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Treatment Briefs

May, 1998


Efavirenz's Complications

DuPont Merck, which is soon to become simply DuPont Pharmaceuticals as the result of a recent buyout by DuPont, sent out a warning on May 21 concerning use of its new NNRTI (nonnucleoside reverse transcriptase inhibitor) efavirenz (Sustiva) along with the protease inhibitor saquinavir (Fortovase). Preliminary findings in an HIV-negative cohort indicate that efavirenz cuts saquinavir blood levels by 60% over the course of a day. This reduction stems from efavirenz's stimulation of the CYP3A4 liver enzyme that degrades saquinavir. The company is urging patients not to take the two drugs together until further information on correct dosing is available. An exception to this warning concerns use of the dual protease inhibitor combination saquinavir/ritonavir (Norvir). This combination is the most common saquinavir regimen. It is taken by 22% of the persons in the efavirenz expanded access program. Ritonavir strongly inhibits liver enzymes and may reverse efavirenz's effect on saquinavir, but no data are yet available to determine the result of taking the three drugs together. One possibility that some doctors are trying is to double the saquinavir dose to 800 mg twice a day when efavirenz is administered with ritonavir/saquinavir.

The company intends to present information on the interaction between efavirenz, ritonavir and saquinavir this June-July at the World AIDS Conference in Geneva. Data on the interaction between nelfinavir (Viracept) and efavirenz also will be made public at the Conference, as will the results of a large study comparing the "protease sparing" regimen of AZT/3TC/efavirenz to both indinavir/efavirenz and AZT/3TC/indinavir. Note that DuPont Merck has long recommended increasing the indinavir dose by 25% (to 1,000 mg three times a day) when administering the protease inhibitor indinavir along with efavirenz.

DuPont Merck also expects to file by mid-June for FDA approval of efavirenz for treating HIV infection, whether as first-line or salvage therapy, as part of a multidrug regimen.

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Upjohn to Sell Out?

Rumors, partially confirmed by company officials, indicate that Pharmacia & Upjohn is considering selling its HIV drugs or at least finding a partner for their further development. The product line includes first of all the FDA-approved NNRTI delavirdine (Rescriptor). Sales of delavirdine, which went on the market a year ago, have been disappointing. Delavirdine has suffered in the market mostly because of the lack of trial data demonstrating a solid anti-HIV effect and an inconvenient dosing schedule consisting of four tablets three times a day (see Treatment Issues, April/May 1997). Its skin rash problems are less serious than those of the competing NNRTI nevirapine, however.

Upjohn has continued to research the drug, especially after a trial of AZT/3TC/delavirdine in a treatment-naïve cohort did find HIV suppression comparable at least to nevirapine, if not efavirenz. Ongoing delavirdine trials test various three and four drug delavirdine-containing regimens, a pediatric formulation, and delavirdine's contribution to salvage therapy regimens.

Upjohn also is developing an NNRTI designed to be effective against delavirdine-resistant HIV. The new NNRTI could be combined with delavirdine to form a potent one-two antiretroviral knockout, but this delavirdine backup agent has not yet undergone human testing.

P&U's most intriguing anti-HIV drug right now is its experimental protease inhibitor, which because of its unique structure, should have activity against HIV resistant to the currently available protease inhibitors. Initial dose-escalation studies of this compound, designated PNU140,690, have been completed and a dose of 1,500 mg three times a day selected for further study. This dose requires taking a total of 30 tablets. Upjohn is developing a 300 mg pill in an attempt to reduce the pill burden -- if patients can swallow tablets that large -- and also is exploring formulations that increase the drug's absorption by the intestines.

A salvage therapy trial is about to commence, too, covering individuals with viral loads over 5,000 after taking indinavir or ritonavir plus two other anti-HIV medications for at least six months. Volunteers will replace their previous protease inhibitor with PNU140,690 for four weeks before being allowed to switch the other two drugs too. This approach, which is virtual monotherapy, may favor the development of drug resistance. P&U will have to show that it believes in this drug to get volunteers to swallow a risk like that along with all the tablets. Putting it up for sale is not a sign of faith, though.


