Current public health guidelines call for prophylaxis against PCP for people with HIV infection who have fewer than 200 or less than 20% T-helper cells. Yet physicians of the County Community Consortium in San Francisco are reporting PCP among a significant number of patients with T-helper cell counts in the 200-300 range.
As part of our article on preventing PCP, BETA reports on additional laboratory tests and other information that may help determine the most appropriate time to begin preventative treatment for the disease. We hope this article will generate further discussion about whether or not to modify existing recommendations for primary prophylaxis against PCP.
Pneumocystis carinii pneumonia (PCP) is a life-threatening infection of the lungs which develops in approximately 85% of PWA.* Although the organism that causes PCP is common even in people who are HIV-negative, it rarely progresses to the disease stage because most people's immune systems are able to suppress the infection effectively. For PWA, however, PCP is the leading cause of death. Between 5 and 20% of people with the disease die during their first episode.
In the last year, it has become increasingly clear that prophylactic* use of a variety of drugs may prevent or postpone the onset of PCP. There are two types of prophylaxis*: primary and secondary. Primary prophylaxis attempts to prevent the initial onset of disease; secondary prophylaxis attempts to prevent a subsequent occurrence. PCP is life-threatening, and the risk increases with each occurrence. Prophylactic treatment may reduce the risk of developing the disease. It is also the most cost-effective approach because it prevents or postpones the expensive medical care required for the treatment of acute* PCP. It is important for people at risk for HIV infection to consider taking the HIV-antibody test. Those who are HIVpositive should monitor their immune system health early, and continue to monitor it every three to six months. This close monitoring allows them to consider early prophylactic treatment for PCP if they are found to be at risk for the disease. It is particularly urgent that all people who are HIV-positive determine their risk for developing PCP, because it may occur before any other symptoms of HIV infection appear.
When to Begin Preventative Treatment for PCP
Several indicators of immune system function may be used to decide when to begin prophylaxis. The single most useful guide may be T-helper cell* counts. Both the absolute number of Thelper cells (measured as the number of cells per mm3*) and the percentage of T-helper cells (measured as a percentage of total lymphocytes*) should be used to monitor risk for PCP. The percentage of T-helper cells has been associated with less dayto-day variation than the absolute number, and many physicians consider it more reliable.
Because T-helper cell counts vary widely from day to day and from lab to lab, the T-helper cell count from any single test should always be considered in the context of a series of these tests. Many physicians advise their patients to have their Thelper cells counted every 3 to 6 months. One study that examined data from over 1,500 people not receiving prophylaxis determined the likelihood of their developing PCP within 6, 12, and 36 months depending on T-helper cell counts at the beginning of the study. Among those with fewer than 200 T-helper cells, 8.4% developed PCP after only six months. After 36 months, 33.3% had developed PCP. At the same time, very few patients with between 200 and 350 T-helper cells developed PCP after 6 and 12 months (0.5% and 4.0%, respectively).
As a result of these studies, the U.S. Public Health Service recommends PCP prophylaxis for all people with either fewer than 200 or less than 20% T-helper cells. This recommendation may need to be revised, however. The minutes of the June 1989 meeting of the County Community Consortium in San Francisco indicate that Consortium physicians frequently find PCP in people with 200-300 T-helper cells. Consequently, it may be useful to consider other factors besides T-helper cell counts to help decide when to begin PCP prophylaxis.
A group of UCSF researchers recently studied the use of other laboratory tests to determine risk for PCP. They suggest that abnormal results from two or more of these tests may indicate that the individual is at increased risk for PCP, even when the absolute number of T-helper cells is greater than 200 and the percentage higher than 20%. These abnormal findings include a positive p24 antigen test, more than 3.0 mg per liter beta-2 microglobulin, hemoglobin* less than 13.5 grams per deciliter, and hematocrit* less than 40. A separate article in this issue discusses these and other tests.
In people who are HIV-positive, other conditions such as oral candidiasis*, hairy leukoplakia*, or herpes zoster*, may also indicate increased risk for PCP. Another indicator of PCP risk may be the skin anergy* test, which measures the body's capacity to mount an allergic response against various proteins injected within the skin. A marked depression in response to a number of these proteins may indicate abnormal immune function and increased risk for PCP.
What Preventative Treatments are Available?
Once the need for prophylaxis against PCP has been determined, a treatment strategy must be chosen. At least three drugs are currently used for PCP prophylaxis: trimethoprimsulfamethoxazole (TMP-SMX), which is marketed as Bactrim, Septra and others, aerosolized* pentamidine, and oral Dapsone*. Only aerosolized pentamidine has been approved by the Food and Drug Administration (FDA) as a prophylactic treatment for PCP. However, both TMP-SMX and Dapsone are readily available by prescription, and have long been considered standard treatments for other infections. In making the choice between different prophylactic drugs, the individual and his or her physician should consider, among other things, drug effectiveness, possible adverse effects, cost, and convenience. The individual should also take into account any other medical conditions, such as allergies or other opportunistic infections.
