Adefovir is in trials for treatment of hepatitis B (HBV). In preliminary studies reported on this past year, it has been shown to reduce HBV viral load. In vitro and in a small vivo study data showed that adefovir suppressed 3TC resistance virus. Resistance to 3TC can develop when treating HBV with 3TC. Studies of combining 3TC with adefovir have not been done but the combination may prevent 3TC resistance from developing and may be more effective treatment. In several short-term small studies HBV viral load reductions of 2.5 to 4 log have been seen. In one study reported this Spring, 15 patients were randomized to 60 or 120 mg for 24 weeks once daily (10 were co-infected with HI). All patients were HbeAg positive (antigen). A median reduction of 4.18 log was seen (range- 3.7 to 6.9 log) in the 60 mg group and 4.68 log in the 120 mg group. A person with HBV can have a high HBV viral load, higher than with HIV. So combination therapy may be required to adequately reduce viral load and prevent resistance from developing to the drugs a person is taking.

In study 412, 53 patients with chronic HBV who had elevated blood levels of ALTs (liver function test) received 5, 30 or 60 mg. Study investigators reported changes in HBV viral load, ALTs, and disappearance of the hepatitis B antigen (Hbe-antigen) and appearance of the antibodies specific for these antigen (Hbe-antibody). After 12 weeks, the viral load reduction from baseline was -2.53 log in the 60 mg group, –2.84 log in the 60 mg group, and –1.78 log in the 5 mg group. Study researchers reported that 67% in the 30 mg group and 60% in the 60 mg group had undetectable viral load (Chiron bDNA). A more sensitive PCR assay was used to more precisely assess antiviral activity and the median viral load reduction was 4.0 log. They reported there was no evidence of resistance after 12 weeks in this study. Median ALTs at baseline were 127 in the 5 mg group and were 69 after 12 weeks. ALTs were 93 in the 30 mg group at baseline and reduced to 63 after 12 weeks. And in the 60 mg group ALTs were reduced from 92 to 81.

Sero-conversion was defined as the disappearance of the hepatitis B "e" antigen, a marker of HBV replication, and the appearance of antibodies specific for this antigen. The HBs-antigen can also appear. After 24 weeks of follow-up 4 out of 15 in the 30 mg group and 4 of 15 in the 60 mg group (27%) lost the Hbe-antigen, and 3 of 15 in each of the 30 and 60 mg groups (20%) seroconverted. In the 5 mg group 2 of 9 (22%) lost the antigen and 1 of 9 (11%) sero-converted.

At ICAAC, the AIDS conference recently held in SF, data was reported from a study (n=505) using 120 mg once daily adefovir in individuals with advanced HIV. In a subset of 40 patients with HB sAG+ at baseline the looked at the effect of adefovir on HBV. They performed quantitative serum HBV DNA using the Roche Amplicor Assay. At baseline 85% had CD4s < 100, and 15% had CD4 101-200 with a prior nadir of <50 CD4s. 78% were on 3TC. Median baseline HBV viral load was 2.8 x 10(6th copies/ml) in 15 patients receiving adefovir and 16.4 x 10(6th) in 25 patients receiving adefovir placebo. After 8 months HBV viral load decreased -0.86 log in the adefovir group (n=12) and -0.46 in the adefvir placebo group (n=14).

3TC Resistance. In vitro studies have preliminarily shown that 3TC resistant virus can be suppressed by adefovir. These 3TC mutations caused 8 to 25 fold resistance to 3TC: M552I, M552V, L528M+M552I. Of the famciclovir mutations only V551I displayed significant resistance of 6.2 fold to famciclivor. Investigators reported that all of these mutations, however, remained sensitive to adefovir with inhibition constants increased by less than 2-3 fold. Also reported were the results of treating 3 individuals with chronic hepatitis B who had 3TC resistant HBV virus. Patients 1 & 2 received transplants and were treated with 3TC before and after the transplant. Patient 3 had compensated cirrhosis and was treated with 3TC for 10 months before viral breakthrough was seen. He was unsuccessfully treated in sequence with famcyclovir (750 mg tid) and with interferon (3 MIU qd for 12 mos). Patient # 1 received 10 mg adefovir, patient # 2 received 10-20 mg, and patient # 3 received 30 mg. After 24 weeks of follow-up-- patient 3 had undetectable HBV DNA and ALTs reduced from 378 to 102; patients 1 & 2 also had significant reductions in viral lad and ALTs. The investigators said this is the first demonstration that 3TC resistant virus are sensitive to adefovir in vivo.

These data suggest that combination therapy may prevent the emergence of 3TC resistance. Additional drugs for HBV are in earlier development including—DAPD and FTC.