Due to the high cost of mailing materials, and the additional cost of returned mail from out-of-date addresses, it's essential that you let us know if you'd like to stay on the Network mailing list. Please take time to read this article and, if necessary, mail in the membership form on the back of this newsletter.

For the last five years, The AIDS Treatment Data Network (The Network) has provided case management support, referrals and treatment education in New York City through our Psycho-Educational Support (PES) program. Funding for this program came from Title I of the Ryan White CARE Act, which supports HIV/AIDS programs in the cities hardest hit by the HIV epidemic. New priorities have now been set for New York City Title I funds, and Psycho-Educational Support is no longer a high priority category.

As a result, the Network's PES program closed effective February 28 of this year. Unfortunately, this has meant laying off several staff. The Network salutes the dedication and invaluable contributions of Joel Beard, Eddie Gordon-Berroa and Lizzie Nevárez and thanks them for their continued help and support.

We have tried to minimize the effect of these changes on our nationally acclaimed treatment education, access and advocacy programs, which we will continue to operate. Our publication schedule has been slowed down, however, and we apologize for the long delay in the production of this issue of Treatment Review.

The Network does not accept money from industry or business to advertise, promote or sell any drug, product or service. Since 1988, people with AIDS, their friends and families, and health care and support providers have counted on us to provide them with unbiased and up-to-date information, counseling, and advocacy. We've never charged a fee for any of our services, nor has anyone ever needed health coverage or insurance of any kind to receive our help.

We do not, and will never, take money from any government or private funder that requires that we report our members' names, addresses, or other identifying information to any monitoring agency. We would like to remind all of our members, that these policies are neither flexible nor negotiable. The privacy and confidentiality of our members, and the integrity and objectivity of our resources are our number one priority.

To help us make sure we make the best use of our available resources, we're asking that you let us know if you want to continue to receive Network materials by filling out the membership form on the back of this newsletter. Membership donations are also more important than ever, and if you can afford a donation of any size we greatly appreciate it. If you've already sent in a membership form and/or donation, thank you! - you should have received an acknowledgment and thank you letter, and you don't need to fill out another membership form.

If you're not sure about the status of your membership, please give us a call at (800) 734-7104 and we'll let you know if you're on the mailing list and which materials you're down to receive.

The Network has reported regularly on clinical trial results of new anti-HIV treatments. These trials have shown that strong anti-HIV drug combinations can often lower the amount of virus in the blood (usually called the viral load), improve T4 cell counts, and reduce illness and disease progression in people with HIV.

Now that stronger anti-HIV drugs have been available by prescription for nearly two years, there have been many reports of the effects of these treatments in the real world, outside of clinical trials. Nationally in the USA, deaths from AIDS dropped by 44% in the first half of 1997 compared to the first half of 1996. In New York City during the same period, deaths fell by close to 50%. The state of California has reported an even more dramatic decline of nearly two thirds, from 2,788 in the first half of 1996 to 1,112 in the first half of 1997.

Several studies have also looked at the number of new opportunistic infections in people with AIDS since the approval of more powerful anti-HIV drugs. Johns Hopkins Clinic in Baltimore has reported that new cases of CMV (cytomegalovirus, an opportunistic infection that can cause blindness) fell by 81% in 1996. Mycobacterium avium complex (MAC) is another serious opportunistic infection that most commonly occurs in people with less than 100 T4 cells. A French study found that after the introduction of protease inhibitors in June 1996 only 7 new cases of MAC occurred in 700 people that they were collecting information on. Based on previous years, close to 100 cases of MAC would have been expected in this group of people.

A second French study of 59,256 people with HIV compared the number of opportunistic infections (OIs) diagnosed during the first half of 1996 to the number of OI cases diagnosed during the first half of 1997. There were fewer cases of every OI they looked at: cryptosporidiosis cases fell 82%, CMV 80%, MAC 73%, cryptococcal infection 70%, thrush 69%, PCP 68%, dementia 67%, Kaposi's sarcoma 65%, toxoplasmosis 64%, tuberculosis 50%, lymphoma 44%, bacterial pneumonia 41% and the rare brain infection PML by 28%. A similar American study from New Orleans found significant drops in the number of new cases of CMV, MAC, PCP pneumonia, wasting syndrome and Kaposi's sarcoma.

