On Wednesday, November 19th, Gregg Gonsalves circulated this short and sorrowful e-mail: "One of the great AIDS activists died today. Many of you didn't know him personally, but Carlton was one of the community's key experts on clinical trial design and biostatistics and taught many of us how to look at clinical research and AIDS care. He was a mentor to me and many others." We are all saddened by this great loss and offer our support and condolences to Carlton's family. For those who did not have the honor and pleasure to work with Carlton over these 13-odd years, this excerpt from one of his many web site postings may help to color in the many facets of this incredible man and incorrigible activist.

Let's face it: "Problem patients" often live longer. We may not make a lot of friends in the medical establishment (although it is heartening how many doctors and nurses are beginning to recognize self-empowerment for the positive life force it is), but hey, if making friends were our main objective, I'm sure we could find better places than hospitals anyway. Problem patients have very strong opinions about what is in their best interest, and while willing to listen to reasonable alternatives, are tremendously stubborn when they feel it necessary.

Being a problem patient is easier than it looks. And the results are often quite satisfying. But the point is not to be obnoxious. As a matter of fact, in most situations, you truly can catch more flies with honey than vinegar (the proverb never said why you would want more flies, but maybe they're a necessary evil, like residents...). It's probably best to be Little Susie Sunshine until something comes up that might have serious impact on your health or comfort, and then dig in your heels and become the patient from hell until the problem is resolved, at which point you can go back to smiling angelically and humming "The Sound of Music" or something. Positive and negative reinforcement. That's how you train them. Of course, if you are going to go off half cocked, and make a big noisy scene, it would be much more satisfying (and convincing, so that maybe next time you won't need the Oscar scene) to be right. That obnoxious, patronizing resident is going to listen a little better next time if you gently (and accurately) point out the essential lab test that he or she forgot, and then sweetly observe, "Boy, that might have made one hell of a malpractice case, huh?"

Of course, you may be like me, and be fortunate enough to have a really good doctor who works in a team with you, your significant others, and all the other available resources to make sure that you get the best care possible. If you are so fortunate, your exposure to medical nimrods will be greatly reduced. Unless you happen to get your care in a teaching hospital, in which case all bets are off. But even in a teaching hospital, you may be able to find a half dozen decent "attendings," and a double amount of residents so that you are never out of range of a friendly face. Maybe.

Even if you have the best possible situation, with a tremendously committed, available doctor who has full privileges at the same hospital that your insurance pays for, you can still participate in your own health care, and make a big difference. Your doctor may be one of the best HIV-aces in the country, but he or she just doesn't always have two or three hours to go to the library or to fire up the old PC, and research an obscure complication of HIV disease, or some new treatment made from the wings of Indonesian yellow spotted beetles. Many important innovations in HIV care have come from "problem patients" who have demanded better than the status quo for themselves. The doctor-patient relationship can be a team; after all, the entire endeavor is focused on your body, so you should have some input, right?

Unfortunately, there is a long and infamous tradition in western medicine that you hand over autonomy and control over your own body when you seek care. Put baldly, most of the doors are shut in your face. You can test this, if you don't believe me: go into the hospital or clinic where you receive your care and ask someone other than your own doctor to let you look at your chart. If you are persistent and aggressive enough, you will eventually find out that it is your full right (with a few caveats, like if you are so out of it that someone else has legal custody of you), but most clinicians will just instinctively stonewall you and deny you access. They are just conditioned to treat you as less than a fully autonomous and competent individual. I've even met some clinicians who became very upset when they found out that a patient has full right to access to his or her chart. It's their Ju-Ju. Why, if patients got access to all their sacred knowledge, their status as witch-doctors of the tribe, those-who-are-not-to-be-questioned, might be jeopardized.

Nowhere is this kind of belief set better exemplified than in medical terminology. Hermetic mystical societies have clearer, less obscure jargon. "Erythamateous" instead of the good, old fashioned "red?" There is not a single part of the body that doesn't have a separate medical-speak term. I could understand the need for specialized terms to better delineate and discriminate things that are lumped together in lay terms, but am afraid that I simply don't see the difference between "edema of the lower extremities" and "swollen legs." How about "pulmonary?" "Lung-related" seems to cover that OK. Same with "cranium" and head, "cardiac" and heart, "neoplasm" and cancer, "occluded" for blocked... the list goes on and on. If it were a self consistent rational terminology, it might be more excusable. But it's just an arbitrary mess, with no rhyme or reason to it. Latin and Greek roots are mixed up willy-nilly, sometimes in the same word.

