The exact underlying mechanism of PI-induced diarrhea is unknown,^[7] and treatment is nonspecific and limited. Most information is contained in abstracts and case reports. For those patients refractory to loperamide therapy, 5 other options have been proposed: calcium, oat bran and psyllium, pancrealipase, SP-303, and diphenoxylate/atropine.

Perez-Rodriguez and colleagues^[8] used calcium carbonate (Oscal; 500 mg twice daily) in 15 adult HIV-infected patients with nelfinavir-induced diarrhea. After 48 hours of therapy, 13 (87%) patients had normal stool as reported by survey and 100% noticed dramatic decreases in their symptoms. For pediatric patients, 45 mg/kg/day divided 2-4 times per day could be initiated, with a maximum of 65 mg/kg/day.^[9] Symptoms should be relieved in a few days. If constipation occurs, the dose should be reduced. Abdominal pain and/or nausea may be a reason to discontinue calcium therapy.

Three abstracts have evaluated the use of oat bran and/or psyllium. Hoffman and colleagues^[10] administered 1500 mg of oat bran tablets with each dose of medication to 51 HIV-infected adults with PI-associated diarrhea, 43% of whom were receiving nelfinavir. After 2 weeks of oat bran therapy, the frequency of diarrhea decreased from a mean grading score of 2 (4-7 stools per day) to a mean of 1.04 (<=3 stools per day), and 84% of patients reported their symptoms as being moderately or dramatically decreased. Hawkins and coworkers^[11] conducted a telephone survey of 77 HIV-infected patients who had taken nelfinavir for at least 3 months, to assess the use and efficacy of powdered psyllium. Of the 77, 87% had experienced diarrhea and of those, 30% had tried psyllium for relief. Only approximately one half of these patients reported less frequent stools with the psyllium powder, and all reported poor taste tolerability. In light of this, Ronagh and associates^[12] studied the fiber bar formulation of psyllium: 2 fiber bars were given 1 hour before bedtime for 2 weeks to 16 HIV-infected patients with PI-associated diarrhea. A total of 93% of these patients reported a decrease in diarrhea and better adherence. Both oat bran and psyllium have bloating and flatulence side effects. Equivalent doses for pediatric patients for oat bran, psyllium powder, and fiber bars are 500 mg 1-3 times per day, 0.5-1 teaspoonful 1-3 times per day, and 1 bar 1-3 times per day, respectively. If symptom relief is not seen after 2 weeks, an alternative therapy should be pursued.

Pancrealipase is a combination of pancreatic enzymes, lipase, protease, and amylase. It has been reported to increase the consistency and decrease the frequency of stools. Viokase and Ultrase MT 20 have both been used in HIV-infected patients with PI-associated diarrhea.^[7,13] After failure of over-the-counter medications to treat diarrhea, 55 HIV-infected patients (36 on nelfinavir) were given 1 tablet of Viokase with each meal. Most patients had relief within 12 hours after initiation of Viokase, and diarrhea did not recur in 89% of patients.^[7] Razzeca and colleagues^[13] gave 26 HIV-infected patients with nelfinavir-induced diarrhea 2 tablets of Ultrase MT 20 with meals and snacks. Ninety-six percent of patients responded to therapy as assessed by a substantial decrease in number of stools per day. A pharmacokinetic analysis showed no drug interaction between Ultrase MT 20 and nelfinavir based on AUC, Cmax, and Tmax. Clinical efficacy was also assessed using viral load. All except 3 patients had a significant decrease in viral load, suggesting that Ultrase MT 20 has no detrimental effects on the clinical efficacy of nelfinavir.

SP-303 (SB Normal Stool Formula) is an herbal extract from a plant indigenous to South America Croton lechleri. It has been used for many years in the treatment of symptomatic diarrhea, and is thought to decrease secretion of chloride ions in gastrointestinal cells. A phase 2, randomized, double-blind, placebo-controlled trial in 51 HIV-infected patients was conducted with this compound, in which 500 mg of SP-303 or placebo was given every 6 hours for 4 days.^[14] There was no statistically significant reduction in stool frequency between the treatment groups when comparing mean number of stools per day, although random regression analysis revealed a significant reduction in stool weight and frequency in the SP-303 treated group. No adverse events or abnormal laboratory findings were reported during the study. However, since clinical and adverse effect data in children are lacking, this should not be considered an option for pediatric patients.

