Anti-HIV Treatment Improves Immune System and Fights Sight-Threatening Eye Infection
A combination of anti-HIV drugs appears to help rejuvenate the immune systems of people with AIDS and prevent progression of cytomegalovirus (CMV) retinitis, a potentially blinding AIDS-related eye complication. A paper detailing these findings is published in the November 3, 1999 issue of the Journal of the American Medical Association (JAMA).
Researchers at the Federal government's National Institutes of Health (NIH) found that all 14 patients with CMV retinitis enrolled in the study who took highly active antiretroviral therapy - called HAART - were able to stop taking their standard anti-CMV medications safely and without progression of their retinitis. The study also suggests that with HAART, the immune system of people with AIDS is being partially restored and may be able to fight other serious infections.
"CMV retinitis is not progressing in patients who are receiving HAART, suggesting that somehow HAART is playing a role in strengthening the immune system," said Dr. Carl Kupfer, director of the National Eye Institute (NEI), which conducted the study in collaboration with the National Institute of Allergy and Infectious Diseases (NIAID).
"With HAART, the rejuvenated immune system effectively controls this serious infection and doesn't need the help of specific anti-CMV retinitis medications. Stronger immune systems respond better to HIV and other infections, potentially allowing patients to live longer."
"This study indicates another important advantage of potent antiretroviral therapy," said NIAID Director Dr. Anthony S. Fauci. "We now have clinical evidence that in addition to the rises in CD4+ T cell counts seen in patients taking HAART, there is sustained functional immune recovery to the point that their immune systems can effectively control a major opportunistic infection."
Dr. Kupfer said that HAART, a combination of drugs taken orally, will change clinical practice and lead to a significant improvement in the quality of life for people with AIDS who have CMV retinitis. "Some patients will no longer have to take the standard anti-CMV treatments, which require life-long medication with a variety of anti-CMV drugs. These drugs can have serious side effects, including kidney toxicity and low blood cell counts, and may require daily intravenous administration," he said. "HAART is expensive - it costs an estimated $15,000 annually per patient - but is significantly lower than standard anti-CMV treatment, which can range between $50,000-100,000 per patient each year."
"Prior to the use of HAART, CMV retinitis would progress in many patients despite treatment," said NEI Clinical Director Dr. Scott Whitcup, study chairman and primary author of the JAMA article. "We found that none of the patients in the study had progression of their retinitis, despite being off of standard anti-CMV therapy for an average of 16 months, and in some cases for almost two years. This significant result adds to the body of evidence that some patients who have both CMV retinitis and immune recovery from using highly active antiretroviral therapy may be able to stop their standard anti-CMV medications."
Another indication of HAART's success was that throughout the trial HIV levels remained low or below detectable limits, according to NIAID's Dr. Michael Polis, an AIDS physician and senior author. "We measured no elevation of HIV viral load in the plasma," Dr. Polis said, "and CD4+ T cell counts increased significantly over time, giving us more signs that HAART is restoring some independent immunologic control in our patients."
Despite these positive findings, Dr. Whitcup noted that "to some degree, immune recovery is a double-edged sword. Although we are seeing better control of the CMV retinitis in patients on HAART, we're also seeing more inflammation, or 'immune recovery uveitis,' in these eyes. In patients who took HAART, immune recovery uveitis is seen both in patients who remain on standard anti-CMV therapy and in patients who discontinue anti-CMV therapy. The cause of the inflammation is not clear and requires further study."
HAART is a cocktail of anti-HIV drugs, each having varying costs and side effects. The specific regimen - which can include at least one protease inhibitor and two other antiretroviral agents - varies for each patient and depends on a patient's tolerance to the medications. CMV retinitis is a common complication occurring mostly in the later stages of AIDS and, prior to HAART's availability, had been increasing in frequency as people with AIDS began to live longer. CMV retinitis can cause blindness if left untreated, and previous NEI-supported studies had led to effective treatments for CMV retinitis.
The only people eligible for this trial were those with stable CMV retinitis who had an increase in levels of CD4+ T cell counts to greater than 150 cells per microliter and had been receiving HAART for at least four months. All 14 patients in the study had their anti-CMV medications stopped. "Although there was no control group, the absence of disease progression in all of the patients is significant, since other well-controlled, randomized clinical trials prior to the use of HAART report that the disease progressed after an average of two months despite anti-CMV therapy," Dr. Whitcup said. "Without anti-CMV therapy, the disease can progress in as little as three weeks."
Although no patient in the study had progression of eye disease, Dr. Whitcup cautioned that there may be some patients whose rejuvenated immune systems may be unable to control CMV retinitis, even with HAART. "Scientists are trying to develop blood tests to help predict when this might occur," he said.
Although the study focused on CMV retinitis, the results may be a "gateway" for researchers in treating other opportunistic infections, such as Mycobacterium avium complex (MAC), which also can be controlled by HAART alone, according to preliminary results from NIAID-supported trials. "The study demonstrates that immune recovery associated with HAART is effective in controlling a major opportunistic infection, even in patients with a history of severe immunosuppression," Dr. Whitcup said. "The question is, will immune recovery associated with HAART effectively control other opportunistic infections? The results of this research present an opportunity for scientists to answer this question."
Dr. Whitcup said that patients with CMV retinitis should undergo dilated eye exams. "The study results suggest that if their CMV is inactive and their CD4 counts have responded well to HAART, stopping their anti-CMV medications could be considered," he said.
The NEI and NIAID are both part of the National Institutes of Health (NIH). The NEI is the Federal government's lead agency for vision research that leads to sight-saving treatments and plays a key role in reducing visual impairment and blindness. The NIAID conducts and supports research to prevent, diagnose and treat illnesses such as HIV disease and other sexually transmitted diseases, tuberculosis, malaria, asthma and allergies. The NIH is an agency of the US Department of Health and Human Services.