I am following a patient who has been on therapy for about 12 years. His therapy has included NRTI's, NNRTI's and PI's. He has had 3 major regimen changes. The last one, 6 months ago, was determined by resistance studies which indicated that PI's were no longer effective. A three drug regimen which included NRTI's and NNRTI's initially reduced his viral load from over 200,000 copies to 60,000 copies and increased his T-cell count from 140 to 250. His last tests indicated that this regimen is losing its effectiveness. What recourse is there for a patient who is no longer benefiting from NRTI's, NNRTI's and PI's? Do you think that fusion inhibitors will be available in the near future,and do you think they will be effective in this patient, who has become resistant to so many other antivirals? —mrs
Dr. Brian Conway responds:
This represents a difficult situation. Some researchers have employed regimens referred to as "Mega-HAART", which include as many as 9 agents. Generally speaking, these require the administration of over 25 tablets or capsules twice daily, a strategy that can only be maintained temporarily. Others have considered strategic treatment interruptions (STIs), but current data suggests that this approach may be hazardous to individual patients, and should only be done within the context of a clinical trial. If such a trial is recruiting in your area, you may consider this.
Clinically, a triple-class regimen that is as simple and effective as possible may be the right answer for your patient. As an NRTI, I would consider 3TC, as it is easy to administer, and some theoretical data suggest that drug pressure to maintain the M184V mutation may be beneficial (see related article by Dr. Wainberg). An alternative may be abacavir, which is perhaps more potent in this setting and having the same virologic effect. As an NNRTI, either nevirapine or efavirenz could be appropriate, depending on the risk of neurologic side effects in your patient. As for the PI, the obvious choice is lopinavir/r (Kaletra), as it would maintain activity against viruses that have as many as 7 resistance-associated mutations. In this context, it should be given as 4 capsules twice daily, to achieve maximal drug levels. The use of T-20 as an additional agent here is entirely appropriate, as it would retain activity against viruses never exposed to a fusion inhibitor. Its parenteral route of administration may be a limitation, however. (2/21/2001)
Dr. Mark A. Wainberg responds:
There is every likelihood that your patient could indeed benefit from any of the fusion inhibitors currently being tested. Indeed, the recent Chicago Conference on Retroviruses and Opportunistic Infections contained a number of abstracts that directly address this subject.
For example, T-1249 and T-20 have both been shown to be active against virtually all viral isolates that contain resistance conferring mutations in both the RT and PR coding regions and that are resistant to a wide variety of both nucleoside and non-nucleoside reverse transcriptase inhibitors as well as to protease inhibitors. These abstracts are found as presentations 14, 473, 474, 475, and 681 at the recent conference held in Chicago (click links below to view abstracts).
At the same time, it should be noted that these fusion inhibitors also select for resistance on their own, with relevant mutations located in the gp41 region of the envelope gene of HIV, which is correspondingly the direct target of the T-20 and T-1249 series of inhibitor compounds. Accordingly, while the fusion inhibitors will likely be available in the near future and may be effective against currently resistant viruses, they may also have the potential to select for resistance on their own as time goes by. (2/21/2001)
http://www.retroconference.org/2001/abstracts/abstracts/abstracts/14.htm
http://www.retroconference.org/2001/abstracts/abstracts/abstracts/473.htm
http://www.retroconference.org/2001/abstracts/abstracts/abstracts/474.htm
http://www.retroconference.org/2001/abstracts/abstracts/abstracts/475.htm
http://www.retroconference.org/2001/abstracts/abstracts/abstracts/681.htm
Return to Ask the Experts Home Page
|
