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  AIDS 2002 Barcelona
Barcelona, Spain July 7-12 2002
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New HIV Drugs / Hep C: quicker HCV progression nin coinfection; sumptomatic hyperlactatemia in coinfected patients taking RBV; PegIntron/RBV in coinfected
Report by Jules Levin
  I just came from a 4pm oral session where various entry inhibitors, the Merck integrase inhibitor, and other new drugs were discussed. Researchers from the manufacturers reported the latest updates much of which you are familiar with. the Merck integrase info was reported at the Resistance Wksp & I reported it to you. Its available on my website. The T-20 data I reported to you. More T-20 data will be reported Friday at the Late breaker Oral session here. Roche/Trimeris has T-1249 which is a more potent fusion inhibitor than T-20 and appears to be effective aginst T-20 resistant HIV. Unfortunately these two drugs are administered by subutaneousl injection and are associated with injection site reaction. Progenics Pharmaceuticals reported here on their two attachment (entry) inhibitors in development - PRO542 and PRO140. SCH-C and SHC-D are two entry inhibitors in development by Schering Plough and these were discussed at this session. Rob Murphy reviewed new protease, NNRTI, and NRTI drugs in clinical development and there are a bunch that look effective against HIV resistant to the currently available drugs. Due to the development of new entry and integrase inhibitors we are, as I've been telling you for a while, I think entering a new era of treating HIV. T-20 is expected to be on the market in early 2003; and hopefully the other drugs described will make it through the development process. I am hopeful that in several years we will have enough new entry inhibitors and integrase inhibitors to form an entire regimen. These drugs should not be cross-resistant with currently available classes of drugs. It's like starting over, in a way. 83% of patients were taking HAART
HCV/HIV Coinfected Patients Progress More Quickly Than Monoinfected Patients
In this afternoon's oral session on HCV/HIV coinfection at 2pm there were several interesting presentations. This report will be relatively brief as I have a meeting at 7pm. AH Mohsen from Guys Kings' and St Thomas School of Medicine in London, UK reported on his study comparing the progression of hepatic fibrosis in HCV/HIV coinfected and HCV monoinfected patients. 120 HCV and 50 coinfected patients were studied, if the researchers knew how long their duration of HCV infection was and if they had not received HCV therapy. The known duration of HCV-infection was estimated by the year of first IVD use or transfusion. Plus, they had to have a liver biopsy. Liver biopsies were assessed by one person: Ishak Score- fibrosis stage 1-4; inflammatory grade 0-18. They also reported on the fibrosis progression rate. 80% were IVDUs. 95% caucasian. Average age at infection: 22. Average duration of HCV 15-16 years. Current alcohol intake >0 units/week at biopsy: 55% in HCV group, 24% in coinfected group. ALT at biopsy: 83 in HCV group, 74 in coinfected group. Genotype 1: 56% in HCV group and 53% in coinfected group.
Coinfected patients were reported to progress more quickly than monoinfected patients. The estimated time to cirrhosis from infection was 22 years in the coinfected patients vs 33 years in the monoinfected patients. The rate of progression was faster in the coinfected patients: 0.181 units/year vs 0.121 units/year. Repeat biopsies were performed in 6 coinfected patients: median interval between biopsies 3.5 years (range: 2.1-6 years). the average fibrosis progression rate was 0.29 unit/year and time to cirrhosis was 13.8 years.Patients with coinfection had significantly higher inflammation despite having lower alcohol intake and had higher rates of more advanced fibrosis. The researchers found being HIV+ was significantly associated with development of fibrosis bt 4.38 times (using a multivariate analysis). The duration of HCV-infection was also associated with developing fibrosis: having HCV for >15 years increased risk of developing fibrosis by 3.7 times. Having an ALT >80 was also a risk for faster fibrosis progression by 2.86 times. Having a CD4 count <250 increased risk of progression to stage 3 & 4 fibrosis by 3.75 times (p=0.03). In summary Mohsen reported that coinfected patients had a 1.5 fold increase in fibrosis progression rate.
