TREATMENT ISSUES, Volume 6, Number 8 - September, 1992; The Gay Men's Health Crisis Newsletter of Experimental Therapies
Gabriel Torres, M.D.

AZT Monotherapy

Dr. David Cooper of Australia presented data from a Burroughs Wellcome long-term study of AZT (1000 mg/day) versus placebo in asymptomatic HIV-positive patients with more than 400 T4 cells. The treatment lasted an average of 93 weeks, making it the longest of any placebo-controlled trial using the drug. The study enrolled 993 patients from both Europe and Australia. Results showed that 22 patients (5%) progressed to AIDS or ARC in the placebo group compared to 11 (2%) in the AZT group. Progression to early HIV disease (which included one episode of oral thrush or herpes zoster) occurred in 13% of the placebo group compared to 7% of the AZT group. In addition, 25% of participants receiving placebo had declines in T4 cell counts to less than 350, compared to 15% of patients receiving AZT. The most common side effects in the AZT arm were nausea, headache, weakness and loss of appetite.

There were no differences in survival between the groups, but slowed disease progression was seen in all subsets of patients taking the drug, including those with entry T4 cell counts between 500-750. In the 500-750 T4 cell count group, 7% of the placebo recipients progressed to AIDS/ ARC, compared to only 3% of the AZT recipients. In addition, 13% of those taking placebo with T4 counts between 500-750 progressed to clinical HIV disease compared to 7% of the AZT recipients. The authors conclude from this study that AZT therapy offers a small but definite benefit for preventing disease progression, even in people with T4 cell counts between 500-750. Dr. Paul Volberding reported that the subset of patients in the U.S. study of AZT monotherapy (ACTG trial 019) with T4 cell counts greater than 500 are still in the double-blind phase of the trial. No results are yet available about whether the drug will be beneficial to this group. High-level AZT resistance has not been seen yet among the patients in ACTG 019, despite the two years of therapy with this drug.

Dr. Samuel Broder urged researchers to answer the question: Is the early use of AZT beneficial for asymptomatic people?

Additionally, Dr. John Hamilton presented some follow-up data on the Veterans' Administration study of "early" (when T4 cells drop to 500) versus "late" (when T4 cells drop to 200) treatment with AZT. Progression to AIDS has been reduced in the early treatment group, but no survival benefit has been noted. More anemia, nausea, decrease in white blood cell units, diarrhea and headaches occurred in the early treatment group. The average survival after AIDS diagnosis was longer (17.3 months) in the group that started AZT later than in the group that started the drug early (13.7 months). The overall percentage of patients surviving after two years remains similar for both groups. Dr. Samuel Broder, Director of the National Cancer Institute (NCI), who first tested the use of AZT as a treatment for HIV, raised a question about whether asymptomatic HIV-positive people benefit from early use of AZT. Dr. Broder urged researchers to focus on answering this question.

DDI Monotherapy

The crucial questions regarding ddI monotherapy are still unanswered and little new information was presented in Amsterdam. Dr. James Kahn presented the final results of a large phase II/III U.S. study (ACTG 116B/117) that compares ddI (500 or 750 mg/ day) to AZT (600 mg/day). Participants had AIDS or ARC and less than 300 T4 cells or were asymptomatic with less than 200 T4 cells and had received AZT for greater than 4 months. The study enrolled 913 patients between November 1989 and March 1991. Among the asymptomatic and ARC patients, fewer participants who switched to 500 mg of ddI progressed to AIDS or died than those who remained on AZT. No difference was noted between those who switched to 750 mg of ddI and those who remained on AZT. T4 cell count elevations were higher for those on either dose of ddI than those on AZT. No overall differences in survival between the groups were observed.

An Italian study (ISS901) presented by Dr. Marco Floridia and colleagues corroborated the results of ACTG 116B/117. In a group of 160 patients with AIDS and previous AZT therapy for six months, a trend of improved survival and lower incidence of opportunistic infections and malignancies was seen in participants who switched to ddI, compared to those who remained on AZT. In another randomized multicenter Italian study (ISS902) comparing AZT to ddI in previously untreated ARC patients, no differences in clinical endpoints after six months were seen. However, those who received ddI seemed to have greater T4 cell responses than those who received AZT. These Italian studies are important because the participants were mostly injection drug users and women, unlike most of the U.S. study participants who are largely gay men. Antiretroviral research on women and IDUs is scant and greatly needed.