I guess that this criticism might be more relevant if the intent of medical speak were to improve the precision of communication, but I believe that to be a secondary objective at best. As with all "buzz-words," it's more a badge of office. Like the handshakes of the Masons, or those ridiculous fez's that shriners wear, it's one of those totems that is supposed to indicate "our guys," whoever they may be. You can see for yourself how protective clinicians are of their pet mumbo jumbo. If you come in spouting a bunch of medical terms, particularly if you use them scrupulously correctly, you will be a good way to having a diagnosis of Munchhausen's in many doctors' minds. They restrict access to their pig Latin by making it pathological for a patient to understand what they are saying.

But it's also an essential skill for anybody with a chronic illness to understand this linguistic crazy quilt. If you hear the doctor mumble, "prep for LP" to a nurse as he or she strides out of the room, wouldn't you want to know that means they are about to put a long needle into the center of your spine before the doctor is gone, and you can ask no more questions?

Face it, hospitals are big bureaucracies, as prone to screw ups, communication glitches, and mindless SNAFUs as any others. If you are like the typical person with AIDS, your chart is probably more than two inches thick. Do you really think that every doctor who meddles in your care reads it before charging ahead with treatment? Clearly, having someone with full, intimate knowledge of your case always available is essential. Who better than yourself? Of course, if you are in the hospital, you probably aren't feeling in top form, and maybe you don't feel up to slugging it out with doctors. That's why it's really helpful to make sure that someone else—a family member, your partner or best friend—also knows this stuff, so that he or she can watch the P's and Q's when you don't feel up to it.

But the most important thing is not letting that door be shut in your face. You are buying a service. You have full rights to demand the best possible service, and to use a consumer's prerogatives in safeguarding your interests. Doctors refer to "doctor shopping" as a negative: manipulative, pathological, and a sure sign of the "problem patient." Well, they are partly right. It's certainly the last, as long as the consensual definition of "problem patient" describes someone who demands the best in care for themselves. And if it's "manipulative" to try and influence systems to take care of you properly, so be it. It's better they call you manipulative than if they call you "The late...."

Knowing your way around will also help you to understand exactly what is going on with your care. There is no substitute for being able to read your own lab and consult reports, and to be able to understand any changes in your own health over time. And don't forget, you always get to ask questions. There is a sacred principle in medicine called "informed consent." It means that you have full rights to as much knowledge as you need to make your treatment decisions. Before any major medical procedure is conducted, some one needs to explain to you exactly what will be happening, and what the potential benefits and drawbacks are.

But what informed consent also means is that you get to ask as many questions as you feel you need to. If there is any part that you are unsure of, you can ask them to repeat it, once, twice, or a hundred times. If there are any words you don't know, stop the doctor or nurse right in the middle of what they are saying, and ask them what it all means. Before you sign any consent, make sure that you get the gist of what it says. You have the right to fully understand what is going on with you. That is one of the main intents of those consent forms. (The other, of course, is shielding the hospital from liability.) And despite my somewhat harsh words earlier about the medical profession's possessiveness about their terminology, often a sympathetic doctor or nurse can help you understand things that you need to know. Journal articles, on-line resources and textbooks can hold incredible amounts of information, but sometimes difficult points are much easier to grasp when they are explained personally. Don't hesitate to ask. Some clinicians may be abrupt, or overly confusing, but you will eventually find someone who "speaks your language," who can open lots of doors to you. And never forget. You have a right to know, and to ask, and to decide. It's your body. This isn't just nice philosophy. It's a principle that is woven into many laws and regulations.

There's no way around it. Having HIV or AIDS definitely sucks. But a good knowledge of medicine, your body, and the systems with which you are forced to interact can make the whole thing much easier to deal with. And never forget: you are a consumer of medical services. You should be able to expect good, appropriate care for your body just as you would expect good services from any other service provider. ¤

More of Carlton's writings on HIV treatment and research and his life as a person with HIV/AIDS appear at www.biostat.umn.edu/~carlton.

In October of 2003, Schering-Plough held a meeting with HCV and HIV/HCV advocates where they announced a "new" Schering—one that prioritizes earning the trust of community members and advocates for people with hepatitis C and HIV/HCV coinfection. Tracy Swan reports for TAGline.

