Monotherapy vs multiple-drug therapy: The experts debate
Monotherapy for treatment-naïve patients
By Robert G. Gish, MD
Powerful antiviral medicines with activity against hepatitis B virus (HBV) have long-term records of potency and safety, supporting the case for monotherapy in treatment-naïve patients. Combination therapy has a limited role in the management of HBV infection; if the approach to treatment is rational from the start, then combination therapy can be reserved for cases of treatment failure or resistance.
THE CASE FOR MONOTHERAPY
Three arguments that favor monotherapy with potent medications are cost, low risk of resistance, and unproven benefit of combination therapy.
Cost
The cost of dual-medication therapy is nearly double that of single-drug therapy, while the benefit is unknown in treatment-naïve patients. My choices for first-line therapy are tenofovir or entecavir, highly potent nucleoside/nucleotide analogues that can cost up to $5,500 and $8,000, respectively, per year of treatment.1 The two in combination would cost nearly $14,000 per year, and benefits have not been proven in the treatment-naïve population.
Low risk of resistance
Potent medications have low rates of resistance, in the range of 1% over 2 to 5 years.2–4 If one starts therapy with the highly potent entecavir, discussions about switching or adding on therapy would be superfluous because of the low rates of resistance and failure associated with entecavir monotherapy. At 5 years, the cumulative rate of entecavir resistance in patients with positive HBV DNA at baseline is 1.2%.5 Tenofovir also produces potent inhibition of HBV DNA and is associated with low rates of resistance,6 although follow-up data with tenofovir extend only to 2 years. Starting therapy with the less potent adefovir, followed by the development of resistance, decreases the probability that tenofovir will achieve HBV DNA suppression during treatment.7 The main driver of resistance is nonadherence with therapy, not treatment failure.
Resistance to pegylated interferon has not been encountered. The therapy is limited in duration (24 to 48 weeks), with durable suppression of HBV DNA and high rates of seroconversion from hepatitis B e antigen (HBeAg)-positive to HBeAg-negative status. Parameters for the use of pegylated interferon as first-line therapy have been established, and include patients with genotype A or B who are young, have HBV DNA levels less than 107 copies/mL, have serum alanine aminotransferase (ALT) levels two to three times the upper limit of normal, and lack significant comorbidities.3,4
Unproven benefit of combination therapy
Perhaps the most convincing argument against combination therapy is that numerous studies of combinations have failed to demonstrate a benefit compared with monotherapy in treatment-naïve patients:
- Interferon in combination with lamivudine has not been shown to be significantly more effective than lamivudine monotherapy.8,9 Further, because of limited information on the safety of interferon in combination with nucleoside or nucleotide analogues, use of the combination is not recommended.4 Neuropathy has been reported with the combination of interferon and telbivudine,4 leading to the release of a warning about its use.10
- A 1-year trial by Lai et al failed to show an improvement in virologic and biochemical responses with the combination of telbivudine and lamivudine compared with telbivudine alone.11
- In patients with lamivudine-resistant chronic HBV infection, adefovir reduced serum HBV DNA levels by 4 weeks whether or not lamivudine therapy was ongoing.12
- Although more patients taking a combination of adefovir and the nucleoside reverse transcriptase inhibitor emtricitabine had normalization of ALT and suppression of HBV DNA to less than 300 copies compared with adefovir monotherapy, rates of HBeAg seroconversion were comparable in the two arms.13
- A recent study that compared tenofovir monotherapy with tenofovir and emtricitabine in combination showed comparable effectiveness for both regimens; the authors concluded that further study is necessary before either choice can be recommended as superior to the other.14
RESISTANCE: IDENTIFY EARLY, ADD ON
To minimize the likelihood of resistance and its impact, HBV DNA levels should be monitored every 3 months; at the first sign of a virologic breakthrough, therapy should be added or switched. Resistance to lamivudine is apparent early; models of treatment response indicate that resistance to lamivudine is likely if HBV DNA does not become undetectable by week 4.
In cases of lamivudine failure, adding adefovir early, when the viral load is less than 107 copies/mL, increases the probability of a virologic response.15 In the situation of lamivudine failure, I prefer adding on to switching to reduce the risk of resistance—a practice supported by the study just cited.15 In lamivudine-resistant patients, adefovir monotherapy was associated with virologic breakthrough and resistance to adefovir in 21% of patients, whereas no patient experienced virologic breakthrough or resistance when adefovir was added to lamivudine.
Successful management involves choosing the best medication up front and educating patients about the importance of taking their medication as instructed. For example, entecavir should be taken without food to maximize its bioavailability. With tenofovir, the risk of renal toxicity is low (1%),16 and can be reduced even further with a pretreatment assessment of the patient.
