American Foundation for AIDS Research, October 2004
Gunjan Sinha

August 2004 — In 1990, one of Albrecht Ulmer’s HIV-positive patients was suffering from recurrent high fever. He tried all sorts of medications to lower it, but nothing helped; his patient could barely get out of bed. In frustration, Ulmer added a common anti-inflammatory drug called prednisone to his antiretroviral drug regimen. The patient quickly improved. This was the general practitioner’s first clue that prednisone might help treat people with HIV.

Seven years later, an HIV-positive Rwandan woman walked into Ulmer’s large Stutttgart practice complaining of fatigue and depression. “Her CD4 cell count wasn’t low enough to start her on antiretroviral therapy,” Ulmer recalled. He prescribed prednisone. She, too, began to feel better and her CD4 cell count inched higher. In a few years, the count had nearly doubled.

Since then, Ulmer has prescribed prednisone for over 200 chronically infected HIV patients — those not yet or no longer taking HAART — with varying degrees of success. CD4 cell counts have stabilized or improved in 60% to 70% of his cases. His experience suggests an approach for persons with HIV in the “gray” area of starting treatment — those with viral loads below 30,000 copies/mL and CD4 counts above 300 cells/mm³.

Ulmer’s experience does not warrant prescribing immunosuppressants as standard practice to HIV patients. And few in the AIDS research community are even interested in what he has to say. He is a clinician, not a researcher. He has never worked in a lab or published an academic paper. For years he has tried to capture the attention of HIV researchers at J.W. Goethe University in Frankfurt — the nearest academic center involved in AIDS research — to no avail. “I would call acquaintances and mention that they should study this. I would get no reply or they would tell me the chief isn’t interested,” he lamented.

But an emerging body of evidence suggests that drugs that suppress the immune system may have a place in HIV treatment. “There are a lot of good reasons to be looking at the utility of these therapies in selected situations,” said Michael Lederman, director of the Center for AIDS Research at Case Western Reserve University in Cleveland.

In fact, Lederman and his colleagues just recruited 40 patients for a trial with another immunosuppressive drug called cyclosporine A (CsA). “We want to look at starting CsA and antiretroviral therapy early, when the [HIV] infection is in a dynamic phase. That is a setting where we are more likely to see an effect,” he explained. Other groups are also evaluating CsA during primary infection, including Giuseppe Pantaleo at University of Lausanne in Switzerland and Martin Markowitz at the Aaron Diamond AIDS Research Center in New York.

Immune activation may contribute to disease progression by either driving viral replication or destroying CD4 cells by forcing them to commit suicide (a process called apoptosis). Scientists hypothesize that immunosuppressants may quell this active response, potentially tilting the balance between host and virus in a favorable direction.

“It is based on a sound concept, but not a very well digested concept,” commented Robert Gallo, director of the Institute of Human Virology in Baltimore. Since the mid-1980s, researchers have amassed “abundant evidence” in vitro, in monkeys, and in humans suggesting that HIV progresses via indirect mechanisms. But “it a takes a long time for that kind of concept to be appreciated in the field,” Gallo continued. By the mid-1990s, several scientists abandoned the question as they witnessed the dramatic effects of antiretroviral therapy in their patients.

Adding to the reluctance is the bad reputation of corticosteroids like prednisone. If taken for long periods, they cause uncomfortable, sometimes nasty side effects like insomnia, weight gain, and diabetes. Prednisone can also cause bone loss over time. The very idea of giving an immunosuppressant drug for an immunocompromising disease is “controversial,” said Jean-Marie Andrieu at Centre Biomédical des Saints-Pères, Université René Descartes in Paris. Since corticosteroids suppress the immune system, people become more susceptible to opportunistic infections — clearly not what clinicians desire for their HIV-positive patients.

Nevertheless, researchers have experimented with higher doses than Ulmer’s 5 mg per day and have reported no serious side effects. In 1995 Andrieu was the first to publish research involving people taking prednisone. For 1 year, he studied 44 patients; some were taking AZT (zidovudine or Retrovir) and other medications. Andrieu reported in the Journal of Infectious Diseases (J Infect Dis. 1995 Mar;171(3):523-30) that a daily prednisone dose of 0.5 mg per kg of body weight boosted CD4 cell counts.

Andrieu published a 10-year follow-up of this cohort in May 2004. After the second year, Andrieu continued a prednisone dose of 0.3 mg per kg for only those patients whose CD4 cell counts remained higher than when they entered the trial. And no patient, whether in the prednisone or the control group, took antiretroviral therapy unless their CD4 cell counts dropped below baseline levels.

The proportions of participants who maintained CD4 cells higher than at entry were 43% at 2 years, 11% at 5 years, and 5% at 10 years. Patients whose initial viral loads were less than 30,000 copies/mL maintained significantly higher CD4 cell counts than those whose viral loads were higher. Andrieu observed mild prednisone-related side effects such as darkening of the skin and weight gain, “but they were not severe,” he said.

In contrast, the proportions of control-group individuals whose CD4 cell counts remained higher than at entry were approximately 12%, 1%, and 0% at 2, 5, and 10 years, respectively.

“This retrospective study obviously does not have the demonstrative strength of a prospective randomized trial,” Andrieu added. He based the control group on medical records of patients treated concurrently at his institution, so they were not as carefully selected as controls in a more rigorous, double-blind, placebo-controlled trial.

