Lamivudine (3TC) Approved by John S. James
On November 17 the FDA approved the marketing of lamivudine (brand name Epivir(TM), but still best known by the code name 3TC) for use in combination with AZT "when antiviral therapy is warranted based on clinical and/or immunological evidence of disease progression." The FDA moved very rapidly, approving the drug only 11 days after the Antiviral Drugs Advisory Committee recommended approval at a meeting on November 6. Supplies of 3TC are in many pharmacies now.
The FDA used the "accelerated approval" regulations, which allowed approval because 3TC has shown benefit through markers of disease progression such as viral load and CD4 (T- helper) count. At this time there is no statistical proof from clinical trials that use of 3TC can provide long-term improvement in lifespan or in reduction of the number of opportunistic infections. Trials to gather such proof are now ongoing, but this kind of study takes a long time, because HIV disease progresses slowly.
In pediatric patients, 3TC must be used with extreme caution (if at all) if there is any risk factor for the development of pancreatitis. The FDA -- wisely, we believe -- did not specify any particular T-cell range for which 3TC/AZT combination therapy is indicated. The decision of when to begin therapy is a controversial and difficult one -- and an issue which many believe is separate from the question of whether or not a particular drug can be useful.
The Package Insert
The "package insert" for 3TC -- the document which defines what the FDA will allow the company to say about the drug when marketing it to doctors, and which will be published in the PHYSICIAN'S DESK REFERENCE (probably appearing in the Supplement early next year) -- summarizes the information which the FDA used in granting the approval.
There have been four controlled studies of 3TC in combination with AZT in adults. Two of these studies were for persons who had used little or no AZT, and two were for persons who had used AZT extensively. A total of 974 HIV-positive volunteers were enrolled in these studies (not all of them received 3TC). In those who had not used AZT before, the average CD4 increase was about 50. Those who had used AZT had an increase of about 30. These increases were sustained for longer than 24 weeks. [These figures are from a summary published in an FDA Talk Paper on November 7. The full data are more complex, because of differences between the maximum average CD4 cell rise, and the average at week 24, week 52, or other specific times.]
The package insert contains the following warning:
In two small trials, one studying 3TC alone and one studying it in combination, about 15 percent of pediatric patients developed pancreatitis. No one knows why the risk was so much higher for them than for adults (in whom pancreatitis was observed in only three of 656 volunteers in controlled clinical trials, less than 0.5%); this may have happened because the children were much sicker than the adults when they started treatment.
Comment -- Other Issues
Some areas of concern -- and also praise for Glaxo-Wellcome's commitment to testing pediatric use of 3TC more thoroughly than the law requires -- came out at the Antiviral Drugs Advisory Committee meeting but were not explained in the package insert.
A theoretical risk in using 3TC, in adults as well as children, is that laboratory studies suggest that it might cause virus to rapidly become resistant to ddI and ddC, as well as to 3TC. This concern arose because most patients who use 3TC (even with AZT) develop a mutation at position 184 of the reverse transcriptase gene which gives the virus high-level resistance to 3TC -- and in laboratory tests, the same mutation developed when viruses were exposed to ddI, and it conferred low-level resistance to ddI. No one knows if this is important in practice, however -- especially because patients who become resistant to ddI after treatment with that drug seldom develop the mutation at position 184, but develop other mutations instead.
Controversy on Indications
There was controversy at the Antiviral Drugs Advisory Committee meeting about the recommendation to approve 3TC without restricting the indication to certain CD4 count ranges. A position paper by Michael Ravitch of the Treatment Action Group (TAG), dated November 6 and distributed that day at the hearing, supported the approval of 3TC, but also said that "the FDA should not allow Glaxo to promote the AZT/3TC combination among patients with over 300 CD4+ cells unless the company initiates studies with clinical endpoints in this population... Approval of the requested indication for 3TC would set a terrible precedent. If Glaxo wants an indication for the >300 CD4+ cells population, they should present a plan for a clinical endpoint study in that group."
