Report 4

Preliminary Capravirine (NNRTI) Resistance Data

The data from this preliminary study in HIV-infected NNRTI resistant patients suggests that capravirine may be useful for some patients with NNRTI resistance. In vitro (test tube) testing of viruses from humans with NNRTI resistance in this study shows 50% (26/52) of viruses with resistance to NNRTIs (efavirenz, nevirapine and delavirdine) were fully sensitive to capravirine. When the key NNRTI mutation K103N was present as a single mutation or as part of a multiply mutant virus 18 of 28 (64%) viruses were fully sensitive (4/28 had intermediate sensitivity to capravirine) to CPV while most of these viruses were resistant to nevirapine & efavirenz. The more NNRTI mutations a patient had the less sensitive the patient was to capravirine. When NNRTI resistance was present in these viruses without the K103N being present only 3 of 19 viruses were fully sensitive to capravirine and 3 had intermediate sensitivity to capravirine. This data is preliminary and more human studies must be conducted to evaluate the actual benefit and how to use this drug for patients with NNRTI resistance.

Capravirine is a non-nucleoside reverse transciptase inhibitor (NNRTI) being developed by Agouron/Pfizer for patients with NNRTI resistance. The drug was being evaluated in HIV-infected NNRTI resistant individuals when animal toxicity was discovered. Vasculitis is a condition causing inflammation of the blood vessels and was found during studies in dogs. As a result, the FDA placed development & this study on hold. Twenty patients in this study who had good viral load reductions on the Capravirine containing regimen (I think they were also receiving PI therapy) they were receiving were permitted to continue taking the drug and follow-up data has yet to be released. Agouron is in discussions with the FDA and hopes to resume development of Capravirine.

At this year's Resistance Workshop (June, 2001), Agouron reported Capravirine resistance data from a study of 71 NNRTI experienced individuals. It's been previously reported that resistance to Capravirine (CPV) in vitro emerged more slowly and less frequently, and more often multiple mutations were seen leading to resistance than with other NNRTIs (14th Intl Conference on Antiviral research, Seattle, WA 2001). In Seattle, it was reported that EC50 values (amount of drug) of 114nM or less showed potent antiviral activity against NNRTI resistant viruses from plasma of ART experienced patients. In this study, the authors reported CPV showed potent in vitro antiviral activity with EC50 values <70 nM for 45 of 52 (86%) of patient viral isolates tested. They also reported that of 28 viruses tested from the blood of NNRTI resistant patients, 20 (71%) showed no resistance (n=13) or intermediate resistance (n=7; <10-fold resistance).

BRIEF SUMMARY
In this study of patients with NNRTI experience & resistance, 8 of 9 patients with the single NNRTI mutation K103N were still sensitive to capravirine. Of 12 patients with 2 NNRTI mutations including the K103N, 7 had full sensitivity to CPV and 2 viruses had intermediate resistance to CPV. 3 of 5 viruses with 3 NNRTI mutations including the K103N were sensitive to CPV. Of 19 viruses without the K103N mutation 17 had full resistance to EFV & DLV, 11 were still sensitive to DLV, but only 3 were sensitive to CPV. Three of these 19 viruses had intermediate CPV resistance and 13 had full CPV resistance.

THIS STUDY
This is a study of adults failing a NNRTI containing regimen who were PI naïve (except patients who switched from a PI to an NNRTI while blood HIV RNA was <400 copies/ml). Of the 71 study participants, 62% were failing regimens containing nevirapine (NVP), 32% efavirenz (EFV), 1% emivirine, 5% none reported. Blood samples were collected at baseline and evaluated for phenotypic resistance in 53 patients and/or for genotypic resistance in 55 patients. They had both pheno- and geno- test results available for 51 isolates. The investigators used the Antivirogram (Virco) phenotypic resistance test. Drug specific cut-off values determined by Virco for designating resistance were >8, >6 and >10 fold for NVP, delavirdine (DLV), and EFV, respectively. Because specific cut-off values for CPV have not yet been determined, CPV sensitivity was designated as sensitive, intermediate, or resistant with <4-fold, 4-10 fold, or >10 fold reductions in sensitivity, respectively. Genotypic resistance was determined also with the Virco Vircogen test.

