NOTES FROM THE UNDERGROUND
The PWA Health Group Newsletter
"Access to Information Precedes Access to Treatment"
Spring 1999 Issue 39

Table of Contents

Antiretroviral Chemotherapy
RU-486: Anti-Choice Extremists Block HIV Drug Research
Hepatitis C and HIV

Antiretroviral Chemotherapy A rose by any other name . .   by James Learned

Antiretroviral chemotherapy. It's a term we rarely see in print, either in our community newsletters or in the mass media. Nor do we use the term very often in conversation. When we talk with health care providers, researchers and each other, we say combination therapy or triple combinations or anti-viral therapy.

Yet antiretroviral chemotherapy most accurately describes the treatment regimens that so many people with HIV are now living with or contemplating. Never in the history of medicine have so many people been expected to adhere to such an onerous course of medical treatment without question. There is little data to support its long-term effectiveness. And the long-term side-effects of antiretroviral chemotherapy are becoming clearer: fat redistribution from the face, arms and legs to the abdomen, breasts and/or upper back (sometimes called lipodystrophy); increased blood sugar levels which can lead to diabetes; and abnormally high cholesterol and triglycerides, which are associated with an increased risk of heart disease.

We have no idea when is the best time to begin treatment or the best combinations to use. And as of now, at least, the treatment is expected to be lifelong. Yet even within our own communities, there is little acknowledgement of the enormous complexities involved in personal treatment decisions. In only a few short years, we've moved from critical analysis of research data and respectful support for each individual's treatment decisions to a headlong dive into developing adherence strategies.

Okay, the pill-taking schedules are difficult. Sure, they affect every aspect of your life, from meals, to sleep and work schedules, to issues of disclosure. And yes, all those pills are tough to get down-but just try a little applesauce. As for the side effects. Well, we do acknowledge that some of them are life threatening. And, yes, all of them affect quality-of-life. We all understand that constant diarrhea is unpleasant, for example. But just throw in a little Imodium. What we rarely acknowledge is that antiretroviral chemotherapy is not necessarily the best choice for everyone living with HIV. And it's never an easy choice.

Many of us have watched someone we love with cancer decide whether or not to go through chemotherapy and/or radiation. It's a tough, nearly impossible, decision. Depending on the type and stage of the cancer, the chances of going into remission vary widely. Hair loss, nausea, projectile vomiting and debilitating fatigue are usually part of the package.

We all acknowledge that. When someone makes the decision to go ahead with chemotherapy, we accompany them to their appointments, sit at their bedsides while they recover, and work things out with friends and family to insure that as much support as possible is provided.

When someone decides against the course of treatment, we usually, hopefully, honor the decision. It has taken decades to reach the point where the treatment choice of an individual with cancer is respected. Are we respecting the treatment choices of our HIV+ brothers and sisters?

Looking individually at each of the sixteen pharmaceutical products used to slow down HIV replication is pretty easy. There's data on each one, limited though most of it is. Each drug has particular side effects, some immediate, some temporary, and some long-term. Each drug is dosed to keep enough of it in your blood to do its job-a specific number of pills, taken a certain number of hours apart, with or without food. Each drug interacts with other medications, methadone and street drugs in such a way that some things can't be taken together at all. Either that or dosing adjustments need to be made. If taking only one of these sixteen drugs were useful, the decision-making process would be relatively straightforward. But, of course, taking only one of these sixteen drugs isn't useful at all.

"Strategize" was the catchword of HIV treatment discussions in 1998: Don't use up your options. Watch out for cross-resistance. Choose a regimen that you can stick to. Developing individual treatment strategies continues to be incredibly important, of course. But perhaps 1999 will be the year that we honor the emotional and intellectual complexities central to every individual treatment decision-the decision not to start antiretroviral chemotherapy as well as the decision to begin or switch combinations.

A holistic approach to HIV has always been an important part of PWA self-empowerment. Emphasizing antivirals to the exclusion of other treatment options, including the option to hold off on antiviral treatment, doesn't allow room for imaginative, individual decision-making. Alternative and complementary therapies, from antioxidants to immune modulators, are not being given the attention they deserve.

