- Background on Protease Inhibitors
- August 11 Deadline for Protease Inhibitor
- Another Protease Inhibitor Option
- Treating CMV retinitis
- Cidofovir (HPMPC)
- New Use For Foscarnet
- Albendazole Correction
- $ for Young Adults Study
- Dana Consortium
- Expanded Access to 3TC
- New Spanish language Experimental Treatment Guide
- Our Internet Home Page
- Good Doctors, Good Patients
- Good Results for Stavudine (d4T)
- About Treatment Review
- August 11 Deadline for Protease Inhibitor
Contents
Protease Inhibitors
Protease inhibitors are a new type of anti-HIV drug. Protease inhibitors are meant to inhibit, or block, a piece of HIV's machinery called protease. When this protease is blocked, HIV makes defective copies of itself. Protease inhibitors are different from nucleoside analogues (AZT, ddC, ddI, d4T, and 3TC) in a number of ways. They are more specific in what they do. Protease inhibitors block infected cells from producing new virus, while drugs like AZT cannot prevent the production of new virus. Because of their specific activity, protease inhibitors most likely do less damage to cells than nucleoside analogues.
Studies have shown that protease inhibitors reduce the amount of HIV virus that is measurable in the blood. In some cases, protease inhibitors have increased T4 cell counts even when they were low. These results have encouraged two drug companies that make protease inhibitors to start long-anticipated treatment programs for people with low T4 cell counts.
Most researchers believe that any protease inhibitor will need to be taken with one or more other drugs such as 3TC (an AZT- like drug expected to be approved by the FDA very shortly) to get the most benefit. It is also believed that protease inhibitor monotherapy - taking one protease inhibitor at a time - won't produce the best results, but no clinical studies are presently testing any protease inhibitor combinations. Testing one protease inhibitor at a time may, however, get at least one or more of them approved more quickly.
Studies have shown that, in some cases, the beneficial effects of protease inhibitors used alone quickly wear off, most likely due to the development of resistance. Resistance occurs because HlV makes billions of copies of itself every day. Each new HIV virus that gets made is slightly different, which means that the protease part of the virus might be slightly different, too. This new kind of protease may not be affected by a drug meant to stop the old kind of protease. Signs of resistance have already been seen in people taking all three of the protease inhibitors that are currently in the final stretch of development. Test tube studies have also shown that newer protease inhibitors like Agouron's AG1343 may not be effective in people who have developed resistance to other protease inhibitors. No one yet agrees on the extent or significance of resistance, but there are different opinions.
Many questions about protease inhibitor are still unanswered. Despite concerns about resistance, this class of drugs could be a promising treatment for HIV- infected people. Combining two or more protease inhibitors, or combining them with other anti-HIV drugs may slow down the development of resistance. Protease inhibitors are still experimental drugs. The more data that is collected from people who are actually taking them alone or in combinations, the more answers we'll be able to provide.
Merck Expanded Access Program
A new program for people with less than 50 T4 cells has been announced. Register before August 11, 1995 to be considered for Crixivan, the protease inhibitor made by a drug company called Merck. Registration is by calling 1.800.497.8383. You can call between 8 a.m. and 11p.m., 7 days a week, in English or Spanish. Due to limited supplies of the drug, if more than 1,100 people apply before that date, a lottery will be necessary to determine who gets to participate.
To participate in this program you must be at least 18 years old, and have less than 50 T4 cells. You can be taking, or already have taken 3TC, d4T, ddI, ddC or AZT, alone or in combination. You must have a platelet count greater than 50,000. You cannot have acute hepatitis, and you cannot be pregnant . You are not permitted to take any other another protease inhibitor during the study.
Other required blood values include: hemoglobin greater than 6.5; absolute neutrophil count greater than 500; creatinine less than 6 times the upper limit of normal; and blood urea nitrogen less than ten times the upper limit of normal.
