TREATMENT ISSUES, Volume 6 no. 4 - April, 1992; Gay Men's Health Crisis
Phillip Pierce

This approach is controversial and may include such risks as: the development of resistance; the possibilities of toxic or unanticipated side effects when using several drugs; and the added cost and burden of taking multiple medications.

T4 Cells and OIs

Identifying patients at risk for developing OIs remains difficult. Only recently have studies documented a correlation of T4 counts with the occurrence of specific OIs. The OIs which can occur early in HIV disease are tuberculosis, and candidiasis (thrush) in the mouth, esophagus, or vagina.[1] These are most likely to develop when T4 counts are between 500 - 250. As T4 counts drop from 250 to below 100 the OIs more likely to develop include: PCP; toxoplasmosis; cryptococcal meningitis (CM); and Mycobacterium avium complex (MAC). Additionally 95% of cases of CMV retinitis develop when T4 counts are below 90.[2]

The correlation between T4 counts and OIs may help in assessing the appropriate time to initiate therapy. The key to successful prophylaxis is determining the exact point at which the benefits of preventive drug therapy outweigh the risks. Useful measures in determining the status of the immune system and the activity of HIV include percentage of T4 cells to all lymphocyte cells; ratio of T4 cells to T8 cells, measurement of Beta 2 microglobulin, and measurement of neopterin. (See Treatment Issues, Volume 6, Number 1.)

Tuberculosis (TB)

TB, a serious disease on the rise in New York City and other urban areas, is preventable and generally curable. However, if left untreated it can be fatal; therefore, early testing is of the utmost importance. A simple skin test, PPD (purified protein derivative), can identify 90% of people who have been exposed to tuberculosis with T4 counts over 500.[3] As counts drop, the test may begin to fail to show a positive skin test response, and inactive or latent cases of TB can go unidentified. After waiting about 48 hours, a positive skin test for TB usually appears as a reddened and raised area at the site of the test. Some experts argue that any reaction, no matter how small, at this site should be considered a positive response and may warrant prophylactic therapy. The standard treatment for TB is an oral antibiotic called isoniazid (INH) which is taken daily for 12 months. (For information regarding testing in New York City, see page 3.)

Since HIV-infected people are at particular risk for progressing to active TB disease, early identification of those who are recently or latently infected is critical.[4] Recent reports indicate a strain of TB that is resistant to standard treatment. Active TB disease after a case of multi-drug resistant (MDR) TB, can be deadly in 70% - 100% of cases.

A phase II double-blind placebo controlled trial of INH versus placebo is being conducted in persons with HIV who do not react to skin tests, yet may be infected with TB. It is important for persons interested in enrolling in this trial to first assess risk for TB according to working and living environments. INH is a drug with some considerable side effects, and the trial may be most suited for people who live in areas where TB is epidemic. Trial sites in New York City include: Harlem AIDS Treatment Group at (212) 694-4034; Bronx Lebanon Hospital at (212) 901-8646; Soundview Health Center in the Bronx at (212) 589-8775; and Addiction Research and Treatment Corporation in Brooklyn at (718) 243-2503. Interested persons can also call trail sites in New Jersey: Newark Community Health Centers at (201) 565-0355 and CRI of New Jersey at (201) 648-0350. Other clinical trials are presently recruiting patients comparing the standard year of isoniazid treatment to 60 days of rifampin and pyrazinamide. Call 1-800-TRIALS-A for more information.

Toxoplasmosis

Toxoplasmosis, an infection of the brain, is another serious OI that can affect people with AIDS. Risk of exposure to Toxoplasma gondii, the parasite that causes disease, depends on the area of the country in which one lives. Dr. Paula Sparti, Director of the Community Research Initiative of South Florida, says that in her region "40%-50% of the patients test positive for antibodies against toxoplasmosis. We used to see a lot of cases of CNS toxoplasmosis (infection in the brain) until we routinely started using prophylaxis for patients at high risk."[5] Pyrimethamine is considered standard prophylaxis, but Bactrim and dapsone may also be useful.

At the VI International Conference on AIDS in San Francisco, Dr. Peter Nicholas and others presented a retrospective study using Bactrim for PCP prophylaxis which demonstrated that the drug also seemed to prevent the development of toxoplasmosis.[6] Of 97 patients treated with Bactrim (one double-strength tablet twice a day), four patients who did not take the drug as scheduled developed toxoplasmosis. All of the patients who complied with the study remained disease-free. In the control group of 86 patients, who took aerosolized pentamidine (AP) for PCP prophylaxis, five developed toxoplasmosis. A similar study reported in Florence, found that no patients receiving dapsone developed toxoplasmosis compared to five patients receiving AP.[7] Notably, sulfa drugs like dapsone and Bactrim/Septra may be preferable to AP, since they prevent two OIs quite effectively, sparing the patients cost and toxicity. Sulfa allergies, however, may prevent some people from taking the drugs.