Schering has had an acrimonious relationship with community members, advocates and activists. In his 2001 testimony to FDA's Antiviral Advisory Committee, Brian Klein, founder of the Hepatitis Action and Advocacy Coalition, described meetings with Schering as, "the worst in the industry. Schering's community meetings are a window dressing exercise conducted in the hopes that patient advocates will simply rubber stamp what the company has already decided upon."

A major grievance has been Schering's marketing practices. Schering refused to sell its ribavirin (trade name Rebetol) separately; it was only available in a kit (marketed as Rebetron) along with the Schering brand of alfa interferon (Intron-A). This prohibited patients from combining ribavirin with other types of interferon, and forced them to purchase a fixed dose of ribavirin—whether or not it was the appropriate amount. And Schering's price for ribavirin—a drug they did not even develop—was exorbitant. A year's supply of Intron-A cost about $5,000. When ribavirin was added, the total for a year's worth of Rebetron jumped to $18,000! Activists lobbied Congress and the Federal Trade Commission and testified before the FDA (who encouraged Schering to sell its drugs separately but could not mandate this unbundling), but Schering refused to sell Rebetol separately.

Finally, in October of 2001—months after the approval of its pegylated interferon (Peg-Intron)—Schering announced the unbundling of Rebetol. The price of unbundled Rebetol increased by 52%—to some $1,653 a month—making it more expensive than even the Rebetron kit (at $1,500 per month) which preceded it.

Peg Tales
Pegylation—the attachment of a molecule of polyethylene glycol to interferon—has increased virologic response rates to hepatitis C treatment. Combination therapy with pegylated interferon and ribavirin is the most effective treatment available for hepatitis C.

The FDA approved Schering's pegylated interferon, Peg-Intron (pegylated interferon alfa-2b), in early 2001, and Roche's Pegasys (pegylated interferon alfa-2a) in late 2002. Since then, Schering has lost more than 40% of its market share to Roche. Convenient dosing has contributed to Pegasys's success: it is premixed and administered at a fixed dose. Peg-Intron is dosed by body weight, and until early 2004, when a premixed injection pen device will be available, it must be reconstituted with sterile water before use. Anecdotal reports of Pegasys's favorable side effect profile have been circulating, but these have not been confirmed by a head-to-head study.

In Europe, Peg-Intron was approved for use in combination with weight-based ribavirin dosing. But because of a lack of prospective data on safety and efficacy of weight-based ribavirin, the U.S. FDA approved Peg-Intron with "flat" (fixed dose, 800 mg/day) ribavirin dosing. They also requested that Schering perform a direct comparison of safety and efficacy of flat vs. weight-based ribavirin. Preliminary safety data from this study (Schering's WIN-R) showed that at week 24 there were no significant differences in serious adverse events or treatment discontinuations by ribavirin dose—although anemia (a common side effect of ribavirin) occurred more frequently with weight-based dosing. The efficacy data remain blinded, although Schering has submitted it to FDA. Schering has been unable to tell community members when the data would be available.

Peg-Intron: Still dose finding?

The Case for 1.0
Little research addresses differences in efficacy between the different Peg-Intron doses. Peg-Intron is currently labeled for use as monotherapy in HCV infection at a dose of 1.0 mg /kg, but the approved dose for use in combination with ribavirin is 1.5 mg /kg.

Lindsay and colleagues studied three doses of Peg-Intron: 0.5, 1.0 and 1.5 mg/kg as monotherapy (that is, without ribavirin). Efficacy, discontinuations and dose reductions were roughly equivalent for the two higher doses, supporting approval of the 1.0 mg/kg dose for use as monotherapy. (Relapse rates, however, especially in genotype 1, were high at both 1.0 and 1.5 μg/kg.)

At this year's Digestive Disease Week Meeting, Flamm and colleagues presented interim data from their HCV treatment trial, which compares response rates to 1.0 mg/kg or 1.5 mg/kg of Peg-Intron plus 800-1,400 mg/day of ribavirin. They reported that virologic responses and discontinuations at week 24 did not differ significantly between the two Peg-Intron doses, but the relative success of the 1.0 μg/kg Peg-Intron dose will ultimately be determined by sustained virologic response rates, which are not yet available.

