Hepatitis B Update

Adefovir for HBV

Recently, Gilead Sciences issued a press release reporting interim 48 week results from a Phase III clinical trial (Study 437) evaluating the safety and efficacy of adefovir once daily as monotherapy compared to placebo in patients with chronic HBV infection. Later this year results are expected to be presented at a major liver conference. Gilead reported that results from the intent-to-treat analysis meet the study’s primary endpoint of improvement in liver histology at week 48 compared to baseline. Improvement in liver histology was seen in 53% of patients treated with adefovir (ADV) with 10 mg once daily compared to 25% of those receiving placebo, as measured by liver biopsies (p<0.001).

Study 437 (n=515) is a 2-year, randomized, double-blinded, placebo-controlled Phase III trial. Two doses of ADV were evaluated, including the 10 mg dose for which Gilead will apply to the FDA for approval, and an exploratory 30 mg dose.

At baseline, patients had a median HBV-DNA of 8.36 log and a median ALT of 94 IU/L. patients were required to have less than 1 or 2 weeks previous 3TC therapy and most patients had not received prior treatment for HBV. The effect of 48 weeks therapy was evaluated by improvement in liver histology, rates of seroconversion, changes in HBV viral load, and other markers of disease. Seroconversion is defined as both the disappearance of the hepatitris B "e" antigen (Hbe-antigen negative), a marker of HBV replication, and the appearance of antibodies specific for thios antigen (Hbe-antibody positive).

The discontinuation rates were similar for placebo and 10mg arms (7-8%). Gilead reported that no patients either in the ADV 10mg group or placebo group had increases in serum creatinine of greater than or equal to 0.5 mg/dL from baseline or a serum phosphorous level less than 1.5 mgd/L, as confirmed by two consecutive lab tests, The incidence of grade 3 and 4 lab abnormalities and clinical adverse events was similar between ADV 10mg and placebo arms. Preliminary genotypic resistance analysis from this study after 48 weeks show no ADV mutations were seen. Gilead has reported resistance to ADV is hard to develop.

The study showed similar efficacy between the 10 and 30 mg doses of ADV in terms of liver histology, serocobversion, and reduction in HBV-DNA. However, mild increases in levels of serum creatinine of greater than or equal to 0.5 mg/dL were observed in 9% of patients who received 48 weeks with ADV 30mg, as confirmed by 2 consecutive lab tests.

An additional study (Study 438) is underway in Australia, Canada, France, Greece, Italy, Israel, and Southeast Asia. Results from 438 should be available later this year and expects to apply for approval in first half 2002. Expanded Access programs are planned. Additional information is available by contacting Gilead at 1-800-445-3235 or 1-650-574-3000 from outside the USA.

Adefovir plus HAART shows benefits for HIV/HBV co-infected patients
(presented at EASl April 2001)
Written for NATAP by Harvey S. Bartnof, MD

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.)

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.

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.

C Lai reported on entecavir at (EASL April 2001). He provided background saying Entecavir (ETV) is a guanosine nucleoside analogue which has demonstrated potent activity against hepatitis B virus (HBV) in vitro (ED50=4nM), in animal models and in a previous 4-week dosing trial in adults with chronic hepatitis B.

Lai reported on this early study of ETV looking at the safety and antiviral activity of 3 doses of ETV (0.01, 0.1 and 0.5 mg QD) given for 24 weeks compared to lamivudine (LVD) 100 mg QD were studied in a double-blind, randomized trial in 180 subjects (45/arm). HBeAg-positive and -negative subjects with HBV DNA levels >40 MEq/mL by the Quantiplex‘ bDNA assay who had not received >12 weeks of prior anti-HBV therapy with nucleosides were eligible. The primary endpoint was mean log10 HBV DNA measured by the Roche Amplicor‘ PCR assay at Week 22.

Results: 177 subjects started study drug and 169 were evaluable for efficacy. The majority were male (74%), Asian (57%), HBeAg-positive (81%), with mean ALT of 109 IU/L and mean log10 HBV DNA of 2.8 MEq/mL. 22% of subjects had received prior interferon therapy. All 3 doses of ETV were active, but the 0.01 mg dose was less effective than the 0.1 and 0.5 mg doses. ETV 0.1 and 0.5 mg doses were both superior to LVD with mean log10 reductions in HBV DNA by PCR of 4.3, 4.7 and 3.4, respectively (p=0.0001) at Week 22. Only 6 subjects (4 ETV, 2 LVD) lost HBeAg. There was a suggestion of greater normalization of serum ALT for the 2 higher doses of ETV (83% and 66%) than for LVD (59%), but these differences were not statistically significant. ETV was generally well tolerated. Mild-to-moderate adverse events attributable to the nervous system were more frequent in the ETV 0.5 mg group than for LVD; however, only 1 ETV subject in the 0.1 mg group discontinued after 18 weeks of dosing due to lethargy and photosensitivity.

Lai concluded Entecavir at doses of 0.1 and 0.5 mg once daily has superior antiviral activity to lamivudine and is well tolerated. Phase III Entecavir studies will begin sonn in HBV-infected, and in HBV/HIV coinfected initial study should begin later this year. Ongoing studies will report later this year on Entecavir effectiveness against 3TC resistant virus.

Maureen Myers (Novirio Pharmaceuticals) reported at DDW (May 2001) that L-dT (b-L-2-deoxythymidine) is a new L-nucleoside that has been shown to be a highly specific and potent inhibitor of HBV DNA polymerase and HBV replication in vitro. NV-02B-001 is a blinded, placebo-controlled dose escalation trial to evaluate the pharmacokinetics, safety and antiviral activity of L-dT administered once daily at doses starting at 25 mg. 7 HBeAg (+) patients are to be enrolled in each of the sequential dose cohorts (25, 50, 100, 200 and 400 mg) at a ratio of 6:1 (L-dT:placebo). Dose limiting toxicities (DLTs) must be 2 or less in any given cohort in order to dose-escalate to subsequent cohorts. The primary efficacy measure is plasma HBV DNA, measured by COBAS Amplicor HBV Monitor Assay

Preliminary safety and antiviral activity data have shown L-dT to be active and well tolerated in patients enrolled in the first and lowest dose cohort.L-DT anti-HBV activity at nanomolar concentrations; no mitochondrial toxicity; up to 8 log reduction in WHV animal model; safe in 2 species in sub-chronic toxicology studies at doses as high as 2 g/kg/day. This study was to evaluate dosing, safety, and characterize PK profile. Patients received 5 sequential doses of L-DT:25 to 400 mg daily. 7 patients were in each dose group (1 receiving placebo). After 4 weeks of dosing at highest dose reported on (200 mg) HBV DNA log drop was about 3 logs. Myers reported no serious adverse events or dose limiting toxicity, so higher doses can be explored. Further trials are being planned including in combination with 3TC. Studies in HIV/HBV coinfection need to be planned.