Bulletin of Experimental Treatments for AIDS, No. 3, June 1989
Ron Baker

-- John Bartlett, MD

** Clinical Research Director, AIDS Clinical Trial Unit, Duke University Medical Center. HIV Therapeutics, An Emerging Science. Journal of the American Medical Association 260(20):3051.

"AZT is not a very impressive drug for treating AIDS."

-- Andrew Moss, PhD

** Director of AIDS Epidemiology Group at UCSF affiliated S.F. General Hospital. Remarks to the 73 annual meeting of the Federation of American Societies for Experimental Biology, New Orleans, March, 1989. Reported by CDC Weekly , April 3, 1989, p.3..

"AZT should not be used to treat asymptomatic HIV infected patients until further data are available from clinical trials."

-- Mark Jacobson, MD and John Mills, MD

** Dr. Jacobson is Assistant Professor of Medicine at UCSF. Dr. Mills is Professor of Medicine at UCSF and Chief of Infectious Diseases at S.F. General Hospital. Long term consequences of azidothymidine therapy of HIV infection using Delphi technique. Archives of AIDS Research 111(1,2,3):203 216, 1989.M

[Words in this article followed by an asterisk are defined in the GLOSSARY at end of this whole display -- ed.]

AZT is the only drug approved by the Food and Drug Administration to treat HIV infection, and it continues to receive the lion's share of attention in the research lab and in clinical trials. This issue of BETA reviews the results of recent research on AZT. Among the topics discussed are the role of AZT in increasing survival time for people with AIDS and severe ARC, its possibly transient benefits, newly reported toxicities, and a modified form of the drug, which researchers say is more potent and less toxic.

AZT STUDIES SHOW BENEFIT AND TOXICITY

Increased Survival Time

A U.S. multi-center trial of 4,805 people with previous bouts of PCP* suggests that beginning AZT treatment early after the AIDS diagnosis increases survival time.

** Creagh Kirk T, et al. Survival experience among patients with AIDS receiving zidovudine follow up of patients in a compassionate plea program. Journal of the American Medical Association 260(20):3009 3015, November, 1988.

According to the authors, "...the finding of a strong association between stage of illness at time of initiation of therapy and survival suggests the need for study in patients still earlier in the disease process." Some individuals responded to treatment better than others. People with hemoglobin* levels above 12 grams per deciliter (.10 liter) had a higher survival rate, for instance, while those with transfusion acquired AIDS had a lower survival time. Gender or race did not appear to be factors in survival time. "The trend toward poorer prognosis in untreated women, IDU* and minorities with AIDS, as seen in the New York natural history cohort, was not seen in the present study."

** Ibid

No new information about the drug's toxicity came out of this trial. Only adverse effects requiring hospitalization were reported. Almost 20% of people in the study required 1 or more blood transfusions and 8.3% developed serious depletion of the white blood cells.

** Ibid

Transient Benefits.

A French study of 365 individuals (285 PWA*, 80 PWARC*) underscores AZT's transitory beneficial effects and emphasizes the drug's toxicity.

** Dournon E, et al. Effects of zidovudine in 365 consecutive patients with AIDS or AIDS related complex: a perspective study of 2 to 12 month therapy. The Lancet , 8623:1297 1281, December 3, 1988.

The French researchers concluded that AZT had short term clinical benefits for study participants, but that in general, weight gains and T helper cell increases disappeared after six months.

** Reported in AIDS/HIV Experimental Treatment Directory 2(3):31, December, 1988.

Because of blood toxicity, 214 individuals (58%) had to stop taking AZT for at least 7 days. This study did show increased survival time for those PWA who began AZT sooner after diagnosis.

Fewer Opportunistic Infections.

A study of 80 PWA and 33 PWARC taking AZT reports "improved well being and reduced frequency and severity of opportunistic infections" in the first year of follow.

** Pinching AJ, et al. Clinical experience with zidovudine for patients with acquired immune deficiency syndrome and acquired immune deficiency syndrome related complex. Journal of Infectious Disease , 18(1,S 1):33 40, January, 1989.