Project Inform's statement also argued that restrictive indications would have little effect on the rich and well- insured, but would guarantee the continued dominance of AZT monotherapy in poorer populations, despite its obvious inferiority. It said that decisions about when to begin treatment (with any drug) should be guided by the consensus conferences periodically called for this purpose -- and that these conferences, not the sponsors' advertising, have been the principal determinants of drug use in the past. [The next consensus conference on HIV treatment is planned for early next year.]
Praise on Pediatric Testing
There has long been a major problem in getting drugs tested and approved for infants and children. About 80 percent of drugs now approved have no data to support special prescribing instructions for pediatric use, meaning that physicians often have to guess at what dose to use. (Infants and young children have differences in metabolism from adults, so adjusting the dose only for body size is often inadequate.)
Expanded Access, Price, and Funding
About 35,000 people have received 3TC without charge in Glaxo Wellcome's expanded access program. (There were associated charges, however, such as for CD4 tests, which sometimes had to be paid by patients, as insurance companies were likely to reject payment on the grounds that the drug was experimental.) Now that 3TC is approved it will have to be paid for, although it will now be easier to get private or public insurance coverage for the cost. The price of 3TC to wholesalers is $3.11 per 150 mg tablet, making the annual cost of the drug $2,270 plus the wholesalers' and retailers' markups. This of course is in addition to the cost of the AZT.
PMPA in Perspectiveby John S. James
PMPA is the experimental anti-HIV drug which gained national attention in mid November, after a government-funded study, published in SCIENCE (1), reported that once-daily doses for four weeks completely protected macaque monkeys from SIV (a virus which is closely related to HIV) even when given 24 hours after exposure to the virus; all the untreated monkeys developed infection and disease. No drug toxicity was found. No other potential treatment has been able to do this. AZT, for example, gave six percent protection when given before exposure and zero protection after exposure (in other studies, which were not exactly comparable). And another antiviral, PMEA, which is chemically related to PMPA, protected 10 of 12 monkeys when given before exposure, but only one of five monkeys which received the treatment four hours after exposure to the virus.
While the recent media coverage may seem excessive -- especially since PMPA has never been taken by even a single person, and human toxicity is unknown -- we believe that the new results are of first-rate importance. Besides the obvious potential uses in preventing infection after needlestick injury, and in preventing maternal-infant transmission (which is believed to usually occur at the time of birth), PMPA is clearly an important lead as a possible treatment for established infection. Of course no one knows if it will be useful for this purpose until it is tried.
AIDS Treatment News could not finish an in-depth investigation of PMPA in time for this issue. But due to the widespread interest, we wanted to mention a few background points:
DOXIL Approved for KSby John S. James
DOXIL(R), a liposomal form of the chemotherapy drug doxorubicin which allows much higher concentrations to be delivered to Kaposi's sarcoma lesions or cancer tumors, has been approved by the FDA, under the accelerated approval regulations. It currently has received a fairly narrow indication, "for the treatment of AIDS-related Kaposi's sarcoma (KS) in patients with disease that has progressed on prior combination chemotherapy or in patients who are intolerant to such therapy." However, most cancer drugs are used off label (for uses not specifically named in the indication), and it is widely believed that DOXIL will also be used as first-line therapy for some patients with rapidly progressing KS who need chemotherapy, and in addition will be used in some cancers, including breast, prostate, and ovarian cancer.
DOXIL is expensive, costing about $1,200 per treatment, with one treatment given every three weeks; this is more than twice the cost of treatment with ABV (a combination chemotherapy consisting of Adriamycin [which is another name for doxorubicin], bleomycin, and vincristine, a major alternative to DOXIL when systemic chemotherapy is needed).
More information about a major trial of DOXIL for KS will be presented at the American Society of Hematology meeting on December 5. Of 118 patients in this trial with extensive, progressive KS (and median CD4 count of 13.5) who were randomized to DOXIL, 43.2% had a partial response, and 55.9% were stable; only one of the 118 had progressive disease. Of the 110 patients randomized to ABV, 24.5% had a partial response, 67.3% were stable, 6 patients progressed, and 3 were not evaluable. This trial tested DOXIL as first-line treatment, not after other chemotherapy had failed. Information on another study of DOXIL for treating breast cancer will be given December 12 at a meeting of the San Antonio Breast Cancer Symposium.