In New York, the percentage of persons who are antibody positive for Toxoplasmosis gondii is somewhat lower than in Florida. However, the risk of developing disease is still formidable. One study from Sloan-Kettering Hospital in NY revealed that 32% of patients with AIDS were found to be antibody positive. Toxoplasmosis developed in 24% of this group.[8]

Clinical trials of pyrimethamine as prophylaxis in HIV-infected patients with antibodies to T. gondii are underway. Clindamycin is not useful for toxoplasmosis prophylaxis because it causes diarrhea in a majority of patients.[9] To enroll or get more information in New York City, contact: Denise Bundow, Sloan-Kettering at (212) 639-7426, Mary Ann Kiernan, NYU-Bellevue at (212) 263-6565, Eileen Chusid, Mt. Sinai at (212) 241-3934, and Michael Giordano at Cornell Medical Center at (212) 746-4177. Patients may also enroll through their individual physician if he or she is enlisted in the Observational Data Base of a local Community Research Initiative (CRI).

It should be noted that the antacid buffer in ddI inhibits the ability of the stomach to absorb dapsone, which needs a non-acid medium. This means that the drugs need to be taken at least two hours apart.

MAC

Mycobacterium avium complex, often called MAC, is a difficult OI to treat, let alone to prevent. The organisms causing the infection are everywhere in soil, air, water and food. Treatment is managed with several drugs, and prophylaxis has been tried with some. Recently, based on anecdotal reports, a new drug, clarithromycin, has been hailed as a potential effective prophylaxis for MAC. Since prophylaxis usually uses a lower dose than that for treatment of disease, some physicians are recommending clarithromycin at doses in the lower range: 250 mg per day - 500 mg per day seems to be the most widely prescribed dose.

This growing practice of initiating prophylaxis without definitive data is not without some risk. For instance, mycobacteria are known to develop resistance quite easily. Dr. Jeffrey Greene, a prominent physician at NYU Medical Center, disapproves of this "poly-pharmaceutical approach." One of his foremost concerns is that many drug interactions and toxicities are unstudied and unknown.[10] Indeed, a recent study indicates that clarithromycin alters the ability of the body to absorb and distribute AZT. It may interfere with absorption and decrease peak concentrations by approximately 15% - 30%.[11] The clinical significance of this is unknown.

The risk of developing resistance, particularly when a drug is used at low doses, is another serious concern. Organisms often become resistant when an antibiotic is used for a long time. This fear is particularly acute with clarithromycin because of mycobacteria's well-known ability to become resistant quickly. Dr. Robert Jenkins, of Pacific Oaks Medical Group, counters this fear with the observation that in over a year of clarithromycin MAC prophylaxis, he has seen "only one case of resistance and that emerged from treatment."12 Dr. Paula Sparti likewise feels that "resistance is more likely to emerge from treatment than prophylaxis. Its use in this instance is very appropriate."[13]

Results of a two year study to determine if rifabutin, a drug made by Adria Labs, could prevent or delay MAC, were recently reported by the pharmaceutical company.[14] According to the study of 590 people with AIDS (mostly men), rifabutin did not significantly reduce the incidence of MAC, but did delay its occurrence. In other words, people on rifabutin had significantly longer MAC-free survival than people taking placebo. Since many people taking MAC prophylaxis are also using anti-fungal drugs, either to prevent fungal infections or to treat them, drug interaction studies with fluconazole are needed. Other studies observing rifabutin in combination with dapsone, oral contraceptives and methadone are planned by Adria for this Spring. Final analysis of all known rifabutin data should be released this month.

Cryptococcal Meningitis & Other Fungal Diseases

Cryptococcal meningitis (CM) poses special problems regarding prophylaxis. It occurs in only about 5% of people with AIDS and almost exclusively in those with T4 counts under 100. While the incidence of CM is low, it is a life-threatening disease. In addition, the drug of choice for treatment, amphotericin B, has several draw backs. The drug is highly toxic, requires intravenous administration, and has only a 40% success rate, including a 33% mortality in people with AIDS.[15]

One drug favored for prophylaxis against cryptococcosis and other fungal diseases is flu-conazole. Fluconazole, in a study reported at the VIIth International Conference on AIDS, demonstrated encouraging results for prophylaxis with almost no toxicity. At a dose of 100 mg/day, only one of 329 patients in the fluconazole group versus 16 out of 337 in the historical control group developedcryptococcosis.[16]

However, concern has been expressed about a small European study in which it is hypothesized that fluconazole may have masked early detection of cryptococcal disease, thus leading to irreversible neurological damage.[17] Nine of twenty patients who had been on fluconazole died of CM within five days of starting therapy with amphotericin B. Only one of five patients not receiving fluconazole died.[18] It should be noted that fluconazole is very expensive, and its interactions with other drugs are not well known. As a prophylaxis, fluconazole could interfere with its vital role in maintenance therapy for those who do develop cryptococcal meningitis.

