AIDS TREATMENT NEWS Issue #304, October 2, 1998
John S. James

Efavirenz has been approved for children as well as for adults.

Efavirenz is a "non-nucleoside reverse transcriptase inhibitor"--sometimes abbreviated NNRTI; the other approved drugs in this class are nevirapine (Viramune(R)), and delavirdine (Rescriptor(R)). These drugs target the reverse transcriptase enzyme of HIV-1; but unlike AZT, ddI, etc., which also target this enzyme, the NNRTIs are not nucleoside analogs, as they do not provide "false building blocks" for the DNA created by the virus. All of the approved NNRTIs are not active against HIV-2, a variant of HIV-1 which is found in some parts of Africa.

Viral resistance to NNRTIs can develop rapidly, so these drugs must be used carefully, in combination with other antiretrovirals to which the person has not been previously exposed, so that HIV replication is kept at very low levels, to give less opportunity for resistant virus to develop. Because of cross-resistance within the NNRTI class, once significant viral resistance has occurred to one of these drugs, the other two are also probably ineffective for that patient.

A major question now is whether or not the medical community will be comfortable using efavirenz plus two nucleoside analogs, without a protease inhibitor, when beginning 3-drug treatment (and for which patients?). Or will physicians and patients stay with the now-standard three-drug regimens (protease inhibitor plus two nucleosides), or start with four drugs (protease inhibitor plus efavirenz plus two nucleoside analogs)? These complex decisions involve not only the long- term antiretroviral activity vs. toxicities of the initial drug combination, but also long-term treatment strategy: what drug combinations will be available for later use if the first treatment fails? At this time it is too early to know what medical consensus will develop.

One example of the complexity concerns the consequences of virological treatment "failure." A major trial compared efavirenz plus AZT plus 3TC (lamivudine, brand name Epivir(R)--often combined with AZT in a single pill called Combivir(R)) vs. a standard-of-care regimen (indinavir--brand name Crixivan(R)--plus AZT plus 3TC), in patients who had already been treated with nucleoside analogs except 3TC but had not taken any protease inhibitors or NNRTIs; the efavirenz-containing regimen did at least as well as the indinavir-containing regimen at 24 and 36 weeks, as measured by the proportion of patients whose viral load remained under the 400-copy limit of the test (the same result was also found with a 50-copy limit). (See the FDA-approved "package insert," which summarizes some of the 24-week data; the recent ICAAC conference included data to 36 weeks with similar results.) But even in the efavirenz arm, at 24 weeks fewer than 80% of those originally assigned to the regimen still had a viral load under 400 copies (by the most rigorous method of counting, which considers anyone who dropped out of the study for any reason, or was missing important data, to be a treatment failure).

What happens to the patients, on either regimen, who fail to keep the virus under control? With protease inhibitors there is experience indicating that those who "fail" treatment virologically (in that the viral load becomes measurable again), but who stay on the drugs, still seem to benefit, in that CD4 counts tend to stay higher, and there are fewer AIDS-related illnesses and deaths, than would have been expected for those patients. No one knows why this seems to be the case; possibly the virus which has become resistant to protease inhibitors has become less damaging in some way. But with efavirenz, there is not enough experience yet to know if there could be any similar benefit even after virologic failure occurs.

A major hope for efavirenz is that it may reduce the need for protease inhibitors and therefore reduce the lipodystrophy problems which have become increasingly serious. But at this time no one knows for sure that protease inhibitors are causing these problems, or that efavirenz will not do so in long-term use.

Considerations on Taking Efavirenz (SUSTIVA)

* Efavirenz is taken only once per day, usually at bedtime, with or without food (but not with a high-fat meal, which may increase drug absorption and therefore could cause increased side effects).

* Patients need to be warned that about half or more of the people starting efavirenz have problems with CNS (central nervous system) effects, such as dizziness, trouble sleeping, drowsiness, trouble concentrating, or vivid dreams and nightmares. If these problems occur, they can start within hours. Usually they are mild to moderate, and go away after one has taken the drug for two to four weeks.

