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  ICAAC 41st Interscience Conference on Antimicrobial Agents and Chemotherapy
Chicago, Illinois, December 16-19
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ddI-Tenofovir interaction; ddI-Ribavirin-Interferon interaction; 3TC-ribavirin interaction; elevated glucose & diabetes in HCV/HIV coinfected patients
Written for NATAP by Stephen Piscitelli, Pharm.D., Associate Director, Clinical Pharmacology, Tibotec-Virco and Jules Levin, NATAP
  BRIEF SUMMARY OF THIS REPORT. The studies reported on below found PMPA (Tenofovir) increased ddI blood levels by 40% but we are unsure if this is clinically significant because intracellular levels and not blood levels are correlated with NRTI toxicities. The study authors did not look at intracellular levels. And they reported on a relatively short-term study in humans who received ddI + PMPA which did not show an increase in key ddI-relate toxicities (neiropathy, pancreatitis). Clearly, this is a question that needs further research attention. Second, ribavirin + interferon is the treatment for HCV. Preliminary in vitro (in the test tube) studies find that ribavirin alone and interferon alone may increase the amount of exposure to ddI a patient may see. And when using interfer plus ribavirin the ddI exposure may increase more than when either drug is used alone. Interferon has activity against HIV. Several preliminary studies show interferon can reduce HIV viral load. A study at ICAAC (abstract I-1938) found the Peg-Intron reduced HIV viral load from 0.25 to 0.43 log varying by the Peg-Intron dose used. This suggests that the triple therapy of ddI+interferon+ribavirin may offer an effective treatment for both HIV and hepatitis C. Further studies are needed to address this. Third, a small study of 22 patients was reported at ICAAC finding that patients receiving ddI+d4T and HCV therapy with IFN+RBV were more likely to experience clinical pancreatitis. And perhaps taking d4T or ddI alone could increase the risk for pancreatitis when also taking HCV therapy. Another study found ribavirin reduced 3TC levels in vitro. Taken together it is reasonable to ask what could these data mean towards effects on cholesterol, triglycerides and sugar (mteabilic abnormalities) and perhaps lipodystrophy.
At ICAAC a researcher reported study findings that HCV/HIV coinfected patients receiving HAART may be more likely to experience develop diabetes, insulin resistance, and elevated glucose than patients who had HIV alone. Most of the coinfected patients who experienced diabetes were on a PI regimen. This was a small study and there were a few factors in the study that confound the study findings such as there were more Hispanics in the coinfected group of patients (60% vs 38%) and Hispanics are prone to have diabetes. But I think it's certainly fair to presume that coinfected patients may be more likely to experience metabolic abnormalities and lipodystrophy (as was reported from a study reported at the Retrovirus Conference in Feb. 2001). Further research is needed on this question.

DDI and Tenofovir Interaction
excerpted from ICAAC PK & Drug-Interaction report posted to NATAP site
written by S Piscitelli
An interaction between didanosine and tenofovir was reported at the IAS meeting earlier this year in Buenos Aires.9 Tenofovir increased DDI exposure in healthy volunteers by approximately 40%. Trough levels, peak concentrations and half-life were not significantly changed. There was much debate as to the clinical relevance of this data. Plasma levels of nucleoside RT inhibitors generally do not correlate with efficacy or toxicity since they are prodrugs that must be phosphorylated intracellularly to their active form. In an extension of this study, data from two, 24-week placebo-controlled tenofovir trials, which included 197 subjects receiving DDI, were examined.10 Comparisons in toxicity between groups receiving DDI+TDF and DDI+placebo showed no difference in the incidence of pancreatitis, neuropathy, or increase in amylase. While this analysis does not rule out the possibility of increased DDI toxicity from higher levels with TDF, it does provide some reassurance that there is not an obvious safety problem from this combination. Additional data from Phase IV studies will add additional insight into this interaction and its clinical relevance. Clinicians should not decrease the dose of DDI when using tenofovir unless signs and symptoms of DDI toxicity are present.

DDI + Interferon + Ribavirin
written by J Levin
This study reported on below found that interferon alone may increase the amount of ddI exposure a person gets, ribavirin alone may do this as well, 11 And when IFN+RBV are used together as they are in treating HCV, ddI. exposure (the amount of ddI a person is exposed to) may increase a lot and more than when either RBV or IFN alone are used. This has the potential to increase ddI toxicity and side effects, but it also suggests a potentially effective triple therapy that may be effective in treating both HIV and HCV. A poster was reported on at this ICAAC meeting which found that pancreatitis was seen more often in patients receiving ddI+d4T and receiving HCV therapy. The authors concluded that there appears to be an increased risk of pancreatitis in patients treated with interferon and ribavirin who are also treated with ddI and/or d4T suggesting a synergistic toxicity between these two regimens. The authors said interferon and ribavirin should be initiated cautiously in patients treated with ddI or ddI and/or d4T.