The overall message is that strong anti-HIV drug combinations can dramatically reduce serious illness and help people live longer. Drug side effects, inconvenience and actually remembering to take the drugs are all still a problem, but large reductions in the amount of HIV in the body are clearly linked to better health. Even when the viral load does not become "undetectable" (too low for the test to measure), reducing viral load can lead to improved health and survival.

It's important to realize this information does not mean that everyone that's HIV positive needs to start anti-HIV treatment immediately. Laboratory tests such as the T4 cell count and viral load are used to work out the risk of disease progression, to see if there's a need for treatment. The good news is that someone who is at risk for disease progression now has an excellent chance of preventing illness for a long time with anti-HIV treatment.

The good news described here is not just the result of lots of people having "undetectable" viral load. Many recent reports have found that even a short-term reduction in viral load can produce a long term improvement in health and increase in T4 cell count. Even studies of people for whom anti-HIV treatments seem to be failing (their viral load is increasing despite anti-HIV treatment) are not finding a lot of new illnesses and deaths. Researchers are not quite sure what this means, but there seem to be two theories. It may be that when HIV mutates to become resistant to combination anti-HIV treatment, it's less able to cause damage to the immune system. It's also possible that the immune system can benefit a great deal from even small and short-term reductions in levels of HIV. For example, having a 90% drop in viral load for three months may help the immune system control HIV better for another year or two after the HIV levels increase again. This is like rewinding the clock on the disease process, and some study results suggest that this can happen.

The liver is a large organ, located just below the lungs on the right side of your body. The liver regulates the processing of nutrients and vitamins from the food you eat, both storing nutrients for later use and changing nutrients into forms that the body can use for energy. This is part of the process known as metabolism. The liver has many other important jobs: cleaning dead cells out of the blood, processing or metabolizing drugs, getting rid of toxic substances (alcohol, for example), producing bile (a substance that helps the body digest fat) and making factors that help your blood clot. Medical words for the liver usually start with hepat-, for example a doctor that specializes in the liver is called a hepatologist.

How Are Drugs Processed?
Most prescription drugs are absorbed in the small intestine. This means that the drug must be able to survive travelling through your stomach. From the small intestine the drug is absorbed into the blood and travels to the liver through the portal vein. The drug must travel through the liver so that it can be processed or metabolized by the body. Metabolism means breaking down the drug for distribution around the rest of the body and, in the end, clearance or excretion from the body. The liver may form metabolites, or changed chemical versions of the drug, as part of this process. Some drugs are almost completely gotten rid of the first time they travel through the liver. This is called first-pass metabolism. The problem with the first available protease inhibitor, saquinavir (Invirase), was that it was almost totally cleared from the body by first pass metabolism. In fact, only a measly 4% of the Invirase that a person swallowed made it through the liver into the bloodstream and to the rest of the body. The idea behind the new version of saquinavir, Fortovase, is to prevent some of this first pass metabolism so that more drug makes it to the rest of the body.

Some prescription drugs do not get broken down in the liver. The nucleoside analog drugs (AZT, ddI, ddC, d4T, 3TC) mainly travel through the kidneys. Although these drugs are not metabolized by the liver, the liver sometimes hooks them up with other chemicals so they can dissolve in water more easily and therefore be gotten rid of in the urine.

The Cytochrome p450 System
So what actually breaks down the drugs that are metabolized by the liver? Most of this work goes to a group of more than 25 related enzymes called the cytochrome p450 system. Enzymes are proteins that perform certain jobs in the body. The p450 enzymes do most of their work in the liver, but there are also p450 enzymes in the small intestine that can begin the work of drug metabolism before a drug even reaches the liver.

