Adefovir dipivoxil (Hepsera)

Adefovir dipivoxil (Hepsera) is a licensed treatment for hepatitis B and a failed treatment for HIV.

Adefovir was previously called bis-POM PMEA and GS 840. It is made by Gilead Sciences. As a treatment for hepatitis B, it is known by the brand name Hepsera. As a treatment for HIV, adefovir was called Preveon.

The United States Food and Drug Administration (FDA) refused to approve adefovir as a treatment for HIV in 1999 due to the severity and frequency of kidney toxicity when dosed at 60 or 120mg. However, trials have found the 10mg dose of adefovir to be an effective and safe treatment for hepatitis B. Adefovir became an approved treatment for hepatitis B in the United States in August 2002 and in the European Union in March 2003.

Adefovir is a nucleotide reverse transcriptase inhibitor (NtRTI), but works against hepatitis B by blocking DNA polymerase, an enzyme crucial for the hepatitis B virus to reproduce in the body.

In test-tube studies adefovir has been shown to be active against a broad spectrum of viruses, including herpes simplex viruses 1 and 2 (HSV-1 and HSV-2), Epstein-Barr virus (EBV), cytomegalovirus (CMV), hepatitis B virus and HIV-1 and -2. One study has found that adefovir also reduces CMV levels in semen.

In HIV-negative patients, adefovir is effective in reducing hepatitis B viral loads and preventing damage to the liver.¹ It is also effective against 3TC (lamivudine, Epivir)-resistant hepatitis B and improves liver function in people with ‘pre-core mutant chronic hepatitis B virus’, which is associated with rapid progression to liver disease.²

It is also effective in HIV-co-infected patients. A multi-centre, open label study, 35 people co-infected with HIV and HBV, who had undetectable HIV viral load and proven 3TC-resistant hepatitis B, were given 10mg adefovir once daily, in addition to their existing anti-HIV treatment regimen. After 48 weeks of treatment, significant decreases in HBV viral load were observed across the study group, with an average fall in viral load of 4.0 log₁₀. There were no changes in the patients’ HIV viral loads or CD4 cell counts.³ These findings have now been extended to three years, with sustained suppression of hepatitis B.⁴

The efficacy of adefovir is enhanced when it is combined with nucleoside reverse transcriptase inhibitors (NRTIs), including 3TC, entecavir, FTC (emtricitabine, Emtriva) and telbivudine, or the NtRTI tenofovir (Viread).⁵ There is no interaction between adefovir and tenofovir in terms of blood concentrations or clearance through the kidneys.⁶

Adefovir at the dose studied for its anti-HIV properties can reduce the levels of saquinavir in patients taking the discontinued soft-gel formulation of the drug in combination with low-dose ritonavir (Norvir).^{7 8} It is not known whether this also occurs with the 10mg dose used for treating hepatitis B, or with the hard-gel formulation of saquinavir (Invirase).

When dosed at 60 or 120mg daily, adefovir commonly causes liver or kidney abnormalities. In one study, around 20% of the people taking 120mg adefovir daily developed kidney problems during twelve months of adefovir treatment. The 60mg dose was not as toxic but still caused serious kidney dysfunction in 3% of 1500 people receiving adefovir as a treatment for HIV through an expanded access scheme.⁹

The safety problems observed at the dose used in HIV infection have not been a widespread problem at the 10mg dose used for hepatitis B treatment, although two cases of elevated creatinine have been reported at this dose in patients also receiving indinavir (Crixivan) treatment, which is known to cause kidney toxicity. Placebo-controlled studies conducted over 12 months using the 10mg dosage indicate that adefovir is safe.¹⁰ Few other side-effects have been reported to date.

There are concerns that adefovir monotherapy for hepatitis B may lead to drug resistance. However, although mutations do occur in the presence of adefovir, no pathway to drug resistance has been identified.¹¹

Another concern is that low dose adefovir used for hepatitis B treatment in HIV co-infected patients may select for HIV mutations. This may lead to cross-resistance to anti-HIV drugs such as tenofovir, AZT (zidovudine, Retrovir), d4T (stavudine, Zerit), abacavir (Ziagen), ddI (didanosine, Videx / VidexEC) and 3TC. Studies monitoring the onset of mutations in the reverse transcriptase gene during treatment with adefovir has shown that the adefovir-associated resistance mutations K65R and K70E did not arise after up to 12 months of adefovir treatment at 10mg daily, suggesting that this is a minor risk.^{12 13}