PI Perspective #18

April 1996     View PDF     En español

Opportunistic Infections Update

Significant advances have been made in the prevention and treatment of opportunistic infections in the past few years. Results from trials of new therapies suggest that not only do they have better activity, but they also provide an improved quality of life because they require less frequent dosing or because they no longer require intravenous infusions. Additionally, there have been advances in using the PCR and bDNA (branched DNA) tests for infections other than HIV. These tests may be used to more accurately and more rapidly diagnose different opportunistic infections (OIs) as well as to monitor the effectiveness of therapy.

Developments in CMV (cytomegalovirus)
Two studies examined the correlation between CMV viral load and progression to CMV disease. Both produced results which suggest that viral load testing will become an essential tool in predicting risk of CMV infection as well as for diagnosis. At the moment, however, both PCR and bDNA tests for CMV are only available in the research setting. Additionally, new data shed light on preventing CMV with oral ganciclovir and the FDA approval of cidofovir may advance the standard of care for CMV treatment.

The AIDS Clinical Trial Group (ACTG) study 204 compared CMV viral load in the blood and urine of 310 people taking either valacyclovir or acyclovir for CMV prevention over the course of eight weeks. Results from this study were reported in PI Perspective #17. Twenty percent of the study volunteers developed CMV disease and analysis indicated that those who tested positive by PCR at the beginning of the study were more likely to develop disease. This suggests that PCR testing can predict the risk of disease development.

A second study looked at three groups of people with fewer than 200 CD4+ cells. One study group did not have CMV disease, another had active but untreated CMV, and the third had active CMV and had been on therapy for at least two with probenecid to reduce the risk of kidney toxicity. It is not known whether probenecid will have any drug interactions with commonly used antiretrovirals or OI drugs. Side effects from this study include: increases in protein detected in urine, fevers, elevated creatinine levels (an indicator for potential kidney toxicity) and decrease in white blood cells. Some data suggest that increased hydration before administration will reduce the chance of cidofovir side effects.

Developments in Fungal Infections
Daily use of fluconazole has been shown to be effective at reducing the likelihood of developing thrush (candida) and other fungal infections. Since fungal infections are relatively easy to treat once they occur, many physicians question whether preventive treatment with fluconazole is medically appropriate. A recent study looked at the effectiveness of using weekly versus daily dosing of the drug. Six hundred and thirty-three people with fewer than 100 CD4+ cells received either 200mg of fluconazole a day or 400mg of fluconazole a week. There was no difference between the two doses in the incidence deep fungal infection such as candida in the esophagus or gut, cryptococcal disease or histoplasmosis and the incidence of side effects was similar for both groups. People taking fluconazole daily, however, were less likely to develop thrush (oral candida) compared to people taking fluconazole weekly. No information was reported on the incidence of vaginal thrush. While this study suggests that weekly fluconazole may be as effective as a daily dose, it is still unknown if weekly dosing will increase the risk of developing fluconazole-resistant candida. Developments in MAC (Mycobacterium Avium Complex)

A study looking at routes of MAC infection found that in one hospital three infections out of one hundred were probably due to MAC infection of the hospital’s drinking water. About 25% of common household potting soil is thought to contain MAC but there is no clear link between handling potting soil and developing the disease.

ACTG study 196 compared clarithromycin (500mg twice a day), rifabutin (450mg daily), and the combination for the prevention of MAC disease in 1178 people with fewer than 100 CD4+ cells. This study found that the risk of developing MAC was significantly higher for those taking rifabutin alone compared to clarithromycin or the combination. Serious side effects, including uveitis, were common in the combination arm. Moreover, people receiving the combination experienced more side effects and no additional benefit. Almost 30% of the people receiving clarithromycin who developed MAC also developed resistance to clarithromycin. This is of concern because clarithromycin is the drug of choice for treating MAC disease .The combination, contrary to a previously reported study of azithromycin and rifabutin, did not appear to reduce the likelihood of developing a clarithromycin-resistant strain of MAC.

