Mechanism of action and efficacy

As with the nucleoside analogs, the target enzyme of NNRTIs is reverse transcrip-tase. NNRTIs were first described in 1990. In contrast to the NRTIs, they are not "false" building blocks, but rather bind directly and non-competitively to the enzyme, at a position in close proximity to the substrate binding site for nucleosides. The resulting complex blocks the catalyst-activated binding site of the reverse tran-scriptase, which can thus bind fewer nucleosides, slowing polymerization down significantly. In contrast to NRTIs, NNRTIs do not require activation within the cell.

The three currently available NNRTIs - nevirapine, delavirdine and efavirenz -were introduced between 1996 and 1998. Although studies such as the INCAS Trial or Protocol 0021II had already clearly demonstrated the superiority of triple therapy with nevirapine or delavirdine compared to double nuke therapy (Gallant 1998, Raboud 1999, Conway 2000), the "rise" of the NNRTIs was rather hesitant, and did not receive the media attention given to the PIs.

This was due to the early observation that functional monotherapy with NNRTIs, i.e. the mere addition of an NNRTI to a failing regimen, showed practically no effect (Mayers 1998, D'Aquila 1996). There were also initial difficulties in dealing with the problematic resistance profile of NNRTIs. The risk of cross-resistance is very high, and it can develop very rapidly; one point mutation at position 103 (K103N) of the hydrophobic binding site is enough to eliminate the entire drug class! Resistance has now even been described in mothers taking a single dose of nevirapine at birth for maternal transmission prophylaxis (Eshleman 2002). This phenomenon is not rare. In two large studies, the frequency of NNRTI mutations following perinatal nevirapine prophylaxis was between 14 and 32 % (Cunningham 2002, Jourdain 2004). Real time PCR has recently been shown to detect mutations in 89 % of samples.

It is therefore important to always remember that NNRTI-containing regimens are very vulnerable - waiting too long to switch with insufficient suppression of viral load is almost certain to lead to complete resistance to this class of drugs. Subsequent withdrawal of the NNRTI does not induce any immunological or virological changes (Picketty 2004). This is because NNRTI mutations do not reduce the repli-cative capacity of HIV to the extent seen with PI or NRTI mutations. Both randomized and large cohort studies have now demonstrated that NNRTIs are extremely effective in combination with nucleoside analogs. The immunological and virological potency of NNRTIs in treatment-naive patients is at least equivalent, if not superior, to that of PIs (Staszewski 1999, Friedl 2001, Torre 2001, Podzamczer 2002, Robbins 2003, Squires 2003). In contrast to PIs, however, the clinical effect has not yet been proven, as the studies that led to the licensing of NNRTIs all used surrogate markers. The efficacy of NNRTIs in treatment-experienced patients is probably weaker in comparison to PIs (Yazdanpanah 2004).

Nevertheless, the simple dosing and the overall good tolerability have enabled nevirapine and efavirenz to become important components of HAART regimens, which are often even ranked above those containing PIs. Many randomized studies have been able to demonstrate over the last years that it is possible to switch from a PI to a NNRTI if good virological suppression has already been achieved. Virological control was sometimes even better on NNRTIs than on the continued PI regimen; see also the chapter "When to change".

While delavirdine has lost relevance for several reasons (see below), nevirapine and efavirenz can be considered equivalent. So far, no study has provided definitive evidence that one NNRTI is more potent than another. Cohort studies from the last few years suggest a slight superiority of efavirenz (Phillips 2001, Cozzi-Lepri 2002); however these studies have only limited value as they included very heterogeneous patient groups. Overall, differences are likely to be small, particularly in treatment-naive patients. A randomized pilot study from Spain (SENC Study) at least showed no significant differences between nevirapine and efavirenz in this group of patients (Nunez 2002).

In the 2NN Study ("The Double Non-Nucleoside Study"), both NNRTIs were compared for the first time in a large-scale randomized study (Van Leth 2004). A total of 1216 patients received a nuke backbone of d4T+3TC with either nevirapine 1 x 400 mg, nevirapine 2 x 200 mg, efavirenz 1 x 600 mg or efavirenz 1 x 800 mg plus nevirapine 1 x 400 mg. The proportion of patients with a viral load below 50 copies/ml after 48 weeks was 56 %, 56 %, 62 % and 47 %, respectively. The only significant virological difference was an advantage of the efavirenz arm over the double NNRTI arm, mainly due to higher toxicity in the latter. In the nevirapine arm with 1 x 400 mg, severe hepatic side effects occurred more frequently than in the efavirenz arm; on the other hand, lipids were more favorably influenced in the nevirapine group. The 2NN Study and numerous other switch studies (Fisac 2002, Martinez 2003) demonstrate that the choice of treatment regimen should be based mainly on the different side effect profiles of nevirapine and efavirenz (see below). Nevirapine and efavirenz are both metabolized by cytochrome P450 enzymes (Miller 1997). Nevirapine is an inductor, whereas efavirenz is both an inductor and an inhibitor of the cytochrome P450 isoenzyme. The combination of efavirenz with saquinavir or lopinavir leads to strong interactions that require dose adjustments of the PI.

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