Important note: Information in this article was accurate in January 2001. The state of the art may have changed since the publication date.
American Foundation for AIDS Research, January 2001
David Gilden
Adding to the uncertainty about Kaletra's contribution in salvage therapy that also includes an NNRTI like efavirenz is evidence that HIV mutations conferring resistance to nucleoside analogs at the same time make the virus more susceptible to NNRTIs like efavirenz (Sustiva). At the 4th International Workshop on HIV Drug Resistance last June, Richard Haubrich of the University of California San Diego reported on this phenomenon. He noted that in a cohort of 164 treatment-experienced patients, 26% had HIV "hypersensitive" to efavirenz, 21% to delavirdine and 18% to nevirapine.1
Hypersensitivity was defined as a reduction of at least 60% in the amount of drug necessary to suppress half of a patient's HIV replication as compared to the amount needed to cut "wild type" HIV replication by half. When efavirenz formed part of a salvage therapy regimen, persons with efavirenz-hypersensitive HIV experienced an extra 0.5 log (32%) decrease in HIV levels over those whose HIV was not hypersensitive to this NNRTI. This advantage decreased over the ten months the patients were followed. The effect of the patients' regimens waned overall, and viral loads in the hypersensitive and non-hypersensitive groups converged.
Then there is the randomized, controlled trial ACTG 364, described last winter at the 7th Conference on Retroviruses and Opportunistic Infections.2 This trial was conducted in people who had viral loads above 500 copies/mL and extensive treatment histories on nucleoside analogs but no prior protease inhibitors or NNRTIs. All received two nucleoside analogs plus either efavirenz, the protease inhibitor nelfinavir or both. The efavirenz and combination arms did significantly better than the nelfinavir arm, whose proportion with viral loads below 400 copies/mL rapidly dropped off after week 16. At week 40-48, the proportion below 400 was 35% for nelfinavir, 60% for efavirenz and 74% for efavirenz plus nelfinavir. (The proportions with viral loads below 50 copies/mL at week 40-48 were 22%, 44% and 67%, respectively.)
The efavirenz superiority in this trial might indicate merely that using a once-a-day drug like efavirenz with mild mental side effects may yield better patient adherence to dosing schedules than a three-times-a-day, chronic diarrhea-causing drug like nelfinavir. But the effect of nucleoside analogs in this cohort was no doubt limited. It is hard to imagine why efavirenz resistance would not quickly arise without strong support from these nucleoside analogs. An association of nucleoside analog resistance with hypersensitivity to efavirenz would help to explain ACTG 364's outcome.
Be that as it may, the indications are that hypersensitivity to efavirenz made at best a very limited contribution to the results: As in the San Diego study, the potency of efavirenz in salvage therapy in this trial diminished over time compared to the nelfinavir-efavirenz combination arm. At 16 weeks, the proportion below 50 copies/mL in the efavirenz arm peaked at about 58%. In the combination arm, the week 16 percentage was about 60% and continued to increase through week 32. Countering any suggestion of a long-term role for efavirenz hypersensitivity, predictors of viral load below 50 at week 48 included having HIV with less nucleoside analog resistance rather than more.
Note that although benefits obtained from efavirenz-based salvage regimens may be debatable, the results for initial therapy are much more impressive. For example, in trial 006 performed by efavirenz developer DuPont Pharmaceuticals, 68% of volunteers starting on an AZT/3TC/efavirenz regimen had viral loads below 50 copies/mL after one year. Fifty-nine percent still had this level of success after 112 weeks.3
000110
AM010101
Copyright © 2001 by the American Foundation for AIDS Research (amfAR) and first displayed on amfAR's Treatment Directory web site (http://www.amfar.org/gl). They appear on AEGIS with amfAR's permission. Organizations wishing to reprint or redistribute these materials should request authorization from amfAR's Department of Treatment Information Services (212/806-1600).
AEGiS is made possible through unrestricted grants from Boehringer Ingelheim, iMetrikus, Inc., the National Library of Medicine, and donations from users like you. Always watch for outdated information. This article first appeared in 2001. This material is designed to support, not replace, the relationship that exists between you and your doctor.
AEGiS presents published material, reprinted with permission and neither endorses nor opposes any material. All information contained on this website, including information relating to health conditions, products, and treatments, is for informational purposes only. It is often presented in summary or aggregate form. It is not meant to be a substitute for the advice provided by your own physician or other medical professionals. Always discuss treatment options with a doctor who specializes in treating HIV.
Copyright ©1990, 2001. AEGiS & the Sisters of Saint Elizabeth of Hungary. All materials appearing on AEGiS are protected by copyright as a collective work or compilation under U.S. copyright and other laws and are the property of AEGiS and the Sisters of Saint. Elizabeth of Hungary, or the party credited as the provider of the content.