The Case for 1.5
While 1.0 mg /kg of Peg-Intron may be equally effective as and less toxic than 1.5 μg/kg, data from a small pharmacokinetic study suggests that the lower dose may be suboptimal. Formann and colleagues examined the relationship of Peg-Intron levels in the bloodstream and hepatitis C viral load among 20 people with HCV-1. Participants were randomized to receive 1.0 mg/kg of Peg-Intron once or twice weekly. In the twice-weekly dosing group, Peg-Intron was consistently present at detectable levels. In contrast, nine of ten people in the once-weekly group had undetectable levels of Peg-Intron by day seven. Viral kinetics differed by dosing arm: at day 28, four of ten people in the once-weekly group had decreases in HCV RNA >1 log10 vs. nine of ten people in the twice-weekly group.

Peg to Peg
Data from three large trials reflect roughly equivalent efficacy of Peg-Intron and Pegasys, although there were differences in virologic response rates among a subgroup of participants. This subgroup—those with HCV genotype 1 and high baseline viral loads (>2 million copies/mL or 800,000 IU/mL)—does not respond to treatment as well as those with non-1 genotypes and low baseline viral loads. Since the majority of people with HCV and HIV/HCV coinfection in the United States have genotype 1 and high baseline viral loads, identifying the optimal treatment regimen is crucial.

A comparison of efficacy using data from different studies has limitations and cannot be considered conclusive. Different dosing schemes-flat dosing vs. weight-based-for ribavirin and pegylated interferon, and different participant characteristics influenced response rates. Yet the data from three studies suggest that a higher dose of ribavirin increases virologic response rates among people with HCV-1 and high viral loads. The relative contribution of Peg-Intron or Pegasys to sustained virologic response is unclear.

Neither Roche nor Schering was initially eager to compare products. A comparison of pegylated interferons is not a burning research priority, since the treatment pipeline for HCV looks robust; new drugs will be entering Phase I studies in early 2003. Nonetheless, the results of a head-to-head comparison will be useful because it is likely that pegylated interferon will remain a mainstay of HCV treatment until effective new combinations become available.

The Problem with IDEAL
Although Schering has been touting the IDEAL (Individualized Dosing Efficacy vs. flat dosing to Assess optimaL pegylated interferon therapy) study as the "first head-to-head study of leading hepatitis C therapies," IDEAL is a mere marketing ploy that will fulfill part of Schering's post-marketing commitments to FDA.

IDEAL's 2,880 participants will be randomized to:

• Peg-Intron 1.0 mg/kg per week plus ribavirin (weight-based, 800-1,400 mg/day),
• Peg-Intron 1.5 mg/kg per week plus ribavirin (weight-based, 800-1,400 mg/day),
• Pegasys 180 mg per week plus ribavirin (fixed dose, 1,000-1,200 mg/day).

Schering was asked to study the safety and efficacy of two doses of Peg-Intron (1.0 µg/kg and 1.5 µg/kg) with ribavirin in HCV genotype 1. But because IDEAL combines a dosing study within the overall Peg-Intron vs. Pegasys product comparison, the study does not constitute a head-to-head comparison. Advocates suggested adding a fourth arm to the study (Pegasys with weight-based ribavirin dosing), or changing the ribavirin dosing from fixed to weight-based in the Pegasys arm. Schering refused to consider changes, saying that using the licensed dose of ribavirin with Pegasys was "…the only option."

Before conducting a head-to-head comparison, Schering should identify the optimal dose of Peg-Intron in a separate study. The 1.0 mg /kg dose has been approved for HCV monotherapy, but the dose approved for use with ribavirin is 1.5 mg/kg. Because IDEAL combines a dosing study with the Peg-Intron vs. Pegasys comparison, a higher number of participants will receive low-dose Peg-Intron than would otherwise be required for a stand-alone dosing trial. Greater numbers in each arm are required to reach statistical power, but this may expose a larger than necessary group to a potentially suboptimal dose of Peg-Intron.

Schering was unwilling to consider separate trials, citing expense and competition for participants between the two studies. While participants will be stratified by baseline HCV RNA (<600,000 IU/mL vs. >600,000 IU/mL*), Schering was unable to guarantee that the study would be adequately powered to detect differences in sustained virologic response by baseline HCV RNA levels. Thus, the most important question—"What is the best regimen for people with HCV-1 and high viral loads?"—may never be answered by IDEAL. It's a shame that Schering is squandering so many resources—especially their study volunteers—on a less-than-ideal study. ¤

* Conversion of HCV RNA from international units (IU) to copies per mL differs by assay.