For people on antiretroviral chemotherapy, three-drug combinations may still be the norm, but four and five-drug combinations are increasingly prescribed. No adherence strategy will help if one of your medications interacts with another to decrease absorption levels. In addition to interactions with other antivirals, you need to be aware of interactions with prophylaxis medications, anti-depressants, anti-anxiety medications, TB medications, methadone and birth control. If 90% adherence is required for these drugs to be effective, as many researchers believe, how do side effects like vomiting and diarrhea affect your ability to keep enough drug in your system? We may be expecting the impossible of people on these regimens. And if we expect the impossible of each other, how can we help those who aren't immediately affected understand how truly complex HIV treatment is-and how very far we have to go?

Powerful and easy to live with, promises an Agouron ad for Viracept. Powerful, yes, kind of. Easy to live with? For whom? The climbers on Merck's Crixivan mountain are certainly attractive. But the heroes of the epidemic are not the photogenic models hired by pharmaceutical companies to sell drugs in picturesque settings. Our heroes remain, as always, PWAs who get through each day, making personal treatment decisions that are right for them, wading through the simplistic, sometimes cruel messages of direct-to-consumer marketing, working with and educating their doctors and communities, and, in the process, expanding treatment options for everyone. Each of our heroes is an individual. There is no one-size-fits-all treatment regimen that will be equally right for any two people. As each individual struggles through each day and deliberates over each treatment decision-whether that decision includes antiretroviral chemotherapy or not-our heroes deserve honor, respect and continued support. ¦

Portions of this article were originally published in Positively Aware.

RU-486: Anti-Choice Extremists Block HIV Drug Research  by Maia Szalavitz

Anti-abortion extremists may be preventing development of and access to a drug which potentially reduces HIV replication and may be useful in the treatment of lipodystrophy ("crix belly" "buffalo hump") which is experienced by many people with HIV.

RU-486 (also known as mifepristone), the oral drug used for non-surgical abortions developed in France, shows some promise as an anti-viral and as a treatment for the problems with fat metabolism which particularly seem to affect people taking protease inhibitors.

But we don't know enough yet about how HIV causes disease to warrant human trials of the drug. And there is another drug, currently in clinical trials, which doesn't have the abortion baggage that RU486 does but may have similar effects.

Here's what is known: In 1995, David Weiner and his colleagues at the University of Pennsylvania published a paper in the Proceedings of the National Academy of Sciences which detailed how a class of receptors found in the human body and brain have some interaction with a protein made by HIV.

These receptors are normally occupied by chemicals called "glucocorticoids," which include stress hormones like cortisol and sex hormones like progesterone. RU486 blocks these receptors-and also seems to block a protein made by HIV to regulate its life cycle. Weiner says the data isn't yet clear as to whether the HIV protein actually occupies glucocorticoid receptors in the body-and what effect it has if it does, but in the test tube, RU486 reduces virus production by 70% in macrophages (a type of immune cell).

Weiner cautions that the RU486 formulation used in his research is different from the one designed for use in abortions and that people should not take (if they can even manage to get) the currently available drug to try to treat themselves. "The abortifacient [RU486] includes two different drugs and the drug we used in our lab we made ourselves," he said. "No tests have yet been done on humans and that would be premature at this point," he added.

Increases in glucocorticoids have also been linked to increased risk of Kaposi's Sarcoma (KS). Canadian researchers studied cells from people with HIV and KS and found that drugs which increase the release of glucocorticoids (such as dexamethasone) make both conditions worse by increasing the proliferation of infected cells. Treatment with RU486 completely blocked this effect in the cultured cells.

Researchers believe that RU486 may be useful in treating lipodystrophy because of the similarity between this condition and a disorder called "Cushing's syndrome." In fact, patients with lipodystrophy were often believed to have Cushing's syndrome at first because it also produces increases in waist size, buffalo hump at the back of the neck and higher cholesterol and triglycerides.

