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Clinical implications of drug-dependent viruses
- HIV-1 drug-resistance and drug-dependence

The evolution of drug-dependent HIV-1 variants has an obvious clinical relevance. The appearance of such variants during antiviral therapy may be an indication to modify the drug regimen. The switch to an alternative and effective drug regimen will obviously solve the problem, but we will discuss some other scenario's that specifically relate to the presence of a drug-dependent virus. Another problem is that the drug-dependence phenotype is easily overlooked in diagnostic drug-resistance tests. Improved screening assays would be of great advantage to patients as physicians could better define the therapy regimens. It is therefore important that current drug-resistance screening assays are modified to be able to detect the appearance of drug-dependent variants.

Should the treating clinician change the drug regimen when a drug-dependent HIV-1 variant is selected? One could consider stopping with the particular drug to which the virus has become dependent. However, the impact on the viral load will only be transient as archived drug-resistant and wild-type viruses will reappear quickly. Because the wild-type virus is likely to have a higher fitness (without drug) than the drug-dependent virus (with drug) it may in fact be better to continue treatment. An alternative approach would be to provide only sub-optimal amounts of the drug in question, which should lead to down-regulation of the viral load, yet prevent the reappearance of the wild-type virus. However, drug-resistant variants are likely to be favored in this context. Perhaps an alternating on/off treatment scenario provides a good treatment alternative. With drug, the drug-dependent virus will rapidly dominate the quasispecies. Without drug, the wild-type (and resistant) viruses will reappear. It is unclear if this on/off regimen is beneficial for the patient. Similar drug holidays are generally not advised, but the situation will be different with the presence of drug-dependent viruses.

An interesting difference between drug-resistant and drug-dependent viruses is at the level of the human population and virus transmission. Drug-resistant viruses are known to spread within the current epidemic [38], but this would seem impossible for T20-dependent viruses because the antiviral inducer drug is not available in the newly infected individual. The actual situation will differ for different drug-dependencies. Entry and RT inhibitor dependence will prevent the establishment of the integrated DNA provirus in the recipient. Drug-dependence that acts at later steps (e.g. Protease drugs) will also block virus replication, but only after an initial DNA provirus integration. In general, drug-dependent viruses will not be able to spread in the population, which could be another reason to try to maintain such variants in patients with a high risk profile of infecting others.

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