Individual agents Special features and problems

Nevirapine (Viramune™) was the first licensed NNRTI. Nevirapine with AZT+ddI is probably the oldest HAART combination of all. It has been investigated since 1993, starting with the ACTG 193A Study, and proved superior to monotherapy and dual therapy in severely immunocompromised patients. This was true for both survival and progression - although the difference in survival was not significant (Henry 1998). The AZT+ddI+nevirapine combination has been well investigated since the INCAS and ACTG 241 Studies (Raboud 1999, D'Aquila 1996). INCAS demonstrated a suppression of the viral load to below 20 copies/ml after one year with AZT+ddI+nevirapine in 51 % of patients - compared to 12 % of those on AZT+ddI and 0 % on AZT+nevirapine. Clinical progression rates were at 12 %, compared to 25 % and 23 %, which was not a significant difference due to the small sample size (p=0.08). In pretreated patients in ACTG 241 (AZT+ddI plus nevirapine or placebo), however, no trend could be shown in favor of this combination.

Nevirapine has also been tested against protease inhibitors in randomized studies. In the Atlantic Study, combination with d4T+ddI was comparable to combination with indinavir (van Leeuwen 2003). Given with AZT+3TC in the Combine Study, there was at least a trend towards higher virological efficacy in comparison to nelfinavir (Podzamczer 2002).

Nevirapine causes elevation of liver enzymes in up to 16 % of patients, which may be severe in rare cases. Lead-in dosing is always required. A recently published study showing that lead-in dosing is not required if efavirenz was previously administered (Winston 2004) still requires confirmation. During the first eight weeks on nevirapine, biweekly monitoring of transaminases is recommended. A rash develops in 15-20 % of cases and leads to discontinuation in up to 7 % of patients (Miller 1997). In the case of an isolated rash or isolated elevation of transaminases (up to five times the upper limit of normal), treatment may usually be continued. Prophylactic administration of antihistamines or steroids does not prevent the rash (GESIDA26/02 2004, Launay 2004). However, it is recommended to stop treatment if a rash occurs together with even slight elevation of transaminases (>2-fold of norm). Patients with chronic hepatitis are at a higher risk (Sulkowski 2000); in addition, there seems to be a correlation to drug plasma levels (Gonzalez 2002). However, other studies have not been able to confirm this (Almond 2004, Dailly 2004). An increased risk has also been reported for patients with good immune status. Women with CD4 cell counts above 250/^l have a 12-fold elevated risk (11 % ver sus 0.9 %); the US FDA even issued a warning relating to this in 2004. It is important to note that hepatic toxicity may occur even after several months (Sulkowski 2002). Permanent and significant y-GT elevations are very common, which may subject patients to false suspicions of excess alcohol consumption.

Nevirapine has a good lipid profile. In studies such as Atlantic or 2NN, patients receiving nevirapine had favorable lipid changes for cholesterol and triglycerides, increasing HDL (Van der Valk 2001, Van Leth 2004). The Spanish Nefa Study demonstrated this too, as well with efavirenz, albeit to a lesser extent (Fisac 2002). Whether these positive effects will have clinical relevance over time and really help to prevent cardiovascular events remains to be seen.

The pharmacokinetics of nevirapine seem to allow once-daily dosing (Van Heeswijk 2000). Various studies such as 2NN, SCAN, VIRGO or Atlantic have already successfully used 400 mg once daily (Garcia 2000, Raffi 2000, van Leeu-wen 2003, Van Leth 2004).

Efavirenz (Sustiva™, Stocrin™) was the third NNRTI to be approved, and the first for which it could be shown that NNRTIs were at least as effective and probably even better than PIs in untreated or only slightly treatment-experienced patients. In particular, the 006 Study is now seen as a milestone in HIV therapy - it demonstrated that efavirenz was superior to indinavir in combination with AZT+3TC (Staszewski 1999). Since then, efavirenz has been compared to other drugs in many large randomized studies. Efavirenz usually did well - in the CLASS Study, efavirenz in combination with ABC+3TC was significantly more effective than d4T or boosted amprenavir (Bartlett 2002). In ACTG 5095, efavirenz in combination with AZT+3TC was better than abacavir (Gulick 2004); in ACTG 384 it was better than nelfinavir (Robbins 2003, Shafter 2003); and in AI424-034 it was at least as effective as atazanavir (Squires 2004).

Efavirenz may cause mild CNS side effects and should therefore be taken in the evening. Patients should be warned about these possible side effects, which usually include dizziness and somnolence. Nightmares also occur frequently. In addition, patients should be warned about potentially hazardous tasks such as driving or operating machinery. The side effects probably correlate with high plasma levels (Marzolini 2001). Newer studies show that efavirenz disrupts the architecture of sleep (Gallego 2004). In one study, after four weeks of treatment with efavirenz, 66 % of patients complained of dizziness, 48 % of abnormal dreams, 37 % of somnolence and 35 % of insomnia (Fumaz 2002). Although these symptoms seem to resolve during the course of further treatment, they may persist in about one fifth of patients (Lochet 2003). In such cases, efavirenz should be replaced if possible. Liver problems occur less frequently than with nevirapine, and lead-in dosing is not necessary. Once-daily dosing is safe due to the long half-life. However, lipids are by far not as favorably affected as with nevirapine. Gynecomastia is also typical for efavirenz, which is not only a psychological burden, but may be painful (Rahim 2004). In such cases, efavirenz should be replaced with nevirapine if possible. Efa-virenz is contraindicated in pregnancy.

Table 2.2. Frequencies of the most important side effects of nevirapine and efavirenz (numbers are based on various studies referenced in this chapter)

Nevirapine

Efavirenz

CNS side effects Severe CNS side effects

Rare Very rare

Hepatotoxicity Dyslipidemia Gynecomastia Rash

Frequent

Delavirdine (Rescriptor™) was the second NNRTI that was licensed by the FDA in April 1997. Due to a high pill burden and the required three times daily dosing, delavirdine is currently rarely prescribed. The need for prescription should be carefully considered. In 1999, an application for licensure in Europe was rejected due to insufficient efficacy data. Nevertheless, delavirdine is likely to be as virologically effective as the other NNRTIs (Wood 1999, Conway 2000). In the DLV 21 Study, using 369 mostly treatment-naive patients, delavirdine was investigated together with AZT+3TC and compared with AZT+3TC and AZT+delavirdine. After one year, 68 % had a viral load below 50 copies/ml in the triple combination arm compared to less than 10 % in the other two arms (Para 1999). Rashes are probably even more frequent than with the other two NNRTIs. In DLV 21, the rate was 30 %, which was also confirmed in other studies (Sagest 1998). Delavirdine increases plasma levels of various PIs, including ritonavir, nelfinavir and saquinavir (Fletcher 2000, Harris 2002). However, use of this characteristic as a boosting strategy has not yet been widely accepted.

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