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Success of protease inhibitors can depend on dietary factors

For people taking protease inhibitors, the goals of maximizing absorption and enhancing drug levels are intricately linked to diet. Intake of specific foods and timing of meals is more critical in maximizing absorption of protease inhibitors than for any other class of HIV drugs. Since side effects of protease inhibitors interfere with adequate intake of food, fluids and medications, eliminating or minimizing such side effects is critical.

Always remember: the first priority of this treatment is to make sure the person taking protease inhibitors is benefiting through reduced or eliminated symptoms of HIV-disease, is functioning well, and certainly, that they are not experiencing a reduced quality of life as a result of taking these medications. The latter consideration is crucial, especially since many people skip or reduce doses if they cannot tolerate the medications. Malabsorption is another danger, and must be avoided as well. Both missed doses and sub-optimal absorption reduce the effectiveness of protease inhibitors and increase the possibility of resistance to these drugs.

Adjusting diet and activities to orchestrate the timing of meals and medications is fundamental. Meal and medication schedules must be individualized, because each person has unique sleeping and eating habits, work/school/family obligations, abilities to manage side effects and medical concerns, as well as other variables.

side effects to medications that directly impact intake and absorption include loss of appetite, diarrhea, nausea and/or vomiting. Intake and absorption can be indirectly impacted by other adverse side effects when the ability or desire to prepare and eat food is reduced by fatigue, pain or depression. (One encouraging piece of news: it has been reported that in some cases, side effects of protease inhibitors decrease over time.) It is always important to be armed with the knowledge of which side effects may be associated with each medication. All side effects should be discussed with the patient's physician in order to minimize discomfort. A registered dietitian should also be consulted to develop diet modification strategies to reduce severity of side effects.

The identification of hyperlipidemia, hyperglycemia and altered body shape with successful potent antivetroviral therapy has given another imperative reason for each HIV-infected individual to receive early and ongoing nutritional assessment. This medical nutrition therapy would include body composition and shape measurements.1

One tip to help coordinate medication dosing with a healthy diet to improve compliance: patients should write out their typical activity schedules, including times for taking medications and eating meals.

The following is a review of dietary considerations for each of the four protease inhibitors currently available in the U.S.: Fortovase (saquinavir, Hoffmann-La Roche) is the brand name for a new soft-gel formulation of saquinavir that was made available last November. Invirase, the name of the original hard gel capsule of saquinavir, is not absorbed well (bioavailability 4%). Both Fortovase and Invirase must be taken at a dosage of six 200 mg capsules, three times daily (every eight hours). At that dose, however, Fortovase can achieve drug levels 10 times that of Invirase. The manufacturer had expected the higher drug levels achieved by Fortovase to eliminate the need to take it with another drug solely for the purpose of increasing the level of saquinavir. However, Fortovase is often prescribed with another protease inhibitor, ritonavir, to dramatically boost Fortovase's bioavailability. When prescribed together, dosage and food intake requirements are reduced, though no studies have been published to date examining this relationship.

To be absorbed, both Invirase and Fortovase need to be consumed with a large amount of food and fat. Fortovase should be taken every eight hours, either with a mealor up to two hours after a mealfor optimal absorption. Until much-needed dietary investigation and guidelines are developed, the best advice is to eat as much food and fat as can be tolerated when taking Fortovase depending upon appetite, stomach capacity and gastrointestinal complications or disturbances.2 A simple eating tip might be to plan to take Fortovase with a meal or large snack that includes a protein food of high biologic value, like meat, milk, cheese or eggs, and which also includes some friendlier fats, like those found in nuts, seeds, avocados or olive oil.

Packaged in a fat base of inactive ingredients, medium chain mono- and di-glycerides and 80 mg of alpha-tocopheral (vitamin E), Fortovase mixes with food in the stomach and is carried into the small intestines for digestion. There is a seven-fold improvement of Fortovase drug levels when taken with "a standard English breakfast" (containing 48 g protein, 60 g carbohydrates, 57 g fat and 1006 calories) when compared to fasting drug levels.

Unlike Invirase, Fortovase does not contain lactose: therefore, it may be better tolerated by people with lactose intolerance. On the other hand, it causes more GI symptoms than the milder Invirase. Fortovase, however, must be kept refrigerated (36-40°F) until dispensed, then stored at room temperature for three months. For people in hot climates (temperatures above 77°), precautions (such as keeping Fortovase in a cold pack) should be taken. If kept in the refrigerator, it can last up to one year, but Fortovase should not be frozen.

The most frequent adverse reactions seen in clinical trials of Fortovase were diarrhea, nausea, abdominal discomfort and dyspepsia (poor digestion). All of these conditions can directly impair optimal nutritional intake and function and require the intervention of a physician or dietitian, if not quickly resolved. Flatulence, fatigue, headaches and non-fasting high triglyceride levels have also been observed in conjunction with Fortovase.

Norvir (ritonavir, Abbott), sold in 100 mg capsules or as an oral solution of 600 mg per 7.5 ml, is usually prescribed at 600 mg (six capsules) or 7.5 ml twice daily to be taken orally, preferably every 12 hours. The capsules need to be kept refrigerated and stored in the original container. The medication can be kept out of the refrigerator up to 24 hours if kept below room temperature, but exposure to heat or sunlight must be avoided. Many patients take precautions and keep Norvir refrigerated, or in a cold pack at all times.Norvir is also available as an oral solution which is stable for 30 days at room temperature, thus making it ideal for travel. The oral solution of Norvir can be mixed into chocolate milk or protein shakes to mask its flavor. Once mixed, it must be taken within one hour.