You must also live in the United States and have an address where you can be reached by mail. (Someone else can register for you, and even can receive mail for you if you give your permission for them to do so.)
Anyone not selected will be placed on a waiting list in case some of the selected people decide not to take part in the study. The study may also be expanded to include those on the waiting list as more drug becomes available.
Another Option for under 50 T4 Cells
Crixivan is also being studied in a clinical trial. Like the expanded access program, less than 50 T4 cells are required to participate in this program. The trial will study 3 different drugs in combination and alone for the treatment of HIV infection. The drugs are Crixivan (MK-639), AZT and 3TC. You must have taken and tolerated AZT for more than 6 months at the standard dose to be eligible to participate. Participants will be divided into three groups. The first group will take AZT and 3TC. The second group will take the protease inhibitor. The third group will take all three study drugs together.
There is also a special, open label arm of this study for people who can't take AZT, have used AZT for less than six months, or have taken 3TC before.
CMV Treatment
CMV retinitis is a condition caused by a herpesvirus called cytomegalovirus (CMV). It can affect many parts of the body. When it affects one or both eyes, it's called CMV retinitis. CMV retinitis usually causes blindness if left untreated. Treatment should start as soon as the disease is detected. Treatment does not cure the disease, but does usually get it under control for several months or longer. Two drugs are approved to treat this condition: ganciclovir (Cytovene) and foscarnet (Foscavir).
Both treatments are given by intravenous infusion. Both drugs require a catheter. A catheter is a small tube that is placed in a vein. This allows the drug to easily go into the vein. It also avoids having to find a new vein every time the drug needs to be given. Sometimes a catheter is placed in the arm. Powerful drugs like ganciclovir and foscarnet, however, can wear out the veins in the arm, so almost everyone who needs to take these drugs on an ongoing basis gets a permanent catheter.
Researchers are looking for treatments for CMV retinitis that aren't so demanding to take. A pill form of ganciclovir was recently approved by the Food and Drug Administration (FDA) for maintenance treatment of CMV retinitis. It is expected that this pill will also be approved for the prevention of CMV.
Studies have also shown that ganciclovir implants - small pellets of drug that are placed directly into the eye during a typically uncomplicated surgical procedure - are effective at treating CMV retinitis, although they are still being investigated. At this point it appears that the pellets only need to be inserted about once every six months - an obvious benefit over daily infusions.
One very important reason clinical trials are conducted is to determine the safety of a drug, including what side effects a drug might cause in the short and long term. Only one in ten experimental drugs makes it through the clinical trial process because testing shows that the drug is too toxic, or has other problems. Yet, many drugs used to treat cancer (chemotherapy) have well known toxicities. The FDA approves them, doctors prescribe them, and people with cancer are sometimes cured by them.
The seriousness of the problem for which the drug is being tested, such as life- threatening cancers or potentially fatal AIDS-related opportunistic infections, gives researchers license to push toxicity limits. Although few patients are eager to tolerate harsh or severe side effects, some are willing to tolerate the side effects if the benefit is great enough. There are also sometimes ways to lessen or eliminate the side effects of drugs. When foscarnet was first approved there were very real concerns about kidney toxicity. Doctors are often able to reduce possible side effects, however, by first giving infusions of saline solution (salt water) to hydrate the kidneys.
Cidofovir (HPMPC)
The drug cidofovir, also known as HPMPC, is now in clinical trials. In earlier studies, this drug caused kidney damage (renal toxicity). It also demonstrated strong activity against CMV, for an extended period of time. When the effect of the first infusion wears off - in about 7 days - the second infusion appears to have the same effect, and last the same amount of time. At this point it is not known whether the drug actually ever stops working against CMV. Both foscarnet and ganciclovir eventually stop working, and CMV progresses after about 6 months.
