April 18-22, 2001
Prague, Czech Republic
There were a few reports at the 36th EASL that addressed issues among HIV/HBV co-infected patients. One of the more interesting ones was about the experimental drug adefovir dipivoxil.
An update about adefovir added to HAART (highly active antiretroviral therapy) for patients co-infected with HIV and HBV (hepatitis B virus) and who have HBV-resistance to 3TC was presented by Yves Benhamou, MD of Hospital Pitie Salpetriere in Paris, France. Dr. Benhamou first presented interim results of his group's observational study at the 8th Retrovirus Conference last February in Chicago. Adefovir is a nucleotide analog drug with activity against HIV and HBV. Previously, an FDA subcommittee had recommended against approving adefovir for HIV, in part due to kidney toxicity at the doses used (120 mg). However, potent anti-HBV activity occurs at lower doses of adefovir, 5-60 mg, including activity against "wild-type" HBV and strains with resistance to 3TC (lamivudine, nucleoside drug, Epivir, Epivir-HBV, Zeffix).
Dr. Benhamou first reviewed that chronic hepatitis B is emerging as an increasing problem among those with HIV infection, with approximately 10% of HIV positives having HIV/HBV co-infection (determined by the presence of hepatitis B surface antigen). This percentage is higher in certain geographic areas. Also, those with HIV/HBV co-infection have a higher rate of liver cirrhosis than those with chronic hepatitis B alone. As a result, HBV co-infection among those with HIV decreases survival.
While 3TC is effective against HBV, monotherapy in HBV mono-infected patients leads to resistance in over 1/3 of patients after 2 years, 1/2 after 3 years and 2/3 after 4 years. In the absence of HAART, these rates are higher among HIV/HBV co-infected patients: approximately 1/2 after 2 years and 90% after 4 years. (One report at this Conference by L.M.M. Wolters, MD found a similar rate among HIV/HBV co-infected patients as among HBV mono-infected patients, except when the CD4 count is low, see below.)
Adefovir 10 mg Added
to HAART with 3TC HBV Resistance
Dr. Benhamou then presented the interim results after 48 weeks of adding adefovir 10 mg once daily to HAART (highly active antiretroviral therapy) for HIV/HBV co-infected patients having HBV resistance to 3TC. All patients were on stable HAART (undetectable HIV RNA, lower limit of 400 copies/mL) that included 3TC (150 mg twice daily) with detectable HBV DNA for at least 6 months. (HBV is a DNA virus, not an RNA virus like HIV and HCV, hepatitis C virus.) 3TC-resistance was determined by the presence of HBV mutations "M550V" or M550I" in the DNA polymerase gene. Also, all patients had a normal creatinine (kidney function, less than 133 micromoles per liter or µmoles/L) in blood serum (no cells) and a normal phosphate (greater than 0.65 millimoles per liter). (At much higher doses, adefovir is associated with increased creatinine and decreased phosphate.)
Baseline information at the time of adding adefovir for the 35 patients (3% women) were as follows: mean age 41 years; 9% injection drug use history; mean prior 3TC treatment duration 45 months; mean time of HBV resistance to 3TC: 24 months; mean CD4 count 423 cells/microliter; and mean HIV RNA 2.88 log (759) copies per milliliter. Hepatitis B "e" antigen was present in 94%, with the remaining 6% having both "e" antigen and "e" antibodies. The HBV DNA polymerase mutations were: "M550V + L526M" in 83%; "M550I + L526M" in 11%; "M550I" only in 3%; and "M550V + M550I + L526M" in 3%. The mean baseline HBV DNA was 8.64 log (436 million) copies/mL (Hybrid Capture test), while the mean ALT (alanine aminotransferase, liver enzyme) level was 103 IU/L (international units per liter, normal is less than 35 IU/L). All had the common 3TC-resistance mutation to HIV ("M184V").
Two-thirds of the patients had a liver biopsy within 18 months before adding adefovir: among those, the mean METAVIR fibrosis (scarring) score was 2.0 (5-point scale from F0-F4) with a mean "activity" score of 1.4 (4-point scale from A0-A3). Cirrhosis (F4) was present in 22% of those with liver biopsy information.
Week 48 Interim Results
The interim results at 48 weeks were presented for the 29 patients (83%) who reached that time point. (A total of 94% completed 20 weeks and 89% completed 44 weeks; 6% discontinued at week 7, see below.) The mean HBV DNA reduction was highly significant at 4.01 log (10,232-fold), leading to an approximate level of 4.63 log (42,657) copies per milliliter (PCR or polymerase chain reaction test, p<0.0001). The viral load reductions after 2 weeks and then every 4 weeks were statistically significant, when compared with baseline. Three patients (9%) achieved an undetectable HBV DNA (limit 3 log or 1,000 copies/mL), all at week 36. Two patients (6%) "seroconverted" to hepatitis B "e" antibody positive (and losing "e" antigen), at weeks 32 and 36, respectively. Another 5 patients (14%) had transient detection of "e" antibodies ranging between 8-40 weeks, but were all negative at week 44.
