Kaletra in PI Experienced; Liver Transplants; New Entry Inhibitor in Early Development
     Reported by Jules Levin

N Clumeck from Brussels presented follow-up data from study M98-957 which looks at Kaletra in combination with efavirenz in multiple PI experienced but NNRTI-naive individuals.

 Patients started with Kaletra (400 Lopinavir/100 Ritonavir) bid +EFV +NRTIs in two arms. In Arm A patients switched to 533/133 after week 24 and in arm B patients switched to 533/133 after 14 days. After measuring drug levels Kaletra dose was increased and efficacy data for both arms were reported tigether because results were the same. Kaletra trough was reduced 33% and AUC by 25%. When dosed at 533/133 bid Kaletra exposure was equal to 400/100 when dosed without EFV. Baseline viral load was 4.5 log (31,600 copies/ml) and CD4 was 220. 57 patients had used an average of 7 ARV drugs previously and 3 PIs. 68% of patients had baseline cross resistance >4 fold resistant to 3 or more PIs. 11 patients discontinued before week 48: 4 due to virologic failure, 2 CNS side effects, 1 lactic acidosis.

At week 48 CD4s increased 94. By ITT M=F analysis 65% had <400 copies/ml (80% by On Treatment analysis), and 56% (ITT) had <50 copies/ml (71% On Treatment). 92% of patients with 0-5 genotypic PI mutations had <400 copies/ml, 71% with 6-7 PI mutations, and 33% with 8-10 mutations. Mutations from 11 mutations associated with reduced susceptibility to Kaletra (10, 20, 24, 46, 53, 54, 63, 71, 82, 84, 90). Using phenotype baseline resistance--93% with <10 fold resistance had <400 copies/ml, 73% with 10-40 fold resistance had <400 copies/ml, and 25% had <400 copies/ml with >40 fold resistance. These data give a sense of how to evaluate potential susceptibility to Kaletra.

Most  common adverse events: 12% diarrhea, 11% asthenia (n=57). Lab abnormalities: total cholesterol >300 mg/dL 40%, triglycerides >750 mg/dL 40%, ALT >5 ULN 4%, amylase >2X ULN 9%, neutrophils <0.75x 10-9/L) 7%. Triglycerides went up from 200 on average at baseline to about 400 and cholesterol from 200 to 250 at week 48 (judging by graph on slide).

In a State-of-The-Art Lecture today by Gregory Reyes, MD, from Schering Plough, talked about the entry inhibitors they are developing. In "Development of CCR5 Antagonists as a New Class of Anti-HIV Therapeutic", Reyes presented data on SCH-C, the Schering CCR5 entry inhibitor.

• It has synergy with AZT/indinavir
• it showed 2.4-3.6 log reduction in HIV in mice
• there was no shift to CXCR4 as an entry point after CCR5 was blocked
• resistance can occur
• it had a brain/plasma drug level ratio of 0.17 which Reyes said was ok
• it showed a dose dependent viral load reduction in mice
• single oral doses (25-600 mg) in humans showed good dose dependent PK profile & dose proportional
• there were no observed effects by gender, age, or body surface
• the 2nd generation SCH-D is 10 times more potent, has better absorption, more bioavailable

BUT, in vitro SCH-C showed potential for a cardiac problem. Therefore, I was told that they will have to reformulate the drug but they ought to be able to address this problem.

In a poster today on liver transplants in HCV/HIV coinfected persons, the 4 patients with HCV related cirrhosis all died of complications due to HCV infection within 25 months of transplantation. The poster said this contrasts with the 62% 10 year survival of non-HIV infected patients who underwent transplant for HCV. The reason was HCV reinfection from extra-hepatic HCV. The study investigator suggested that with more effective therapy from pegylated IFN, survival may be improved.

In speaking with a transplant poster investigator at the conference session today, she told me of several transplants in HCV/HIV coinfected where the patients are doing well about one year after the transplant. So, it seems we need more time & data to evaluate liver transplants in HCV/HIV coinfected.