Cushing's syndrome is characterized medically by a higher than normal level of the stress hormone cortisol, often caused by a tumor in the adrenal glands. Cortisol has immuno-suppressant effects as well. RU486 has been studied in the treatment of Cushing's syndrome, which can be fatal. The research found that half of those with inoperable tumors causing Cushing's syndrome not only experienced complete reversal of the symptoms, but also control over the disease. In 1990, two people whose lives were saved by this treatment testified before Congress to push for approval of the drug.

When the abnormalities which usually cause Cushing's syndrome were ruled out in people with HIV, researchers knew that the lipodystrophy they were experiencing could be related either to HIV infection itself or to medications the people were taking. Lipodystrophy does seem more likely amongst people on protease inhibitors (some 75% of people on PI regimens will experience some form of it after two years on these drugs), but some people with HIV who are not taking PI's have also developed similar symptoms.

People with HIV have also long been known to have problems with blood cortisol levels and cortisol regulation (the levels are supposed to change at certain times of day), and these seem to become even further dysregulated as HIV progresses. Perhaps this not only helps HIV to kill more cells, but also helps cause lipodystrophy? Perhaps protease inhibitors somehow advance the process that causes lipodystrophy, even while reducing levels of the virus itself? Perhaps this is caused by interactions between HIV proteins and glucocorticoid receptors?

RU486 research could help answer these questions and possibly offer an important new anti-viral treatment option for people with HIV, and a new way of fighting the often-disfiguring lipodystrophy.

But abortion politics may stand in the way.

The FDA has issued an "approvable" letter for the drug, but it is not yet actually available in the U.S. Because of fears about anti-abortion violence, importation for personal use, while technically possible, is highly difficult because foreign sources won't make it available to Americans. And there is no manufacturer currently producing the type used for HIV experiments in Weiner's lab.

An American manufacturer, the Population Council, expects to have the abortifacient form of the drug available to researchers and for compassionate access early in 1999.

Long term effects of the drug have been described in Nature Medicine as "slight to moderate," although some patients may develop problems due to elevated ACTH (a hormone) and cortisol in the blood, which can be extremely serious, even fatal.

Dr. Donald Kotler of St. Lukes/Roosevelt Hospital says that before RU486 trials can be considered, more studies are needed on the relationship between cortisol and lipodystrophy. "If cortisol doesn't cause lipodystrophy but is just related to it, there would be no reason to study RU486," he said.

"We know that there is some problem in HIV-infected people with cortisol-with synthesis, secretion or the sensitivity of the body to it." he said. "I have some evidence of hypersecretion in lipodystrophy, not huge, and it doesn't mean that it causes it, but I do have some evidence of it. We need more research."

Kotler also points out that HIV lipodystrophy is similar to a fat metabolism problem called "Syndrome X," which is linked with early heart attacks and strokes. "Within a few years we may see thousands of people having heart attacks at age 35 if we don't figure out how to do something about this," he says.

Another glucocorticoid blocker, which doesn't have the political baggage that RU486 does, may be the answer. A drug called Anticort, manufactured by a Las Vegas company with the awkward name Steroidogenesis Inhibitors, has just been approved by the FDA to enter phase 1B and 2A trials for HIV treatment. This means that the drug has passed safety tests, but still needs to be tested to see which dose might be most effective.

A paper presented at the 1996 AIDS conference in Vancouver of an open trial of the drug found that T-cells increased by 35-40 cells per month in patients on drug and that CD8 cells came back to normal levels. Also, according to author Dr. Alfred Sapse, who works for the company, "It dramatically reduced depression." Sapse says this isn't surprising because high cortisol levels are linked with depression in general.

The AIDS Research Alliance in Los Angeles is currently enrolling patients for the dosage trials. For more information, contact Dr. Steven Brown at 310-558-2423. The trials should start this spring, according to Dr. Sapse.

DOES YOUR LIVER QUIVER Hepatitis C and HIV   by Brian D. Klein

Hepatitis C (HCV), a chronic viral illness, has a lot in common with HIV. And if you're coinfected, or chronically infected, with both HIV and HCV, there are important interactions you need to know about.

Both HIV and HCV produce astronomical amounts of virus each day. HIV produces billions of virons (virus particles) every day. HCV produces more, possibly a million times the billions that HIV produces. This is why needle sticks and other blood exposures are more likely to transmit HCV than HIV. There are just more of those critters running around.