The first studies of cidofovir indicate that the best way to give the drug is once a week. The new study that is described below will give the drug once a week for the first two weeks, then once every two weeks. If this turns out to be an effective way to give this drug, it would certainly be more convenient and less invasive than the usual once or twice a day infusions of the already approved drugs.
To participate in this trial you must have failed previous treatment. Requirements for failing previous treatment vary according to the location of the CMV infection in your eye. All participants are treated with cidofovir. After the two week induction period, participants are randomized to 2 different doses. Treatment is once a week for 2 weeks and once every other week after that. Clinic visits may require two days of visits, all outpatient. All participants receive probenicid and saline hydration at the same time. Probenicid helps protect the liver from possible side effects due to treatment with cidofovir. Probenicid is a pill. Cidofovir is given by intravenous infusion.
To participate, you must be 18 years or older with CMV retinitis that has progressed while on foscarnet or ganciclovir for at least a 4 week period. You may not have been treated with ganciclovir or foscarnet within 2 days of starting the study. You may not have ever been treated with cidofovir. You must do a one week washout from anti-CMV investigational agents. If you have an intravitrial implant with ganciclovir, the implant will have to be taken out before starting the study. For more information about this study, or the treatment or prevention of CMV, call The Network at (800) 734-7104.
Although there is no guarantee that the drug cidofovir will not cause side effects, researchers and some people with AIDS support the continued testing of this drug because it holds great promise. By adding the drug probenicid to the study, researchers hope that the kidneys will not be damaged. This drug has been used for this purpose with other drugs.
Treatment Briefs
New Use For Foscarnet - The drug foscarnet has been approved by the U.S. Food and Drug Administration for treating herpes infections that are resistant to the standard treatment, acyclovir (also known as Zovirax). Herpes infections include herpes simplex, which can cause nerve pain and sores around the mouth and genitals, and herpes zoster (commonly known as shingles), which causes painful lesions on the body.
Up until now foscarnet was only been approved for the treatment of one specific kind of herpesvirus infection called CMV retinitis. It has been commonly used to treat other herpesvirus infections that haven't responded to acyclovir.
The Network has heard from people in the past that have had to go into hospital to get foscarnet treatment for their acyclovir-resistant herpes infections, because their insurance wouldn't pay for the drug otherwise. Now that the drug has full approval for acyclovir-resistant herpes, people in this situation will be able to receive treatment at home.
Albendazole Correction - Gargoyles slipped into our printer's shop and changed the number we had listed for the compassionate use program for the drug albendazole. This drug is available through a compassionate use program for the treatment of microsporidiosis. The right number is (800) 877-7074, extension 3909.
$ for Young Adults Study - A new information gathering study called Teams Linking Care (TLC) has opened. This project focuses on improving the health and quality of life of 14 to 23 year olds. Young adults meet in small groups with others living with HIV or AIDS, and also meet individually for interviews every three months. TLC pays you $20 each time you complete an interview and $10 for each group session you attend. The three parts of the group meetings are: Staying Healthy, Acting Safe, and Keeping Up. Each series is 12 two hour group sessions held weekly with a three month break between series. Younger people will also be considered. Groups are conducted in Spanish and English.
Dana Consortium - This error was our fault. In last month's issue of Treatment Review, the article about the vitamin E-like drug on the front page mistakenly referred to the Dana Farber Institute. This trial for a treatment for HIV-related dementia is part of the Dana Consortium, a university consortium devoted to investigating treatments for AIDS Dementia Complex. The Dana Consortium is not related to the Dana Farber Institute in any way, and we apologize for the misprint.
3TC Expanded Access Program Changes Again - The experimental anti-HIV drug 3TC has been available through an expanded access program for some time now. 3TC is a nucleoside analog like the other approved anti-HIV drugs AZT, ddI, ddC and d4T. Studies seem to indicate that it has less side effects than the approved drugs, and works particularly well in combination with other anti- HIV drugs.Doctors have been able to obtain the drug for their patients directly from the company that makes it, Glaxo Wellcome. Due to problems with drug supply, the entry criteria for this program were recently restricted so that only people with under 100 T cells could be enrolled, and a maximum of 350 people could enter the program each week. Glaxo Wellcome has now announced that as of August 15th, 1995 people with less than 300 T cells can ask their doctor to enroll them in the program by calling 1.800.248.9757. The number of people that can be enrolled each week has also been increased to 650.
