Since the first presentation and subsequent publication of study DPC-006 in 1998-1999, NNRTIs have gained in favor as initial antiretroviral therapy.[1] That large, controlled (although unblinded) study showed that the combination of 2 nucleoside analogues with efavirenz produced virologic suppression as frequently as PI-based combinations when used as first-line therapy. At first, though, the fact that a single mutation conferred high-grade phenotypic resistance to agents in this class raised concern about the durability of efficacy of NNRTI-based therapy. At the 8^th Conference on Retroviruses and Opportunistic Infections (8^th CROI), however, Levy et al presented 96-week data showing that NNRTI resistance can be avoided as long as the drug is used as part of a highly effective initial regimen.[2] In this regard, 80% of 422 patients taking AZT, 3TC and efavirenz for 2 years were found to have maintained HIV RNA levels <50 copies/mL (abstract 325).[2] However, there is clearly a need to develop additional agents for use in patients who have developed resistance to currently available agents, which is usually associated with the K103N mutation.

One such agent may be TMC120, a novel dianilinopyrimidine (DAPY) derivative. At the 8^th CROI, TMC120 was shown by De Bethune et al to have equivalent in vitro activity against wild-type HIV-1 isolates and isolates carrying the K103N, Y181C or G190A/S mutations (see table below).[3] However, activity against L100I and Y188L mutants was reduced as much as 50-fold.

An initial clinical trial of TMC120 in drug-naive individuals has now been completed.[4] Forty-three patients were randomized to receive TMC120 50 mg bid, TMC120 100 mg bid (both as monotherapy) or placebo for 7 days. On day 8, patients who received TMC120 50 or 100 mg bid were found to have mean reductions in plasma HIV RNA of 1.44 log₁₀ copies/mL and 1.51 log₁₀ copies/mL, respectively. While these results are very encouraging, it will be most interesting to see the performance of this drug in patients with isolates carrying the K103N mutation, to see if it represents a significant advance in this field, rather than another "me too" drug.

Another new NNRTI is capravirine (AG1549; abstract 323), which appears to have some in vitro activity against strains with the K103N mutation.[5] It has now been evaluated within the context of a phase II study of 75 PI-naive patients with virologic failure on an NNRTI-containing regimen. Study subjects received nelfinavir and 2 nucleoside analogues with either 1400 or 2100 mg capravirine bid. Over 12 weeks, virologic suppression was achieved in 50% patients, with the higher dose appearing to be more toxic. Although further studies evaluating 1400 mg bid are planned, they may be delayed in light of recent reports of vasculitis associated with the use of capravirine in beagle dogs. However, vasculitis has not been reported in >600 patients who have received capravirine in clinical trials to date (see related article by Robert Shafer).

The current agents in this class are proving to be highly effective. Delavirdine, due to its relatively high pill burden, has not been used extensively as part of first-line therapy. However, its beneficial pharmacokinetic interactions with protease inhibitors may make it an ideal agent for use within second- or third-line triple-class regimens. Careful pharmacokinetic studies have now demonstrated that the combination of delavirdine 600 mg and saquinavir-sgc 1400 mg bid produces high plasma levels of both agents (abstract 331).[6] When used along with one or two NRTIs, this combination is quite potent, as was shown in drug-naive individuals, as well as in previously treated patients (ACTG 359, abstract 338; see related article).[7]

Efavirenz has now been evaluated within a number of once-daily regimens, and it appears to retain its efficacy in this setting. A group of 75 drug-naive individuals were given ddI/3TC/efavirenz therapy (abstract 320).[8] Over 48 weeks, 80% patients remained on this treatment, with the vast majority (>95%) achieving maximal virologic suppression (78.3% by ITT analysis). There were 4 cases of virologic failure with resistance, all carrying the M184V mutation, one also showing K103N. Another pilot study was done using once-daily emtricitabine (FTC)/ddI/EFV (abstract 321).[9] At week 64, 36 of 40 (90%) drug-naive individuals exhibited virologic suppression below 400 copies/mL. These data are encouraging, and support the growing trend towards the use of more convenient once daily regimens.

Nevirapine’s hepatotoxicity has been seriously questioned in light of two reported deaths associated with liver failure in a controlled trial conducted in Africa (abstract 19).[10] In this study, patients were assigned to receive d4T and an NNRTI along with either 3TC or FTC. Patients with plasma viral loads above 100,000 copies/mL received efavirenz as their NNRTI (n= 83), while others received nevirapine (n=385). Both deaths occurred in the nevirapine group. Overall, grade 3-4 liver function abnormalities were seen in 9.4% patients receiving nevirapine as part of this study, as compared to 18/213 (8.5%) patients in three other controlled studies presented at the meeting (abstracts 326, 327, 673).[11-13] Further, a retrospective review of 298 patients receiving NNRTIs (202 on nevirapine and 96 on efavirenz) showed the incidence of hepatotoxicity of both drugs to be 1.2-1.3 cases/100 person-months. It may be that there is no fundamental difference between these two agents in this regard. This would be particularly encouraging, given that nevirapine is a highly effective drug, as shown in the COMBINE study.[12] In this trial, fully 66.7% (ITT analysis) of 72 drug-naive patients receiving Combivir/nevirapine exhibited maximal virologic suppression (HIV RNA <20 copies/mL) over 9 months, as compared to 38.6% patients on Combivir/nelfinavir.

Some researchers have advocated the sequencing of currently available NNRTIs as part of a strategy for salvage therapy. In this light, a study was conducted in 104 patients with virologic failure to an NNRTI (efavirenz in 39, nevirapine in 46, NVP followed by EFV in 19; abstract 449).[14] All patients failing efavirenz harbored a mutation conferring resistance to nevirapine (K103N, Y188L, G190S). Among patients failing nevirapine, 35 (80%) had efavirenz cross-resistance (K101E, K103N, Y188L), while 9 (20%) did not (V106A, Y181C). Patients who received both agents were clearly cross-resistant to all available NNRTIs. Thus, in a minority of patients failing a nevirapine-based regimen, efavirenz may still be effective, but this concept has yet to be clearly validated in a clinical setting. We still need new drugs in this class with more divergent resistance patterns.

Finally, the concept of hypersusceptibility to NNRTIs has been widely discussed over the past year. This issue was recently examined in 62 NNRTI-naive but heavily NRTI-experienced patients (abstract 454).[15] Hypersusceptibility to NNRTIs was only present in 0% to 5% of cases, while 26% had a 4-fold (or greater) reduction in susceptibility to nevirapine. In vivo, hyper-susceptibility did not lead to a more vigorous virologic response to nevirapine -based therapy. This theoretical construct must be evaluated more carefully before it is incorporated into clinical guidelines or clinical practice.

In summary, the NNRTIs remain an exciting class of compounds that are highly effective when used in the right setting. The 8^th CROI has given us important insights into how this can be achieved. Ultimately, however, what we need most is new drugs, to help us expand the options that we can make available to our patients living with HIV/AIDS.

Related Article:
Salvage Therapy: More Data on New Drugs Against Old Targets
Robert Shafer, March 9, 2001