March 25, 2008

Charting the Future of Protease Monotherapy

It has been suggested that using a Norvir (ritonavir)-boosted protease inhibitor (PI) without the use of other antiretrovirals to treat HIV is less effective, and more likely to cause drug resistance, than standard three-drug regimens in clinical trials. However, in an editorial published in the March 30 issue of AIDS, researchers argue that PI monotherapy has the potential to guard against side effects and preserve future treatment options, thereby keeping it in the limelight as a potential treatment option that deserves further research.

The option of using a single protease inhibitor—boosted with a low dose of Norvir—was initially proposed by Joseph Gathe, MD, a clinician and researcher in Houston. In 2003 Gathe first published data showing that Kaletra (lopinavir/ritonavir) used without other ARVs was effective in reducing viral loads to less than 50 copies in people starting HIV treatment for the first time.

More recently, the Abbott-funded Monark study compared Kaletra monotherapy to Kaletra plus Combivir (zidovudine plus lamivudine) in 136 first-time treatment takers. Unfortunately, after 48 weeks of treatment, only 67 percent of people on Kaletra monotherapy had viral loads less than 50 copies compared with 75 percent of people on the three-drug regimen. The difference was statistically significant, meaning that it was too large to have occurred by chance. What’s more, three people who had a virologic failure on the monotherapy arm developed HIV drug resistance, compared with just one person on the triple-drug regimen.

Monark’s disappointing results, however, have not quashed the possibility of ARV monotherapy. Andrew Hill, MD, of the University of Liverpool in the United Kingdom, and his colleagues argue in their editorial that, despite the uneven performance of Kaletra monotherapy in Monark and three other studies, the relatively high efficacy seen and the low number of people developing resistance is still remarkable for a single-drug regimen.

They also point out that 90 percent of people on monotherapy whose virus dropped to less than 400 copies by the fourth week of treatment in the Monark study went on to maintain undetectable viral loads for 48 weeks of treatment. Because of this, they reason, it may be possible to attempt a short course of monotherapy in treatment-naive patients, and quickly determine who is likely to respond, thus guarding against the development of drug resistance.

Moreover, Hill and his colleagues highlight a strategy used successfully in the monotherapy trials. In Monark and other trials, if a person on Kaletra monotherapy first achieved an undetectable viral load, but then had a return of detectable virus, they had their treatment “intensified” by adding two nucleoside reverse transcriptase inhibitors, such as Combivir. In such cases, people were almost always able to achieve an undetectable viral load again and thereby prevent the development of drug resistance.

“A strategy of PI monotherapy for most patients, with intensification for the few who need it, may be attractive for many patients and clinicians,” writes Hill and his colleagues.

Several new monotherapy trials are moving forward—some using Kaletra, and others using Reyataz (atazanavir) or Prezista (darunavir) boosted by Norvir. In most cases, people are being treated initially with three-drug regimens to reduce their viral loads to undetectable before switching to monotherapy. Hopefully, monotherapy will be associated with better long-term efficacy in these studies than in trials completed thus far.

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Previous Comments:

Tim Horn, AIDSmeds.com, New York, NY, 2008-03-27 09:22:31
DaveR -- Apologies for the confusion. I have edited the sentence in question so that the reporting is more clear.

Tom, , 2008-03-26 20:49:40
Assuming that people with strong anti-HIV1 immune responses are selected for the studies, this is an idea that is long overdue. We know, from twenty years of clinical studies, that the people who do the best are those with the highest CD4+ T cell nadirs. And we have seen positive results in Induction-Maintenance studies. So, I would expect a select group of patients to realize a benefit from these types of studies. Keep me informed of the studies that open. Thanks!

DaveR, NYC, 2008-03-26 18:44:14
why are Monark's results referred to in this article as "questionable?" There's nothing in the article that suggests any problems with his study . . . Who wrote the article? I copy the curious lines below - More recently, the Abbott-funded Monark study compared Kaletra monotherapy to Kaletra plus Combivir (zidovudine plus lamivudine) in 136 first-time treatment takers... Monark’s questionable results, however, have not quashed the possibility of ARV monotherapy.