Glaxo Buys in

While Upjohn moves to reduce its presence in the HIV arena, Glaxo just gets in deeper. The company already has two new antiretrovirals, abacavir and amprenavir, that will reach the market by the end of this year. In addition, it recently bought a family of sturcturally related NNRTIs from Hoechst Marion Roussel to complete its anti-HIV product range.

The original lead NNRTI was HBY 097, which has already been tested in a small number of humans and looked very good in its initial run-through. Viral load drops of greater than one log (90%) after 14 days of monotherapy were observed, without the appearance of drug-resistance mutations in participants' HIV. During a 1996 interview with Treatment Issues, famed HIV drug discoverer Eric DeClercq said of HBY 097, "It's...within the top few compounds that we have analyzed ourselves. I hope it will be developed."

But development of HBY 097 was in fact terminated. The compound's short half-life in the body and large required dose led to an onerous dosing schedule and concerns about possible toxicities and interactions with other drugs. Glaxo is now starting back at the beginning with the compounds, evaluating candidate NNRTIs for anti-HIV activity and drug-resistance profiles.


Viagra and Protease Inhibitors

Everyone who uses Pfizer's new anti-impotence drug Viagra should know by now that it should not be used with poppers, or indeed any other nitrate compound (such as nitroglycerin, which is administered during heart attacks). Nitrates and Viagra have complementary effects, and when present together can lead to dangerous drops in blood pressure.

Many people with HIV are still wondering, though, about Viagra's effect on protease inhibitors since Viagra is metabolized in the liver by the same CYP3A4 enzyme that protease inhibitors are. According to Pfizer, there should be little effect on the protease inhibitor levels in the body, but on the other hand, the protease inhibitors may have a major effect on Viagra. Drugs that strongly inhibit CYP3A4, including ritonavir, will sharply retard Viagra's breakdown. Persons taking ritonavir and other such drugs (nelfinavir also inhibits CYP3A4) should first try Viagra at 25 mg instead of the usual 50 mg. Future doses can be adjusted upward based on an individual's experience with efficacy and side effects (headache, facial flushing, digestive upset and impairments in color vision are the most common).


KS Drug Goes to FDA

Ligand Pharmaceuticals has filed a request for FDA approval of Panretin gel (9-cis retinoic acid) as a topical treatment for Kaposi's sarcoma. The submission is based on two 12-week phase III trials. In one conducted in North America, 35% of those applying Panretin gel showed some improvement in index KS skin lesions compared to 18% of those applying a placebo. The response rate in this 268-person trial increased to 49% during an open-label extension phase of the trial. In an international trial, the 12-week response rates were 42% and 7% for Panretin versus placebo.

In a further analysis of the North American data, Ligand found that the response rate was independent of the strength of concurrent anti-HIV therapy. This is a major issue since many opportunistic infections improve after people switch to highly active antiretroviral therapy -- see the article on NTZ and cryptosporidiosis in this edition of Treatment Issues.

A French study published in the May 7 edition of the journal AIDS looked at the effect of initiating protease inhibitor therapy in nine persons with HIV-related KS. In eight of the nine, lesion clearance or regression occurred along with reduction in levels of the KS herpes virus. But 74% of the participants in the Panretin North American trial were taking protease inhibitors, including 82% in the placebo arm. Panretin's benefit appeared regardless of antiretroviral therapy.

Ligand is also developing a capsule form of 9-cis retinoic acid for systemic KS therapy. In a phase II trial reported in May at the annual meeting of the American Society of Clinical Oncology, an intent-to-treat analysis found a 37% response rate after 16 or more weeks of treatment. Equivalent results were obtained in another phase II trial, which was presented at the AIDS Malignancy Conference in April. The oral and topical formulations may have had the same results in these trials, but Ligand argues that the capsules will be easier to use for persons with large numbers of KS lesions. Oral Panretin also may be effective against KS in internal organs, although this remains to be demonstrated.

An open-label phase I/II trial that combines Panretin capsules with alpha interferon therapy is now ongoing. Ligand plans to ask the FDA for permission to market the oral version sometime next year.




  
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This article was provided by Gay Men's Health Crisis. It is a part of the publication GMHC Treatment Issues. Visit GMHC's website to find out more about their activities, publications and services.
 

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