AIDS TREATMENT NEWS Issue #236, December 1, 1995
John S. James

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.

* In laboratory studies, 3TC has been shown to be synergistic with AZT, meaning that the combination works better than would be expected from how well the two drugs work separately.

* In patients, when 3TC is given alone, resistant virus emerges rapidly, usually within 12 weeks. Resistance to 3TC is believed to be caused by a mutation at position 184 in the gene which codes for the viral enzyme reverse transcriptase. In some patients who had AZT-resistant virus when they started 3TC, sensitivity to AZT was restored after 12 weeks of 3TC treatment.

* Combining 3TC with AZT delayed the emergence of 3TC- resistant virus.

[Note: As the three items above suggest, it is difficult for HIV to be resistant to both AZT and 3TC at the same time. But it is not impossible; the package insert points out that strains simultaneously resistant to both drugs have been found.]

* 3TC may be taken with or without food. (When taken with food, absorption is slower; the maximum blood levels are less, but apparently longer lasting, than if the drug is taken while fasting. The total systemic exposure to the drug -- the "AUC", or area under the curve -- is about the same in either case.)

* 3TC is mostly eliminated unchanged in the urine. In persons with kidney impairment, the dose needs to be decreased because elimination is slower; specific instructions are given in the package insert.

* A five-day study found that in persons using double- strength TMP/SMX (Bactrim, or Septra) once a day in combination with 3TC, the total blood level of 3TC (the AUC) was increased about 44%. The effect of higher doses of TMP/SMX has not been studied. [This suggests that the dose of 3TC might be reduced for persons using Bactrim or Septra; however, the package insert does not include instructions for doing so.]

* There is no information in the package insert about interaction of 3TC with other drugs (besides AZT and TMP/SMX) which persons with HIV may be using. And there are no studies of such interactions going on now.

* No studies have been done to see if the pharmacokinetics (absorption, elimination, etc.) of 3TC vary between races or between sexes, or are different in persons age 65 or older.

* The recommended dose of 3TC for adults and adolescents (12- 16 years) with average body weight is 150 mg twice daily, in combination with AZT. For adults weighing less than 50 kg (110 lbs), the recommended dose is 2 mg/kg twice daily. For infants and children, different doses and precautions are recommended. The drug is supplied in 150 mg tablets, and also in a strawberry/banana flavored solution for oral administration, containing 10 mg of 3TC per ml.

* Animal studies found no evidence of birth defects even at doses far higher than the human dose; however, there was "some evidence of early embryolethality" in rabbits at the human adult dose and higher, but none in rats at up to 130 times the human dose. 3TC "should be used during pregnancy only if the potential benefits outweigh the risks." Since there are no adequate studies of 3TC in pregnant women, an Antiretroviral Pregnancy Registry has been established, and physicians are encouraged to register pregnant patients, so that in case there are any problems with this drug in pregnancy, they can be identified as early as possible.

* Mothers should discontinue nursing if they are using 3TC.

Adult Studies

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 average decrease in viral load was about 0.9 logs (7.9- fold) in AZT-naive volunteers, and about 0.7 logs (5-fold) in those who were AZT-experienced, when the doses of 3TC and AZT were the same as those now recommended. However, there was much variation from patient to patient; the standard deviation of the decrease was 0.8 logs in each case.

Pediatric Use

The package insert contains the following warning: "Pancreatitis in pediatric patients: In pediatric patients with a history of pancreatitis or other significant risk factors for the development of pancreatitis, the combination of Epivir(TM) and Retrovir(R) (zidovudine) should be used with extreme caution and only if there is no satisfactory alternative therapy. Treatment with Epivir should be stopped immediately if clinical signs, symptoms, or laboratory abnormalities suggestive of pancreatitis occur (see Adverse Reactions)."

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. At the meeting of the Antiviral Drugs Advisory Committee, data were presented showing that there were generally predisposing factors in the infants and children who developed pancreatitis; however, little of this data was included in the package insert. (The package insert did note that high amylase levels, a danger sign for pancreatitis, occurred in 23% of pediatric patients with abnormal baseline amylase values, vs. only 3% for those with normal baselines.)

A major pediatric study is now ongoing, so there will be more data eventually on the risks and benefits of pediatric use. Unfortunately this trial is still recruiting, and it is likely to remain blinded for two years after the last patient is enrolled, meaning that there may be no data available for well over two years.

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.

Cross Resistance

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.

The concern is that patients might be able to start treatment with AZT plus ddI, or AZT plus ddC, and then benefit from switching to AZT plus 3TC when the first combination failed -- but that going the other way might not work, because the mutation which caused resistance to 3TC might also cause cross resistance to ddI or ddC. On the other hand, there may be no such problem at all. No one knows, because while many people who have previously used ddI or ddC have used 3TC, few have started with 3TC and then switched to ddI or ddC later; there do not even seem to be anecdotal reports. Now that the combination of AZT plus 3TC has been approved -- including for first line use -- many people are likely to be starting therapy with it.

Fortunately it would be easy to answer the question of whether this theoretical concern has any practical importance. All that would be needed is a small, rapid trial to see if persons who have used 3TC for some time do or do not still show an antiviral response to ddI. Since this trial would look for changes in viral load when ddI was started -- and viral load can change in days or weeks in response to an antiviral drug -- we could have the answer in a few months. Glaxo has said that it will continue to address the question of cross resistance, and that it is looking at existing laboratory data in the U.S., and will look at data from clinical trials in Europe.