* The drug can also cause rash, which usually goes away without change in treatment, but can be serious in a small number of patients.

* Efavirenz must not be taken by pregnant women, because it caused birth defects in an animal test. If a woman does become pregnant while taking the drug, she should notify her physician immediately. The physician can enroll the patient in a voluntary pregnancy registry.

* Some drugs must not be taken at all with efavirenz, because the combination could cause serious or life-threatening side effects. Other drugs require dose adjustment if taken with efavirenz. All your doctors and pharmacists need to know that you are taking efavirenz, and they should know all the medications you take, so that harmful interactions can be avoided.

* Because resistance can develop rapidly, it is especially important to avoid running out of medicines or otherwise interrupting treatment unnecessarily.

* If you are using efavirenz, be sure to get at least the "patient package insert" a one-page fact sheet on this drug, published by DuPont Pharmaceuticals. It should be available from your physician, clinic, or pharmacist. (The current version is not called a patient package insert, but begins, "SUSTIVA(TM) (efavirenz) capsules: Patient Information about SUSTIVA*(sus-TEE-vah)...")

* You may also want to get the "package insert," which is several pages of small print written primarily for physicians; despite the name it usually does not come with the package you get from the pharmacy, but may be available from your physician, and will be published in future editions of the PHYSICIANS' DESK REFERENCE. More information can also be found on the Web or through electronic mailing lists; the company's Web site is www.sustiva.com, and it includes both the package insert and the patient package insert. For a directory of the treatment Web sites which AIDS TREATMENT NEWS has found most useful overall, see www.aidsnews.org.

Also, the company has set up a phone line (800-4PHARMA), allowing callers to question an information specialist (in English or in many other languages, using an AT&T translation service). Persons can also request a package insert or patient package insert by fax or by mail. (For mailed information a full name is required, since to maintain confidentiality, the company will not mail a package which may be opened by the wrong person.)

Efavirenz Pricing Controversy

Well over 100 organizations and 200 individuals have signed a consensus statement protesting the price of SUSTIVA, which was set well above the price of the other drugs in the NNRTI class. [Note: This writer is a member of the Fair Price Working Group, which circulated the statement.] A particular concern is that this price will delay acceptance by many state ADAPs (AIDS Drug Assistance Programs), which will have to balance efavirenz against other important drugs which they will no longer be able to provide, due to the additional expense. As we go to press, negotiations are focusing on providing relief to the ADAPs. (Medicaid and the Veterans Administration already have low drug prices; and due to the expense of AIDS drugs, few individuals can pay for them out of pocket.)

We will report on the pricing situation as it develops. You can contact the Fair Price Working Group by email to linda_grinberg@prodigy.com, or by fax at 310-471-4565.

Reimbursement Assistance, and Expanded Access Contacts

DuPont Pharmaceuticals has assured the community that it will not deny access to SUSTIVA if somebody needs the drug. Persons who need help getting the drug paid for can call 1- 800-334-4486, for reimbursement counseling to advise patients on public or private programs under which they may be eligible. There is also a patient assistance program to provide drug without charge to patients who meet certain financial qualifications and have no other way to have the drug paid for.

Persons on expanded access when SUSTIVA is approved will be given a one-month supply to allow time to make arrangements to pay for the drug. According to DuPont Pharma, no one on expanded access will be denied the drug, even if they have no way to pay and fail to meet the financial criteria for the patient assistance program. If they are initially turned down for the patient assistance program, they can appeal, and all these appeals will be granted. A letter explaining the transition from the expanded access program will be sent to the investigators for delivery to patients at their next visit.

Approval is pending in Canada and Europe; meanwhile, the expanded access programs there will soon begin to enroll children. For more information, patients in Canada can call 800-998-6854, or in Europe, call +44 (0) 38 842779.

Note: Efavirenz will be marketed as SUSTIVA only in the U.S., Canada, UK, Spain, France, Germany, and Italy. Elsewhere Merck will market efavirenz under the brand name Stocrin(TM). Apparently the companies could not agree on a price for the rights elsewhere.

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