Bulletin of Experimental Treatments for AIDS, No. 2; November 1988

In the June 1988 issue of BETA we referred to the standard "full dose" of AZT as 200 mg every four hours (1200 mg every day). Recent studies, however, suggest that a half dose of AZT (600 mg every day) may be as effective . [56] In a study presented at Stockholm, researchers found that there was no difference in the antiviral effect of AZT at a half dose (200 mg every four hours). After eight weeks, the rise in T-helper cells was higher in individuals receiving the half dose than in individuals receiving the full dose. The researchers suggested more studies using a half dose regimen because it may limit the toxicity of AZT.

Other researchers have noted that more convenient dosage schedules, such as every six or twelve hours, may be just as effective as every four hours. [57] More convenient dosage schedules may give bone marrow time to recover from the effects of AZT.

One study reports that a dosage schedule of 250 mg every 6 hours reduced antigen levels in the cerebrospinal fluid (CSF)*. [58] It is currently unknown if a half dose of AZT (600 mg/day) would be effective in producing this same result.

Rare HIV Rebound Effect After Dose Reduction of AZT

In a study reported in The Lancet, a small number of PWA developed severe meningoencephalitis* after dose reductions of AZT. [59] One hundred and six individuals participated in the study. Twenty-one had their AZT dose reduced because of bone marrow suppression. Within 17 days of the dose reduction, 4 of these individuals developed acute meningoencephalitis episodes, including fever, headache, neck stiffness, and confusion. These symptoms resolved in 3 of the 4 patients within 2-4 weeks.

Many physicians, however, have observed no rebound effect when reducing or stopping AZT. According to Marcus Conant, MD [60], "Physicians will be looking for this rebound effect now to see if it is real. Physicians and patients should be aware that this effect has been reported from this group in London. Whether it is real or not is difficult to say." Harry Hollander, MD [61] commented, "Given my own experience taking people off AZT and after speaking to a number of physicians following patients on AZT, I feel if this rebound effect occurs at all, it is rare."

Acyclovir and AZT

In the June 1988 issue of BETA we discussed the possibility that a combination of acyclovir and AZT may work better than AZT alone. A multi-center trial in Europe reported on using AZT alone and AZT and acyclovir in PWA. [62] For 48 weeks individuals in this study took either 250 mg of AZT alone every 6 hours or 250 mg of AZT with 800 mg of acyclovir every 6 hours.

During the first 24 weeks on combined therapy the only observed benefit was a decrease in herpes virus infections (herpes zoster, herpes simplex and cytomegalovirus). In the second 24 weeks, however, the researchers noted "significant improvement in survival and a reduction in the incidence and severity of opportunistic infections in individuals receiving the combination compared with those given AZT alone."

AZT and Vitamin B12

The San Francisco County Community Consortium will begin a study this year of vitamin B12 and AZT. This trial will test the hypothesis that vitamin B12 can help reduce the anemia caused by AZT.

Vitamin B12 promotes the production of thymidine monophosphate, a substance in the body which is important for red blood cell formation. This substance is also important in the breakdown of AZT. Researchers theorize that when the body is flooded with AZT,the drug competes with the production of red blood cells for thymidine monophosphate. Monthly intramuscular injections of vitamin B12 may help produce enough thymidine monophosphate in the body to break down AZT as well as promote production of red blood cells.

Some physicians believe that B12 levels should be closely monitored in individuals using AZT because individuals who have low B12 levels show a greater tendency to develop anemia when they start AZT. Dr. Conant recommends monthly monitoring of B12 levels in individuals using AZT, and he suggests a monthly intramuscular injection of the vitamin for some people.

AZT and Cryptosporidiosis

Researchers have found that AZT may be an effective therapy for cryptosporidiosis*, a life-threatening infection in PWA. [63] Until now, there has been no effective treatment for this infection. Sixteen PWA with cryptosporidiosis received either 600 or 1200 mg of AZT every day. Five had cryptosporidiosis as their only opportunistic infection, while the others had one or more other opportunistic infections and/or KS.

Of 13 individuals for whom testing for cryptosporidium could be performed, 9 were repeatedly negative after therapy with AZT. Before treatment with AZT these individuals experienced diarrhea for an average of 18 weeks. After four months of treatment the diarrhea disappeared in 12 of 16. After seven months on AZT there was a marked improvement in diarrhea (no diarrhea in 6, improvement in 10, stability in 3, and worsening symptoms in 2).

The researchers found that the 600 mg/day dose was just as effective in the treatment of cryptosporidiosis as the "full" dose of 1200 mg.

AZT and Toxoplasmosis

Researchers have reported on the possible benefit of AZT for PWA with toxoplasmosis. [64] Researchers first treated the toxoplasmosis with regiments of pyrimethamine and sulfadiazine. Twenty-five individuals began AZT an average of 19 weeks after their toxoplasmosis diagnosis. Seventeen did not receive AZT; 8% of this group survived for 1 year. Eight received AZT; 41% of this group survived for 1 year.