Incidentally, there is even a theoretical possibility that the mutation at position 184 might be useful in some cases. Some researchers believe that it makes the reverse transcriptase enzyme work more accurately when it makes copies of the virus, thereby reducing the rate at which new mutations develop. For some time it has been noted that when 3TC is used alone (which is not recommended), the viral load greatly declines, and then quickly comes back up again as resistance develops -- but usually it does not come all the way back to baseline, despite the fact that the virus then has high-level resistance to 3TC when that is the only antiviral the patient is using. No one knows why this happens; one theory is that the resistant virus cannot mutate as fast as the wild-type virus, and therefore the immune system can keep up with it better. If it turns out to be true that 3TC resistance slows HIV mutation, then it might make many kinds of antivirals work better, not only those targeted against the reverse transcriptase gene. As of today all this is only theory, however.

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." TAG's major concern seemed to be that two large clinical trials showed no survival benefit from starting AZT early, compared to starting AZT later -- even though the CD4 count seemed to show that those receiving the early treatment were doing better. Should AZT plus 3TC be approved regardless of T-cell range, when there may never be a trial to prove that it increases survival if started in early disease?

Most activists argued against restricting the CD4 count range, however. For example, Project Inform's November 6 statement noted that the AZT plus 3TC combination had been found superior to AZT in every population tested, and that, "While it might be ultimately desirable to see the drug tested in every imaginable subset of the HIV-infected population, there is no reason to require this prior to making the drug fully available and we believe it may even be unethical to do so. With the number of new drugs likely to become available over the next six to twelve months, it will simply be impossible to test for the clinical effects of each drug at each and every arbitrary stage of HIV disease." 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.]

Both Ravitch and Delaney spoke at the hearing, which included a public comment period. This writer also spoke; like Delaney, we urged the Committee not to restrict the CD4 range. We also said that standards for accelerated approval could be maintained primarily by the professional consensus of physicians and researchers; only when companies flout the professional consensus need the FDA step in to punish them (by restricting indications, or otherwise). That has not happened here, since many researchers and physicians believe that a clinical trial to prove superiority by clinical endpoints (mainly death and AIDS progression) is probably not feasible in early HIV disease. [It would take a long time to obtain any endpoints from persons with early HIV disease -- and much longer to obtain enough endpoints for statistical proof. And if the two or more treatments being compared were approximately equal, it would probably be impossible to ever show superiority, which the proposed trials would be attempting to do; but if the treatment arms were significantly different, people would become aware of the difference, and the trial would have to keep many people on a treatment widely believed to be inferior, for a time long enough for many of them to suffer serious harm.]

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.)

To help make new drugs for serious and life-threatening conditions more available for children, the FDA finalized a new rule this year to allow a drug to be approved for children based on trials in adults, when there is pharmacokinetic and other information supporting pediatric use, and the drug and the disease are similar enough in adults and children to permit the adult data to be extrapolated. In developing 3TC, Glaxo-Wellcome went beyond what the new rule requires, and is conducting a major efficacy trial in children. It is fortunate that they have done pediatric studies -- which were not legally required -- because otherwise the pancreatitis problem would probably not be known to this day, and the drug would have been approved with no warning to physicians, which could have caused many preventable deaths.

Arthur Ammann, M.D., of the Pediatric AIDS Foundation, supported the accelerated approval of 3TC for pediatric use, and commended Glaxo-Wellcome for developing this drug almost simultaneously for children as for adults. He reviewed the pediatric data before the meeting, and noted the pancreatitis problem, but also noted the benefits of increased body weight, increased CD4, and decreased viral load in children -- despite the fact that they had more advanced disease when they began treatment than persons in adult trials.

"My final comments are a plea," Dr. Ammann concluded. "The early formulation of promising new drugs for serious and life-threatening diseases in children requires the performance of safety and pharmacokinetic studies from birth to adult life. They must become an industry standard. This company has set an example with 3TC. Tragically there will be a new class of drugs, protease inhibitors, which are likely to receive approval for adults without supporting data for use in infants. The urging of the pediatric community alone is insufficient to correct this inequity. As new drugs are reviewed for approval during all stages of development, questions must be asked by the Agency, and the Advisory Committees, as to why data for certain members of the HIV/AIDS community are lacking."

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.

For help with reimbursement, patients and physicians can call Glaxo Wellcome's reimbursement assistance line, 800/513-3028, from 8:30 a.m. to 7:00 p.m. Eastern time. There is a patient assistance program for persons with no other way to pay for the drug, but the company requests that one use the assistance line to check out other options first. Persons currently in the expanded access program have been about a one-month grace period to make arrangements to pay for the drug; the company has programs in place with the intention that no one will be dropped.

While traditional insurance has usually reimbursed for treatments which are FDA approved, managed-care plans often have formularies, lists of drugs which are regularly reimbursed. Not all FDA-approved drugs are included. Public- assistance programs are likely to have more severe limitations. The increasing number of expensive drugs, plus Congressional cuts in support for Medicaid and other programs, are rapidly leading to a crisis in drug reimbursement. Unless companies can restrain prices, and also improve the value of their products by providing better data on how to use them, their drugs will not be widely used in the future.

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