While the p450 enzymes do a good job of breaking down drugs, there is a potential problem with this system. The activity of the p450 enzymes can be affected by the very drugs they are metabolizing. Some drugs increase the activity of p450 enzymes. These drugs are called inducers. When there is more p450 enzyme activity because of an inducer, any drug metabolized by that enzyme is going to be metabolized faster. This means that less of the drug will get to the rest of the body where it's needed. For example, the anti-tuberculosis drug rifampin is a strong inducer of p450 enzymes. Other drugs metabolized by these p450 enzymes can be cleared from the body too fast if they are taken with rifampin. Protease inhibitors are among the many drugs cleared too fast from the body when taken with rifampin, so these drugs should not be used together. This is an example of a drug interaction.

There is also another kind of drug interaction that can happen in the p450 enzyme system. Different drugs can compete to be broken down by the same enzyme. The protease inhibitor ritonavir (Norvir) is a good example of a drug that competes for several different p450 enzymes in order to get metabolized or broken down. Ritonavir usually wins the competition for metabolism when other drugs are also trying to get metabolized by the same p450 enzyme. What's the result of this? Any other drug has to wait to get cleared from the body until the p450 enzyme is finished with ritonavir. While the drug is waiting to be cleared, the drug levels in the body get higher and higher. This is another example of a drug interaction. This effect also gets called p450 inhibition.

One example of this kind of interaction is with the commonly used antihistamine drug Seldane. Ritonavir competes for the p450 enzyme that usually clears Seldane from the body. The result is that Seldane levels get higher and higher as the drug gets backed up in the body because ritonavir is blocking (also called inhibiting) its normal metabolism. High levels of Seldane are very toxic and are known to cause potentially fatal changes in heart rhythm. This example shows how dangerous drug interactions can be. In fact, Seldane was recently taken off the market because of this potential danger.

Occasionally, however, drug interactions can be used to produce good effects. The reason that the protease inhibitors ritonavir (Norvir) and saquinavir (Invirase, Fortovase) sometimes get prescribed together is because of a useful interaction. Just like the above example with Seldane, ritonavir competes for the p450 enzyme that usually metabolizes saquinavir. As a result, saquinavir levels in the blood get much higher than normal. Because saquinavir is usually not well absorbed, this interaction is seen as a good thing - the higher levels of saquinavir produce stronger anti-HIV effects. The dose of saquinavir given with ritonavir is much lower than the standard dose because of this interaction.

Some drugs can both induce, increasing the activity of p450 enzymes, and also compete for those enzymes with other drugs. Again, ritonavir is a prime example of this double effect. Ritonavir induces the enzymes that helps clear the drug methadone from the body. Ritonavir itself is not metabolized by the same enzymes and so it does not compete with methadone to be metabolized. The end result? Ritonavir lowers methadone levels (see In The News, Page 15).

In most other cases, although ritonavir induces extra production of p450 enzymes, it hogs (competes for, and wins) most of these extra enzymes for its own metabolism. The end result? Ritonavir raises the levels of other drugs (such as Seldane and saquinavir) that need these p450 enzymes in order to be cleared from the body.

Protease Inhibitors and NNRTIs
As a class of drugs, protease inhibitors usually compete more than they induce - therefore they are more likely to increase levels of interacting drugs rather than reduce them. The most dangerous interactions are with the antihistamine drug astemizole (Hismanal), the digestion/heartburn drug cisapride (Propulsid), the sedatives triazolam (Halcion) and midazolam (Versed) and a group of drugs known as ergotamine derivatives. These drugs cannot be taken with any of the four approved protease inhibitors: indinavir (Crixivan), nelfinavir (Viracept), ritonavir (Norvir) and saquinavir (Fortovase). Additional restrictions may apply to each individual protease inhibitor - particularly ritonavir, which competes for p450 enzymes more than other protease inhibitors.

There are now three experimental anti-HIV drugs available through expanded access programs for people running out of treatment options. All three programs have recently been changed to make them easier to access.

efavirenz (Sustiva, formerly DMP266)
Sustiva is a new drug in the class called non-nucleoside reverse transcriptase inhibitors (NNRTIs). Other drugs in this class are nevirapine (Viramune) and delavirdine (Rescriptor). Sustiva is still being studied in clinical trials, but is far enough along that the FDA is allowing the drug company to make it available through expanded access.