The overall conclusion that can be made from these ddI studies is that the drug appears to be beneficial in patients with AIDS or ARC who have received 4-6 months of AZT therapy. Clinical effects and responses in T4 cell counts have been demonstrated in asymptomatic patients and patients with ARC with T4 cells less than 200. Only a T4 cell benefit has been demonstrated in patients with AIDS. In patients with ARC and T4 cells between 200-500 the data suggest a benefit for ddI but are not entirely conclusive. Why the clinical benefit seems to be more evident in those with earlier HIV disease is unclear but may be related to a greater degree of AZT resistance in more advanced patients, predisposing them to ddI resistance. The question of whether ddI should be added to, or substituted for, AZT after six months of AZT therapy is still unanswered, as is the question about which drug is preferable for initial therapy.

DDC Monotherapy

Relatively few presentations addressed the use of ddC as monotherapy in patients with advanced HIV disease. The "expanded access" ddC program which enrolled nearly 3500 patients in the U.S.A. was presented by Dr. Judith Lieberman of Hoffmann-La Roche which compared the toxicity of ddC in the high dose (0.75 mg every 8 hours) versus low dose (0.375 mg every 8 hours) groups.[1] Peripheral neuropathy occurred twice as commonly (15% vs. 8%) in the high versus low dose group. Rare toxicities included inflammation of the pancreas (less than 1%), ulcers in the esophagus (less than 1%) and in one patient, seizures. Half of those who developed pancreatitis had previous history of the condition. Many who had ddI-induced pancreatitis were able to tolerate ddC without recurrences of pancreatitis. No difference in survival has been seen between the high and low dose groups.

A Canadian group also presented the experience of the open label use of ddC in patients intolerant to AZT or ddI.[2] Of 425 patients enrolled in January, 1991, only 152 (36%) remained on therapy. Thirteen percent discontinued therapy and 6% died while on therapy. Side effects included peripheral neuropathy in 38 patients and mouth ulcers in 15 patients. Another poster from New York by Barr et al compared AZT, ddI, and ddC to no anti- retroviral therapy in patients with late stage disease.[3] While all the nucleoside analogues were superior to no therapy in terms of the development of opportunistic infections, ddC seemed to provide a survival benefit to those who switched from AZT to ddC over those who switched to ddI or remained on AZT.

D4T (STAVUDINE)

Various presentations on the use of this new nucleoside analogue, manufactured by Bristol-Myers Squibb, showed that it improved T4 cell counts and decreased HIV replication in human subjects. The largest study presented by Dr. Lisa Dunkle combined the data from six phase I and phase II trials that together enrolled 264 patients in d4T studies at 10 sites in the U.S.[4] Improvements in T4 cells of 50% or greater were seen in some patients and were sustained for a year. Other beneficial effects included declines in p24 antigen levels, weight gain and improvement in senses of well-being. Side effects were seen mostly at high doses and included peripheral neuropathy and elevated liver enzymes. The doses that were tolerated best were less than 2 mg/kg/day. Side effects were usually reversible when the dose was reduced to 1 mg/kg/day.

Pentoxifylline (Trental) showed rises in T4 cells and a slowing in weight loss with few toxicities.

In another d4T study with 38 HIV-positive patients who had less than 500 T4 cells at entry, the drug reduced HIV in peripheral mononuclear blood cells and acid-dissociated p24 antigen levels at a dose of 2 mg/kg/day but not at lower doses after ten weeks of therapy.[5] Another study showed that d4T had similar cognitive enhancing effects as AZT as measured by neuropsychological tests.[6] A phase II/III study being conducted at many sites in New York and Philadelphia comparing d4T to AZT is up and running for people with under 500 T4 cells. For more information about trials in your area call Bristol-Myers Squibb at 1-800-662-7999. Rumor had it that phase I trials by the company continue to require that women entering d4T studies be sterilized. However, the company denied the rumor, but women are still required to use approved forms of birth control in larger trials of the drug.

3TC

A new reverse transcriptase inhibitor, 3TC, under development by Glaxo, is under study in phase I/II trials. Preliminary data were presented by researchers describing more than 170 patients who have received doses between 0.5 mg/kg and 12 mg/kg per day. The drug was well tolerated in asymptomatic patients as well as ARC and AIDS patients, and the changes in T4 cell counts and p24 antigen levels seem to suggest that the drug has antiviral activity. Isolated cases of bone marrow damage, elevated amylase levels or peripheral neuropathy have occurred. Further studies will try to evaluate which is the best dose to be used in phase II trials. Trials for children who have received little or no antiretroviral therapy are being conducted by the NIH. For more information call (301) 402-1387.