AZT and Kaposi's Sarcoma (KS)

Two studies presented at the Stockholm conference suggest AZT therapy may benefit HIV-related Kaposi's sarcoma. In both studies, many individuals experienced either stabilization or regression of their KS lesions. In one study, 20 people with KS took AZT for an average of 6-1/2 months. [65] Thirty percent had their lesions stabilize, and 40% had their lesions shrink at least 50% or disappear. In the second study, 31% had lesion stabilization, and 27.5% experienced regression of lesion size while using AZT. [66] Clinical trials are under way to treat individuals with KS using a combination of AZT and alpha and beta interferon.

AZT and Muscle Toxicity

There have been reports that AZT has a toxic effect on muscles. Some individuals on AZT develop a weakness or tenderness in muscles due to the release of an enzyme known as creatine phosphokinase (CPK). CPK is a measure of injury to muscles. Some individuals infected with HIV who are not taking AZT, however, experience these same muscle problems. Reacting to this situation, Dr. Hollander commented, "How much the muscle problem relates to the drug and how much relates to HIV is open to debate at this point."

AZT and Children

Recent studies show that AZT produces improvements in children with AIDS. Twenty-one symptomatic children between the ages of 14 months and 12 years showed significant improvement in their mental function after taking the drug. [67] Thirteen of the 21 with neurological problems showed improvements. The researchers also noted decreases in swollen lymph nodes and increases in T-helper cell numbers. Enlarged livers and spleens subsided. Almost all of the children in the study gained weight.

Unfortunately, two-thirds of the children required blood transfusions to offset the bone marrow toxicity caused by AZT. Five died in the year-long study. Researcher Philip Pizzo told the Wall Street Journal he had begun alternating AZT with ddC as a possible means of minimizing the adverse side effects of both drugs. Dr. Pizzo said that so far the 17 children using the AZT/ddC combination show no toxicity.

It is difficult to decide whether to treat infants born to seropositive mothers. Only about half these infants are actually infected with the virus. Some may have antibodies from their mothers and may not be infected with HIV. Those infected may not produce antibodies during their first 15 months. It is difficult to tell which infants are actually infected and which are not, and therefore, which to consider treating. The Polymerase Chain Reaction (PCR) test, a new HIV test, may be of great value in this situation (see below).

A Proposed Prophylactic Treatment for MAI

Mycobacterium avium-intracellularae (MAI) is a serious infection that affects 15-60% of all PWA. The infection can produce a wasting syndrome with symptoms such as fever, fatigue, night sweats, severe diarrhea and weight loss. MAI can go undetected because its symptoms are similar to those of other opportunistic infections and because it may appear in areas of the body that require invasive procedures for diagnosis.

MAI organisms are resistant to the antibiotics currently used to treat the infection (rifabutin, clofazamine and amikacin). Unfortunately, the toxicity of the drugs used to treat MAI often outweighs their small benefit, according to Dr. Hollander. "MAI is a very difficult, if not impossible, infection to treat successfully," he says. A two-year clinical trial planned for San Francisco General Hospital will study the possible benefit of a daily dose of clofazamine as a prophylactic* treatment for MAI. Fifteen physicians in the San Francisco County Community Consortium will also conduct a clofazamine trial among individuals in their private practices.

Individuals who have had one bout of PCP* will participate in the San Francisco General Hospital study. Half will receive a daily dose (50 mg) of clofazamine and half will take a placebo. According to Dr. Gorter, "We cannot cure MAI at this time. However, if we can suppress it, then this is a relative success because, if we can improve the quality of life, perhaps the individual will survive longer."

The side effects of clofazamine include skin discoloration, diarrhea, rash and itching. Body fluids and stools can also become discolored.

The Polymerase Chain Reaction (PCR) Test

The Polymerase Chain Reaction (PCR) test can detect infection with HIV much earlier than other tests such as the antibody test or viral culture. Some preliminary studies of individuals at high risk for HIV infection indicate that a small but possibly significant number of these people will test positive on the PCR even though they test negative on other tests. Researchers plan more extensive studies to determine the sensitivity and specificity of the PCR in comparison to antibody testing and viral culture.

In the future the PCR may have significant clinical applications: it may eventually be possible to estimate how much HIV an individuals carries. [68] People with a large viral load might choose to begin early anti-HIV therapy. The test may also help settle the question of whether some HIV-positive individuals can eliminate the virus from their immune system. [69]

One immediate clinical use for the PCR is to enable doctors to discover whether HIV-positive infants are really infected with the virus. Using the antibody test alone, physicians cannot be certain because infants born to seropositive mothers may receive HIV antibodies from their mothers without acquiring the virus itself. Using the PCR can help in deciding whether or not an infant should be given AZT, for instance.

Individuals can get the PCR test by prescription from a physician for approximately $150. In the Bay Area, call Pathology Institute (415-540-1638) or Golden Gate Family Medical Clinic (415-626-2212). Individuals should ask their physicians not to record the test result in their medical records.
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Copyright © 1988 - Bulletin of Experimental Treatments for AIDS (BETA). Reproduced with permission. BETA is published four times a year by the San Francisco AIDS Foundation. All rights reserved. Noncommercial reproduction is encouraged. Subscription lists are kept confidential. Call 415.487.8060; FAX: 415.487.8069. Mailing Address: P.O. Box 426182, San Francisco, CA 94142-6182.  beta@sfaf.org  http://www.sfaf.org/beta.html