Taking the drug: The current dose of Sustiva is 600 mg taken once a day at bedtime. If side effects are troubling, the dosage can be divided in half and taken 2x/day.

Resistance: At the moment, researchers think Sustiva in combination with other anti-HIV drugs may have some effect against HIV that's become resistant to the other NNRTIs. This has yet to be shown in any human studies.

Drug interactions: Be sure you talk to your doctor about other drug interactions, as many medications interact with Sustiva and require a change in dose. Sustiva when taken with indinavir (Crixivan) lowers the amount of indinavir in your body so your dose of indinavir may need to be raised to 1000 mg every 8 hours. Sustiva may raise nelfinavir (Viracept) levels slightly, but no dose adjustment is recommended.

Side effects: The main side effects of Sustiva are light headedness, dizziness and rash. So far, the rash seems milder than with other NNRTIs. There have been no cases of Stevens-Johnson Syndrome, a severe allergic reaction that is a rare side effect of other NNRTIs.

Trial results. In one trial participants took Sustiva with the protease inhibitor indinavir (Crixivan). Two-thirds of the participants had already taken anti-HIV drugs. The participants' average T4 cell count was 238 and average viral load was 250,000. After six months, almost 90% of the participants had undetectable viral loads.

In another trial, different doses of Sustiva are being given with AZT and 3TC. In the group taking the highest Sustiva dose (600 mg a day), all of the 21 participants that have reached six months on the study have undetectable viral loads. This study is ongoing. The participants had never taken anti-HIV drugs before and started with T4 cell counts over 50 and viral loads over 10,000.

Expanded access: Requirements to participate in the Sustiva expanded access program are:

• you must have a T4 cell count under 400,
• in the judgment of your doctor, you don't have enough options to make an effective anti-HIV drug combination because of side effects or drug resistance.

You don't necessarily have to have tried a protease inhibitor to qualify for this program. Enrollment is through your doctor. You or your doctor can call (800) 998-6854 for more information.

abacavir (Ziagen, formerly 1592U89)
Abacavir, also known as 1592U89, is a new anti-HIV drug in the same class as AZT. The class is called nucleoside analogs or NRTIs and includes AZT, ddI, ddC, d4T and 3TC. Early results suggest that abacavir may be one of the strongest anti-HIV drugs in this class.

Abacavir study results: In early studies, abacavir lowered viral load by over 98% over 12 weeks. This study involved 60 people who had very little previous anti-HIV treatment. In a later study, abacavir was added to either ddI/d4T, AZT, or AZT/3TC in people whose viral load was over 10,000 despite treatment with these drugs. People on ddI/d4T had their viral load reduced by more than 90% after adding abacavir. For people taking AZT, abacavir reduced their viral load by only about 30%. In the group taking AZT/3TC, adding abacavir had hardly any effect on viral load.

Resistance and abacavir: The changes in HIV that cause drug resistance are called mutations, and different mutations cause resistance to different drugs. In studies, if the HIV already had several mutations that made it resistant to approved nucleoside analogs, the HIV quickly became resistant to abacavir too. This greatly lessened the anti-HIV effects of abacavir.

Side effects: Allergic reactions to abacavir have been reported in approximately 3-5% of people in the clinical trials. Symptoms began an average of 11 days after starting the drug. Symptoms were malaise, low grade fever and nausea with or without vomiting. In some people, a rash appeared 1-3 days after onset of these symptoms. All symptoms resolved within 1-2 days after stopping treatment. If treatment was started again at reduced doses, life-threatening drops in blood pressure occurred and one person is reported to have died as a result. Study participants are now being told to report any flu-like symptoms with or without rash beginning several days to 4 weeks after starting treatment, and to stop treatment immediately if symptoms occur. Treatment should not be restarted.

The other side effects that have been seen so far with abacavir include increased fatigue, changes in liver function tests, headache, abdominal pain, constipation, diarrhea, nausea, vomiting, sleeplessness, skin rash, and dizziness.

