The Risk of Resistance From Treatment Interruptions

Yesterday, I reported on treatment interruptions in a large study reported in Glasgow by Bernard Hirschell. The issue of the safety of treatment interruptions has been raised and was discussed in the report. The possibility of resistance developing following repeated interruptions is a concern that has not yet been well addressed or resolved. Some interruption studies have reported not seeing resistance develop but I think this concern has not yet been adequately addressed. What is the concern? When a person stops a treatment regimen the drugs in the regimen may not all be eliminated completely at the same time. For example, if a person is taking AZT, 3TC and indinavir and stops all 3 drugs at once, it's possible that low levels of one of the drugs may linger in the blood after other drugs have been eliminated. It's possible that resistance to that one drug could develop since there isn't enough pressure on replication and viral replication could start. Repeated interruptions may increase the risk for resistance to develop. Since protease inhibitors may increase blood levels of another drug, after stopping all drugs in a regimen, it's possible that one of the drugs may have low levels of drug still in the blood after others have been eliminated. Ritonavir inhibits the elimination system more than other protease inhibitors.

This safety concern may be greater if a person is taking a NNRTI such as efavirenz or nevirapine. These two drugs have long half-lives and remain in the blood for several days at decreasing levels before being eliminated. These NNRTIs can remain in blood after other drugs have been eliminated thus having suboptimal pressure on viral replication. Repeated interruptions may lead to the development of resistance.

A person may currently be virally well suppressed on HAART but has archived resistance from previous therapy, which could have been from mono- or dual NRTI therapy or prior HAART therapy. Lingering suboptimal drug levels in blood may encourage resistance to emerge.

Many of these risks discussed above have not been truly established or eliminated as risks but are possible. Until adequate studies have addressed this question, there may be risk associated with treatment interruptions.

The risk of resistance developing following multiple treatment interruptions has not been well tested and eliminated as a possible source of concern. Please bear this in mind when considering experimenting with strategic therapy interruptions.