The Bay Area Reporter - September 23, 1998
Stephen J. LeBlanc

On September 18, the U.S. Food and Drug Administration (FDA) granted accelerated approval to the 11th drug brought to market specifically to combat HIV. The drug, brand named Sustiva (generic name efavirenz and research code DMP-266), is a non-nucleoside-analog reverse transcriptase inhibitor (NNRTI), and is the third drug approved in that class. Clinical trails conducted by the company suggest that the drug is at least as effective as the other NNRTIs, is associated with fewer serious side effects, and because of its long half-life can be taken once a day.

While AIDS patients have welcomed the availability of Sustiva, some doctors, scientists, and activists have raised serious questions about marketing claims made for the drug, and have expressed outrage at the price. With a price to AIDS Drug Assistance Programs (ADAPs) of at least $3,942 per year - and a 20 percent higher "list wholesale" price to pharmacies - Sustiva is about 75 percent more expensive than other NNRTIs and nearly as pricey as the most popular protease inhibitor. Activist groups have warned that at the price announced for the drug, reimbursers and ADAPs may delay or not cover Sustiva, and may instead steer patients wanting to use an NNRTI to more cost-effective alternatives.

With Sustiva's approval, there are now 13 available anti-HIV prescription drugs: the five nucleoside analogs d4T (Zerit or stavudine), 3TC (Epivir or lamivudine), ddI (Videx), AZT (also known as Retrovir, zidovudine, or ZDV), and ddC (Hivid), the four protease inhibitors Crixivan (indinavir), Nelfinavir (Viracept), Norvir (ritonavir), and Fortovase (Invirase or saquinavir); the three NNRTIs Viramune (nevirapine), Rescriptor (delavirdine), and now Sustiva (efavirenz or DMP-266); and hydroxyurea (Hydrea), an anti-cancer drug not FDA-approved for use against HIV, but now widely prescribed for its demonstrated anti-HIV effect.

Protease sparing combo?

Although just approved, Sustiva has for several months been promoted by its manufacturer DuPont Pharmaceuticals Company as the foundation for "a protease sparing" combination. But some respected doctors and scientists have attacked the idea of "sparing" protease inhibitors. They have argued that everything we know about treating infectious diseases indicates that the most successful strategy is to use the strongest possible combination of drugs that can be tolerated and use them together to suppress the disease organism enough so that it cannot develop resistance. [See Cocktail Therapy, Bay Area Reporter 12/07/95, available at www.actupgg.org/BAR/art0015.html.]

"I don't agree with the idea of 'sparing' protease inhibitors," Dr. Marcus Conant told several hundred attendees at a San Francisco treatment forum last fall. "What are you 'sparing' them for? We know from other infectious diseases, like tuberculosis, that when you decide to treat you should treat aggressively enough to completely suppress the disease organism. What you absolutely don't want to do is start off with a less-effective combination and then try to switch to a stronger combination when you fail. That is a recipe for creating multi-drug resistant virus."

When contacted for this article, Conant reaffirmed his position and continued: "We have data in Geneva showing sustained effectiveness from protease inhibitors going out to three years, but nothing similar on the protease inhibitor sparing combinations. Now, there are patients who can't take protease inhibitors, perhaps up to 7 to 10 percent with severe side effects, but I don't think you should begin therapy with that perspective. You should start therapy using the most aggressive combination possible and can fallback to a combination where there is less data if necessary. Physicians and patients should be very suspect of drug companies, like DuPont or Glaxo-Wellcome, who are promoting 'protease sparing' combinations for marketing reasons, rather than because we have any medical data or knowledge suggesting that is the best strategy."

DuPont warns that Sustiva must be used in combination with other potent anti-HIV drugs or else resistance will develop quickly. A critical question for people considering Sustiva is whether to use it with two nucleoside analogs (such as d4T + 3TC) in a three-drug combination, or whether to use it with two NAs plus one or two protease inhibitors. DuPont has not conducted any studies comparing Sustiva used with nucleoside analogs, versus Sustiva used with protease inhibitors and nucleoside analogs. When question by AIDS activists why such a study was not done, DuPont has not given a sensible answer. With the announced price of Sustiva, some activists, including this author, believe the answer has become clear - corporate greed.

In company press releases, marketing surveys, and arguments to state ADAPs, DuPont has pitched Sustiva as a replacement for a protease inhibitor, and has used that rationale as a justification for charging a protease inhibitor price.

Warning: don't use without a protease inhibitor

However, one study, not conducted by DuPont, suggests that Sustiva is best used in a combination with a protease inhibitor. ACTG (AIDS Clinical Trial Group) 364 is an ongoing 48-week study in 196 nucleoside analog (NA) experienced patients. The study compared three different combinations: Sustiva plus new NAs, Nelfinavir (a protease inhibitor) plus new NAs, or Sustiva plus Nelfinavir plus new NAs. At 24 weeks of treatment, nearly 80 percent of patients on the Sustiva plus Nelfinavir plus new NAs arm had viral loads less than 500, while in the Sustiva plus NAs arm, just 60 percent of patients had viral load of less than 500.

