A new non-nucleoside reverse transcriptase inhibitor under development by Agouron/Warner-Lambert shows just as much potency on its own as triple therapy, researchers reported today. However, the first reported data on a dual NNRTI combination proved disappointing, and provided further proof that Triangle Pharmaceutical’s NNRTI emivirine is going to be difficult to sell to doctors and people with HIV.
AG-1549, or capravirine, was tested in treatment-naïve individuals at five separate doses, and compared with AZT/3TC/nelfinavir. The highest dose, 2100mg twice daily, reduced viral load by 1.69 log after ten days, whilst the triple combination reduced viral load by 1.65 log after ten days. The drug was well tolerated, with no evidence of rash, but some clinicians feel that capravirine will need to be tested for longer to determine whether rash is a problem because this side effect may take longer to emerge (as it can do in other NNRTIs). Mild nausea, vomiting and headache were the most frequently reported side effects (Hernandez).
Emivirine, on the other hand, exhibited less stellar characteristics in a number of studies presented to today. As salvage therapy for people who had failed on PI, emivirine was tested in combination with efavirenz and two nucleoside analogues. Eight patients took emivirine and efavirenz for eight days before adding NRTIs, but researchers found that emivirine seems to have a negative effect on efavirenz levels that is not improved when the efavirenz dose is increased from 600mg to 800mg per day. Three of eight individuals also discontinued therapy due to serious rash, and only three of eight patients had a sustaind virological response at week 16 (Hicks).
A separate analysis of three large studies of emivirine in combination with two NRTIs found that the drug performed poorly in individuals with viral load above 50,000 copies. In study MKC 302, only 30% of patients with baseline viral load above 100,000 copies had viral load below 400 copies at week 24, and only 10% had viral load below 50 copies. Even in the MKC 301 study for individuals with viral load below 50,000 copies, only 37% had viral load below 50 copies at week 24.
The one bright prospect for emivirine is the evidence that it is probably possible to use other NNRTIs subsequently in about 50% of people who suffer viral rebound on the drug. Only 45% of people who developed NNRTI mutations displayed a pattern that would indicate cross-resisistance to efavirenz, but the picture for nevirapine resistance was less clear (Sereni).
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References
HernandezJ et al. Short-course monotherapy with AG1549, a novel nonnucleoside reverse transcriptase inhibitor (NNRTI) in antiretroviral naïve patients. Abstract 669, Seventh Conference on Retroviruses, San Francisco, 2000.
Hicks C et al. Dual NNRTI therapy (MKC-442, emivirine (EMV) and efavirenz (EFV) for patients failing PI regimens: pharmacokinetics and short-term efficacy. Abstract 670, Seventh Conference on Retroviruses, San Francisco, 2000.
Sereni D et al. Antiviral activity, safety and tolerability of emivirine (Coactionon, EMV, MKC-442) in a protease inhibitor-sparing regimen with two nucleoside reverse transcriptase inhibitors (NRTI) in treatment-naïve patients: pooled analysis of three controlled clinical trials through 24 weeks. Abstract 671, Seventh Conference on Retroviruses, San Francisco, 2000.