Two studies looked at two- and three-drug combinations of clarithromycin, clofazimine, and ethambutol for the weeks. Not surprisingly, people with no CMV disease generally had lower CMV viral levels than those with active but untreated CMV. People with active but untreated CMV had viral levels of at least 1,000. Three people with active but untreated CMV, with an initial CMV viral load of over 30,000, suffered disease progression even though they began using anti-CMV therapy. Those who began the study with active treated CMV all had levels less than 100.

The question of when to use PCR to look for CMV infection presents problems because CMV commonly falls to undetectable levels in the blood then resurfaces as an active infection. Also, because CMV outbreaks are associated with lower CD4+ cell counts, CMV viral load tests should probably begin at some point measured by CD4+ levels but no one is sure what that level is, or how often this test should be done.

Another recent study found that oral ganciclovir is useful to prevent the development of CMV retinitis. The study looked at 725 people who were given either oral ganciclovir or a placebo. The results indicated that the risk of developing CMV retinitis on placebo was about twice that seen among people using oral ganciclovir. Additionally, the study shows that using oral ganciclovir reduced the risk of developing sight-threatening retinitis even more than it reduced the risk of the retinitis spreading to other parts of the eye. This is thought to be because higher levels of the drug are achieved in the area of the eye where CMV retinitis threatens eyesight (known as “zone 1”).

Cidofovir (Vistide) in CMV Disease
The use of cidofovir for treating recurring CMV retinitis has been examined recently. One hundred people with either relapsing CMV retinitis or who were intolerant to standard therapies were given 5mg/kg intravenous cidofovir once a week for 2 weeks, then a maintenance dose of 3mg/kg or 5mg/kg every other week. People on the lower maintenance dose relapsed more rapidly, at an average of 49 days compared 115 days for people on the higher dose. The recurrence rates compare favorably to either intravenous ganciclovir or foscarnet with the added benefit of a greatly reduced dosing schedule resulting in an improved quality of life. However, like other CMV treatments, cidofovir can cause harmful side effects and must be taken treatment of MAC. A CCTG study looked at clarithromycin + clofazimine compared to clarithromycin + clofazimine + ethambutol in 80 people with positive MAC cultures. The doses used in this study were 1,000mg of clarithromycin twice a day, 100mg daily of clofazimine and 800mg of ethambutol daily. There were no additional side effects when ethambutol was added. The addition of ethambutol significantly reduced the risk of relapse and delayed the emergence of clarithromycin-resistant strain of MAC in those who did relapse.

The second study compared various anti-MAC regimens in 106 people, 89 of whom started the study with positive blood cultures for MAC. People received 500mg of clarithromycin twice a day and 15mg/kg of ethambutol, with or without 100mg of clofazimine daily. During the study, only one person developed a resistant strain of MAC. Interestingly, people who did not receive clofazimine fared better than those who did. There were also significantly fewer deaths among people receiving the two drug combination compared to those receiving the triple combination.

These studies suggest that the optimal treatment regimen for MAC disease is clarithromycin and ethambutol and that clofazimine should not be used. It remains to be seen whether the adding another anti-MAC drug to the clarithromycin + ethambutol combination will result in additional benefit.

Developments in Toxoplasmosis Prevention
ACTG study 154 compared pyrimethamine (50mg three times a week) to placebo as prevention against toxoplasmosis in 554 people. People receiving pyrimethamine were analyzed as two groups; those with drug levels in the blood above and below 0.5mg per liter. For people who achieved higher levels of drug in the blood, risk of developing toxoplasmosis was cut in half. These data suggest that pyrimethamine may be useful in treating toxoplasmosis only if optimal dosing and blood levels of drug can be achieved. People who did not achieve high blood levels of drug were no better off than placebo recipients.

Baboon-to-Human Transplant

LAST      NEXT

Government Health Programs