Who should take abacavir? For someone not responding to current treatments, trying to figure out which combination of anti-HIV drugs will work is very difficult. If you are already resistant to most NRTIs, using abacavir as part of an anti-HIV drug combination may add very little anti-HIV effect. The result is that HIV then has an easier time getting resistant to the other anti-HIV drugs in the combination. If possible, it's best to use abacavir with at least two new anti-HIV drugs that have a good chance of working. However, it's also important to remember that for someone with few treatment options, even a little extra anti-HIV effect may help a new anti-HIV drug combination work for longer.

Expanded access: To enroll in the abacavir expanded access program, you must be unable to put together an effective anti-HIV drug combination using available drugs because of side effects or drug resistance. Providers can call (800) 501-4672 for more information.

adefovir dipivoxil (Preveon)
Adefovir dipivoxil (also known as bis-POM PMEA, the new trade name is Preveon) is the first of a new class of anti-HIV drugs called nucleotide analogs. Nucleotide analogs work against HIV's reverse transcriptase enzyme like the nucleoside analog drugs AZT, ddI, ddC, d4T and 3TC. The difference is that the nucleoside analogs have to go through some complicated chemical processing inside cells in the body in order to work against HIV. Nucleotide analogs like adefovir go through a simpler chemical process.

Trial results: Recently reported studies suggest that adefovir can add a little extra anti-HIV effect to a treatment combination. One clinical trial enrolled 442 people who were already taking combination anti-HIV drugs, but whose viral load was over 2,500 copies. About half the trial participants added adefovir to their treatment, the other half added a placebo or dummy pill. The group that added adefovir had an average decrease in viral load of just over 40% after six months. There was no further change in viral load in the group that added the placebo to their treatment. Another study found that adefovir could reduce hepatitis B levels by more than 99%.

Side effects: The main side effects seen so far have been nausea, diarrhea and elevated liver function tests. There have also been cases of kidney problems caused by adefovir. In studies, two doses of adefovir have been tried: either 60 mg or 120 mg, taken once a day. It has recently been discovered that 40% (more than a third) of the people in studies who took the 120 mg dose for more than six months are developing signs of serious kidney damage known as Fanconi-like syndrome. To watch out for this side effect, people taking adefovir must have their kidney function checked each month. Kidney function is checked by laboratory tests that look for serum creatinine and protein in the urine. If abnormal values are found, it may be necessary to stop the drug or reduce the dose. The expanded access program is providing adefovir at either 60 mg or 120 mg a day. It appears that the lower dose has less risk of kidney damage and about the same anti-HIV effect, but this is still being studied.

Taking the drug: Adefovir usually comes as one pill, taken once a day. Because adefovir reduces the amount of L-carnitine, a natural substance needed for converting fats into energy within human cells, you also have to take a daily L-carnitine supplement with adefovir.

Expanded access: To enroll in the Preveon expanded access program, you must have received treatment with at least two nucleoside analog anti-HIV drugs and one protease inhibitor, and these treatments must be failing. There are no longer any T4 cell count or viral load requirements for this expanded access program. For more information call Gilead Sciences at (800) GILEAD-5 (445-3235).

Hydroxyurea is an old anticancer drug that may help certain anti-HIV drugs work better. Researchers have been studying this drug in people with HIV for several years now, with some promising results.

How Does Hydroxyurea Work?
HIV reproduces itself in the body using T4 cells. HIV has a genetic blueprint for making more virus that's called RNA. The way HIV reproduces is by turning its RNA into DNA. DNA is the basic building block of all living things. All of the cells in your body have DNA in them, including T4 cells. HIV DNA gets mixed up with the T4 cell's DNA and uses it as a kind of factory for making more copies of HIV.

DNA itself is made up of smaller building blocks, called nucleotides. These nucleotide building blocks are called guanine, thymidine, adenine, and cytosine. Cells contain spare nucleotides that get used when the cell needs to make more DNA. HIV steals these spare nucleotides from the cell to make HIV DNA.