Andrieu planned to publish his results after 3 to 5 years of follow-up, “but at that time we were in the story of antiretroviral therapy and the spirit of the clinicians was completely blocked to anything outside of it,” he said.

Mark Milano, a treatment educator at the AIDS Community Research Initiative of America (ACRIA), has taken prednisone for over 10 years and reports none of the nasty side effects associated with high doses. He credits this to a regimen of 15 mg of the hormone every other day. “I have literally no side effects. The critical thing is alternate [quote]day dosing,” exhorts Milano, who has lived with HIV for 23 years and managed to remain HAART free. Before switching to alternate day dosing, Milano suffered swelling and joint pain. Now his only complaint is difficulty gaining muscle mass at the gym.

Despite reportedly minimal long-term side effects, researchers are leery of potential harm from prednisone. Only Michael Lederman has published data regarding the drug’s benefit in HIV-infected patients, and he also remains cautious. “Recognize that this approach is unproven. We should only administer [such drugs] in the setting of carefully designed studies,” Lederman cautioned.

In a 2001 study, coauthor Grace McComsey reported that while a prednisone dose of 0.5 mg per kg for 8 weeks was well tolerated, it affected CD4 cell counts only slightly (AIDS. 2001 Feb 16;15(3):321-7). But prednisone did lower crucial proteins that signal immune activation. Her team also learned that patients with CD4 cell counts above 200 tolerated the drug better than patients with lower CD4 cell counts — supporting Andrieu’s earlier work.

That study inspired coauthor Robert Wallis to launch another one and publish its results in 2003. For 8 weeks, researchers gave a daily 40-mg dose of prednisone to 24 HIV-infected patients with CD4 cell counts greater than 200 cells/mm³, then a 20-mg daily dose for another 4 weeks. All patients were also taking HAART. After 8 weeks, average CD4 cell counts increased 40% above baseline levels. Side effects included weight gain and elevated cholesterol. But the study ended early when two patients showed signs of osteonecrosis. “Although we were not sure if these abnormalities would progress to clinical disease or were directly caused by the prednisone, we were not prepared to take the risk,” explained Lederman.

Lederman’s group has since scrapped its work with prednisone in favor of CsA because CsA is not a steroid and offers “a more targeted immunosuppressive approach,” he explained. Their ongoing study is similar to Pantaleo’s, which demonstrated that CsA can boost CD4 cell counts when given early in infection and with antiretroviral therapy.

“We wanted to rapidly down-regulate this immune activation to preserve some cells that would otherwise get eliminated,” Pantaleo said. In that pilot study, nine patients took CsA plus antiretroviral therapy and 29 took antiretrovirals alone. At Week 8, all patients stopped taking CsA but maintained antiretroviral treatment. CD4 cell counts spiked in patients taking antiretrovirals and CsA — almost doubling within the first week compared with a historical control group whose counts dropped slightly but not significantly. Plus the CsA group maintained elevated CD4 counts even after stopping CsA — up to 15 months post treatment compared with controls.

“We were a bit surprised by the magnitude of the effect and the rapid recovery of CD4 cell counts,” said Pantaleo. His group hopes to have results from a follow-up study of the same patients soon. Pantaleo is considering supplying CsA for HIV patients during treatment interruptions, periods when they stop taking antiretroviral therapy, to investigate whether the drug can prevent CD4 cell counts from sinking.

“CsA is highly selective for T cells,” Pantaleo explained. “It does not suppress any other type of cell.” And Pantaleo has no plans to study prednisone. “Prednisone has a very broad mechanism [of immunosuppression], which is why using steroids is not a good idea.”

Besides, he continued: “You cannot give prednisone in patients with chronic infection. The toxicity associated with steroids is extremely worrisome. It makes no sense.”

Pantaleo disregards Andrieu’s reports of mild side effects with long-term prednisone. “He used a lot of steroids and, at the same time, he was reporting minimal side effects. That was not credible,” he said. Ulmer counters this by claiming that although the drug is toxic in high doses, the low 5-mg to 7-mg doses he prescribes are therapeutic and cause few side effects.

Over the long term, CsA also causes side effects, so Pantaleo’s group stopped CsA therapy at 8 weeks. “We don’t think that cyclosporine should be given to patients with chronic infection or that it should be administered for a longer time. Just long enough to obtain the results you aim for.”

Despite criticism, Ulmer has plowed ahead. He recently presented his work at an HIV meeting in Toulon, France, as well as at the recent International AIDS Conference in Bangkok. The poster retrospectively compared 60 therapy-naïve HIV-positive patients taking a 5-mg daily dose of prednisone with 133 controls. After 3 years, the group taking prednisone showed an average increase in their CD4 cell counts of 127 cells/mm³, while the control group showed an average decrease of 193 cells/mm³. Ulmer also observed that patients who take prednisone during treatment interruptions retain higher CD4 cell counts than those who do not take it.

By Ulmer’s thinking, prednisone could buy HIV patients months, perhaps years, of life free from antiretroviral therapy and its associated toxicities and costs. The drug costs about $96 a year in the US. And Ulmer’s Rwandan patient? She has been taking prednisone for seven and a half years, is feeling well, and her CD4 count remains stable.

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