The researchers also noted more rapid improvement in lung tests during recovery from PCP, and transient increases in platelet* counts. There was also a consistent decline in p24 antigen* levels during treatment, but the rise in T helper cell counts seen in the first few months of therapy did not continue. Individuals with low T helper counts and those using ganciclovir* or dapsone* along with AZT experienced more bone marrow toxicity than those taking AZT alone. This study also discusses the muscle toxicity that can occur with long term use of AZT and the meningoencephal- itis* associated with reducing the dose of the drug.

HIV DEVELOPS RESISTANCE TO AZT

Researchers have found strains of HIV that "resist" AZT. This means the drug may become less effective in blocking repli- cation of the virus. These laboratory findings may help explain why the improvement seen in some PWA and PWARC taking AZT goes away over time. The development may also have important implica- tions for the timing of AZT therapy: if HIV resists AZT in the blood of severely ill individuals, a similar outcome may develop in healthier HIV positive people taking the drug.

Researchers emphasized that this discovery did not appear to affect the clinical status of the individuals, who were all severely immunocompromised. "It will be necessary to study isolates* from asymptomatic, seropositive individuals who have experienced prolonged zidovudine therapy to evaluate the effect of immune status on development of resistance."

** Larder BA, et al. HIV with reduced sensitivity to zidovudine (AZT) isolated during prolonged therapy. Science , 243:1733, March 31, 1989.

They also said that after consulting with other AIDS experts, a consensus emerged that this new information would not require changing AZT therapy for PWA or PWARC. The present structure of clinical trials using AZT should not be altered, they concluded. "Patients who are receiving AZT and benefitting from its use should continue to take the drug," said NIAID* director Dr. Anthony Fauci.

** Press release, March 20, 1989.

AZT MAY IMPROVE NEUROLOGICAL FUNCTIONS

HIV infection can cause several neurologic* disorders: cognitive problems (forgetfulness, confusion, impaired reasoning), peripheral neuropathy*, paraplegia*, poor coordination, and progressive dementia*. Subtle symptoms of AIDS related dementia often appear before infections such as PCP or KS.

Two hundred eighty eight people with AIDS or severe ARC participated in a study to find out if AZT therapy would improve neurologic functions.

** Schmidt FA, et al. Neuropsychological outcome of zidovudine (AZT) treatment of patients with AIDS and AIDS related complex. New England Journal of Medicine , 319(24):1573 1578, December 15, 1988.

Individuals taking AZT, especially PWA, showed improved cognition (memory, mental speed, and visual attention) and motor func- tion compared to people who took a placebo.

"Longer clinical trials may be necessary to document the positive neurologic effects of the drug in earlier stages of HIV infection," according to the researchers. "Such studies will be particularly crucial in the long term treatment of these patients, because improvement in intellectual functioning due to zidovudine [AZT] treatment has the potential to improve the quality of life of patients with HIV infection.

** Ibid

NEW AZT DRUG

Researchers at Tulane University report that in lab experiments with mice a modified form of AZT is 2.5 times more effective than the original drug and is half as toxic to the bone marrow cells.

** Remarks at the 73 annual meeting of the Federation of American Societies for Experimental Biology in New Orleans (March, 1989). Reported by CDC AIDS Weekly , April 10, 1989, p 3.

Scientists developed the new drug, DP AZT*, to help deliver AZT directly to brain cells, Dr. Dudhir Gogu told BETA.

** Personal communication, April 14, 1989.

To treat or prevent AIDS related dementia, an antiviral drug must penetrate into the brain cells. Most researchers agree that AZT reaches the cerebrospinal fluid, even though none or only a small amount of the drug may directly reach brain tissue. AZT's ability to enter the cerebrospinal fluid may explain how the drug improves neurological* symptoms in some individuals.

ERYTHROPOIETIN FOR AZT RELATED ANEMIA.

The experimental use of a genetically engineered form of erythropoietin (EPO), a natural hormone, may allow anemic HIV infected individuals to use AZT while requiring fewer or no blood transfusions.

One of the major adverse side effects of AZT therapy is that it can cause severe anemia (loss of red blood cells). The drug brings on this condition by attacking the bone marrow, which produces red blood cells in the body.

Early studies of EPO on HIV negative individuals with kidney disease show the drug increases red blood cell production.

** Winearls CG, et al. Effect of human erythropoietin derived from recombinant DNA in the anemia of patients maintained by chronic hemodialysis. The Lancet , II:1175, 1987.

The March 1989 issue of Treatment Issues.

