VENICE Study Nevirapine Full Dose/Dose Escalation

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