The mean ALT increased between weeks 8 and 20 by approximately 30-50 IU/L, but then decreased with each successive 4-week visit up to 48 weeks, when there was a mean overall decrease of approximately 25 IU/L. Those results trended towards statistical significance, when compared to baseline (p=0.087).
The patients' HIV disease activity remained stable, with a non-significant increase in the CD4 count of approximately 40 cells/µL (p=0.9) and a decrease in the HIV RNA of approximately 0.2 log (1.5 fold, p=0.5). Those results suggest that the addition of adefovir might have contributed to an additional decrease in the dominant HIV strain's "replication capacity," although those benefits also might have accrued by maintaining HAART without the addition of adefovir. Eleven patients were tested for adefovir resistance to HIV at weeks zero, 12, 24 and 48. However, no mutations at "codons" 65 or 71 (previously found in laboratory tests) were detected. Liver biopsy results were not presented, (Editorial note from Jules Levin: so we don't know yet if there were improvements in the liver correlated or not correlated with HBV DNA reductions. In HCV, improvements in the liver often occur whether or not there was a reduction in HCV viral load).
Adverse events included one patient with mild insomnia at week 7 that was possibly related to adefovir, since it resolved when the drug was discontinued. Also, one patient developed diabetes at week 7 that required insulin injections that were still necessary after adefovir was discontinued. However, Dr. Benhamou said that this patient had other risk factors for diabetes, including a positive family history.
Newly reported since the 8th Retrovirus Conference were two patients who developed transient increases in creatinine (kidney function). A significant increase was defined as at least 0.5 mg/dL (44 µmoles/L). The first patient developed a maximum creatinine of 2.0 mg/dL (180 mmoles/L) at week 32. However, this patient also was taking indinavir (Crixivan, protease inhibitor or PI drug), which can also cause an increased creatinine. Both adefovir and indinavir were discontinued for 4 weeks, at which time the creatinine returned to normal and, adefovir was restarted with normal creatinine levels persisting for the next 12 weeks. Another PI or NNRTI (non-nucleoside) anti-HIV drug had been added.
The second patient had a maximal creatinine of 1.4 mg/dL (126 µmoles/L) at week 28. However, the patient also was taking acyclovir (Zovirax, anti-herpes simplex and anti-herpes zoster ["shingles"] drug) that can also cause kidney toxicity, including increased creatinine. The acyclovir was discontinued, while the adefovir was maintained, and the creatinine returned to normal within one week and has remained as such since.
Dr. Benhamou said that adefovir was not related to the creatinine increases in either patient. This is supported by the fact that neither of them had any changes in blood phosphate or other "electrolytes" (salts) that can occur with kidney toxicity. However, it is possible that adefovir might have represented a potential co-factor for creatinine increases in these 2 patients. Other abnormalities that might have helped to determine the potential, relative attribution of the various drugs were not presented, including urine testing. Other, non-drug factors might have contributed as well, including for example, relative dehydration.
Dr. Benhamou concluded that adding 10 mg of adefovir for 44-48 weeks to HAART with 3TC in HIV/HBV co-infected patients with resistance to 3TC resulted in a significant 4-log reduction in HBV DNA, with a trend towards a decrease in ALT and stable HIV RNA and CD4 counts. Hepatitis B "e" antigen "seroconversion" occurred in 6%. He also said that there were no significant changes in electrolytes and creatinine (kidney function) that could be attributed to adefovir. The drug was well tolerated overall. Lastly, additional observation of these and similar patients will be necessary to determine the durability and potential additional decreases in HBV DNA, "e" antigen seroconversion, ALT improvements, liver biopsy changes, long-term tolerance, and potential resistance to adefovir. Phase III study results of adefovir for HBV mono-infected patients are expected later this year.
Benhamou Y and others. An open label, pilot study of the safety and efficacy of adefovir dipivoxil in HIV/HBV co-infected patients with lamivudine resistant HBV. Abstract and oral presentation 1253 (session S28) at the 36th Annual Meeting of the European Association for the Study of the Liver (EASL 2001); April 18-22, 2001, Prague, Czech Republic. Journal of Hepatology 2001 April;34(suppl 1):24.
Benhamou Y and others. An open label, pilot study of the safety and efficacy of adefovir dipivoxil in HIV/HBV co-infected patients with lamivudine resistant HBV. Abstract and oral presentation 36 at the 8th Conference on Retroviruses and Opportunistic Infections. February 4-8, 2001; Chicago, Illinois.
Wolters LMM and others. Development of hepatitis B virus resistance for lamivudine in a Dutch cohort of HIV-HBV co-infected patients. Poster board presentation 585 (abstract 675) at the 36th Annual Meeting of the European Association for the Study of the Liver (EASL 2001); April 18-22, 2001, Prague, Czech Republic. Journal of Hepatology 2001 April;34(suppl 1):155.