Taking Norvir with a substantial meal that is fairly high in fat and protein improves tolerance to the drug and increases absorption by 15%.3 According to the manufacturer, however, this small increase does not necessarily translate into a clinical benefit. Side effects may include fatigue, weakness, diarrhea, nausea, vomiting, loss of appetite, abdominal pain, headaches and runny nose or cold symptoms. It may also cause abnormal sensations around the mouth, such as burning, numbing, prickling or "circumoral parathesia" (the sensation of small insects crawling). Cholesterol and triglyceride levels can become abnormally high for people on Norvir. Keeping this side effect in mind, people taking Norvir may want to consider diet modifications and a reduction in total fats, saturated fats and fried foods, as well as a greater emphasis on monounsaturated and polyunsaturated fats and fiber-rich foods (whole grains, vegetables, fruits). Norvir may elevate liver enzymes (SGOT, SGPT or AST, ALT) as well, so it is strongly advised that patients avoid any social drugs or alcohol while using the drug. anabolic steroids may have the potential to increase both lipids and liver enzymes, therefore when these agents are coadministered with Norvir, laboratory studies should monitor their effects carefully.

Crixivan (indinavir, Merck & Co.) is usually dosed at two 400 mg or four 200 mg capsules every eight hours, around the clock, on an empty stomacheating nothing for two hours after the last meal, taking the medication, then waiting for another hour before eating the next meal or snack. The most popular schedules for Crixivan are: 6AM, 2PM & 10PM or 7AM, 3PM & 11PM. An alternative twice-daily dosing schedule is being evaluated in clinical trials. In these studies Crixivan is given as 1,200mg at 10am and 10 pm. These schedules include medication times that avoid typical mealtimes.

Studies have shown that eating a snack very in low fat and protein does not reduce the absorption of Crixivan. The macro-nutrient profile for this snack would include no more than any of the following: two grams fat, 5.6 g protein, 65 g carbohydrates and 301 calories. The HIV/AIDS Dietetic Practice Group of The American Dietetic Association developed a list of 40 foods with quantities fitting these specifications; a few examples are: n One cup non-fat pretzels; half can of soda or juice (not grapefruit juice). n One cup tomato soup made with water and six oyster crackers; one cup tea with two tablespoons of skim milk and one teaspoon of sugar. n One cup dry cereal with no nuts, seeds, granola or more than two grams of fat per cup; half cup of non-fat milk; one medium banana.

Because three-hour "fasting" periods typically happen three times a day, it is very important that intake of food during the other three five-hour "feeding" periods include protein- and nutrient-dense foods.

Crixivan can crystallize in the kidneys. Drinking at least eight eight-ounce cups of safe water each day is recommended to minimize risk; think of this amount of water as three-quarters of a one gallon jug or two 1.5-liter bottles of safe drinking water. A word of caution regarding beverages other than water: coffee can act as a mild diuretic, decrease appetite and speed up gastric motility to cause (or worsen) loose stools. These problems often become manageable when coffee is cut out or intake is reduced. Additionally, grapefruit juice reduces drug levels of Crixivan by 26%thus it may be wiser to avoid it while taking Crixivan.

Viracept (nelfinavir, Agouron) is packaged in 250 mg capsules and is usually prescribed as three capsules, to be taken three times daily, preferably every eight hours to assure consistently high blood drug levels. Viracept is being investigated in a twice-daily dosing schedule as 1,250mg taken with breakfast and dinner. Capsules should be kept in their original bottle, tightly closed, at room temperature. Taking the medication with food increases the absorption of nelfinavir as much as three-fold. At this time, it is still not clear what kind of food achieves that particular effect. There was no difference in absorption between a meal of 517 calories with 17 g fat, and a meal of 759 calories with 34.7 g fat. Until there is better information, it seems prudent to take Viracept with a meal or substantial snack that includes two to three ounces of animal protein, complex carbohydrates and a little fat, or with a healthy protein shake that includes fruit, such as a banana or frozen blueberries. People on Viracept reported side effects such as diarrhea, nausea and headaches. Some doctors anecdotally report good results from prescribing pancrelipase to assist in the digestion of fats and reducing diarrhea.

Many questions remain concerning nutrition and protease inhibitors. Some of the more disturbing results of protease inhibitor therapyincluding shifting fat deposits to the belly, breasts and back of the neck and increasing blood lipid levelsneed to be explored more fully. It seems reasonable that the primary care provider, working with the registered dietitian, should track quarterly fasting lipid panels and anthropometrics (the measurements of the size, weight and proportions of the body). Anthropometrics would include waist-hip ratio, mid-arm and mid-thigh circumferences, weight, body mass index, bio-electrical impedance for body cell mass and fluids, and, of course, height. Medical nutrition therapy should be done two to six times a year, depending on acuity of nutritional concerns.

For people who have had hepatitis or liver problems, lab values must be monitored more cautiously. A physician or registered dietitian can help explain which chemicals and foods exacerbate and mitigate liver involvement.

It is important to remember that the basis for good diet is to concentrate on plenty of safe protein- and nutrient-rich foods, animal proteins, whole grains, complex carbohydrates, colorful fruits and vegetables, at least eight eight-ounce glasses of safe water. The bottom line? Don't miss medications, meals or snacksand drink more water. References

1. Fenton M, Silverman E, and Vazzo L. Adult HIV/AIDS Medical Nutrition Therapy Protocol final draft. In Medical Nutrition Therapy Across the Continuum of Care, 2nd Edition. The American Dietetic Association, projected publication: October 1998.

2. Goldberg, I and Posch, R. Personal Communication. 11/21/97.

3. Macronutrient profile of this test meal was 771 calories, 46% fat, 18% protein, and 37% carbohydrate. Package insert, Abbott Pharmaceuticals.

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