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On the face of it, combination therapy for management of chronic hepatitis B would seem to make a lot of sense. Combination therapy refers to the approach where more than one medication is used to manage the same disease.

For hepatitis B virus (HBV) therapies, there are really just two basic categories: the injected interferons and the orally available polymerase inhibitors (antivirals). Interferons are relatively large molecules (proteins) with multiple cellular targets and complex modes of action. Polymerase inhibitors are small molecules that are nucleoside/ tide analogues with specific known targets.

The polymerase is the viral protein that makes new viral DNA. Doctors have already tried combinations of interferons with the polymerase inhibitor lamivudine. The clinical endpoints were reductions in viral load and eAg seroconversion.

Many early results were disappointing, possibly because those treated had already failed to respond to one or the other drug. Although there was some evidence of increased benefit with the combination, the enhancements were more incremental, rather than dramatic. This may be due to the design of most combination trials that made it difficult to detect favorable interactions.

On the other hand, perhaps the interferons and antivirals were actually working on the same viral targets, thus a combination of the two would not result in significant “synergy.” Finally, it may be that effective HBV combination therapy may require more than two drugs.

Other combination trials used two antivirals with the goal of enhancing antiviral efficacy and increasing eAg seroconversion rates – again, with lackluster results. This is puzzling since expert groups generally agree that combinations are very logical.

If combination therapy is abandoned or determined to not be useful for HBV, it would be something of a first in the chronic infectious disease world.

In HIV, for example, combination therapy is the norm. It would now be generally considered irresponsible to use only one antiviral medication in managing HIV.

That’s because the endpoint of combination in the management of HIV is the avoidance of drug resistance, not reductions in viral load.

Think about it. If an antiviral such as lamivudine can itself effect a 5 log (105 or 100,000 fold) reduction in virus load, it’s hard to improve upon that by just adding another drug. The first drug is probably getting into most of the infected liver cells, and with its affinity for (ability to bind to) the viral polymerase, it will only get in the way of a slightly better drug.

Perhaps, a mediocre antiviral drug in combination with a better one will result in a virus reduction that falls somewhere in between the two.

But that is disappointing if the only endpoint of value is reducing viral load. The question is then, what should be the goals of combination therapy? Efficacy is ideal, but may be unsuited for the types of combinations currently possible. A more logical goal may be improving durability of a drug’s antiviral effect and/or, more reasonably, avoiding resistance.

This is no small point. The oral medications for HBV are pretty good. Their Achilles heel is that mutant virus, resistant to the drugs, develops.

Thus, an otherwise good drug loses its value, and doctors are reluctant to use a “good drug” prematurely in chronically infected individuals. They must, therefore, try to guess and calculate the right time to intervene. If combinations can reduce (or, ideally, eliminate) the emergence of resistance, a less effective drug can continue to be used.

Using drugs in sequence (one after another) is not the same as using them in combination, when it comes to dealing with resistance. This is for statistical reasons. If a person takes drug #1 and develops resistance, and then this drug confers partial resistance to drug #2, the mutant virus is just as likely or, in some cases, even more likely to become resistant to the second drug. In combination therapy, where drugs are taken at the same time, a virus must become resistant to both drugs simultaneously. Hence, combination therapy creates a far tougher hurdle than using single drugs in sequence.

When effective drugs with diverse mechanisms become available, non-resistance endpoints should be considered. But until then, it seems most logical to use antivirals that get the virus load as low as possible and use combinations to suppress resistance.

Combination therapy to suppress resistant virus should thus be considered to be a worthy goal, itself, since resistance is one of the greatest threats to the early use of antivirals.

Timothy Block, PhD, Hepatitis B Foundation and Drexel U. College of Medicine Timothy Shaw, Victorian Infectious Diseases Reference Laboratory Stephen Locarnini, MD, PhD, Victorian Infectious Diseases Reference Laboratory