could cure the disease, but it was soon clear that eradication of the virus was impossible and that treatment would have to be continued indefinitely. Chronic treatment became more difficult because of the frequent onset of adverse events or extremely complex regimens with a high pill burden that had to be administered several times per day, often with dietary restrictions.1,2 In this context, adherence was difficult, efficacy was far from optimal, and the patient's quality of life was noticeably reduced. The subsequent appearance of non-nucleoside analogue reverse transcriptase inhibitors (NNRTI)-nevirapine and efavirenz-considerably improved some of the disadvantages of PIs. Today, the combination of 2 NRTIs and an NNRTI is considered the regimen of choice when starting antiretroviral therapy. Efavirenz is considered the gold standard for initial antiretroviral therapy and is widely used in clinical practice.

More than half of the patients who start treatment with efavirenz present adverse effects, although these are generally well tolerated and decrease with time. Approximately 3%-8% of patients have to suspend efavirenz due to adverse effects, which are mainly neuropsychiatric. In these cases, efavirenz is usually replaced by nevirapine.

Nevirapine is a substrate and potent inducer of the hepatic cytochrome P450 enzyme system (CYP3A4 and others) and continuous administration leads to progressive autoinduction of its own metabolism. The recommended dose is 200 mg every 12 hours. If this dose is administered from the start of treatment, the plasma concentrations reached during the first few days are much higher than those reached later. Therefore, and because the toxicity of nevirapine is associated with its plasma concentrations, the recommended initial dose is 200 mg/d for the first 14 days followed by 200 mg every 12 hours indefinitely. There are no specific recommendations on dosage when nevirapine replaces efavirenz; therefore, it is administered at increasing doses according to the summary of product characteristics.

Efavirenz is also a potent inducer of CYP3A4 and increases the metabolism of other drugs that use this metabolic pathway. Enzyme induction is by increased synthesis of the enzymes involved, with the result that, when the inducer is suspended, the enzyme induction effect persists for a few days until the excess enzymes are catabolized. Furthermore, the half-life of efavirenz is very long. Consequently, the plasma concentrations fall progressively for more than a week after the drug is withdrawn. Therefore, when efavirenz is replaced by nevirapine, the residual enzyme induction that persists might lead to a fall in the plasma concentrations of nevirapine. Given that NNRTIs have a low genetic barrier for the development of resistance, the fall in plasma concentrations of nevirapine for the 14 days during which it is administered at 200 mg/d can generate resistance mutations and virologic failure.

When efavirenz is switched for nevirapine, it is unknown whether nevirapine should be started at increasing standard doses (200 mg/d for the first 14 days plus 200 mg bid thereafter) or at the full dose (200 mg every 12 hours) as a consequence of the enzyme induction caused by efavirenz.

Currently available data do not enable us to make a recommendation on the dose with which treatment with nevirapine can be started in patients who required efavirenz to be withdrawn and for whom nevirapine was chosen as an alternative. Nevertheless, despite small sample sizes, preliminary studies suggest that this strategy could be effective and safe. Therefore, randomized clinical trials that enable us to evaluate this strategy appropriately are necessary

Conditions

HIV Infections

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Blinding Strategy: NONE

Study Groups

1

Full-dose nevirapine from baseline (200 mg bid).

Group Type: EXPERIMENTAL

nevirapine

Intervention Type: DRUG

Full-dose nevirapine from baseline (200 mg bid).

2

Nevirapine with an increase in the initial dose (200 mg once daily for 14 days and 200 mg bid thereafter)

Group Type: ACTIVE_COMPARATOR

nevirapine

Intervention Type: DRUG

Nevirapine with an increase in the initial dose (200 mg once daily for 14 days and 200 mg bid thereafter)

Interventions

nevirapine

Full-dose nevirapine from baseline (200 mg bid).

Intervention Type: DRUG

nevirapine

Nevirapine with an increase in the initial dose (200 mg once daily for 14 days and 200 mg bid thereafter)

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Age ³ 18 years
• Chronic HIV-1 infection confirmed by Western blotting
• Patients treated with a HAART regimen containing efavirenz for a minimum of 15 days before the baseline visit
• Patients who present a neuropsychiatric adverse reaction to efavirenz (see list in Appendix D) and require it to be withdrawn.
• Ability of the patient to follow treatment during the period established
• Acceptance and signing of the informed consent document

Exclusion Criteria

• Liver function test (AST, ALT, GGT) results > 3 times the upper limit of normal.
• Elevated creatinine levels (>1.5 mg/dL)
• CD4+ T-cell count > 400 cells/µL in men or > 250 cells/µL in women, unless the benefit outweighs the risk (warning in the summary of product characteristics) and always at the investigator's discretion
• HIV plasma viral load > 50 copies/mL in those patients who have been taking efavirenz for more than 3 months
• Suspected or confirmed resistance to efavirenz and/or nevirapine
• Patients who are currently taking a drug that might interfere in the absorption, distribution, or metabolism of nevirapine
• Presence of opportunistic infections and/or neoplasm during the 3 months before the start of participation in the trial
• Any medical condition(s) that, in the investigator's opinion, might interfere with the patient's ability to participate or fulfill the requirements of the present protocol
• Pregnancy
• Suspected primary infection of less than 6 months' duration

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Clinical Trial Agency of HIV Study Group

OTHER

Sponsor Role: lead

Responsible Party

Clinical Trial Agency of HIV Study Group

Principal Investigators

Esteban Ribera

Role: STUDY_CHAIR

Clinical Trial Agency of HIV Study Group

Locations

Hospital General Alicante

Alicante, Alicante, Spain

Hospital General de Elche

Elche, Alicante, Spain

Hospital Germanas Trias i Pujol

Badalona, Barcelona, Spain

Hospital del Mar

Barcelona, Barcelona, Spain

Hospital Santa Creu y Sant Pau

Barcelona, Barcelona, Spain

Hospital Clinic

Barcelona, Barcelona, Spain

Hospital Vall d´Hebrón

Barcelona, Barcelona, Spain

Hospital General de Granollers

Granollers, Barcelona, Spain

Hospital Provincial Reina Sofía de Córdoba

Córdoba, Cordoba, Spain

Hospital Príncipe de Asturias

Alcalá de Henares, Madrid, Spain

Hospital de la Princesa

Madrid, Madrid, Spain

Hospital Gregorio Marañón

Madrid, Madrid, Spain

Hospital Ramón y Cajal

Madrid, Madrid, Spain

Hospital La Paz

Madrid, Madrid, Spain

Hospital Virgen de la Victoria

Málaga, Malaga, Spain

Countries

Spain

Other Identifiers

GESIDA-4905

Identifier Type: -

Identifier Source: org_study_id