RESULTS
The authors reported no significant reduction in susceptibility (<4-fold) was seen in 26 of 52 (50%) of patient viral isolates tested. These isolates were tested for sensitivity to NVP, EFV and DLV. And 13% (7/53) were sensitive to NVP, 17% (9/53) to EFV, and 38% (20/53) to DLV. This was established using the cutoffs defined by Virco of <8, <6, and <10 fold for each drug, respectively. Genotypic test results showed the key NNRTI mutartion K103N was the predominant mutation occurring and was seen alone or with up to 4 additional NNRTI mutations in 29 of 55 (53%) of isolates examined. Full sensitivity to CPV was reported to be seen in 18 of 28% (64%) of K103N containing isolates tested. But, only 5 of the 28 K103N isolates remained sensitive to NVP, EFV, or DLV. Two viruses (7%) of the 28 viruses with the K103N remained sensitive to NVP, 4 (14%) to DLV, and 3 (11%).

CPV Potency Against Virus Containing Single NNRTI K103N Mutation

In an analysis of 28 of 29 isolates available that contain the K103N and for which they had genotypic and phenotypic resistance test results, 9 patients had the K103N alone (1 patient had the K103N/K). Of these 9 patients with the K103N as their only NNRTI mutation, 8 had 3.9 or less CPV resistance and 1 patient had 9.5 fold CPV resistance. All the 9 patients had high level resistance to NVP, DLV, and EFV (72 fold or greater).

CPV Potency vs Virus Double NNRTI Mutations (including K103N)

12 of these 28 isolates had two NNRTI mutations also containing the K103N mutation. The additional mutation included A98G, A98S, V108I, Y181C, Y188L.H, P225H, P225H/P, G190G/A, and K238T. All of these patients had high level resistance to EFV, NVP and DLV (1 patient had only 8.2 DLV resistance). 9 of the 12 patients had no or intermediate CPV resistance. 7 of the 12 patients were sensitive to CPV. They had 3.1 fold CPV resistance or less (range 0.4-3.1). 3 of the 12 patients with double NNRTI mutations including the K103N had high level CPV resistance (range 13.3-61.4).

CPV Potency Against Viruses with 3 or More Mutations (including the K103N)

There were 5 viruses with 3 NNRTI mutations each also containing the K103N, and 3 of these 5 viruses were sensitive to CPV (range 0.7-2 fold CPV resistance). The 4th virus had 16 fold CPV resistance. 3 of the 4 viruses had high level resistance to EFV, DLV, and NVP. One virus had 3 genotypic NNRTI mutations including the K103N, but little or no resistance to all the NNRTIs including CPV (5.6 fold resistance to NVP, 2.3 fold to DLV, 1.1 fold to EFV and 0.7 fold to CPV). The fifth virus had 3 mutations including the K103N and had high level resistance to CPV as well as the other NNRTIs.

Two viruses had 4 or 5 NNRTI mutations including the K103N. One virus had high level resistance to NVP, EFV and DLV and intermediate resistance (7.9 fold) to CPV. The 2nd virus was 17.1 fold resistant to CPV, and had high level resistance to EFV and NVP (but no resistance to DLV).

Viruses Without the K103N Mutation

There were 25 patient virus isolates without the K103N mutation and CPV was not sensitive to most of these viruses. 21 of the 25 had single, double, triple or 4 NNRTI mutations without the K103N. These other mutations included Y181C, Y188L, G190A/Q/S, A98S, V108I, M230L, K238T/K. 4 of the viruses had no NNRTI or NRTI mutations suggesting they may not have been treatment experienced, and these patient viruses had no NNRTI resistance. Investigators could not determine the genotypic resistance to 2 of the 25 viruses. One of these 2 viruses had high level NVP & EFV resistance but no DLV resistance and was 8.6 fold (intermediate) resistant to CPV. The second virus was sensitive to CPV (2.2 fold) and had high level NVP resistant but was sensitive to DLV & EFV.

Of the 20 viruses for which they had genotypic & phenotypic test results, 3 were sensitive to CPV, 13 had high level CPV resistance, 3 had intermediate CPV resistance (6.4-8.6 fold), and they were unable to determine the phenotypic resistance to 1 virus. Interestingly, 11 of these viruses without the K103N mutation were high level resistant to EFV and NVP but 9 were sensitive to DLV. This suggests that if you fail EFV or NVP without the K103N mutation you may still be able to use DLV. But you might still be on the way to DLV resistance, which could occur with a little more viral evolution.