The drug has also displayed effectiveness at a dose of 150 mg/wk in preventing candidiasis in the mouth and esophagus from recurring.[19] But some concern exists about using fluconazole as a prophylactic agent, since it may lead to the emergence of resistance. In one study, three patients developed resistant strains of candida, causing severe thrush, unresponsive to therapy, after a year of fluconazole prophylaxis.[20]

Topical, dietary, and so called "alternative" remedies may all have value in preventing candida infections. Anecdotal results support use of Peridex, a prescription mouthwash and support reduced sugar, yeast, and alcohol intake. A recent study in the Annals of Internal Medicine reported that eating eight ounces of yogurt containing Lactobacillus acidophilus at least once a day dramatically decreased cases of vaginal thrush in women with recurrent vaginal thrush.[21]

CMV

Prophylaxis for CMV disease is extremely controversial. While the effectiveness of high-dose acyclovir for prevention of CMV disease is widely disputed, a recent British study demonstrated significant survival advantage for patients with a T4 count of fewer than 150 cells.[22] By suppressing Epstein Barr Virus (EBV), acyclovir in high doses may theoretically prevent some cases of lymphoma, and by suppressing herpes viruses, including Human Herpes Simplex Virus-6 (HHSV-6), it may slow down HIV disease. (See Treatment Issues Volume 6 Number 2 for an in-depth discussion of this issue.)

Developing an oral drug capable of effective treatment and prophylaxis for CMV remains one of the most important in AIDS research. BW256U87 is an antiviral agent made by Burroughs Wellcome which is rapidly turned into acyclovir once it is metabolized by the body. It has been so far tested in phase I trials for safety and absorption. The drug appears capable of reaching blood levels three to four times higher than that of acyclovir. A phase II CMV prophylaxis trial is presently being planned by the ACTG with BW256U87. It is hoped that another arm of the trial will include oral ganciclovir (DHPG) for comparison. However, Syntex Corporation, maker of oral DHPG, claims to have a "drug supply problem."

Other Preventive Strategies: Immunization

Vaccines play a crucial role in preventing common infections in people with HIV disease. Yearly immunizations for influenza and a one-time-only immunization with Pneumovax, a vaccine for prevention of bacterial pneumonia, are recommended for all HIV-positive people. One of the problems with these vaccines, though, is that HIV-positive people may not achieve the high levels of protective antibodies that the vaccine is meant to trigger. However, merely increasing this protection may be beneficial.

A recent study with HIV-infected patients injected with Pneumovax showed that antibody levels rise twice as high if AZT is administered for a period of four weeks before the immunization.[23] It is speculated that antivirals may prove useful prior to the administration of other vaccines.

Prevention Strategy At a Glance

While there is by no means an agreement among clinicians in the area of prevention, the following is a broad prescription of what some community doctors are advising:

Receive pneumovax one time only (vaccine to prevent one type of bacterial pneumonia).

Take a PPD (Purified Protein Derivative) skin test for Tuberculosis (most accurate in early HIV illness). If positive but asymp-tomatic, treat with Isoniazid (INH).

Take a syphilis test taken at least once, repeatedly if other STDs are present.

Receive a yearly flu and influenza vaccination.

Take a toxoplasmosis blood tests for antibodies against the parasite. (if negative, retest once a year. Avoid changing cat litter, or wear mask and gloves when doing so. Avoid under-cooked meat).

Schedule an eye exam to examine the retina for CMV (repeat every 3 months if T4's cells are below 100).

Receive a PAP smear and pelvic exam every 6 months.

Test for the Hepatitis B virus; if antigen and antibody negative, get the Hepatitis B vaccination. For information call 1-800-HEP-B-873.

Sites for testing TB in New York City

The New York City Department of Health offers free testing at the following clinic sites:

Chelsea 303 Ninth Avenue (212) 239-1749

Washington Heights 600 W 168th Street (212)304-5427

Morrisana 1309 Fulton Avenue (212) 901-6536

Bedford 485 Throop Avenue (718) 574-2462

Brownsville 259 Bristol Street (718) 495-7258

Bushwick 335 Central Avenue (718) 574-2964

Fort Greene 295 Flatbush Avenue (718) 643-8357

Corona 34-33 Junction Blvd. (718) 476-7638

Rockaway 67-10 Rockaway Beach (718) 474-2100

Richmond 51 Stuyvesant Place (718) 983-4530

Tests are also available at the Community Health Project (CHP) in Manhattan for $10. Call (212) 675-3559.

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