Seattle Treatment Education Project (STEP) Perspective, Vol. 5, No. 2 - July 1993 * 127 Broadway E. Ste 200 Seattle, WA 98102
Stephen Tabet, MD

MDR-TB results when patients fail to take all their prescribed antibiotics consistently for the six to 12 months necessary to fully overcome the TB organism. Nationwide estimates indicate that close to 25% of TB-infected individuals do not finish an appropriate full course of anti-tuberculosis therapy. In U.S. cities with high rates of homelessness, poverty, and injection drug use, up to 50% of individuals with TB do not complete their prescribed course of treatment. Many of these individuals are spending so much of their time and energy on basic needs such as food and shelter that they simply are unable to take their medications. Another reason for these high rates of noncompliance is that individuals often feel better after a few weeks of treatment and cease taking their TB medications, or they may suffer unpleasant medication side effects and stop taking one or all of them. For whatever the reason, individuals who do not take all of their TB medications for the prescribed amount of time may develop drug-resistant tuberculosis.

The majority of MDR-TB cases has occurred in New York City, California, and Florida. In New York City, one-third of TB isolates are resistant to at least one drug. The spread of MDR-TB has been reported when individuals with the condition are not in respiratory isolation and have contact with other patients and health care workers. These outbreaks have almost exclusively affected HIV infected persons in hospitals, clinics, residential facilities, and correctional institutions. Strict isolation techniques and appropriate ventilation have been shown to be effective in controlling the institutional spread of MDR-TB.

Traditional TB is usually treated with combination therapy: isoniazid (usually abbreviated INH), rifampin, and pyrazinamide. Treatment of MDR-TB often requires complex regimens of second-line TB medications (with therapy lasting for up to two years), which can produce serious side effects. Even with treatment, however, the death rate for MDR-TB patients is 40% to 60%. This death rate climbs to 80% in patients with both HIV and MDR-TB. The course of MDR-TB is often quite rapid. The time from diagnosis to death for most individuals with MDR-TB and HIV may be only months, as they are often left without treatment options.

In conclusion, erratic and incomplete treatment has led to the emergence of MDR-TB. Outbreaks of MDR-TB have affected almost exclusively HIV infected inividuals in institutionalized settings. Individuals with MDR-TB, and especially those with concomitant HIV infection and MDR-TB have very high death rates. Treatment for TB is long term and can be associated with unpleasant side effects. New methods to combat this old disease need to be developed. Current drug regimens involve multiple tablets which need to be consolidated into one tablet. In addition, new methods of medication delivery (such as implantable therapy) should be researched. All individuals need to be informed of the dangers of not taking medications. Also, institutions need to implement more effective respiratory isolation systems to decrease the spread of TB.

Erythropoietin (also known as EPO, Erythropoietin alfa, Procrit) is a glycoprotein which stimulates red blood cell production. It is produced primarily in the kidney, and to a small extent, in the liver. It stimulates cells in the bone marrow to divide and differentiate into red blood cells. In the body, production of erythropoietin is normally regulated by the level of tissue oxygenation. Hypoxemia and anemia generally increase the production of erythropoietin which, in turn, stimulates erythropoiesis (the production of red blood cells).

Erythropoietin is manufactured by recombinant DNA technology, and has the same biological effect as endogenous erythropoietin. It has been approved by the FDA for the treatment of anemia in AZT treated HIV infected individuals or anemia caused by chronic renal failure.

When and how is it used?

Recombinant erythropoietin is indicated for the treatment of anemia that is found in HIV infected individuals being treated with AZT (Zidovudine). It is not indicated for the treatment of anemia in HIV infected individuals due to other factors such as gastrointestinal bleeding, folate or iron deficiency, or hemolysis. However one study has suggested that erythropoietin may also be beneficial to some individuals with non-AZT related anemia. Response to erythropoietin in AZT-treated HIV infected individuals is manifested by reduced transfusion requirements and/or maintenance or elevation of red blood cell levels seen in the hematocrit and hemoglobin.

Responsiveness to recombinant erythropoietin depends on the individual's serum erythropoietin level prior to treatment. Individuals with blood erythropoietin levels less than 500 mU/ml and who are receiving a dose of AZT less than or equal to 600 mg/day, are more likely to respond to erythropoietin therapy. (Normal endogenous erythropoietin levels are 4-26 mU/ml.) Individuals with serum blood levels greater than 500 mU/ml do not appear to respond to erythropoietin therapy. Erythropoietin, at a dose of 100 U/kg intravenously or subcutaneously three times per week for eight weeks is the recommended starting dose in individuals with blood levels less than 500 mU/ml and who are receiving a dose of AZT less than or equal to 600 mg/day. Hematocrits should be monitored weekly and if after eight weeks the hematocrit has not risen or the red blood cell transfusion requirement has not decreased, erythropoietin can be increased by 50-100 U/kg every four to eight weeks, to a maximum of 300 U/kg. When the hematocrit exceeds 40%, erythropoietin should be discontinued and restarted at a 25% less dose when the hematocrit drops below 36%. erythropoietin doses should also be titrated based on an increase or decrease in AZT dose.

A clinically significant increase in hematocrit is usually not observed in less than two weeks and may require up to six weeks in some individuals. This is related the half-life of red blood cells and the several days it takes for red blood cell progenitors to mature and be released into the circulation.

What does the research show?

Erythropoietin was studied in four placebo-controlled trials enrolling a total of 297 anemic (hematocrit less than 30%) HIV infected individuals receiving AZT. In the group of individuals with prestudy erythropoietin levels equal to or greater than 500 mU/ml, the mean cumulative number of units of blood transfused per person who received erythropoietin was reduced by approximately 40% as compared to the placebo group. During the second and third months of treatment with erythropoietin, 43% of the individuals who required transfusions at the beginning of the study were transfusion independent, versus 18% in the placebo group. In the subgroup of the individuals with baseline erythropoietin levels greater than or equal to 500 mU/ml, erythropoietin therapy did not increase the hematocrit or decrease the individual's transfusion requirements.

What are the side effects or precautions?

Adverse effects in clinical trials with erythropoietin in AZT-treated HIV infected patients seemed to be consistent with the progression of HIV infection. In studies involving approximately 300 individuals, there were no statistically significant differences in the incidence of adverse effects between the treatment group and the placebo group. The most commonly experienced side-effects were fever, fatigue, headache, cough, diarrhea, and rash.

Peripheral white blood cell counts and platelet counts remained unchanged following erythropoietin therapy. If the blood counts are not carefully monitored and the dose adjusted appropriately, the hematocrit can become too high and the erythropoietin should be temporarily withheld.

While transient rashes have occurred, no serious allergic or anaphylactic reactions have been seen in patients receiving erythropoietin therapy. As with the administration of all biologic products, the person should be made aware that an allergic reaction can occur and the appropriate precautions taken. Prior to and during erythropoietin therapy, the person's iron levels and ferritin should be evaluated. Supplemental iron may be required to increase or maintain levels that will adequately support erythropoietin stimulated red blood cell production. If an individual fails to respond to endogenous erythropoietin, other etiologies should be considered and evaluated.
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Copyright © 1993 - Seattle Treatment Education Project (STEP) - All rights reserved. Noncommercial reproduction is encouraged. STEP is published four times a year by the Seattle Treatment Education Project, 127 Broadway East, 3rd Floor, Seattle, WA 98102.    Email: step100@aol.com  STEP web page