Gay Men's Health Crisis: Treatment Issues, Volume 8 no. 3 - May, 1994
Gabriel Torres, M.D.

AZT for Primary HIV Infection

A Swiss group reported the results of the first completed placebo-controlled trial of zidovudine (AZT) in primary HIV infection.[1] The study found significant benefits from using AZT soon after the onset of symptoms that indicate recent infection with HIV.

Primary HIV infection, also called acute retroviral illness, is the flu-like syndrome associated with the entrance of HIV into a person's body. This initial infection precedes seroconversion and is characterized by fever, sore throat, headache, skin rash and swollen glands. In this study, 77 patients with primary HIV infection were randomized to receive either AZT (500mg/day) or placebo after a mean period of 23 days following the onset of symptoms. Sixty-four patients were evaluated after completing 24 weeks of therapy and an average follow-up of 54 weeks. Half of the group received AZT and the other half received placebo.

After six months of therapy, 32 percent of the placebo recipients had a drop in CD4 cells to below 350, compared with only four percent of the AZT recipients. After one year, those receiving AZT had a higher mean CD4 count than those receiving placebo. In addition, placebo recipients had increases in p24 antigen levels indicating active viral replication that persisted up to a year. In terms of progression of disease, there were five persons in the placebo group who progressed to an AIDS-defining event after 363 days of follow-up, compared to none in the AZT group. A similar study is being conducted through the DATRI program of the National Institute of Allergy and Infectious Diseases (NIAID), although enrollment has been slow. The implications for use of AZT during primary HIV infection are momentous for those persons identified early in the course of disease.

Roche Protease Inhibitor Update

At a Hoffmann-La Roche-sponsored satellite symposium to the Conference, Dr. Stefano Vella from the Istituto Superiore di Sanitê in Rome presented updated data from the European trials of the Roche protease inhibitor Ro 31-8959 (saquinavir).

Up to a 98 percent reduction in HIV RNA levels (as measured by the PCR test) was recorded in the European studies. In the British study, which included patients with CD4 cells under 500 and no previous AZT treatment, there was a median increase in CD4 cell counts of 41 after six months of treatment with 600mg three times daily. This compared to decreases of 33 to 65 cells per cubic millimeter in the groups treated with lower doses.

In the Italian study, which included AZT-untreated patients with CD4 cells under 300, those who received AZT in combination with 600mg of saquinavir had a median rise of 74 cells after six months, compared to a rise of only 29 cells in those who received AZT alone or a rise of 40 cells in those who received saquinavir alone. The results of this study suggest that saquinavir is just as good if not better than AZT alone, is synergistic with AZT, and maintains activity up to six months. Longer term follow-up will determine if the CD4 elevations translate into clinical benefit and if chronic use of the drug leads to resistant virus and waning of its effects.

Combination Nucleoside Analog Therapy

Two studies at the European conference suggest that the combination of AZT and ddI is slightly superior to, but not as well tolerated as, the combination of AZT and ddC. A German study enrolled 66 patients who had received AZT for greater than six months and had either experienced a drop in CD4 cells of at least 25 percent or showed clinical signs of disease progression.[2] Trial participants were randomized to one of two regimens: ddI (200mg twice daily) or ddC (.75mg twice daily) in combination with AZT (500mg/day). After a year of follow-up, the patients receiving the AZT-ddI combination had a more sustained rise in CD4 cells than the patients in the AZT-ddC group. The CD4 cell increases mainly occurred in patients whose baseline CD4 cell counts were between 100 and 200. Both regimens were effective in reducing p24 antigen levels by 50 percent in about 70 percent of patients. There were less frequent AIDS-defining events in the AZT-ddI group, yet the clinical progression rate in that group was not significantly different from that of the AZT- ddC group. More patients had to discontinue ddI therapy (due to nausea and diarrhea) than ddC therapy.

A second combination study, sponsored by Burroughs Wellcome Co., was presented by Robert Schooley, M.D., from the University of Colorado.[3] This multicenter study (BW 35,225- 02) examined whether adding either ddI or ddC to AZT therapy prevented the emergence of AZT-resistant virus in patients with little AZT experience. In the study, 260 patients with less than 4 weeks of previous AZT and CD4 cell counts less than 300 were randomized to one of three groups: AZT (600mg/day), AZT in combination with ddI (200mg/day) or AZT in combination with ddC (2.25mg/day). After a year of follow- up, both combination groups had higher and more sustained rises in CD4 cell counts than those receiving AZT monotherapy. Five new AIDS-defining events occurred in the AZT-ddI group compared to eleven in the AZT-ddC group and eleven in the AZT monotherapy group. The data on viral resistance still has not been analyzed.

