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Confab’s Clarion Call: “Get It Down and Keep It Down,” with Hints–And Only Hints–Of How To Get There

Heyday for RNA

At long last, the data nearly justifies the hype! Activists, doctors and researchers were almost giddy with excitement following the 3rd Conference on Retroviruses and Opportunistic Infections in Washington, D.C. Data on new anti-HIV therapies suggest possibilities for a more significant impact on AIDS than ever before. As one journalist in attendance pointed out, though, follow-up studies will undoubtedly limit some of the early excitement.

Get Thee to a Protease Inhibitor?

Abbott Laboratories presented data on its protease inhibitor, ritonavir (Norvir), in patients with fewer than 100 CD4+ cells. The study, modeled on TAG’s large, simple trial proposal, looked at an advanced patient population–rather than the large numbers of patients–to increase statistical power. Patients were randomly assigned to receive ritonavir or a placebo in addition to their other anti-HIV therapy. Virologic and immunologic information was collected on a subset of participants.

After nearly seven months of follow-up, the death rate in patients taking ritonavir was about half that of patients taking the placebo (p=0.021). While ritonavir caused some nausea, vomiting and diarrhea, the drug decreased the risk of hematologic abnormalities.

These study results are also remarkable because they demonstrate that clinical endpoints can be collected faster than surrogate endpoints. When the study began, Merck was ahead of Abbott in the protease development race. When Abbott submitted its application for approval in December of 1995, however, Merck had to scramble to catch up. Merck has since submitted an application for Accelerated Approval, while Abbott is applying for full approval. The FDA Advisory Committee, with special guest appearances by TAG members Spencer Cox and Lynda Dee, will consider the two applications on February 29th and March 1.

Hitting it Early. Hitting it Hard

Several researchers presented data from Merck on its protease inhibitor, known as Crixivan (indinavir). In patients with CD4+ cell counts 50-400, HIV RNA counts of > 20,000 copies/ml, and more than six months of previous AZT therapy, the combination of indinavir+AZT+3TC reduced plasma RNA levels to < 500 copies/ml in 90% of patients. CD4+ cell counts on the three-drug combination increased by an average of 125 cells. The only major side effect was elevated bilirubin levels. So far, these patients have been followed for up to six months with no viral rebound–although the number of patients available for analysis at 6 months is a very small subset of the total.

Danger, Will Robinson

Patients who are considering mixing protease inhibitors should be warned of the possibility of severe pharmacologic interactions that could be dangerous. Data have already been presented showing that ritonavir changes the way that Roche’s saquinavir is processed by the body. The same kind of interaction exists between all protease inhibitors currently in large-scale studies, and with the non-nucleoside RTIs nevirapine and delavirdine. Already there are anecdotal reports of patients experiencing severe liver toxicities while combining ritonavir and indinavir. Merck is very responsibly warning patients not to mix these drugs until further studies of the interactions have been completed. Protease inhibitors–notably saquinavir and ritonavir–also have important interactions with other drugs (e.g., rifabutin, rifampin, ketoconazole, Prednisone) which may impair their effectiveness.

Finally, there is no word on the price of these new anti-protease drugs. As was noted in last month’s TAGLine, many state ADAP programs are simply unable to afford saquinavir, which wholesales at some $5,800/patient/year. With more compelling data to support the use of these new protease inhibitors, it is unlikely that ritonaivr or indinavir will be any less pricey. To help make sure that the promise of these drugs is fully realized by wide accessibility, readers can contact TAG’s Legislative Affairs Committee by calling Gregg Gonsalves at (212) 533-9740. TAG is also part of a coalition to ensure that New York State’s ADAP program has the funds needed to include these drugs in its formulary.

In other news, virologists from Upjohn (now Pharmacia Upjohn) made an impressive presentation on the predictive value of a viral load assay that is very similar to Hoffmann-La Roche’s RNA PCR test. Even activists who have been skeptical about the over-promoted utility of these assays were convinced that the company had made a compelling argument that therapy-induced changes in plasma viral RNA can have important implications for the clinical status of HIV-infected patients.

Results from three studies of delavirdine, the company’s non-nucleoside reverse transcriptase inhibitor, were presented. Without regard to what therapy patients were on (participants could have been taking any of several doses of delavirdine, AZT, ddI, AZT/delavirdine or AZT/ddI), patients who experienced at least a .5 log drop in plasma RNA after 8 weeks of antiretroviral therapy had a significantly reduced risk (2 1/2-fold) of developing a new opportunistic infection or dying at 6-18 months. Larger decreases in viral burden at 8 weeks caused more profound reductions in the hazard of a new OI or death. The size of the CD4 response, interestingly, was not predictive of the hazard of developing a new OI or dying. Individuals earlier in the course of disease, who had not taken previous antiretroviral therapy, required a smaller reduction in plasma RNA to show clinical benefit (about .3 log reduction), while those later in disease who had been heavily pre-treated required a slightly larger reduction (.8 log decrease).

These compelling results undoubtedly require verification by applying the same analysis to other large data sets. Also, completion of the CPCRA study of the clinical significance of therapy-induced changes in plasma viral load, where patients are randomly assigned to receive care using the viral load information or not, will help to elucidate exactly how clinically important the plasma RNA information is. Should these results hold up, patients and physicians would potentially have an important new predictive tool in their arsenal. It is not yet clear that average changes in viral load following use of an antiretroviral therapy should be used as a final determination of the utility of new therapies. Such surrogate markers are always insensitive to toxicity, and may also miss therapies which bestow a clinical benefit that is not mediated through a strictly antiviral mechanism.

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