Antibody tests are certainly helpful in screening for both illnesses. But these tests can give a negative reading during the acute phase of HIV or HCV, as well as at other times, particularly when one is co-infected. So if you test negative for either or both, test again every six months. Quantitative viral load tests, called PCRs, are the only certain way to be sure of accurate diagnosis for both HIV and HCV.

Nearly all infections are chronic in both diseases, over 85% in HCV and over 99% in HIV. Chronic infection means that your body is not able to rid itself of the disease and is continually trying to fight it. It also means that you can pass on the infection to someone else through a transmission route; predominantly blood-to-blood contact with HCV. Sexual transmission is documented with HCV, but this is not the major transmission route. Clearly, though, safer sex guidelines should be followed as with HIV.

With both infections, the higher the viral load the faster the disease is likely to progress if it is not treated. When someone is co-infected with both HIV and HCV there is evidence that their viral loads, before any treatment, tend to be higher for both diseases than people who are infected with only one of these viruses. Some doctors believe that liver damage can progress as much as 10 times faster in people co-infected as in people with HCV alone.

When treatment is indicated for HIV or HCV, the goal is to reduce the viral load as much as possible and as quickly as possible to halt or at least slow disease progression. HCV treatments is moving in the direction of combination therapies, some to boost the immune response (e.g., interferons), and others that are actually anti-viral in action. Combinations seem to be more effective than using any single agent. Just as in HIV, we will be seeing in the next few years protease inhibitors and other inhibitors that will interfere with the life cycle of the HCV virus. These will most likely be used in combination with interferons or the currently available interferon + ribavirin combination.

Treatment for HCV usually starts with low doses of interferon injected 3 times a week for 12 to 24 months. This has proven to be effective for only 15% of patients, however. If the viral load is not below the level of detection and the liver enzymes (shown on blood tests) are not near normal levels within the first 3 months of treatment, it most likely will not succeed. Most people will stop treatment at this point. Recently a combination of low dose interferon with oral ribavirin has shown better results; possibly up to 45% of patients treated have seemed to benefit. This treatment has been approved for 6 months of usage, but may soon be expanded to at least a year to increase the number of people who are successful at suppressing viral load. It has been approved for people who relapse after trying low dose interferon alone, as well as for first use treatment. Some studies show that just using higher doses of consensus interferon alone (an interferon that is bio-engineered to match more closely naturally occurring interferons in the body) may get at least a 56% effectiveness rate.

In HIV we know that using prescribed levels of medication and adhering to regular dosing schedules is more effective over time, in keeping viral loads maximally suppressed. It is also important to suppress viral load as rapidly as possible to prevent drug-resistant strains of the virus from evolving. Cutting edge research shows that this is true for HCV as well. But most physicians are still suggesting low dose interferon 3 times a week. This is ineffective for the vast majority of people. Since interferon clears from the body rapidly, this intermittent dosing often allows the virus to reproduce between interferon doses. Clearly, more interferon (higher dosing) is better; longer therapy is better; combination therapy with ribavirin is better; daily dosing is better; high dose induction (starting with a high dose for several weeks and then cutting back) is better.

Sadly, all of these methods lead to more side effects such as cytopenias (blood cell component problems, including anemia in the case of using ribavirin). Many of these side effects can be treated. Reducing side effects can help you to feel better and stick with the treatment. However, this is where most gastroenterologists (stomach and bowel specialists) and hepatologists (liver specialists) still seem to be timid. They tend to reduce the dosing of the HCV medication (most likely reducing the effectiveness of treatment) instead of treating the blood toxicity problems that HIV treating physicians are more familiar with and know how to handle. State-of-the-art research would suggest that we insist that our HCV-treating physicians try to treat these problems before reducing the dosage of therapy that may lead, in turn, to a reduced chance of HCV viral suppression.

Another side effect of all of these treatments can be depression, sometimes severe enough to have suicidal thoughts. Often this can be prevented or reversed by using antidepressant medication. Some people start an antidepressant two weeks before starting any HCV treatment to reduce the possibility of depression.

