New potential dual NNRTI-based combinations

Despite a concern over competition for the same binding site when using dual-NNRTI combinations, the potential for this approach excited many researchers and activists long before manufacturers agreed to collaborate on joint research, particularly in view of the benefits shown from dual-protease combinations.

A small pilot study from Los Angeles looked at a once-daily regimen of nevirapine/efavirenz/ddI in 15 treatment naive and 11 treatment experienced patients. All three drugs were used at the standard daily dose, and although pharmacokinetic data would suggest increasing the efavirenz dose to 800mg QD would be necessary to compensate for an interaction with nevirapine, no alteration was made.

Baseline CD4 count was 351 cells/mm3 (110 – 800, median 312) versus 368 cells/mm3 (1 – 800, median 310) and baseline viral load was 38,600 copies/ml (range 576-180,000, median 33,000) and 2,000 copies/ml (<400-18,000, median <400) in the treatment naive and experienced groups respectively. Results are shown in Table 1 below.

Table 1

All patients became undetectable after nine months (including to less than 25 copies by 9 months). Each group started with an mean CD4 count of around 350 – and saw quite remarkable increases of around 440 and 370 in the naive and experienced groups respectively.

There were five discontinuations due to side-effects (2 with nevirapine-associated rash and 3 with efavirenz-associated CNS symptoms or insomnia). Although the study commented that there was no increased incidence of treatment-limiting side effects from combining two NNRTIs – even at 19% – the low numbers in this study make that difficult to assess.

If these results stand up to a larger trial (the 2NN study currently being run by NATEC includes UK sites and a double-NNRTI arm in treatment naive patients) this PI- and nuke-sparing approach could be one of the pointers to changed treatment strategy that came out of the Durban conference. Given that cross-resistance generally limits the benefit from NNRTIs to one use only, if nevirapine and efavirenz produce an additive or even synergistic effect, this could play an important part in an overall approach to planning treatment strategy. It may also offer an important option now for in salvage therapy salvage therapy – dual NNRTIs were also included in the multi-drug mega-HAART protocol used by Julio Montaner – although with the caution that this should be supported in individual cases with concomitant drug level monitoring.

	naive	experienced
N	15	11
<25 at 9 month	12/12	9/9
<400 at 52 wk	11/12	8/9
% <400 (on-treatment)	92%	89%
% <400 (ITT)	73%	72%
CD4+ (cell/mm3)	+438	+367
Discontinuations	3	2