La capravirina (Pfizer), NNRTI di seconda generazione, ha fallito l’outcome virologico versus placebo in uno studio a 48 settimane in persone resistenti agli NNRTI. Criticabile il disegno dello studio della casa farmaceutica, ma il fallimento è realmente sorprendente.Lo studio a 48 settimane, su 179 persone, ha randomizzato persone resistenti agli NNRTI a ricevere 700 o 1400 mg di capravirina, bis in die, versus placebo. Tutti i partecipanti hanno anche ricevuto nelfinavir bis in die + 2 NRTIs a seconda del proprio genotipo e della loro storia terapeutica. Nessun partecipante era mai stato trattato con IP prima dello studio.
Sorprendente il fallimento del farmaco da un punto di vista dell’outcome virologico. Riportiamo di seguito i dettagli.
Trial enrollees had moderately advanced disease, with an average viral load around 4.4 log copies/mL and median CD4 counts of 206 cells/mm3 in the placebo group, 248 cells/mm3 in the 700-mg capravirine group, and 249 cells/mm3 in the 1400-mg capravirine group. Resistance to NRTIs and NNRTIs was similar across the study arms.
Pesano reported 48-week failure rates—defined as failure to reduce the viral load by 0.5 log by Week 4, or rebounding after a 0.5 log reduction—of 24% with placebo, 15% with 700 mg of capravirine, and 13% with 1400 mg, differences that were not statistically significant. The reductions in viral load from baseline to Week 48 also did not differ significantly: 2.1 logs, 2.3 logs, and 2.4 logs, respectively.
A 48-week noncompleter-equals-failure analysis determined that 58% of patients taking 1400 mg of capravirine twice daily had a viral load below 400 copies/ml, compared with 43% taking 700mg twice daily, and 46% taking placebo. These differences also fell short of statistical significance.
In a preplanned analysis of nonrandomised subgroups who began treatment with virus resistant to zidovudine and lamivudine, 54% in the 1400mg group had a viral load under 400 copies/ml at Week 48, compared with 36% taking 700mg, and 31% taking placebo. This trend was not statistically significant, however.
The better noncompleter response with 1400mg of capravirine partly reflects the high dropout rates in the other 2 arms—44% with placebo, 42% with 700mg capravirine, and 30% with 1400mg capravirine. Whereas 15% of patients stopped the 700mg dose because of side effects, 7% stopped the 1400-mg dose for that reason.
Diarrhoea affected 65% in the 1400mg group and 53% in the 700mg group. However, diarrhoea also was reported by 49% given placebo, and the incidence of diarrhea in all treatment arms may have been due to nelfinavir therapy. Rates of nausea were 35% with 1400mg, 27% with 700mg, and 20% with placebo.
Dr. Pesano noted that the high failure rates in all three study arms came as a surprise, since people started nelfinavir with no protease inhibitor experience and also began carefully chosen NRTIs. The study outcomes will be further scrutinized as the development of capravirine continues.
Pesano R et al. 24-week safety, tolerability, and efficacy of capravirine as add-on therapy to nelfinavir and 2 nucleoside reverse transcriptase inhibitors in patients failing a nonnucleoside reverse transcriptase inhibitor-based regimen. Twelfth Conference on Retroviruses and Opportunistic Infections, Boston, abstract 555, 2005.