While other mutations in the viral RT may also affect viral "fitness", none apparently does so to as great an extent as the 184V substitution. This helps explain why patients who are taken off 3TC treatment may quickly lose the presence of detectable 184V-containing viruses and why this happens to a lesser extent with mutations associated with resistance to other drugs, such as AZT. In addition, the fact that three distinct, and possibly independent, effects are associated with the 184V substitution suggests that this mutation may possibly confer clinical benefit by rendering HIV less capable of undergoing rapid replication and, by inference, of mutating into new forms. The "184V fidelity hypothesis" articulates that such viruses might have a reduced capacity to become resistant to drugs that impose a "high genetic barrier", such as certain protease inhibitors, or to escape immunologic effector mechanisms as quickly as do wild-type viruses.
A number of clinical studies now suggest that patients who harbor the 184V mutation may continue to benefit from treatment with 3TC, in spite of the fact that no possible anti-viral effect can continue to be exerted by this compound. Therefore, the major benefit of 3TC, in the aftermath of such resistance, may be to maintain antiviral pressure so that the 184V mutation remains in place. In this context, it could be argued that patients who harbor this mutation might benefit from a switch in therapy from 3TC to either ddI or abacavir, since both of these drugs might also serve to maintain pressure to keep the 184V substitution, while at the same time exerting an anti-viral effect. This concept can and should form the basis for clinical trials in which patients with the 184V mutation would be randomized to a number of alternate regimens that would or would not be expected to maintain the 184V mutation.