Symptomatic Hyperlactemia in Patients Receiving Interferon+Ribavirin & on HIV Therapy and PegIntron plus Ribavirin in Coinfected Patients
DH Smith (UCSD) reported on patients taking d4T and ddI and were also receiving Pegasys plus ribavirin in the Apricot Study. Symptomatic hyperlactemia (SHL) has been seen uncommonly in patients on nukes, specifically on d4T or ddI. SHL has also been seen in coinfected patients treated with ddI and ribavirin. SHL is defined here as symptoms consistent with elevated lactate, fatigue, abdominal pain, bloating, shortness of breath, nausea, vomiting & parsasthesis (numbness). Elevated lactate is >2.0 mM/l. Smith reviewed cases of SHL in the 853 patients in APRICOT, which is a large study of Pegasys alone, Pegasys plus ribavirin, or interferon plus ribavirin in coinfected patients. Ribavirin was administered at dose of 400 mg twice a day. There were 8 SHL cases: before starting this study 5/8 were on d4T plus ddI; 2/8 on d4T, 1/8 on AZT; 4/8 on PI; 4/8 on NNRTI. Patients were on HAART an average on 18 months, had cd4s of 560, and 75 copies of viral load; ALT was 101; fibrosis stage was 1.8 (0-6), necroinflammatory Score (0-18) 6.3. On average these patients were 41 years old, 3/8 were female, on HCV treatment for average 8 months, had an HCV viral load reduction of 5.5 log, and 3/8 had <600 copies of HCV RNA. Their average peak lactate level was 5.4 mMol/l.
2 patients required hospitalization, and 1 died from complications of pnuemonia. Both were male on d4T and ddI. Peak lactate were the highest among the cases at 15 and 19 mMol/l. At presentation with SHL, 7/8 stopped HAART and 4/8 stopped HCV therapy. Upon resolution of SHL symptoms, one patient restarted HAART, while 2 of 4 restarted HCV therapy. Patients on d4T were 2.2 times more likely to develop SHL (p=0.04). Patients on ddI were 8 times more likely to get SHL (p<0.01). 88% of patients getting SHL were on d4T and 50% not getting SHL were on d4T. 63% getting SHL were on ddI and 18% not getting SHL were on ddI. Smith reported the rate of SHL in the Apricot Study was not different than the rate for patients on HAART, 8/725 patient-years vs 7/516 patient-years. But the implication from this study taken with results presented with another study presented in this session suggested a potential association between d4T, ddI and ribavirin. In Apricot SHL developed within 17-104 days. While the overall trial incidence was 1% for SHL, at one site out of 1001 sites the rate was 21% (5/26 patients (p<0.01). Smith summarized during combination HCV/HIV therapy SHL is a rare but potentially fatal disease. Symptoms are non-specific and vague, and require a high degree of suspicion. d4T and ddI use are risk factors for the development of SHL. Female gender may also be a risk factor. Smith said since the rate was similar in the Apricot study to those receiving HAART alone this complication could be due to HCV treatment or an unmasking of subclinical multifactorial hepatic mitochondrial injury by HCV treatment.
Rafael Esteban reported preliminary results from a study of coinfected patients receiving standard interferon plus ribavirin vs PegIntron plus ribavirin, plus HAART. Patients received interferon 3 MIU/3x/wk plus 800 mg RBV daily or PegIntron 1.5ug/kg plus 800 mg RBV daily. In the IFN/RBV group (n=34) ALT was 149, 24/34 had genotype 1 or 4, HCV RNA was 6 million, HIV RNA was <80 in 21/34, CD4 was 526. In the PegIntron group (n=30) ALT was 109, 18/34 had genotype 1, HCV RNA was 6.4 million, 22/34 had <80 copies HIV RNA, and cd4s were 580. 42% receiving Peg/RBV had sustained response (ITT) vs 33% getting IFN/RBV. This difference may not be significant. 31% with genotype 1 or 4 receiving Peg/RBV had SR vs 13% receiving IFN/RBV. This was I think reported to be significant but they did not report how patients with high vs low viral load before therapy performed. Plus I don't think they reported what level of HCV RNA was undetectable. There was no difference in response between IFN/RBV & Peg/RBV for genotype 2/3 patients: 67% for IFN/RBV vs 55% for Peg/RBV. CD4s went down from 550 to 412 but CD4% did not decline. HIV RNA did not increase. hemoglobin went down significantly from 15 to 13.2, platelets went down just a little, neutrophils decreased from 3020 to 1990. 4 patients (14%) reduced PegIntron dose mostly due to neutropenia, 10% on Peg/Rbv and 13% on IFN/RBV reduced RBV dose. Esteban reported significant hyperlactatemia requiring reduction or discontinuation of RBV can occur - I think he reported 8% incidence- and is more frequent in patients with established cirrhosis and those with a prior history of antiviral hepatoxicity. Esteban talked about an assay he developed, a test for mtDNA copy number in PBMC, which may be more useful than blood lactate levels in monitoring patients to prevent mitochondrial DNA depletion. He reported its use in this study and that it appeared effective in detecting mtDNA damage. This test should be validated in studies. Although this complication appears to be uncommon, the potential development of this and the report of SHL above raise an important concern about the development of this problem in HCV+ patients.