ACYCLOVIR

Several studies presented at the Amsterdam conference suggest that the use of acyclovir may be beneficial in patients with HIV infection. Dr. Michael Saag of the University of Alabama at Birmingham presented a poster with the results of a large trial comparing AZT (600 mg/day) to AZT (600 mg/day) plus high dose acyclovir (4800 mg/day). The 677 participants had ARC and T4 cell counts between 200-800. After more than 18 months of follow-up, a significant improvement in T4 cell response (an average of 25 cell difference) and less frequent herpes infections were noted in participants taking the combination therapy. No other significant clinical differences were seen.in the two arms.

Dr. Michael Youle from the U.K. presented the final results of the European-Australian Acyclovir Study which had been reported in the London Times and in Treatment Issues several months ago. The original goal of this study was to determine if high dose acyclovir (800 mg four times daily) could prevent CMV in HIV-positive patients with T4 cells under 150. Three-hundred- two HIV-positive patients with evidence of CMV infection but no active disease were randomized to receive acyclovir or a matching placebo in 19 centers.

The effect of acyclovir on survival was most evident in, but not limited to, patients receiving AZT therapy and those with T4 cell counts less than 50. Acyclovir seemed to reduce the risk of dying by 50%. The explanation for the improvement in survival is unknown, though it is speculated that high dose acyclovir could be inhibiting a cofactor (such as CMV or human herpes virus-6).

AZT/INTERFERON-ALPHA

Studies suggest that the combination of AZT and interferon may enhance T4 cell responses and reduce levels that mark HIV activity. Interestingly, though, none showed a definitive clinical benefit. Dr. Clifford Lane from the National Institute of Health (NIH) presented an update on the large trial comparing AZT (600 mg/ day) alone, alpha-interferon (5 million units/day) alone, or the combination in asymptomatic patients with T4 cell counts greater than 500. The study started with 60 patients in each group; however, after 16 months more than 25% of the patients had to be withdrawn from the study. Toxicities included muscle wasting (AZT alone), headache and depression (Interferon alone) and hepatitis, weight loss, nausea, and vomiting (combination arm). A slight improvement in T4% was seen in the combination arm, leveling off by 24 weeks. The reduction in p24 antigen levels was more pronounced in the combination arm compared to the other two arms, and there was a delay in the emergence of AZT-resistant virus in the combination arm.

NEVIRAPINE

Dr. Sarah Cheeseman from the University of Massachusetts presented early data from ACTG studies 164/168 comparing AZT (600 mg/day) in combination with one of four doses (12.5, 50, 200 and 400 mg/day) of nevirapine. This drug is a non-nucleoside reverse transcriptase inhibitor, made by Boehringer Ingelhelm, which had been shown in early experiments to lead to resistance within several weeks. In the nevirapine alone arms, p24 antigen levels declined within the first few weeks and then rose again, indicating the onset of viral resistance to nevirapine. A dose-response relationship was noted with increasing doses of nevirapine in terms of p24 antigen reduction. A trend for more profound suppression of p24 antigen levels in the combination arm (especially with the 400 mg dose of nevirapine) was noted, compared to the nevirapine alone arms. No consistent effects on T4 cell counts were observed that could be attributed to nevirapine. However, in a poster presentation, Dr. Douglas Richman presented data from the same study which showed an initial boost in T4 cells that correlated with a p24 antigen reduction and disappeared by week 4 when resistance had developed.[7] Side effects of nevirapine included sleepiness, fevers, and rashes occurring mostly with the 400 mg dose.

AZT/DDI

A study which was initially reported in the May/June 1992 Treatment Issues demonstrated significant T4 cell increases with the use of AZT and ddI together, compared to monotherapy with either agent. Dr. Robert Yarchoan studies 164/168 comparing AZT of the National Cancer Institute presented a study comparing an alternating regimen of ddI (500 mg/day) and AZT (600 mg/day) to a regimen where both drugs are taken together (AZT 300 mg/ day and ddI 250 mg/day). Patients enrolled had AIDS and entry T4 cell counts between 200-350 and less than three months of previous antiretroviral therapy. Patients in the alternating arm switched from AZT to ddI every three weeks. After a follow-up period of 63 weeks, a statistically significant benefit in T4 cell counts was noted in the patients taking the two drugs together. Superior weight gain and reduction in p24 antigen levels were also more sustained in participants taking the drugs together. New opportunistic infections occurred in two patients in the simultaneous arm and five patients in the alternating arm. Toxicities in participants on either regimen were similar. In general, therapy with the lower dose combination of AZT and ddI was well-tolerated and associated with more sustained T4 cell elevations than the drugs taken in an alternating fashion.