** Monthly newsletter on AIDS treatments published by the Gay Men's Health Crisis in New York.

Reports on two ongoing EPO studies with PWA at St. Luke's Hospital in New York. Researcher Randy Levine told Treatment Issues that of the 3 PWA who have completed his study, 1 has a "50% decreased need for transfusions" and the other two now have hematocrit levels* in the high 30's... just below normal range.".

** Treatment Issues 3, March 30, 1989.

A three year, half million dollar grant from the NIH* will allow scientists at Thomas Jefferson University to study the potential benefits of EPO for 64 individuals with HIV related or related anemia. The researchers hope those receiving EPO will need fewer transfusions than those taking a placebo. EPO appears to be a promising, but expensive treatment for anemic individuals who want to use AZT or other bone marrow suppressive drugs. The FDA* may make EPO available as an investigational new drug..

AZT AND ACYCLOVIR.

Is the combination therapy of AZT plus acyclovir (ACV) more effective than AZT alone? Used alone, ACV shows no anti effect either in the test tube or in humans, but some researchers believe that the drug significantly increases the antiviral effect of AZT.

A 10 week study of 20 asymptomatic* HIV positive individuals by researchers from Burroughs Wellcome, the San Francisco Department of Public Health and UCSF showed no antiviral effect from low dose AZT (100 mg five times a day) and high dose ACV (400 800 mg five times a day).

** Hollander H, et al. 1988 IV International Conference on AIDS, Stockholm. Abstracts 3134 3136.

Preliminary results of a small study (24 PWARC) showed more promising, but inconclusive results. Nine p24 antigen positive individuals taking AZT and ACV (50 or 100 mg AZT every 4 hours and 800 mg ACV every 4 hours) for 12 weeks showed significantly lower p24 antigen levels than other individuals treated with AZT alone.

** Collier AC, et al. 1988 International Conference on AIDS, Stockholm. Abstracts 3137 3138.

Final results of this study have not been published.

Researchers from Europe and Australia report that after 24 weeks of AZT plus ACV (250 mg AZT and 800 mg ACV every 6 hours), PWA showed significantly better survival rates. They also had decreased numbers and severity of opportunistic infections when compared to those given AZT alone.

** Fiddian AP, et al. Zidovudine Plus or Minus Acyclovir in Patients with AIDS or ARC. European/Australian Collaborative Study Group. Abstract, 28th Interscience Conference on Antimicrobial Agents and Chemotherapy. Los Angeles, October, 1988.

This is a large, multi center study of over 400 people with AIDS or ARC.

Burroughs Wellcome is also conducting a double blind placebo controlled trial with over 400 PWA and PWARC individuals at several European medical centers.

** Reported in AIDS/HIV Experimental Directory 2(3):43, December, 1988.

Preliminary results on 108 PWA and PWARC after 36 weeks of com- bination therapy (250 mg AZT every 6 hours plus 800 mg ACV a day) or AZT alone (250 mg every 6 hours) showed the following results: 11 people on combination therapy and 24 people on AZT alone had to stop treatment because of toxicity; 25 on the combination required AZT dose reduction as compared to 14 on AZT alone; 5 people died in the group using AZT plus ACV and 15 died in the group using AZT alone.

** Ibid

To help settle the question of the effectiveness of AZT with or without ACV, the NIH is now recruiting for a large, multi center, 2 year study of 600 individuals with early ARC. Researchers will evaluate four groups on a 4 times a day dosing schedule with the following combinations: (1) 100 mg AZT (no ACV) (2) 100 mg AZT plus 800 mg ACV (3) 200 mg AZT plus 800 mg ACV (4) 200 mg AZT plus placebo.

Some researchers believe that the herpes viruses, especially herpes simplex* and human herpes virus 6*, may play a co factor role in HIV infection. For this reason, people infected with HIV and any herpes virus may benefit from prophylaxis* with acyclovir, regardless of whether or not the drug increases the antiviral effect of AZT.

NEWLY REPORTED TOXICITIES

Liver Damage

AZT can damage the liver of some individuals.

** Dubin G and Braffman M. (Letter) Annals of Internal Medicine , January, 1989. Reported in The New York Times Gina Kolata, January 3, 1989.