In one study, people with KS were given TMP-SMX orally twice daily as primary prophylaxis, along with 5 mg of leucovorin calcium* once daily. During the 36-month study, none of 30 people receiving prophylaxis developed PCP, while 53% of 30 people not receiving prophylaxis did develop the disease. Despite prevention of PCP, more than half of those receiving prophylaxis died during the course of the study. Nevertheless, those on prophylactic treatment lived an average of 10 months longer than untreated patients.
Other studies confirm the effectiveness of TMP-SMX in preventing or delaying the onset of PCP. However, most studies show that 40-60% of people using the drug experience adverse effects, and, as a result, many of them must stop treatment (TBO 4, p. 196). The most common adverse effects are reduced white blood cell count, skin rash, nausea, vomiting, itching, and an altered sense of taste. Serious adverse effects, often requiring immediate treatment termination, include fever and severe, life-threatening skin rash. The high frequency of adverse effects is the major drawback of TMP-SMX. Despite this, many physicians initially recommend TMP-SMX because of its potential effectiveness and low cost.
Recently, aerosolized pentamidine also has been shown to be effective in preventing PCP. In May 1989, the FDA approved the drug for PCP prophylaxis in people with fewer than 200 T-helper cells, or with a previous episode of PCP. In a study done by the County Community Consortium, 87% of 139 people receiving 300 mg every four weeks did not develop PCP in the first year of treatment (TBO 3, p. 196). This dose seemed to be most effective, especially as a secondary prophylaxis for people who had a previous episode of PCP.
Because treatment with pentamidine relies on proper inhalation of the aerosolized drug, how it is administered is critical. It should be used under the supervision of a respiratory therapist. There has been much debate about the most effective respirator used to deliver the drug. The San Francisco researchers recommend the Respirgard II respirator (sold by Marquest) because it makes droplets with sizes between one and two microns (TBO 3, p. 196). Larger droplets do not seem to reach the small alveolar sacs* of the lungs where the infection most often resides. In addition, some physicians recommend lying down when inhaling the drug to help maximize distribution into the upper portions of the lungs. The efficacy of this position has not been proven, however.
Until recently a major drawback of aerosolized pentamidine had been its high cost -- approximately $160 per month in the US. Lyphomed, Inc. announced in October that it plans to distribute the drug free to people who cannot afford it, including those whose insurance policies do not cover the cost of the drug. The cost of aerosolized pentamidine may not actually be significantly higher than that of TMP-SMX because aerosolized pentamidine does not require the frequent blood tests needed to monitor the toxicity of TMP-SMX.
Few people using aerosolized pentamidine experience serious adverse effects. Mild adverse effects include coughing spasms and wheezing, but bronchodilating* drugs are available to help prevent these coughing spasms. Nevertheless, the risks in using aerosolized pentamidine are disputed. The intravenous* use of pentamidine for treating acute PCP may cause serious adverse effects, and some physicians caution that aerosolized pentamidine may cause similar problems. Some cases of low blood sugar level have been reported.
Other drawbacks to aerosolized pentamidine are the result of the manner in which the drug is administered. Physicians have noted that because the aerosol is deposited primarily in the lower lungs, people using it are more likely to experience PCP in the upper lungs. There may also be increased risk of developing pneumocystis infection in other organs of the body, including the liver, spleen, middle ear, and brain. Consequently, some doctors prefer to recommend a systemic* prophylaxis, such as TMP-SMX or Dapsone, if the individual can tolerate these drugs.
A third alternative for PCP prophylaxis is Dapsone, an antibiotic* similar to TMP-SMX. A study presented at the V International Conference on AIDS in Montreal indicates that oral Dapsone seems to be as effective as TMP-SMX for prophylaxis against PCP (TBO 4, p. 196). Doses of 50-100 mg per day have been used effectively (TBO 5, p. 196). Its side effects include nausea, vomiting, skin rash, anemia, fever, and headache, but these were less severe than the side effects of TMP-SMX and were experienced by only 10-20% of the people taking the drug (TBO 4 and TBO 5, p. 196). However, people with G6PD* deficiency may experience severe anemia. Like TMP-SMX, Dapsone is relatively inexpensive, costing a few dollars per month. Because its effectiveness is less well documented, however, many physicians recommend Dapsone only after first considering TMP-SMX.
Some physicians recommend the use of combination therapy to prevent PCP. Because PCP can occur in organs other than the lungs, combining a daily dose of a systemic treatment like TMPSMX or Dapsone with monthly administration of aerosolized pentamidine may prove more beneficial than either treatment alone. However, there are risks involved in this treatment regimen because of the possible side effects from using TMP-SMX and Dapsone. No studies have been done to evaluate the possible effectiveness of this approach to preventative treatment for PCP.