Dr. Ann Collier presented follow-up data on 69 patients enrolled in a six-arm study of AZT / ddI combinations compared to AZT alone. All groups had rises in T4 cells, but data showed that patients on the combinations using 600 mg of AZT and either 334 or 500 mg of ddI did better. Reductions in HIV, as tested by PCR, were demonstrated in 78% of patients on combination compared to 14% of patients on AZT alone. Patients on combination therapy also gained more weight and developed less anemia than patients on AZT alone.

AZT/DDC

Relatively little new information was presented in Amsterdam about the use of AZT and ddC in combination. At a symposium sponsored by Burroughs Wellcome Company, Dr. Robert Schooley of the University of Colorado, reviewed the data from the studies that led to the approval of the combination of ddC and AZT in patients with T4 counts less 300. In one study, participants receiving AZT alone had an average increase of 50 T4 cells compared to a 100 cell increase among those on the combination.[8] These increases were sustained for six months. Two studies conducted by community researchers in San Francisco showed that AZT/ddC combination therapy was well tolerated and associated with rises in T4 cells.[9] A final study described 51 patients who took ddC, obtained through buyer's clubs, and experienced average rises in T4 cells of 47 cells after six months of therapy.[10]

PENTOXIFYLLINE

Pentoxifylline (brand name Trental) is a drug which reduces levels of tumor necrosis factor (TNF), a cytokine which enhances HIV replication and contributes to the development of wasting syndrome in AIDS. The first phase I trial, conducted through the AIDS Clinical Trials Group (ACTG), was presented in Amsterdam by Dr. Bruce Dezube from Boston. Twenty five AIDS patients with T4 cell counts under 300 who had been on AZT or ddI for at least two months were treated for 16 weeks with pentoxifylline (400 mg three times daily). Most patients had T4 cell counts of under 100. Seventeen patients completed eight weeks of therapy. Eight had to discontinue because of noncompliance (2), chemotherapy (2), PCP (2), cryptococcal meningitis (1) and fever (1). In 11 of 13 patients studied, levels of TNF dropped. A slowing down of weight loss was also noted, though it was not statistically significant. Decreases in levels of triglycerides, a surrogate marker of cytokine activation, were also noted. However, no changes in neoptrin (a marker of macrophage activation) were found. In four of seven patients T4 cell counts rose. These preliminary results are very encouraging given the relatively low cost and toxicities associated with pentoxifylline. Future trials are planned which will use higher doses of the drug. Pentoxifylline is FDA-approved for treatment of leg cramps and poor circulation.

TAT ANTAGONIST (24 - 7 4 2 9)

The TAT antagonist is a drug found to inhibit a gene product of HIV, called TAT, that is responsible for regulating transcription of the virus. Test tube experiments have demonstrated that it decreases cell-associated viral codes in acutely and chronically infected cells. It also seems to be active against HIV-2 and strains of HIV-1 which are resistant to non-reverse transcriptase inhibitors such as nevirapine. A study to determine how well the body absorbs the drug was presented by Dr. Paul Lietman from John Hopkins University. Three cohorts of HIV-infected volunteers received doses of 60 mg, 200 mg, or 600 mg of the drug, or a placebo. Accumulation of the drug over time was noted at the dose of 600 mg/day. Mild side effects were noted in 16 of 18 patients, the most common were headache, discoloration of urine, and drowsiness. The latter was not unexpected since the drug is chemically very similar to diazepam (Valium). Notably, activists were able to convince Hoffmann-La Roche to drop the criterion requiring women to be sterilized in order to participate in TAT trials.

N-ACETYLCYSTEINE (NAC)

Robert Walker from the NIH presented the results of a phase I study of NAC, an amino acid precursor which has been shown in test tube studies to inhibit HIV transcription and replication. Twenty-three patients with T4 cell counts under 500 were enrolled in the study and assigned to different doses of intravenous NAC three times a week for six weeks followed by daily oral NAC. Most of the patients had been or still were receiving AZT, ddI or ddC. Side effects seemed to occur more often with the intravenous drug including allergic reactions, fatigue, flushing, and gastrointestinal symptoms. The highest tolerated dose was 100 mg/kg and the bio-availability of the drug was found to be less than 5%. There were no changes in T4 cells, p24 antigen levels or plasma viremia during the first 12 weeks of therapy.