A 39 year old man developed jaundice* and liver dysfunction within a week after starting the drug. When he stopped taking AZT, his liver recovered. After beginning the drug for a second time, his liver dysfunction reappeared. Again his physicians stopped the drug and his liver functions returned to normal.

Reaction with Pyrimethamine

Laboratory tests show that AZT counters the action of pyrimethamine, one of the drugs used to treat toxoplasmosis infection.

** Iraelski DM, et al. Zidovudine antagonizes the action of pyrimethamine in experimental infection with toxoplasmosis gondii AIDS Targeted Information Newsletter February, 1989, p.17.

AZT also countered the beneficial effect of pyrimethamine in mice infected with Toxoplasma gondii

** Ibid

PWA with toxoplasmic encephalitis* taking AZT and pyrimethamine should be monitored carefully. Researchers suggest that if individuals respond poorly to the combination therapy or appear to have a relapse, AZT treatment should stop.

** Ibid

Bone Marrow Damage

Some researchers are concerned that the bone marrow changes produced in individuals taking AZT do not always stop when treatment stops.

** Mir N and Costello C. Zidovudine and Bone Marrow (letter). The Lancet , ii(8621):1195 1196, November 19, 1988.

Dr. Naheed Mir and Dr. Christine Costello of St. Stephen's Hospital in London suggest that long term treatment with AZT may damage the bone marrow cell pool* and cause adverse changes in other cell lines as well.

** Ibid

These findings may have serious implications for using AZT in HIV positive but symptom free individuals as well as symptomatic PWA and PWARC.

AZT TREATMENT AMONG INJECTION DRUG USERS

AZT therapy for injection drug users (IDU) is just beginning to be studied. A recently published study begun in March 1987 looks at 40 individuals treated with AZT, 25 of whom were former or current users.

** Cowan FM, et al. Use of zidovudine for drug users infected with human immunodeficiency virus. Journal of Infectious Disease , 18(1 1):59 66. January, 1989.

Eighteen individuals took various kinds of narcotics either occasionally or regularly while on AZT therapy.

The researchers report that no adverse clinical effects were observed from the simultaneous use of AZT and narcotics, whether used orally or by injection. "In our experience, it is possible to treat safely current and former injection drug users with zidovudine (AZT)."

** Ibid

NIAID AIDS program director Dr. Daniel Hoth reports that a study of the interaction of AZT with methadone is under way.

** Remarks to the 73rd meeting of the Federation of American Societies for Experimental Biology, New Orleans, March 1989. Reported by CDC Weekly , April 3, 1989, p.3.

AZT AND HIV RELATED THROMBOCYTOPENIA (ITP)

Thrombocytopenia* (also called ITP*) can be the first clinical sign of HIV infection. Five to ten percent of individuals infected with the virus develop this disorder, with symptoms which may include easy bruising, bleeding gums, or nosebleeds. ITP is the result of an abnormal decrease in the number of platelets*, which normally range from 150,000 to 300,000 per mm of blood.

ITP can go away without treatment. However, some people with the disease need therapy. One study of ten people with mild cases of ITP showed that platelet counts increased in each individual while taking AZT.

** Hirshel B, et al. Zidovudine for the treatment of thrombocytopenia associated with HIV a prospective study. Annals of Internal Medicine , 109(9): 718 721, November, 1988.

While taking a placebo, these same individuals' platelet counts did not increase. Other researchers also report successfully treating HIV related thrombocytopenia with AZT.

** Pottage JC, et al. Treatment of human immunodeficiency virus related thrombocytopenia with zidovudine. Reports of three cases. Journal of the American Medical Association 260(20):3045 3048, November 25, 1988.

One otherwise asymptomatic individual with severe HIV related thrombocytopenia responded quickly and successfully to full dose AZT.

** Neil BJ, et al. Zidovudine therapy for severe human immunodeficiency virus related thrombocytopenia. American Journal of Medicine , 85(5):744 745, November, 1988.

However, Dr. Donald Abrams, Assistant Director, AIDS Activities, UCSF affiliated San Francisco General Hospital, cautions against using AZT in people who are asymptomatic except for low platelet counts. "I generally feel that people [without bleeding complications] really don't need to be treated with anything just to raise their platelet counts... Running the risk that the person's virus will ultimately become resistant, this treatment [with AZT] may not be the wisest tack to take."

** Interview with Ron Baker, March 29, 1989.

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