Diphenoxylate/atropine (Lomotil) has also been suggested as treatment for PI-associated diarrhea at a dose of 2.5-5.0 mL up to 4 times pr day. However, in one report there was no response when Lomotil was used in 6 patients who were refractory to loperamide therapy.^[13]

Recommendations

In light of the above clinical data, and given the relative cost of the therapies (see Table), some general recommendations can be made for the treatment of pediatric patients who develop PI-induced diarrhea refractory to loperamide. Calcium therapy should be initiated at a maximum of 65 mg/kg/day in 2-4 divided doses. If diarrhea does not decrease after 2-3 days, psyllium or oat bran therapy may be used. Children's doses of psyllium powder should not exceed 1 teaspoonful 3 times daily, doses of fiber bars should not exceed 1 bar 3 times daily, and doses of oat bran should not exceed 1500 mg/day. If response is not seen within 2 weeks, pancreatic enzyme therapy should be offered next, although pancrealipase is expensive and efficacy data are limited. Ultrase MT 20 would be the preferred agent since pharmacokinetic and efficacy studies have shown no significant interaction with nelfinavir. The lowest dose needed to reduce diarrhea should be used: initiate 1 tablet with meals and snacks, and titrate to a maximum of 2 tablets per dose. If response is not seen within 2-3 days, Lomotil could be tried, although there is little evidence of its efficacy in PI-associated diarrhea, and it is expensive. Pediatric dosing of the liquid formulation should be 0.3-0.4 mg/kg/day divided 4 times per day. The use of SP-303 is not recommended, since it is not regulated by the Food and Drug Administration and there are no data in pediatric subjects.

Table. Costs of Agents Used to Treat PI-Induced Diarrhea

References

1. Viracept® (nelfinavir) Product information. Agouron Pharmaceuticals, Inc. La Jolla, Calif; Jan 25, 2001.
2. Krogstad P, Wiznia A, Luzuriaga K, et al. Treatment of human immunodeficiency virus 1-infected infants and children with the protease inhibitor nelfinavir mesylate. Clin Infect Dis. 1999;28:1109-1118.
3. Starr SE, Fletcher CV, Spector SA, et al. Combination therapy with efavirenz, nelfinavir, and nucleoside reverse-transcriptase inhibitors in children infected with human immunodeficiency virus type 1. N Engl J Med. 1999;341:1874-1881.
4. Division of AIDS (DAIDS) toxicity table for grading severity of pediatric (>3 months of age) adverse experiences. September 1993.
5. Razzeca K, Odenheimer S, Davis M, Landeck K. The treatment of nelfinavir induced diarrhea. Program and abstracts of the 12th World AIDS Conference; June 28-July 3, 1998; Geneva, Switzerland. Abstract 12383.
6. Weber R, Ledergerber B, Zbinden R, et al. Enteric infections and diarrhea in human immunodeficiency virus-infected persons. Arch Intern Med. 1999;159:1473-1480.
7. Sherman DS, Fish DN. Management of protease inhibitor-associated diarrhea. Clin Infect Dis. 2000;30:908-914.
8. Perez-Rodriguez E, Gonzalez J, Kopp B. The role of calcium supplements in the treatment of nelfinavir-induced diarrhea. Program and abstracts of the 39th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 26-29, 1999; San Francisco, California. Abstract 1308.
9. Siberry GK, Iannone R, eds. Johns Hopkins: Harriett Lane Handbook. 15th ed. Mosby's Inc.; 2000:651.
10. Hoffman M. Oat bran tablets are an effective natural supplement for the management of protease inhibitor-induced diarrhea. Program and abstracts of the International Conference on the Discovery and Clinical Development of Antiretroviral Therapies; December 13-17, 1998; St. Thomas, West Indies. Abstract LB7.
11. Hawkins T. Nelfinavir-associated diarrhea is manageable with nonprescription medications. Program and abstracts of the 12th World AIDS Conference; June 28-July 3, 1998; Geneva, Switzerland. Abstract 12401.
12. Ronagh T, Schroeder D. Psyllium husk fiber bars are efficacious in the treatment of protease inhibitor (PI)-induced diarrhea. Program and abstracts of the 39th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 26-29, 1999; San Francisco, California. Abstract 1307.
13. Price J, Shalit P, Carlsen J, Becker MI, Frye J, Hsyu P. Pharmacokinetic interaction between Ultrase MT—20 and nelfinavir in HIV-infected individuals. Program and abstracts of the 39th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 26-29, 1999; San Francisco, California. Abstract 340.
14. Holodniy M, Koch J, Mistal M, Schmidt JM, O'Hanley P, Porter S. SP-303: a new treatment for AIDS-associated diarrhea. Program and abstracts of the 12th World AIDS Conference; June 28-July 3, 1998; Geneva, Switzerland. Abstract 321106.