In this study 22 coinfected patients receiving HCV therapy were identified by reviewing case folders for patients at Parkland Hospital and University of Texas Southwestern Medical Center in Dallas. All had normal lipaseon initiation of their IFN+RBV therapy. 5 developed clinical pancreatitis. All patients were on their HIV regimen stably for at least a month prior to starting HCV therapy. 4/5 patients were treated with ddI/d4T and 1/5 was receiving d4T. Pancreatitis developed within 12 weeks of initiation of therapy for HCV for 4/5 patients, and within 36 weeks for 1 patient. 3/5 had abdominal pain and one required hospitalization. 9/17 patients, about half of the patients, did not have pancreatitis and were treated with ddI or d4T.The authors said the attack rate of pancreatitis with the initiatio of interferon+ribavirin was 36%. The rate tended towards statistical significance and perhaps would reach significance if they looked at larger numbers of patients, and the published rate of pancreatitis from ddI alone (1%-7%).
editorial note: Older in vitro studies have shown that ribavirin can increase ddI exposure. At the 8th CROI (Retrovirus) Conference in February 2001, researchers (Klein, Wainberg et al) from Montreal reported on the effect on ddI exposure in vitro (in the test tube) when ddI was combined with interferon, ribavirin, and both interferon+ribavirin, 12. Klein reported IC50 ddI (the amount of ddI needed to suppress HIV was greatly reduced when ddI was combined with either of the 3 (IFN or RBV alone, or the combination of IFN+RBV). This study found much less ddI may be needed (80 times less) to suppress HIV when combined with interferon + ribavirin. They found this to also be true when combining ddI with either interferon or ribavirin.
In the study reported at Retrovirus: DDI IC50 was 6.83 uM; ddI IC50 was 0.37 when RBV was combined with ddI; ddI IC50 was 0.10 when ddI was combined with IFN; ddI IC50 was 0.05 when ddI was combined with IFN+RBV.
3TC Interaction Found with Ribavirin
Finally, in abstract I-1939 at ICAAC Korean researchers reported that in vitro ribavrin reduced 3TC blood levels. When higher amounts of 3TC were used the effect of ribavirin was lost. Whether or not this will hold true intracellularly and for humans in clinical trials remains to be seen.
Elevated Glucose Found in HCV/HIV Coinfected Patients on HAART
ML Hoffman-Terry has been reported on studies on HCV/HIV coinfected patients at HIV conferences for a while. At this ICAAC, she reported on a retrospective case control review HIV-infected and HCV/HIV infected patients receiving HAART (abstract, H-740). She matched 53 coinfected matients with 53 HIV-infected patients. They were matched for sex, age, and body mass. Greater than 50% of the patients were followed for 12 months. Most patients, 64%-70%, were receiving a PI regimen. There were some differences between the 2 groups: there were 60% hispanics in the coinfected group vs 38% in the HIV group; mean ALT was consistently higher in the coinfected group.
Hoffman-Terry found that blood glucose values were significantly higher in the coinfected patients at months 3. 6, and 9. CD4 counts showed a trend towards being significantly lower in the coinfected patients. Other studies have suggested that CD4 response to HAART may be blunted in coinfected patients. Hyperglycemia developed in 6 coinfected patients vs none in the patients infected only with HIV (p=0.012). 5 patients developed non-insulin dependent diabetes mellitus while 1 had hyperglycemia with evidence of peripheral insulin resistance. All had high body mass indexes (BMIs) of >25, 5/6 were on a PI regimen. 4 of the 6 with hyperglycemia had liver biopsies and the Scheur biopsy grade was more advanced at 3.3. Overall coinfected patients had higher Scheur grades tha HIV-infected (1.84 vs 0.99). Coinfected patients need close monitoring for glucose and diabetes during HAART therapy and after starting HCV therapy on HAART.
9. Kearney B, Flaherty J, Sayre J, et al. A multiple dose randomized crossover drug interaction study between tenofovir DF and lamivudine or didanosine. 1st IAS Conference on HIV Pathogenesis and Treatment. Buenos Aires, Argentina, July 8-11, 2001, abstract 337.
10. Flaherty J, Kearney B, Wolf J, et al. Coadministration of tenofovir DF and didanosine: a pharmacokinetic and safety evaluation. 41st Interscience Conference on Antimicrobial Agents and Chemotherapy. Chicago, IL, September 22-25, 2001, abstract I-1729.
11. Hester J, Keiser P, Berggren R, Pancreatitis: an emerging complication of HCV treatment in HIV coinfected patients treated with ddI/d4T containing regimens. 41st ICAAC, Chicago, IL, Dec 16-19, abstract H-739.
12. Klein, Campeol, Lalonde, Wainberg. A highly synergistic triple antiviral combination with potential activity against both HIV and hepatitis C viruses. 8th Conference on Retroviruses and Opportunistic Infections, Feb 4-8, Chi, IL., abstract 308