Both of these studies seem to confirm that combination therapy with AZT-ddI or AZT-ddC produces significant rises in CD4 cell counts, and at least in AZT-naive patients, may be more effective than AZT monotherapy. AZT-ddI seems to provide a better CD4 cell response than AZT-ddC, and there is a hint of superior clinical efficacy. Definitive conclusions about combination therapy may be available from ACTG 175 and the Delta study, two much larger trials comparing ddI-AZT, ddC- AZT and AZT monotherapy in asymptomatic patients with CD4 counts between 200 and 500.

Loviride (TIBO Drugs)

Two new non-nucleoside reverse transcriptase inhibitors (NNRTI) from Janssen Pharmaceuticals' TIBO family of compounds were evaluated by a group of researchers from Belgium in a placebo-controlled trial.[4] In the test tube, these compounds, known as R18893 and R89439 (loviride), had demonstrated synergy with AZT and ddC. A phase I trial showed good oral bioavailability (absorption) with few side effects (diarrhea and liver enzyme elevations). Loviride has proved to be more selective and less toxic than R18893. It was also able to achieve ten times higher levels in the blood. The trial included 114 patients with CD4 cell counts greater than 400 who were randomized to receive either R18893, loviride or placebo. After six months of treatment, the loviride group demonstrated a more sustained rise in CD4 cells as compared to the placebo group, as well as decreases in viral load (as measured by HIV RNA PCR). No mutations were found in viral isolates from patients who received loviride, although mutations at codons 188 and 181 occurred rapidly in the lab when the virus was exposed to these agents. Side effects attributable to loviride included itching and a rash involving the elbows and hands. This trial suggests that loviride is a relatively safe NNRTI that deserves further study alone and in combination with nucleoside analogs and protease inhibitors.

Nevirapine and AZT

A poster presentation reported on a study of nevirapine, another NNRTI, in 49 HIV-positive patients who had detectable p24 antigen levels and a history of taking AZT for 70 to 84 weeks.[5] Participants were randomized to treatment with nevirapine (200mg/day) for two weeks followed by 400mg/day in combination with AZT or to AZT monotherapy. The combination group demonstrated a rapid decline in HIV viral load (which was associated with an increase in CD4 cell count) compared to the AZT monotherapy group. The p24 reduction was sustained for at least sixteen weeks in the majority of patients. The main side effects of nevirapine were rashes and liver enzyme elevations.

Several U.S. trials at the present time are studying nevirapine in combination with AZT and ddI.

Thalidomide for Wasting

A French poster reported on the use of thalidomide at a dose of 100mg/day in three patients with AIDS-associated wasting.[6] Thalidomide inhibits tumor necrosis factor (TNF), a cytokine that increases HIV replication and contributes to the clinical signs and symptoms of wasting. All of the patients reported dramatic clinical improvement with a mean increase in weight of four kilograms (about nine pounds) after three weeks of treatment. Fever and muscle aches resolved although there were no effects on HIV replication or CD4 cell counts demonstrated. A study of thalidomide in AIDS-associated wasting is being conducted at the Rockefeller University in New York (For more information on this trial call 212/327- 7177).

Anti-CD4 Monoclonal Antibody

An artificially produced antibody directed at the CD4 molecule (the surface marker on the CD4 cell to which HIV attaches via its gp120 envelope molecules) was used in a pilot study of ten asymptomatic HIV-positive patients in Germany.[7] The strategy behind these injections is to prime the body to produce a new antibody that combines with and helps eliminate the injected foreign antibody. This new antibody will have a shape similar to the CD4 molecule and therefore, it is hoped, will also efficiently link up and block gp120. The linkage would destroy HIV's ability to infect new cells by anchoring itself to CD4 in classic "neutralizing antibody" fashion.

In the trial, eight of ten patients experienced an increase in CD4 cells that persisted after boosting with another injection of the monoclonal antibody. Two patients became p24 antigen negative. Serum antibodies of four patients had increased capability of inhibiting the interaction between gp120 and the CD4 molecule. There were no systemic toxic effects or allergic reactions associated with the administration of the monoclonal antibody. A larger phase II trial is under development to test whether this monoclonal antibody can be used as a therapeutic vaccine in early-stage HIV-positive patients.

References: 1 Kinloch S, et al. Fourth European Conference on Clinical Aspects and Treatment of HIV Infection. Abstract Book. Milan, March 16-18, 1994. abstract O39, page 169.

2 Mauss S, et al. abstract O38, page 168.

3 Schooley R, et al. abstract O52, page 217.

4 Staszewski S, et al. abstract O41, page 170.

5 Carr A, et al. abstract P269, page 185.

6 Couderc L-J, et al. abstract P321, page 225.

7 Sutor CG, et al. abstract 049, page 278.

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