Monotherapy vs multiple-drug therapy: The experts debate
Multiple-drug therapy is the wave of the future
By Pierre M. Gholam, MD
A concise rationale for multiple-drug therapy is that resistance to monotherapy will occur eventually, with serious consequences in some patients and grave public health implications over the long term. Data from France and Australia indicate that multidrug-resistant HBV is a reality in individual cases. Resistance may be less likely when combinations are used, although little evidence exists at present to support this contention.
COMBINATION THERAPY IS COMMON SENSE
Much of the evidence supporting combination therapy for HBV is common sense:
- Most patients with HBV infection require treatment indefinitely, and duration of therapy that is not finite will inevitably lead to resistance.
- Your first shot is your best shot. Once resistance develops, treatment response will eventually decline.
- Sometimes the stakes are too high to risk breakthroughs. In particular, in patients who have cirrhosis and in those awaiting or following liver transplant, flares and recurrences can have disastrous consequences.
Treatment duration and resistance
As Dr. Gish demonstrated, tenofovir and entecavir are highly potent drugs that suppress viral loads effectively and have high genetic barriers to resistance. On an intent-to-treat basis, HBV DNA levels below the threshold level of detection are achieved at impressive rates with tenofovir and entecavir at 2 years in patients who are either HBeAg negative or positive.5,6,17 When the analyses are limited to patients who actually received the drugs, suppression of HBV DNA to undetectable levels exceeds 90%. Resistance to tenofovir is 0% at 2 years,3 and resistance to entecavir is 1.2% at 5 years.5
Although such data appear to favor monotherapy, most HBV-infected patients who commit to treatment will be treated indefinitely; this applies to patients who are HBeAg negative, who constitute most HBV-infected individuals in the United States and worldwide, or HBeAg positive. There are no established end points for treatment termination in HBeAg-negative patients. The only treatment termination end point that is deemed acceptable in HBeAg-positive patients is a period 6 to 12 months after the loss of HBeAg and the development of antibody to HBeAg, or e antigen seroconversion. Even after many years of treatment that includes the first-line agents tenofovir and entecavir, the likelihood of achieving this end point is fairly low.2,5,18
Adherence is also a consideration. Studies of patients with hypertension, heart disease, and other chronic diseases have shown that strict adherence to therapy over decades is unlikely. The same adherence pattern probably applies to the treatment of chronic HBV infection.
Antiviral drugs used in the treatment of chronic HBV infection are associated with certain resistance mutations that confer additional risk of developing resistance to a subsequent drug. Furthermore, with indefinite duration of therapy, it is realistic to expect that resistance will develop.
Other factors play roles in the development of resistance:
- Mutant viruses. We do not fully understand the potential problem of transmission of mutant viruses. This phenomenon is becoming apparent in endemic areas where treatment-naïve patients harbor mutant viruses acquired through sexual contact with HBV-infected patients who have been treated and in whom the virus has subsequently mutated.
- Barriers to resistance. The genetic barrier to resistance for a single drug will eventually be overcome. It may take longer than it took for adefovir, which is associated with a 30% rate of resistance at 5 years.3 It may take a much longer time for entecavir or tenofovir, but resistance is a biological certainty and we need to contend with it. With human immunodeficiency virus (HIV) infection, we are able to genotype for mutations and tailor treatment accordingly. This strategy is not currently recommended for HBV infection, partly because it is expensive and not routinely available.
- Misuse of therapy. Finally, wider use of antiviral agents for the treatment of HBV may lead to wider misuse, and therefore more resistance. Realistically, not every practitioner will start therapy with entecavir or tenofovir; many of the less potent agents have associated rates of resistance, and these in turn may confer an additional risk of resistance if tenofovir or entecavir is eventually used.
Declining response
Colonno et al19 studied the likelihood of entecavir resistance developing in patients with existing lamivudine resistance. The likelihood of resistance to entecavir at 3 years was 1.2% among patients who had never been exposed to lamivudine. Among patients in whom lamivudine resistance had developed and who were subsequently started on entecavir, resistance to entecavir was 32% at 3 years.19 Resistance has consequences; 25% of lamivudine-resistant patients develop viral breakthrough.
Dr. Gish and I agree that the addition of adefovir to lamivudine is better than switching to adefovir monotherapy in the case of lamivudine failure. Compared with switching, the adefovir-lamivudine combination leads to a lower incidence of virologic breakthrough, a lower likelihood of adefovir resistance over time, a greater probability of achieving undetectable levels of HBV DNA (< 35 copies/mL), and a lower cumulative rate of resistance.20 The superiority of combination therapy in achieving undetectable levels of HBV DNA confers a lower risk of developing resistance over time; by year 4, the likelihood of adefovir resistance is only 4% among lamivudine-resistant patients treated with the combination of adefovir and lamivudine.20
In a study of nucleoside analogue–experienced patients who did not achieve viral suppression, response to tenofovir, defined as HBV DNA less than 400 copies/mL at month 12, was 85% overall and only 30% in adefovir-resistant patients.7 These data demonstrate that, if not starting with combination therapy, it is preferable to initiate treatment with a potent drug that is highly successful at HBV DNA suppression. A second monotherapy will be less successful than the initial attempt.
Consequences of resistance
The consequences of resistance in patients with cirrhosis are significant, prompting strong consideration of combination therapy as a potential means to avoid resistance.
One consequence is a well-documented potential for decompensation in the setting of new-onset resistance as a result of flares. Another is post-transplantation recurrence of HBV, leading to poor outcomes. These risks converge in the patient who is awaiting liver transplantation, in whom combination therapy seems to make the most sense to prevent the development of a flare and a recurrence of HBV infection after transplantation.
WHO SHOULD RECEIVE MULTIPLE-DRUG THERAPY?
The American Association for the Study of Liver Diseases recommends combination therapy as the preferred rescue therapy for primary failure of a first-line agent, citing the possibility of resistance with switching in some circumstances and the superiority of adding on as opposed to switching.2 No data clearly support de novo multiple-drug therapy. Although a number of studies have failed to show an advantage of combination therapy over monotherapy, they were of relatively short duration and focused primarily on viral suppression rather than the occurrence of resistance over time. Long-term studies are needed to determine whether combination therapy is an option de novo.
De novo multiple-drug therapy might be reasonable if a patient is at high risk for resistance—for example, for patients with extraordinarily high levels of HBV DNA or in whom resistance can lead to dire consequences, such as patients with cirrhosis or pretransplant patients.
The HIV pandemic serves as a paradigm for combination therapy. Many agents used to treat HBV infection also have anti-HIV effects; their use as monotherapy should be avoided in order to prevent the development of HIV drug resistance. HIV regimens that include only one HBV antiviral agent with a low genetic barrier to resistance (eg, lamivudine) should also be avoided in order to minimize the risk of HBV drug resistance.
I agree with Dr. Gish that cost and potential toxicity, especially renal toxicity, may limit the widespread use of combination therapies.