Another study of NAC was presented as a poster by Dr. Bonaventura Clotet from Barcelona, Spain. In this study, 32 patients received either NAC (3000 mg intravenously) or placebo.[11] All patients were also receiving AZT and PCP prophylaxis. In the NAC group levels of p24 antigen fell from 171 pg/ml to 75 pg/ml after 14 days of therapy. No other changes in surrogate markers occurred. Three patients developed a rash during the last few days of the infusions. Further studies of NAC will use higher doses to determine if the drug truly has an antiviral effect in humans.

GLQ223 (COMPOUND Q)

The results of a phase 1B study of GLQ233 (trichosanthin) were presented by Dr. Ken Gorelick from Gene Labs Technologies, sponsor of the drug. Data demonstrated that intravenous infusions of the drug were associated with dose-related increases in total number of T-cells and beta-2 microglobulin levels in patients with AIDS or ARC.[12] Side effects included muscle pain, headache, and fever, most of which were controlled by over-the-counter medicines. Dr. Larry Waites of Project Inform also presented data on a long term tolerance community study of GLQ2333. He showed that the drug was relatively well-tolerated in combination with other treatment, such as AZT, ddI, ddC and PCP prophylaxis. A phase II trial is currently underway comparing GLQ223, AZT and the combination of both drugs in participants with T4 cell counts between 200-500 and at least 9 months of AZT treatment. In New York, the trial is enrolling at St. Vincent's Hospital. For more information, contact Kerry McIntyre or Noel George at (212) 790-8605. In San Francisco, contact Carol Arri at (415) 476-4082, extension 84094.

PROTEASE INHIBITORS

Researchers from five different pharmaceutical companies reported on compounds that are able to inhibit the HIV protease enzyme. The protease enzyme is responsible for cutting large precursor proteins into smaller peptides that eventually form the mature virus parts. The main problem in the development of protease inhibitors has been that the candidate compounds are poorly absorbed into the body. Dr. Daniel Norbeck of Abbott Laboratories demonstrated that an oral form of the compound named A-80987, achieved good plasma levels in rats, dogs and monkeys in an oral form of the drug and was able to significantly inhibit HIV activity in the test tube. Significantly, Dr. Norbeck stated that A-80987 should enter phase I trials "soon after the conclusion" of the conference. Another researcher, Dr. Michael Otto, of DuPont showed that HIV strains resistant to protease inhibitors can occur in the laboratory. This seems to be caused by a single mutation. Another investigator from Upjohn showed that the Upjohn version of the protease inhibitor (U-75875) was able to shut off HIV replication in chronically infected macrophages. Despite these advances, the research on protease inhibitors continues at a slow pace, and there were no data released on the ongoing studies of these compounds being conducted by Hoffmann-La Roche.

CONCLUSION

Reports about antiretroviral drugs confirmed some preliminary reports from earlier studies. Clinicians and community members disagree about what is the most optimum time to start AZT or combination regimens in people with asymptomatic disease. Information concerning antiretroviral drugs and women and the effect of these drugs on menstruation and the female hormonal system was notably lacking from most reports. Additionally, some of the hopeful drugs of the 90s are turning out to have many more resistance problems than projected. On the positive side, however, data from the few studies of combination regimens offer some new proposals to doctors and people living with HIV.

FOOTNOTES ---------

1. VIII Int'l Conf on AIDS. #Po. B. 3004, Amsterdam, July, 1992.

2. VIII Int'l Conf on AIDS. #Po. B. 3006, Amsterdam, July, 1992.

3. VIII Int'l Conf on AIDS. #Po. B. 3001, Amsterdam, July, 1992.

4. VIII Int'l Conf on AIDS. #WeB. 1011, Amsterdam, July, 1992.

5. VIII Int'l Conf on AIDS. #WeB. 1010, Amsterdam, July, 1992.

6. VIII Int'l Conf on AIDS. #PoB. 3033, Amsterdam, July, 1992.

7. VIII Int's Conf on AIDS. #PoB. 3576, Amsterdam, July, 1992.

8. VIII Int'l Conf on AIDS. #PoB. 3592, Amsterdam, July, 1992.

9. VIII Int'l Conf on AIDS. #PoB. 3006, Amsterdam, July, 1992.

10. VIII Int'l Conf on AIDS. #PoB. 3005, Amsterdam, July, 1992.

11. VIII Int'l Conf on AIDS. #PoB. 3013, Amsterdam, July, 1992.

12. VIII Int'l Conf on AIDS. #PoB. 3442, Amsterdam, July, 1992.

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