After 48 weeks of treatment, the new NRTI elvucitabine appears comparable to lamivudine (3TC) in terms of anti-HIV activity, CD4 cell response, side-effects and safety, according to phase II trial results presented on Sunday at the 48th Interscience Conference on Antimicrobial Agents and Chemotherapy in Washington DC.
Elvucitabine is an investigational nucleoside reverse transcriptase inhibitor (NRTI) being developed by Achillion Pharmaceuticals, Inc. Laboratory studies and several phase I/phase II clinical trials have demonstrated that elvucitabine – a cytosine analogue – has significant potency against HIV. The most recently reported trial, a a seven-day Phase II monotherapy trial in 24 patients, showed a maximal viral load decrease of 1.73 log10 copies/ml at 10 mg once-daily doses of elvucitabine alone.
To obtain more information about the safety and effectiveness of elvucitabine in combination with other anti-HIV drugs, investigators conducted a Phase II clinical trial involving HIV-positive patients who had never taken antiretroviral therapy.
This study, ACH-015, has a prospective, randomised, blinded design lasting 96 weeks; interim 48-week data were presented. Participants were randomised to receive either elvucitabine 10mg daily or 3TC (lamivudine, Epivir) 30mg daily in combination with efavirenz (Sustiva) and tenofovir (Viread).
A total of 77 patients were recruited to the study from multiple sites in the US and India. There were no significant differences on entry to the study between the patients in the two study arms. Baseline CD4 cell counts were 328 cells/mm3 in the 39 patients randomised to elvucitabine, and 324 cells/mm3 in the 37 randomised to 3TC; baseline HIV viral loads were 4.7 log10 copies/ml and 4.9 log10 copies/ml respectively.
A total of 55 patients completed 48 weeks of the study. More elvucitabine than 3TC patients discontinued the study, especially earlier on: by week 12, nine patients had discontinued in the elvucitabine arm and three in the 3TC arm; by week 48 the numbers were fourteen and eight respectively. Most of these, including the discontinuations due to adverse events, were not judged to be drug-related.
The investigators conducted two sets of analyses. The first included all of the patients recruited to the study, regardless of whether they completed the full course of treatment: i.e., all patients who dropped out were counted as having failed (an intent-to-treat analysis). This showed that after 48 weeks, 65% of patients receiving elvucitabine had a viral load below 50 copies/ml, compared to 78% of those receiving 3TC. However, this difference was not statistically significant (p = 0.07) and was largely attributable to the higher dropout rate in the elvucitabine arm.
In the second analysis, only those patients who completed the full course of treatment were considered (an on-treatment analysis): patients who had discontinued were not counted. The on-treatment analysis showed that an equal proportion of patients treated with elvucitabine (96%) and 3TC (97%) had an undetectable viral load at the end of 48 weeks.
The mean increase in CD4 cell count was 132 cells/mm3 in those on elvucitabine versus 203 cells/mm3 in those on 3TC. Increases in CD4 cell percentage were comparable between the two treatments (a 10% increase with elvucitabine and a 9% increase with 3TC).
There was no significant difference in the incidence, frequency, type, or severity of side-effects (adverse effects, or AEs) between the two drugs: grade 3 or 4 AEs were reported in 9/39 on elvucitabine and 11/37 on 3TC; serious AEs (SAEs) in 10/39 on elvucitabine and 8/37 on 3TC.
In the discussion after the presentation, presenter Edwin DeJesus acknowledged that these rates are surprisingly high. He suspected that non-drug-related factors may have accounted for many of the reported adverse event rates – for instance, respiratory infections were common in this group of study participants. Events judged to be drug-related, such as neutropenia, were less frequent and were comparable between the two arms. In answer to a related question about the high number of study dropouts, DeJesus also said that many were simply lost to follow-up.
On the basis of these results, DeJesus concluded on behalf of the study team that a daily dosage of 10 mg elvucitabine, combined with tenofovir and efavirenz, "resulted in excellent virologic and immunologic responses", was "well-tolerated with a favourable safety profile", and "provided suitable [pharmacokinetic] exposure in all patients".
At 48 weeks in treatment-naïve patients, elvucitabine and 3TC appeared to result in comparable viral suppression and CD4 cell responses, with a similar safety profile and little difference in side-effects.
De Jesus E. et al. Elvucitabine phase II 48 week interim results show safety and efficacy profiles similar to lamivudine in treatment naïve HIV-1 infected patients with a unique pharmacokinetic profile. 48th Interscience Conference on Antimicrobial Agents and Chemotherapy, abstract H-892, Washington, 2008.