Treatment Issues, Vol 11, No 1; January 1997
Theo Smart

New classes of antiretrovirals such as integrase, fusion blockers and zinc finger inhibitors all seem a long way off, and people's needs are more immediate. There are, of course, the new drugs now well along in the development pipeline, but getting the pharmaceutical companies to release those drugs to all who need them has not been an easy task. The last six expanded access programs in the U.S. have been extremely small, opening only a few months before FDA approval of the drugs in question. Participants were generally only offered access to the new treatment if they had very low CD4 cell counts and had failed or were intolerant to approved therapies. And the programs for the three protease inhibitors now on the market included lotteries for eligible applicants to further restrict the amount of drug distributed.

No one would contest that those most ill should receive experimental drugs first, but it has become clear that combination therapy can turn around the course of disease in people with AIDS. In contrast, the effect of monotherapy or virtual monotherapy (the addition of the expanded access agent to an ongoing, failing regimen) is transient at best and potentially harmful due to the drug-resistant HIV to which it gives rise. This is not what activists had in mind when they first fought for novel expanded access programs like parallel track.

There are those in the pharmaceutical industry who agree: "Someone needs to say, once and for all, that expanded access can't work the way it used to," said Maureen Myers, Ph.D., Director of Clinical Research--Virology for Boehringer-Ingelheim, the company that makes the now-approved nevirapine. "When designing these programs, you have to position the drug in such a way as to offer some benefit to the patients taking it."

Boehringer's nevirapine is a perfect example of a drug that offers little benefit when misused. Nevirapine needs to be taken in combination with several other agents that a person's has not yet had a chance to develop resistance to -- otherwise, resistance develops within weeks. Extending nevirapine access only to those who have failed all other medications would be an exercise in futility. That futility probably was the experience of most of the participants in the American expanded access program, who were treatment-experienced and had CD4 counts under 50. (We will never know for sure , though, what enrollees' experience was because of the minimal amount of data collected under the nevirapine program.)

Boehringer wants to take a different approach in Europe, according to Dr. Myers. Although not all the details have been worked out, the company is considering a larger program, open to those with higher CD4 cell counts. The protocol would expressly recommend nevirapine use in combination with other drugs that a person has never tried before. Companies have allowed participants in some previous expanded access schemes to use additional antiretrovirals -- this would be the first time that it is mandated. Boehringer is taking a similar approach in the United States, where it has adjusted its pediatric expanded access program to grant nevirapine to children with less advanced disease and those who are treatment-naive, as well.

Agouron: Nelfinavir

Agouron has the largest expanded access program currently in place and is now enlarging it. The company is now offering its protease inhibitor nelfinavir (Viracept) to children between the ages of two and 13. According to Joy Schmitt, Agouron's Manager of Public Relations, the company should be able to extend access to children below two years of age within the next month or so, once Agouron considers that it has enough safety data. The importance of this initiative cannot be overemphasized, since pediatric formulations are not available for the three protease inhibitors now on the market.

The adult (age 13 and up) program also has changed substantially. It is now open to anyone unable to take indinavir and/or ritonavir due to intolerance and/or failure (as defined by a patient's personal physician) and who has had a CD4 count below 100 at some point over the history of one's illness. To enroll in either program call 800/621-7111 Monday through Friday, between 8 a.m. to 6 p.m., Eastern Standard Time.

The new adult protocol is considerably more generous than the old one. The former program had required applicants to fail or be intolerant to all approved protease inhibitors, (including saquinavir). Now people have the option of using nelfinavir in combination with saquinavir. According to Agouron, nelfinavir increases blood levels of saquinavir five-fold, not as potently as ritonavir (which effects a 20-fold increase), but significantly nonetheless.

The old protocol's worst feature was the requirement that an individual's CD4 cell count had to be below 50 at the time of entry into the expanded access program. If that count was still elevated from earlier, transiently effective antiretroviral therapy, the applicant would have to wait until it slipped below 50, regardless of whether he or she had high HIV levels or was afflicted with potentially fatal opportunistic infections.

Of course, program participants still must fail or be intolerant to ritonavir "and/or" indinavir. This poses a problem, because of broad spectrum cross-resistance among protease inhibitors. Nelfinavir may give rise to a unique HIV drug resistance mutation when it is the first protease inhibitor used, but scientists from Merck and Abbott believe that most who fail on their drugs will benefit little from switching to nelfinavir. Agouron's drug resistance specialist, Amy Patick, Ph.D. says that she has no data to confirm whether or not indinavir and ritonavir cause cross-resistance to nelfinavir but commented, "It wouldn't surprise me [if cross-resistance arises] because the 82 mutation is in such a critical site on the enzyme." (The mutation at amino acid 82 is the key HIV protease mutation conferring resistance to indinavir and ritonavir.)

The question must be answered as quickly as possible, because there is more at stake than simply not responding to nelfinavir. Many entering the expanded access program have failed most of the approved therapies. If they are pre-resistant to nelfinavir and start it in combination therapy with the one or two commercially available antiretrovirals that they still have not taken, they risk exhausting the benefit from those remaining background therapies too. The French government considers the danger so great that it is refusing to implement a proposed nelfinavir expanded access program because the company has shown its regulatory agencies no data to suggest that nelfinavir would be of any use in patients resistant to the other protease inhibitors.