Hydroxyurea works by reducing the number of spare nucleotides inside cells, making it harder for HIV to build its DNA. In fact, hydroxyurea reduces the amount of one particular type of nucleotide, adenine. However, when hydroxyurea is used alone it doesn't affect HIV very much. HIV still has enough adenine nucleotides to choose from to build its DNA. This is where other anti-HIV drugs come into the picture.

The way that nucleoside analog anti-HIV drugs (AZT, ddI, ddC, d4T, 3TC) work is by turning into fake nucleotides inside cells. When HIV tries to use these fake nucleotides to build its DNA, it's like throwing a wrench in the works, and the DNA doesn't work and can't get mixed up with the cell's DNA. This is how the nucleoside analog drugs protect cells from infection by HIV. Different nucleoside analog drugs make different fake nucleotides. AZT and d4T are fake thymidine nucleotides, ddC and 3TC are fake cytosine nucleotides, and ddI (Videx) is a fake adenine nucleotide.

When hydroxyurea is taken with ddI, there's less natural adenine nucleotides in the cell for the HIV to steal when making DNA. This makes it more likely that HIV will use the fake adenine nucleotide provided by ddI. Therefore HIV is more likely to make DNA that doesn't work and can't take over the cell. This is why ddI and hydroxyurea taken together have a stronger anti-HIV effect than ddI alone. In the test tube, adding hydroxyurea to ddI even works against HIV that is resistant to ddI alone.

Study Results
Several small studies of hydroxyurea and ddI have been reported. In these studies, adding hydroxyurea to ddI produced a stronger anti-HIV effect than ddI taken alone. These studies also suggested that adding hydroxyurea to ddI can work against HIV that is resistant to ddI in people, not just in the test tube.

In one French study, ten people have been treated with ddI/hydroxyurea for a year. Six of these people have viral loads less than 200 copies (undetectable using the PCR viral load test). The other four people had an average drop in viral load of over 95%, from an average of 85,838 copies of HIV at the start of the study to an average of 4,330 copies of HIV after one year. The average T4 cell count of these ten people increased an average of 163 cells, from 482 at the start of the study to 645 after one year. As you can see, people had relatively high T4 cell counts at the start of the study.

There isn't much information on hydroxyurea treatment for people with low T4 cell counts. A study in Spain gave ddI/hydroxyurea to seventeen people with an average of 145 T4 cells. Eleven participants had never taken ddI before, the other six had been taking ddI for more than three months before starting the study. After six months, viral loads had dropped by about 95%. The average increase in T4 cells was 60 cells.

Several recent studies have looked at hydroxyurea taken with ddI and d4T (Zerit). A group of researchers in Switzerland divided 144 people with HIV into two groups. One group took ddI and d4T. The second group took ddI/d4T/hydroxyurea. The average T4 cell count at the start of the study was 370, and the average viral load was about 30,000 copies.

After three months, 39 of the 72 participants in the ddI/d4T/hydroxyurea had viral loads less than 200 copies, compared to 20 out of the 72 participants in the ddI/d4T group. The average drop in viral load was over 99% in the ddI/d4T/hydroxyurea group, compared to about 95% in the ddI/d4T group.

However, in when it came to T4 cell counts, the increase in T4 cell counts after three months was greater in the ddI/d4T group: they had a 107 cell increase compared to 28 cells in the ddI/d4T/hydroxyurea group. Researchers think this difference is because hydroxyurea can sometime stop T4 cells from making copies of themselves - when a T4 cell divides to make more T4 cells, it needs adenine nucleotides to make new DNA, so hydroxyurea can affect this process.

Side Effects
The side effects of hydroxyurea depend on the dose, and happen more often at the higher doses used in cancer chemotherapy. The major side effect of hydroxyurea is suppression of the bone marrow. The bone marrow is where new cells are made, and hydroxyurea can reduce production of new cells because each new cell needs DNA. Bone marrow suppression can show up on laboratory tests as low red blood cells (anemia), low white blood cells (neutropenia, leukopenia), thrombocytopenia (low platelets) or as low numbers of all types of cells (pancytopenia). For people already having bone marrow problems, taking hydroxyurea is probably not a good idea.

Less frequent side effects include hair loss, anorexia, nausea, vomiting, diarrhea and constipation. Rashes, particularly on the face, have also been reported. One study reported that hair loss was most common in people with less than 50 T4 cells. Hydroxyurea has also been shown to cause birth defects in animals and should not generally be taken by pregnant women.

Dosage
Most of the studies described above used 500 mg of hydroxyurea given twice a day. One study tried a lower dose of 500 mg once a day, and even this low dose seemed to help ddI work better than ddI alone. Since resistance is not an issue with hydroxyurea, the lower dose of 500 mg a day may be worth considering if side effects are a problem.

Resistance
Because hydroxyurea works by affecting cells rather than attacking HIV directly, resistance is not a problem the way it can be with other anti-HIV drugs. HIV cannot avoid using adenine nucleotides when making its DNA, because these nucleotides are too important. This may explain why some people in ddI/hydroxyurea studies had long term drops in viral load even if they didn't reach undetectable levels on the viral load test.

What Does It Add Up To?
It appears that ddI/hydroxyurea or ddI/d4T/hydroxyurea could be effective first-line treatments for HIV. Larger studies are needed to confirm this. For people with low T4 cells and more advanced HIV (who have a greater need for new treatments), it is uncertain how well hydroxyurea would work. There is concern that side effects like bone marrow suppression might be more common. Nevertheless, some doctors are trying ddI/hydroxyurea as part of anti-HIV combinations in people who have run out of standard treatment options.

Does Hydroxyurea Have To Be Taken With ddI?
Of the approved nucleoside analog anti-HIV drugs, ddI is the only one that works as a fake adenine nucleotide, so it's the only available nucleoside analog that hydroxyurea helps work better. However, the experimental drug adefovir (Preveon) also works against HIV by acting as a fake adenine nucleotide. Abacavir (Ziagen, formerly 1592U89) has the ability to act as either a fake adenine or a fake guanine nucleotide. So both of these drugs may work better with hydroxyurea. Both abacavir and adefovir are currently available through expanded access programs (see article starting on page 7).

No studies have yet combined abacavir or adefovir with hydroxyurea, although a recent issue of the Gay Men's Health Crisis' Treatment Issues newsletter reported that at least one New York City clinic is combining abacavir with hydroxyurea to try and boost abacavir's anti-HIV effect.

Availability
Hydroxyurea has been used in cancer treatment for over 30 years, and is available by prescription. Since it has become more widely used as an HIV treatment, one of the main manufacturers of hydroxyurea (trade name Hydrea) has set up a patient assistance program for people needing help accessing the drug. The company is Bristol-Myers Squibb, and the patient assistance program can be reached at (800) 272-4878.

There are several reasons why joining a clinical trial may be an option to consider. Not all of the new clinical trials are testing difficult to take combinations. Some are studying new dosing schedules of drugs, such as taking a drug twice a day, instead of three times a day. Although the number of people who have been joining research studies has dropped since the approval of stronger and more effective anti-HIV drugs, there are still new drugs and combinations being tested. There are even a few (although many more are needed) studies for people who are not doing well on their current treatments.

There are many studies for people who have never taken any treatment, as well as for people who have only taken one or more nucleoside analogues (like AZT or ddI). In addition, many studies now offer small and even large amounts of money, or other types of benefits to those who agree to participate. As always, carefully weigh both the risks and benefits of any study you are considering participating in, regardless of the money or other benefits offered.

If nelfinavir (Viracept) is failing: If you are taking the protease inhibitor nelfinavir (trade name Viracept) and your viral load had been lowered but is now increasing, you may be eligible for a new study. The study number is Merck 075. You must still be taking nelfinavir, and have a viral load of at least 10,000. You must also already be taking a combination of nucleoside analogue drugs (AZT, ddI, ddC, d4T, 3TC). You cannot have taken, or be taking, any NNRTI drugs (efavirenz, nevirapine or delavirdine), or any other protease inhibitor besides nelfinavir. You must have a T4 cell count of at least 50.