Choosing to go on treatment is a difficult and very individual decision. And, yes, there is evidence that interferon treatment of any level will help slow liver disease progression even if it does not fully suppress viral replication. But if you choose to go through HCV therapy, why not give it the best chance for success including possible eradication of the virus? Insist that your doctor do whatever it takes to get the most drug possible into you for the longest period of time appropriate. And if he or she is not familiar with drugs that treat hemotoxicities then tell them it's time to become familiar with them.

Now to some special problems specifically for those folks infected with HIV and HCV. Highly active HIV anti-viral treatment regimens usually include use of an HIV protease inhibitor (PI). Strong protease inhibitors have significantly increased survival in many folks with HIV. All PIs undergo extensive hepatic metabolism, meaning that they're processed through the liver. The possibility of liver complications exist for all four of the currently available PIs. In general Crixivan (indinavir) and Norvir (ritonavir) are more hepatatoxic than Invirase/Fortovase (saquinavir) or Viracept (nelfinavir). Many co-infected individuals seem to handle their protease inhibitor just fine. Some folks get initial liver complications and then settle back down after some time and are able to remain on their protease inhibitor therapy. Other folks get an "activation" of their HCV with increasing viral loads and elevations of liver enzymes that do not settle down and cannot be tolerated.

If you are successfully using one or more PIs with minimal effect on your liver, there is no reason to change. But if you are having a problem, you may want to talk to your doctor about switching to a less hepatotoxic protease inhibitor, or to a combination therapy that does not use a protease inhibitor. Keep in mind that the non-nucleosides, Rescriptor (delavirdine), Viramune (nevirapine), and Sustiva (efavirenz) can also be hepatotoxic. Some people are successfully using three nucleosides from the list of: Retrovir (AZT), Zerit (d4T), Epivir (3TC), Videx (ddI), Hivid (ddC) and Ziagen (abacavir). Some drug companies would love you to believe that using an HIV regimen without a protease inhibitor is just as potent and durable as one with a PI. Evidence of long term durability of non-protease regimens is not yet available. But you may want to stick with the most potent regimen you are able to tolerate.

Another special problem for co-infected people is the use of ribavirin in the treatment of their HCV. Ribavirin can interfere with the action of some of those HIV nucleoside analogues listed above, particularly AZT. The levels of these drugs in your blood may decrease, leading to the chance that you could develop viral resistance. The one exception so far is in the use of Videx (ddI) which seems to be increased by ribavirin. Studies are going on now to see if combination therapy for HCV (interferon+ribavirin) can successfully be done with the nucleoside-containing HIV regimens. Early indications show that it can be done. If you choose to use ribavirin, make sure your doctor carefully monitors your bloodwork to make sure you are not getting an increase in your HIV viral load.

Some last minute free advice (maybe that's all it's worth ?!): HCV and HIV treatments are obviously complicated for patients as well as doctors. We will probably have new information every few months. Sometimes the patients know more than the doctors, but don't bet on that all the time. Be actively involved in your own care. Use all the resources available to you; books, the internet, friends, and support groups. But do remember that your doctor is your consultant. Write your questions down before you go to see your doctor. If you do not understand something, insist that your doctor explain it to you so that you are making informed choices. If you have questions after your visit write them down and call your doctor's office to ask that he or she get back to you with answers. Sometimes, in difficult issues such as co-infection, nobody has a clear answer yet. I do not expect my doctors to know everything. I trust a doctor who honestly tells me that he doesn't know something and will either find out for me or lead me to a resource where I can get an answer, as opposed to a doctor who pretends to know. Most HIV doctors learned these lessons long ago from their patients. It's time that our gastroenterologists and hepatologists learn how to work with us too. Insist on it.

Note: I am not a physician. The opinions expressed above are totally my own based on my own experience, examination of the current research literature, and recent public presentations by treating physicians in the field. I strongly recommend that in making any treatment decisions you work with an HCV treating physician that you trust and, if you are co-infected with HIV, you have an HIV treating physician who is closely coordinating care with your HCV doctor.