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Research Seeks Longer Lives for HIV Patients
$7 million in NIH grants supports clinical trials of new drugs and treatment strategies
As recently as 10 years ago, a person infected with the Human Immunodeficiency Virus (HIV) was not expected to live more than a few years. Today, HIV patients can expect to live a longer, more productive life. The dramatic increase in longevity is due to the combination of multiple anti-HIV drugs.
Roberto C. Arduino, M.D.
Roberto C. Arduino, M.D., director of research for the AIDS Program of the Division of Infectious Diseases at The University of Texas Medical School at Houston, is seeking further improvements in treatment for HIV patients.
“We are seeing patients living longer with HIV. The mean age of an HIV-infected person currently is 44. Although we do not know how long people can live with HIV, we are seeing a marked decrease in mortality with the increased use of combination antiretroviral therapy and protease inhibitors,” said Arduino, who also is associate professor of internal medicine-infectious diseases and principal investigator of the National Institutes of Health (NIH)-funded Houston AIDS Research Team.
Arduino and his team have received more than $7 million in NIH grants, along with numerous pharmaceutical grants, in the past five years. The largest, a five-year, $5 million grant, established the Houston AIDS Research Team as one of the Community Programs for Clinical Research on AIDS (CPCRA). The CPCRA provides funds for clinical research in primary care settings that focus on historically underrepresented individuals in AIDS research, namely people of color, women and injection drug users.
“Although there is a decrease in mortality, there is an increase in the number of minority women becoming infected, and these women typically delay treatment,” Arduino said.
“There are only 14 CPCRA units in the country, and most are located in the Northeast. There were none in Texas and virtually none in the South,” he said. This program allows for the study of “patients that otherwise would not have access to clinical trials,” he added. Through the CPCRA, Arduino conducts clinical trials of several promising new drugs and treatment strategies at the Thomas Street Clinic, the Montrose Clinic and the Veterans Affairs Medical Center.
One of the treatment options is a combination regimen using protease inhibitors or non nucleoside reverse transcriptase inhibitors with at least two other antiretroviral drugs. Known as HAART (Highly Active Anti-Retroviral Therapy), the treatment regimen keeps HIV levels in blood as low as possible.
The problems doctors and patients face with the HAART regimen are drug resistance and long term toxicity. Over a long period of time the HIV virus continues to replicate itself and with each replication, it may change its makeup, eventually becoming resistant to the medications. This drug resistance leaves patients vulnerable to opportunistic infections and eventual AIDS.
In August 2003 the New England Journal of Medicine published an important CPCRA trial that followed 270 patients over one year to determine if a fourmonth structured treatment interruption of antiretroviral therapy was beneficial for patients infected with multi-drug resistant viruses. The Houston CPCRA enrolled 25 patients in the clinical trial, which showed that HIV-infected patients who underwent the socalled “drug holiday” had more HIV-related complications and poorer immune response than did individuals who continuously took the antiretroviral drugs.
“The study needed the CPCRA units in order to include an adequate number of patients with long term follow-up to show the results,” Arduino said.
A more extensive CPCRA study dubbed SMART (Strategies for the Management of Anti-Retroviral Therapy) began in October 2001 and is purported to be the largest, most ambitious clinical trial in the history of the HIV/AIDS epidemic. The study involves 6,000 patients and will provide follow-up for as long as eight years.
The SMART study is driven by the widespread recognition that anti-HIV drugs are toxic. With the study, researchers hope to learn whether delayed, discontinuous treatment for HIV can be as effective as the present strategy of immediate, uninterrupted treatment. Researchers also will gather information on the long-term side effects of HIV treatment and its effect on quality of life and will seek to learn whether interruptions in treatment are associated with an increase in unsafe sex and HIV transmission.
Arduino and Ben Barnett, M.D., assistant professor of internal medicine-infectious diseases, are working on a new class of anti-HIV drugs called entry inhibitors. These drugs work to block entry of HIV into a T cell, an important component of the immune system. If the drug is effective, HIV is unable to use the T-cell to replicate itself. The first of these drugs recently released is T-20, or enfuvirtide. The Thomas Street Clinic enrolled patients in the Phase II and III studies of T-20 to evaluate safety and effectiveness.
Arduino and his team also conduct clinical trials of interleukin-2 (IL-2), which in combination with antiretroviral therapy increases the number of CD4 cells, a type of T-cells. Originally IL-2 was a treatment option for the AIDS-related skin cancer, Kaposi’s sarcoma.
Researchers realized that patients using IL-2 had increased CD4 cell counts, signifying a stronger immune system. In collaboration with the NIH, Arduino and his colleagues began researching the phenomenon in a study called the Houston Vanguard IL-2. Vanguards in Bangkok and in Buenos Aires were performed simultaneously.
The results of the initial study led to development of and support for the larger ESPRIT (Evaluation of Subcutaneous Proleukin in a Randomized International Trial) study, which will determine if the CD4 counts resulting from IL-2 therapy will decrease the occurrence of AIDS-defining events (contracting opportunistic infections or cancer) for patients with CD4 counts of 300 cells/microliter or greater. The six year study will follow 2,000 patients taking the subcutaneous IL-2 drug named Proleukin and antiretroviral drugs, compared with 2,000 taking only antiretroviral drugs.
The second IL-2 study is the SILCAAT (Subcutaneous IL-2 in HIV-infected Patients with Low CD4 Counts under Active Antiretroviral Therapy). This four-year clinical trial is studying 1,400 patients with CD4 counts between 50 and 300 cells/microliter.
“Much of the research being done in the past was based on white, homosexual males. This does not accurately represent the real-life cases. Today 40 to 50 percent of HIV patients are heterosexual,” Arduino said. “Literally HIV is changing. It is not only limited to the white, gay, male population.”
Houston ranks eighth among U.S. cities in the number of diagnosed AIDS cases, according to AIDS Foundation Houston, which also estimates that one of every 90 Houstonians is living with HIV/AIDS.
— by Dawna Jarvis, Public Affairs