Also of concern, in the Sustiva plus NAs arm, the number of patients with viral loads of less than 500 decreased from a high of 80 percent at week eight to 60 percent at week 24 with the slope of the curve continuing downward. This suggests that resistance to Sustiva was quickly developing in a substantial number of patients. These results were submitted by DuPont at the request of the FDA and are available at www.Sustiva.com/Sustiva1/pdf/label12c.pdf, Figure 2.

Because DuPont chose not to perform any studies itself comparing Sustiva with a protease inhibitor to Sustiva without a protease inhibitor, this one uncompleted ACTG study provides the only data patients have to help them answer the question of whether to use Sustiva to "spare" protease inhibitors, as the company suggests, or in combination with protease inhibitors.

A fair conclusion from this study suggests that, at least for people who have already used NAs, using Sustiva alone will cause 40 percent or more people to develop resistance to Sustiva and all other NNRTIs within six months (and possibly a higher percentage within a few more months), whereas half or more of those people would have not developed resistance if they had used Sustiva with a protease inhibitor.

Dr. Robert Schooley, who chairs the ACTG's executive committee, echoed the findings of these data, stating that Sustiva will not replace current treatments. "We need to use them together ... to have the most effective control of viral replication. With some drugs the virus has to make multiple mutations to escape the drug. With Sustiva, one mutation and it's gone and the other two drugs in the class are gone - you can't use them again. You lose all three."

Side effects

While the company has stressed that Sustiva is well-tolerated, the company also reports that a majority of patients studied experienced some type of side effect on Sustiva. Fifty-two percent of patients receiving Sustiva reported central nervous system and psychiatric symptoms. These symptoms included dizziness, impaired concentration, sleepiness, abnormal dreams, and insomnia. In controlled trials, these symptoms were severe in 2.6 percent of patients receiving Sustiva 600 mg. once per day. These symptoms usually begin during the first or second day of therapy and generally resolve after the first two to four weeks. The company reports that dosing at bedtime improves the tolerability of these symptoms. The company does not explain, however, that these symptoms can also be reduced by taking smaller doses of the drug three times a day, rather than the single daily dosing formulation that the company is aggressively promoting.

DuPont also states that patients receiving Sustiva should be alerted to the potential for additive side effects when Sustiva is used with alcohol or psychoactive drugs.

In controlled clinical trials, 27 percent (124 of 455) of patients treated with 600 mg. Sustiva experienced new skin rash, compared with 17 percent (61 of 351) of patients treated in control groups. Very serious rash occurred in 1 percent. The median time to onset of rash in adults was 11 days and the median duration, 14 days. The discontinuation rate for rash in clinical trials was 1.7 percent. Sustiva should be discontinued in patients developing severe rash associated with blistering or fever. Appropriate antihistamines and/or corticosteroids may improve the tolerability and hasten the resolution of rash. (The author experienced moderate rash at approximately day 10 of treatment with Sustiva. After the rash failed to respond to antihistamines, the author did one five day course of prednisone which cleared the rash. The rash did not return.)

Price gouging

Sustiva is the third NNRTI brought to market. The previous two NNRTIs were Rescriptor (delavirdine), approved in April 1997, and Viramune (nevirapine), approved June 1996. These three NNRTIs share many characteristics. All are very strong inhibitors of HIV. All, when used as monotherapy or in ineffective combinations, quickly lose effectiveness due to HIV mutations that cause resistance. Sustiva and Rescriptor can be taken with or without foods. While the early data presented regarding Viramune and Rescriptor was not very impressive, in many case that can be attributed to poor combinations and poor study design. More recent studies have shown impressive results for Viramune and Rescriptor when used in strong combinations. DuPont has not presented any data showing a direct comparison between Sustiva and the earlier NNRTIs, and it is difficult to compare data from different studies because of differences in patient populations and different measures of effectiveness.

Where the drugs differ dramatically, however, is their price. When introduced in 1997, the price of Rescriptor was set at an average wholesale price of $2,700 per patient per year (with a discounted cost to ADAPs of about $2,200). The average wholesale price announce for Sustiva, however, is close to $4,900.

AIDS activists from across the country charge that this price for Sustiva is unconscionable. When the first protease inhibitors were brought to market, with an average annual wholesale price range of $5,400 to $8,000, people with AIDS were told repeatedly that high price was justified by the high development cost of the drugs, the uncertainty of bringing such drugs to market without reliable easy measures of their effectiveness (viral load testing was just becoming available), the expense of running studies for FDA approval, and the expense and difficulty of manufacturing the drugs.

None of these justifications are true of Sustiva. Community activists have been told for two years that one of the advantages of the drug is that it was substantially easier to manufacture than any protease inhibitor. During earliest development of the drug, viral load testing was widely available and accepted as a rapid measurement of drug effectiveness, reducing development costs. The success of other anti-HIV drugs has proven that a substantial number of people who begin on a drug such as Sustiva may wind up taking it for many, many years, thus increasing the lifetime revenue available from any one additional patient. Given the far less risky development environment of Sustiva, its easier manufacture, and the likelihood of a substantially increased market, activists had hoped for a price for Sustiva that was in line with or less than that of other NNRTIs. Instead, the company has apparently followed an all-the-market-will-bear pricing strategy and priced the drug at $2,200 higher than Rescriptor, a possible alternative for the drug.

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