The most serious danger of ordinary doxorubicin chemotherapy is toxicity to the heart, which occurs when a large cumulative dose is used. While DOXIL might be less toxic, there is too little experience with high cumulative doses to establish how much can be tolerated. Therefore, the same guidelines used for ordinary doxorubicin are being used for DOXIL -- that irreversible cardiac toxicity may occur when the total cumulative dose approaches 550 mg/m(2) (or less if patients have had certain other systemic chemotherapies, or have certain risk factors); physicians must use special monitoring if they treat beyond this level.
DOXIL can also cause other toxicities, including neutropenia, which must be carefully managed by the physician. Toxicity information is based on experience in 753 patients treated with DOXIL, in four trials. Because these patients had advanced HIV disease (median CD4 count 21, with half having a CD4 count under 50), and because they were also using many other drugs, it was often difficult to know whether particular adverse effects were due to DOXIL. The median cumulative dose was 120 mg/m(2), with only 3% of the patients receiving over 450 mg/m(2).
DOXIL must be given only by intravenous infusion. The developer of DOXIL is Sequus Pharmaceuticals, Inc. (formerly Liposome Technology, Inc.), of Menlo Park, California.
Liposomes are microscopic globules of fat which can be used to carry certain drugs, achieving a different targeting of the therapy than if the free drug is used. DOXIL, for example, has a half-life in the blood of about 50 hours, compared to about 10 minutes for ordinary doxorubicin. DOXIL tends to concentrate in KS lesions and in cancer tumors more than ordinary doxorubicin; why it does this is unknown, but it may be because lesions and tumors tend to have poor blood vessels. According to this theory, DOXIL remains in the bloodstream for a long time, allowing the liposomes to leak into the lesions.
DOXIL Available in Government Trial
An important government study is now recruiting 120 volunteers with advanced KS to compare DOXIL alone vs. DOXIL plus BV (bleomycin and vincristine). Everyone in this trial will get DOXIL; half of the participants will get the other drugs too. Both treatment will be given every two weeks, for a maximum of 25 treatments. There is no charge for participants.
New Double Vs. Triple by John S. James
A clinical trial at 25 sites across the U.S. is now enrolling 225 volunteers to compare three different combination anti-HIV treatment regimens. Participants must have a CD4 count between 200 and 500, and not have previously used antiretrovirals. The trial will last one year.
Each volunteer will be randomly assigned to either:
The study will compare the effects of these different regimens on viral load, CD4 count, and perhaps other "markers" of disease progression. This trial, known as protocol ICC-002, is sponsored by the Inter-Company Collaboration for AIDS Drug Development, a consortium of most of the large companies developing AIDS drug. For more information, or to find the location and contact information for a site near you, patients or physicians can call 800/925-AIDS, from 9 a.m. to 5 p.m. Eastern time.
Internet Censorship: by Bruce Mirken
A House/Senate conference committee will shortly meet to sort out conflicting proposals passed by the two houses of Congress aimed at restricting online access to "obscene" or "indecent" material and other matter deemed objectionable. AIDS activists and service organizations are concerned that some of the proposals under consideration such as Senator James Exon's "Communications Decency Act" (CDA) passed by the Senate last summer, could greatly interfere with both online distribution of HIV/AIDS information and certain AIDS activism (see "Exon Amendment: Threat to AIDS Prevention and Activism?," AIDS Treatment News issue #227, July 21, 1995).
Essentially, the choice the conference committee faces boils down to two options:
Recently, some religious right organizations have begun urging the committee to adopt even more restrictive language than the original Exon proposal. As we go to press it remains unclear exactly when the committee will take up this issue, but it is expected to be quite soon. A broad coalition of organizations is encouraging everyone concerned with freedom of speech to contact the committee members and encourage them to oppose all proposals that would censor online communication. Opposition to
Name, Address, Party and Phone
Arkansas Rep. B. Lambert-Lincoln (D-AR)
[Note: Excellent analysis of problems with the telecommunications bill as a whole -- not only the censorship provisions -- can be found at the World Wide Web sites of the Computer Professionals for Social Responsibility, http://www.cpsr.org/nii/cyber-rights/telecom.html, and of the Center for Media Education, http://www.access.digex.net/~cme/bill.html .]