VENICE Study Nevirapine Full Dose/Dose Escalation

HIV Infections Clinical Trial

— VENICE  

Official title:

Randomized Multicenter Study to Compare Starting Nevirapine at the Full Dose With Dose Escalation in Patients Who Require Efavirenz to be Withdrawn Due to Adverse Reactions

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00704249
• Other study ID #: GESIDA-4905
• Status: Completed
• Phase: Phase 4
• First received: June 22, 2008
• Last updated: February 10, 2009
• Start date: July 2006
• Est. completion date: February 2009

Study information

• Verified date: February 2009
• Source: Clinical Trial Agency of HIV Study Group
• Contact: n/a
• Is FDA regulated: No
• Health authority: Spain: Spanish Agency of Medicines
• Study type: Interventional

Clinical Trial 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.

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 80
• Est. completion date: February 2009
• Est. primary completion date: July 2008
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label

Related Conditions & MeSH terms

• HIV Infections

Intervention

Drug:
• nevirapine
Full-dose nevirapine from baseline (200 mg bid).
• nevirapine
Nevirapine with an increase in the initial dose (200 mg once daily for 14 days and 200 mg bid thereafter)

Locations

Country	Name	City	State
Spain	Hospital Príncipe de Asturias	Alcala de Henares	Madrid
Spain	Hospital General Alicante	Alicante
Spain	Hospital Germanas Trias i Pujol	Badalona	Barcelona
Spain	Hospital Clinic	Barcelona
Spain	Hospital del Mar	Barcelona
Spain	Hospital Santa Creu y Sant Pau	Barcelona
Spain	Hospital Vall d´Hebrón	Barcelona
Spain	Hospital Provincial Reina Sofía de Córdoba	Cordoba
Spain	Hospital General de Elche	Elche	Alicante
Spain	Hospital General de Granollers	Granollers	Barcelona
Spain	Hospital de la Princesa	Madrid
Spain	Hospital Gregorio Marañón	Madrid
Spain	Hospital La Paz	Madrid
Spain	Hospital Ramón y Cajal	Madrid
Spain	Hospital Virgen de la Victoria	Malaga

Sponsors (1)

Lead Sponsor	Collaborator
Clinical Trial Agency of HIV Study Group

Country where clinical trial is conducted

Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	The proportion of patients with a trough concentration of nevirapine in plasma within the therapeutic range (3000 to 8000 ng/mL) after 7 days of treatment.		7 days	No
Secondary	The proportion of patients with a plasma viral load of less than 50 copies/mL will be obtained. The change in CD4+ T-cell count will also be measured from baseline to weeks 4 and 12.		12 weeks	No
Secondary	The proportion of patients who experience adverse events (proportion of patients with exanthema and proportion of patients with liver toxicity)		4 weeks	Yes
Secondary	Proportion of patients with resolution of the neuropsychiatric adverse reaction to efavirenz that led to it being withdrawn		12 weeks	Yes