Book Available for Shipping Costs - A book on relations between doctors and their patients is available for the cost of shipping and handling. The book is called: Good Doctors, Good Patients: Partners in HIV Treatment. The book is written for people with HIV, their caregivers and doctors, and reflects the authors' professional and personal experiences. The authors are Judith Rabkin, PhD, MPH.; Robert Remien, PhD; and Christopher Wilson, RN, MPH. Copies of Good Doctors, Good Patients may be obtained from NCM publishers for $4.50 for shipping and handling. Requests should be sent to NCM publishers at: NCM Publishers, Dept. JL, 200 Varick St., New York, NY 10014.
Good Results for Stavudine (d4T) - In June, 1994 the FDA approved the drug d4T, a nucleoside analogue similar to 3TC, AZT, ddI, and ddC. A randomized trial comparing AZT and d4T, the preliminary results of which were originally presented to the FDA for approval, was recently concluded and presented along with data from the d4T parallel track program. In the first study, participants who took d4T developed fewer opportunistic infections and sustained T-cell counts over those who continued on AZT. This benefit has not been seen in clinical trials involving a switch from AZT to ddI or ddC. Quality of life was also improved in participants who switched to d4T. In terms of side effects, the rate of peripheral neuropathy was higher in participants who switched to d4T, whereas the rate of anemia and neutropenia was higher in participants who remained on AZT.
The open label parallel track trial in 12,551 participants compared a dose of 40 mg. twice daily of d4T to a lower dose of 20 mg. twice daily. The trial concluded that both doses are safe and that the higher dose is slightly superior to the lower dose in prolonging survival. Increased weight and fewer hospitalizations were also seen in the higher dose. More data will be required to learn more about the effectiveness in HIV+ people who have no previous AZT therapy. Furthermore, the impact of d4T on viral load and the possibilities of combination therapy will also need to be studied further.
Network Home Page - The World Wide Web is a rapidly growing part of the Internet. The Network now has a home page on the World Wide Web called The InterNetwork. Expanded access programs and clinical trials are listed according to condition and are updated the minute we get any new information. Treatment updates and announcements, as well as all The Network's publications are stored here, ready to be read or printed out. Our internet home page address is http://health.nyam.org:8000/public_html/network/index.html.
About Treatment Review - The information in this review is not meant to replace the advice or care of a medical professional. Always discuss your treatment options with a trained health care provider. We donÍt manufacture, test or sell any of these drugs or therapies. We do not endorse them, nor do we guarantee their safety or efficacy. Treatment Review is published 8 times a year. A $16.00 a year contribution is requested, but not required. Treatment Review is edited by Ken Fornataro, and written by Joel Beard, Ken Fornataro, Tim Horn, and Richard Jefferys. Thanks to Felix Cruz, Bill Valenti, MD, Paul E. Cothran, Marlene Diaz, and Rick Loftus. If you want to copy, reproduce or excerpt this information, please give us a call at (800) 734-7104. This helps us to keep track of where and how this information is being used. Treatment Review and other Network resources are available by E-mail, and are on the Internet. Drop us a line at AIDSTreatD@AOL.com. The AIDS Treatment Data Network (The Network) is a not-for-profit, independent organization. We receive support for our work from individuals, foundations, government, and corporations. We appreciate and encourage contributions for our work. Special thanks go to Robert D. Farber, The Farber Family, Fund for the City of New York, Pfizer,Inc., The Stadtlander's Foundation, and The Ryan White Emergency Care Act of 1990, Title I.
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