But a broader program that covers people who have not failed ritonavir or indinavir would conflict with Agouron's clinical endpoint study. This trial compares disease progression in those taking nelfinavir plus nucleoside analogs to the experience of those taking ritonavir plus nucleoside analogs. It will enroll 1,300 participants with CD4 counts below 100. (The study is being conducted by the Community Programs for Clinical Research on AIDS (CPCRA); call 800/TRIALS-A for site information.) In any case, the expanded access issue is rapidly becoming moot in the U.S.: Agouron has completed nelfinavir's New Drug Application with the FDA, and the protease inhibitor is expected to be on the market in a few months, only about a half year after Agouron commenced the expanded access program.

Glaxo: 141W94 and 1592U89

An activist consensus statement has called on Glaxo Wellcome to release 1592U89, the most potent anti-HIV nucleoside analog ever tested in people with HIV, immediately through a compassionate use/salvage program and subsequently through a more traditional expanded access program. The proposed salvage protocol would be open to: 1) anyone with a CD4 cell count below 50 or viral load over 40,000 copies per ml who has failed approved reverse transcriptase inhibitors and at least one protease inhibitor; or 2) anyone with a diagnosis of AIDS dementia complex unresponsive to existing therapies. The second phase of the proposed expanded access would be a little more open. It would cover those who cannot participate in ongoing 1592 trials, who have HIV viral loads over 20,000 despite ongoing therapy, or evidence (such as genetic analyses) that their HIV is resistant to current therapies.

Other activists, including this author, have recommended that the second phase of this program be a dual expanded access program for both 1592 and Glaxo Wellcome's protease inhibitor, 141W94, open to patients with less than 200 CD4 cells who have failed or are intolerant to indinavir and/or ritonavir. (This would not conflict with 141W94's clinical endpoint study which will be a head-to-head comparison of 141 and indinavir plus participant's choice of additional anti-HIV agents.)

A dual program is possible since both drugs are in similar stages of clinical development. The protocol would be in effect a large simple trial that would randomly assign participants to one of three arms, 1592, 141 or the combination. All patients would be free to use their choice of additional therapy in addition to the experimental treatment(s). This allowance could extend to concurrent use of other protease inhibitors as drug interaction data becomes available.

An expanded access protocol of this sort could yield valuable information about the use of 1592 and 141 together. Unfortunately, data collection requirements generally impair entry into expanded access programs since most public health clinics and doctor's offices lack the staff and resources to do the paperwork.

Novel mechanisms for improving data collection must be developed and implemented in order to gather more complete information on the safety and efficacy of drugs supplied through expanded access. One solution might be to collect data in a sizable subset of the total expanded access population. Another is to employ a contracted research organization that would collect pertinent data directly from the patients' files, provided permission to do so is included in the informed consent form that patients sign to accept the expanded access program's conditions.

Glaxo Wellcome is meeting with a number of activists this month, to discuss expanded access proposals, and its own revised proposal should be available shortly.

Gilead: Adefovir

There are other experimental antiretrovirals that should be candidates for expanded access programs, too. Some, such as Gilead's adefovir, have been in clinical trials as long as, if not longer than, the two from Glaxo. Adefovir has fallen through the cracks, overlooked by activists and clinicians. The half-log (70%) reduction in viral load that this drug achieved in studies of antiretroviral therapy-experienced people last year was overshadowed by the potency of 1592, the protease inhibitors and non-nucleoside reverse transcriptase inhibitors (NNRTIs). But, aside from 1592 and perhaps 3TC, the drug is as potent as any of the nucleoside analogs in the treatment-experienced population -- and few would dispute that agents such as AZT, d4T and ddI still have a role in combination regimens. Furthermore, adefovir's effect as a monotherapy is much more durable than the NNRTIs. Gilead claims that the drug's antiviral activity is sustained out to at least nine months, the longest anyone has been followed so far.

Of great importance to people who have exhausted most of the other antiretroviral options, HIV isolates resistant to all the other nucleoside analogs and NNRTIs remain susceptible to adefovir, according to data presented in November at the Third International Conference on Drug Therapy in HIV Infection in Birmingham, England. Add to this the drug's activity against CMV and hepatitis B, its lack of affect on the blood and cellular levels of other antiretrovirals and its once-a-day dosing, and you have a compound that could play a valuable role in combination regimens. Gilead says that it is considering an expanded access program, but is unsure how to design it. Part of the problem is that such a plan could interfere with recruitment for adefovir's pivotal clinical endpoint (disease progression) trial, which opened this month at CPCRA sites across the country.

The trial has a targeted enrollment of 2,000 people with CD4 counts under 100. Participants will receive adefovir or placebo in addition to their choice of background therapy. This trial design is essentially the same Abbott used in the study that won full (as opposed to accelerated) FDA approval for ritonavir in advanced HIV infection.

Anyone included in the pivotal adefovir trial could be randomized to placebo even if their HIV still is sensitive to only one or two other antiretrovirals. Such people would then receive what is certainly suboptimal therapy. The most ethical solution is to exclude individuals with a long history of treatment failure and offer them adefovir through expanded access.

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