Clinical trial NCT00704249: VENICE Study Nevirapine Full Dose/Dose Escalation
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Study to Compare Starting Nevirapine at the Full Dose With Dose Escalation in Patients Who Require Efavirenz to be Withdrawn Due to Adverse Reactions
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: HIV Infections
Keywords: HIV infection
nevirapine
Treatment Experienced
Lead sponsor: Clinical Trial Agency of HIV Study Group
Sponsor class: OTHER
First posted: 2008-06-24
Enrollment: 80
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL

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

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

Primary outcomes:
measure: 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.
timeFrame: 7 days
Secondary outcomes:
measure: 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.
timeFrame: 12 weeks
measure: The proportion of patients who experience adverse events (proportion of patients with exanthema and proportion of patients with liver toxicity)
timeFrame: 4 weeks
measure: Proportion of patients with resolution of the neuropsychiatric adverse reaction to efavirenz that led to it being withdrawn
timeFrame: 12 weeks
Other outcomes:
Locations:
city: Elche
country: Spain
facility: Hospital General de Elche
state: Alicante
city: Badalona
country: Spain
facility: Hospital Germanas Trias i Pujol
state: Barcelona
city: Granollers
country: Spain
facility: Hospital General de Granollers
state: Barcelona
city: Alcala de Henares
country: Spain
facility: Hospital Príncipe de Asturias
state: Madrid
city: Alicante
country: Spain
facility: Hospital General Alicante
city: Barcelona
country: Spain
facility: Hospital del Mar
city: Barcelona
country: Spain
facility: Hospital Santa Creu y Sant Pau
city: Barcelona
country: Spain
facility: Hospital Clinic
city: Barcelona
country: Spain
facility: Hospital Vall d´Hebrón
city: Cordoba
country: Spain
facility: Hospital Provincial Reina Sofía de Córdoba
city: Madrid
country: Spain
facility: Hospital de la Princesa
city: Madrid
country: Spain
facility: Hospital Gregorio Marañón
city: Madrid
country: Spain
facility: Hospital Ramón y Cajal
city: Madrid
country: Spain
facility: Hospital La Paz
city: Malaga
country: Spain
facility: Hospital Virgen de la Victoria
Study officials:
affiliation: Clinical Trial Agency of HIV Study Group
name: Esteban Ribera
role: STUDY_CHAIR
References: