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What's New in Treatment Information?

Excerpts From Hotline Memos of February 2000
from the Information Department of Project Inform

March, 2000

NIH Study Cautions Use of St. Johns Wort

A study conducted by the National Institutes of Health (NIH) found a significant interaction between the herbal therapy, St. John's Wort (hypericum perforatum), and the protease inhibitor, indinavir (Crixivan®). In this study, indinavir blood levels were substantially decreased when the two drugs were used together. As a result, indinavir's activity was significantly decreased, which can lead to the development of resistance to indinavir and other protease inhibitors.

This study also found that St. John's Wort significantly decreased blood levels of the immune suppressive drug, cyclosporine (Neoral®), used primarily in organ transplantation to prevent organ rejection. It's also being investigated as a potential anti-HIV therapy.

St. John's Wort is also likely to greatly decrease blood levels of other protease inhibitors as non-nucleoside reverse transcriptase inhibitors. People who use these drugs should not use St. Johns Wort.

People commonly use St. Johns Wort as an antidepressant. It's also used for antiviral purposes because in lab studies, St. Johns Wort has some anti-HIV activity. It also shows activity against other viruses, although very high doses would be needed to achieve any worthwhile activity.

It's not known whether other complementary therapies or nutritional supplements interact with protease inhibitors or other commonly used therapies. But as this study illustrates, there's a definite potential for some of these herbal and nutritional supplements to reduce the effectiveness of anti-HIV drugs. Anyone who uses these kinds of supplements should discuss them with his or her healthcare provider about possible interactions.

Niacin and the Treatment of Hypercholesterolemia

A recent question from the hotline asked whether there's any information on using niacin for treating elevated cholesterol levels, or hypercholesterolemia.

High dose niacin of 2-9 grams per day has been used to treat HIV-negative people with hypercholesterolemia. It has been used with some success in combination with cholestyramine. However, high doses of niacin can cause many side effects including elevated uric acid levels of the kidneys, elevated glucose (sugar) levels, stomach irritations, flushing of the face, and severe itching.

Most researchers working in the field of lipid abnormalities and lipodystrophy in people with HIV do not recommend using niacin or fish oils to treat hypercholesterolemia. Rather, they recommend changes in diet and increase in exercise. If cholesterol levels are still elevated, then they recommend using a statin inhibitor and/or a fibrate depending on whether triglyceride levels are also elevated.

"Statin" Drugs May Interact with Protease Inhibitors

New information on the statin drugs used to lower cholesterol and their interaction with protease inhibitors show that they should be used with caution. Fifty-two volunteers took ritonavir (Norvir®) and saquinavir (Fortovase®) at the standard 400mg dose each taken twice a day. They also took one of three statins: pravastatin (Pravachol®), simvastatin (Zocor®) or atorvastatin (Lipitor®). The statin dose was 40 mg once a day.

The study found that pravastatin levels decreased 47%, atorvastatin increased 343% and simvastatin increased 2,676%. These results suggest that pravastatin can be used safely with protease inhibitors without a dose adjustment. Other statins like fluvastatin (Lescol®), cerivastatin (Baycol®) and lovastatin (Mevacor®) behave similarly to pravastatin, atorvastatin and simvastatin respectively.

The activity of the statins are not directly related to their drug levels found in blood, but statin side effects are directly related. Atorvastatin should be used with great caution. Simvastatin should not be used with ritonavir and saquinavir and likely applies to other protease inhibitors as well.

One serious side effect associated with increased statin levels is a muscle disorder called rhabdomyolysis. People experiencing muscle aches should report this to their healthcare providers. People with mild kidney dysfunction (a creatinine clearance above 1.5 mg/dL) are more at risk for developing statin side effects. Gemfibrozil (Lopid®), a drug sometimes combined with the statins to lower triglyceride levels, can also result in muscle disorders and kidney failure.

Avascular Necrosis

Project Inform's Hotline has received a number of calls for information about the death of bone tissue (osteonecrosis) and/or lack of blood going into the bone (avascular necrosis). These conditions mostly affect the hip and may lead to interventions, including hip replacement surgery.

There are several theories about the cause in people with HIV. One is the use of corticosteroids like prednisone, known to be related to these types of bone toxicity. More recently it's speculated that protease inhibitors may cause this bone damage.

Not all orthopedic surgeons are anxious to do hip replacement surgeries on people with HIV; but many still do. Call Project Inform's Hotline for information on accessing these physicians.

Organ Transplant Study Moves Forward

As HIV-positive people live longer, fewer die from infections usually related to AIDS. Instead, a rise in other complications, like organ failure, is beginning to threaten the lives of people with HIV. For example, liver disease may be a complication of hepatitis C virus, but it may also be a result of HIV disease itself. Either way, liver disease may be worsened by some anti-HIV therapies. HIV infection and some HIV therapies may likewise cause or worsen other health problems such as poor kidney function. In advanced stages of liver and kidney disease, organ transplants may be the only hope. A recently funded organ transplant study offers new hope for people facing these dilemmas.

Prior to the time when tests were available to assess HIV status, organ transplants took place at normal rates in people with undiagnosed HIV/AIDS. The outcome of these transplants varied: about a third did very poorly, progressing to disease and dying quickly; another third did well for only a short time and then died of underlying conditions; and another third did surprisingly well.

It was concluded that the procedure itself, coupled with the use of immune suppressive therapy to prevent the body from rejecting the new organ would worsen the course of HIV disease. Thus the transplant community made policies disallowing the procedure in people with HIV. In addition, an unwritten concern was that people with the new disease of AIDS died quickly anyway and some physicians felt using precious organs in such instances was wasteful. While these policies were not made on the basis of scientific data, people with HIV have been left with the legacy and barred from accessing a potentially life-saving procedure.

Currently, people with HIV are allowed on waiting lists for organ allocation. However, third-party payers won't cover the cost of transplants and many transplant centers refuse to perform the operations. Recently, the State of California awarded funds to the University of California at San Francisco (UCSF) to reassess transplant safety in a small number of HIV-positive people with kidney or liver disease, in light of the changed environment offered by the use of potent anti-HIV therapy. Also, the National Institutes of Health (NIH) convened a small group of transplant surgeons and HIV specialists to discuss a larger, multi-center study that would include more people.

Now because of activist pressure, the transplant community is reassessing the wisdom of this blanket exclusion and formally studying transplants in people with HIV. Advances in anti-HIV therapy increases HIV specialists' and transplant surgeons' confidence to control HIV and lessen risks of disease progression when performing transplants and/or using immune suppressive therapy.

The ongoing study at UCSF and the planned larger NIH study will provide insight as to whether organ transplants for people with HIV will provide more overall benefit or harm. Current projects are limited to liver and kidney transplants. Additional activist pressure is needed to expand the range of organs being evaluated for transplantation.

Kudos to Jeff Getty of ACT UP/Golden Gate in San Francisco for his efforts on behalf of people with HIV/AIDS to move the study, and funding, forward! For information about the UCSF study, contact at UCSF Kidney Transplant Unit at 415-353-1551. Physicians or patients should let the receptionist know they are inquiring about Dr. Stock's HIV transplant study. Dr. Stock notes that it's best to call 9am-4pm PST to avoid the answering service and increase the likelihood the call will be directed appropriately. (Note: you do not have to be a California resident to participate in the UCSF study).

MK944A Clinical Study Put on Hold

Human studies for the new Merck protease inhibitor, MK944A, have been put on hold because of kidney toxicity seen in rats. MK944A is the combination of L756,423 and indinavir (Crixivan®).

Kidney toxicity (popular necrosis and convoluted proximal renal tubular degeneration) were seen in about a third to half of the rats after sixteen weeks of dosing with similar drug levels as those used in humans. Kidney toxicity has not been observed in dogs or in rats when either drug was dosed alone.

People have taken MK944A for about 24 weeks with no signs of kidney toxicity. It's known that rats are particularly sensitive to kidney toxicity. So Merck is now looking into whether this is effect occurs only in rats or whether it's something that may happen in humans after longer dosing with the drug.

Lodenosine Update

A study with lodenosine (formerly F-ddA) has been put on hold because of four deaths that may be related to the drug. Lodenosine is a nucleoside analogue (similar to ddI) that does not require the same buffer that ddI needs to increase its absorption. As a result, lodenosine can be taken with food and at the same time as other meds.

This study enrolled about 200 people, who took d4T + 3TC + indinavir or d4T + lodenosine + indinavir. Three doses of lodenosine were used (200, 300 and 400 mg), all taken twice a day.

Preliminary data presented at ICAAC in September showed the drug was well tolerated with very few side effects. It also showed promising anti-HIV activity. Although all three doses performed as well as 3TC, it was a surprise that the study was put on hold so soon after these promising results.

What's known is that four people died after the rapid onset of liver toxicity. There were mild increases in bilirubin (a measure of liver function) levels (which was thought to be due to indinavir) and transaminase levels (ALT and AST, also markers for liver function).

The company developing lodenosine, US Biosciences, decided to put the study on hold due to the safety concern. They have also assembled a group of liver experts to better understand the mechanism and cause of this toxicity.

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This article was provided by Project Inform. It is a part of the publication What's New. Visit Project Inform's website to find out more about their activities, publications and services.