Once you are enrolled in the study you will stop taking the nelfinavir, and be given three new drugs. There is also a control group of people who have never taken any drugs except for nucleoside analogs. Because this is an open-label study, everyone will receive the protease inhibitor indinavir (Crixivan), 1000 mg every 8 hours, as well as efavirenz (Sustiva), and adefovir (Preveon). For more information about this study, contact The Network at (212) 260-8868.

If indinavir (Crixivan) is failing: If you have been taking indinavir (trade name Crixivan) for more than six months, and your viral load is between 2,000 and 200,000, you may be eligible for a study called ACTG 359. This trial will study combinations of HIV drugs that include two protease inhibitors, one of which will be Fortovase. Fortovase is the new soft gel capsule version of the protease inhibitor saquinavir. The aim of the trial is to try and figure out the best second treatment for someone whose viral load has gone up while on indinavir. You must be on an unchanged anti-HIV drug combination that includes indinavir for at least 4 weeks prior to study entry.

Participants will be divided into 6 groups. All groups will take Fortovase. The additional treatments will be ritonavir (trade name Norvir) + delavirdine (Rescriptor); ritonavir + adefovir (Preveon); ritonavir + delavirdine + adefovir; nelfinavir (Viracept) + delavirdine; nelfinavir + adefovir; or nelfinavir + delavirdine + adefovir. At weeks 12 and 16, participants whose viral load is under 5,000 or has dropped at least 90% may continue for 24 more weeks. Both the doctor and the participant will know which protease inhibitors are being taken. Neither the participant nor the doctor will know which other anti-HIV drugs are being taken. Total time on study is 24-48 weeks.

Like many other studies, there are restrictions on what other drugs you may have taken in the past. For this study, you can't have taken more than two weeks of ritonavir and/or saquinavir, no NNRTIs, nelfinavir, the experimental protease inhibitor amprenavir (formerly called 141W94), or adefovir . For more information about this study call the national ACTG trials service at (800) TRIALS-A. In New York you can call the New York State Department of Health Experimental Treatment Infoline at (800) MEDS-4-HIV.

Another trial is studying a new protease inhibitor called ABT-378. This trial is for people who are already taking a protease inhibitor as part of an HIV treatment combination. Your viral load must be over 1,000 but under 100,000. There must be at least one nucleoside analog drug (AZT, ddI, ddC, d4T, 3TC) that you haven't tried before.

Participants in this study will be randomly divided into two groups. One group will take 400 mg of ABT-378 and 100 mg of ritonavir every 12 hours. The second group will take 400 mg of ABT-378 and 200 mg of ritonavir every 12 hours. Both groups will continue taking the nucleoside analog drugs they were taking when they joined the study. After 14 days, both groups will add nevirapine (Viramune) and change their nucleoside analog drugs to include at least one nucleoside analog that they haven't taken before. Total time on study is 48 weeks.

Other Studies
Several studies for people who have failed one or more treatments are in the works. ACTG 398 is expected to open in the near future. Another study, called the Harvard Salvage Protocol, is expected to be open at limited sites throughout the country.

Ritonavir (Norvir) and Methadone
Ritonavir (Norvir) is a protease inhibitor. Based on test tube studies, it was thought that ritonavir might increase levels of methadone in the body if the two drugs were taken together. This is known as a drug interaction (see article on page 4). A study of real people taking methadone and ritonavir was finally presented in February of this year. According to this study, ritonavir lowers the level of methadone that gets into the body by 30-40%, or about a third. This means that people on methadone maintenance may experience symptoms of withdrawal if they are also taking ritonavir. It may be necessary to adjust the dose of the methadone if this problem occurs. It is likely that the protease inhibitor nelfinavir (Viracept) will have a similar effect. Researchers predict that the protease inhibitors saquinavir (Fortovase) and indinavir (Crixivan) will not reduce methadone levels. A study with Crixivan and methadone is reported to be ongoing.