In The Clinic

Combating HIV, One Tumor at a Time

Robert Yarchoan, M.D., vividly remembers the day in 1981 when, as a Clinical Fellow in the Metabolism Branch of NCI, he saw a young man who had developed a profound immunodeficiency. That patient, who had almost no T lymphocytes, represented a moment in medical history—the first NIH patient with what would come to be known as acquired immunodeficiency syndrome (AIDS). Since that time, Yarchoan, now Chief of the HIV and AIDS Malignancy Branch and Director of the newly formed NCI Office of HIV and AIDS Malignancy (OHAM), has seen firsthand how HIV/AIDS has risen as a global epidemic, how the development of highly active antiretroviral therapy (HAART) has revolutionized AIDS treatment, how malignancies associated with AIDS have tested both patients and doctors, and how the long-term effects of living with AIDS can bring with them a new host of challenges.

The discovery by Luc Montagnier and Robert C. Gallo of a novel human retrovirus, and Gallo’s demonstration that this virus was the cause of AIDS, were the first major milestones in our efforts to understand, prevent, and treat the disease.

An estimated 35 million people suffer from HIV/AIDS worldwide, about one million of whom live in the United States. However, when the first patient with AIDS crossed the threshold of the NIH Clinical Center in 1981, we had no way of foreseeing the shape that the future AIDS epidemic would take or the global, cultural, and societal impacts that it would have. All we knew was that we were seeing something new. It was soon evident that clusters of cases of rare tumors like Kaposi’s sarcoma were part of this same condition. And over several months, it became apparent that that this disease was widespread in the U.S., and that the more severe patients with AIDS we were seeing represented just the tip of the iceberg.

There was great confusion and distress in the medical community as AIDS first surfaced. Though heroic measures were often utilized to try to treat these patients, they generally died within several months. It was not known how many people had this disease, how it was transmitted, or if anything could be done to treat it effectively.

The NCI had many tools in place to address this new disease, including expertise in immunology, retrovirology, tumor biology, and drug development. I believe that the rapid development of advanced treatments for HIV, in particular highly active antiretroviral therapy (HAART), was the result of a keen and farsighted, though sometimes controversial, research focus at NCI on HIV itself.

To Treat a Virus

The discovery by Luc Montagnier and Robert C. Gallo of a novel human retrovirus, and Gallo’s demonstration that this virus was the cause of AIDS, were the first major milestones in our efforts to understand, prevent, and treat the disease. Prior to these discoveries, most of the research on AIDS was descriptive.

Figure 1. Tireless work on the part of researchers at NCI and other institutions has led to dramatic decreases in the mortality associated with HIV/AIDS and AIDS-related malignancies. But challenges still remain.

Once the scientific community understood what was causing the immunodeficiency, it was possible to envision effective therapy directed at the root cause. Then-NCI Director Vincent DeVita, Jr., M.D., asked Samuel Broder, M.D., and his group, of which I was a member, to spearhead an effort to develop treatments for AIDS. Broder, Hiroaki Mitsuya, M.D., Ph.D., now Head of the Experimental Retrovirology Section of the HIV and AIDS Malignancy Branch, and I constructed the hypothesis that by blocking HIV replication, it might be possible to reverse the immunodeficiency caused by the virus. This idea was somewhat controversial at the time, as no such therapies existed for other progressive viral diseases, and it was not clear that blocking HIV would lead to immunologic improvement. In a short time, our group in NCI developed the first therapies to effectively fight HIV infection, including zidovudine (AZT), didanosine (ddI), and zalcitabine (ddC). AZT was developed in collaboration with Burroughs Wellcome Co., while ddI and ddC were developed within NCI and then licensed to pharmaceutical companies. These drugs all blocked an essential and unique enzyme of HIV, reverse transcriptase. The initial clinical trials of these drugs, both singly and in combination, gave rise to the first effective anti-HIV treatment regimens.

A limitation of these initial regimens was the frequent development of viral resistance. Thus, about a decade later, the first drugs were developed that attacked a different HIV target, the viral protease. The creation of these so-called protease inhibitors, which block the active site of HIV protease, was in part based on structural studies of this enzyme conducted in the NCI-Frederick program. When combined with two nucleoside reverse transcriptase inhibitors (like AZT and ddI), protease inhibitors were able to suppress HIV replication dramatically, often to undetectable levels. This combination drug therapy, the backbone of HAART, revolutionized the treatment of HIV. Patients improved clinically and had marked improvement in their immune function. There was a dramatic drop in the death rate from AIDS. In addition, there was a marked decrease in the number of AIDS-associated tumors, and survival of patients with these tumors improved. For our contributions to the development of HAART, Mitsuya and I were honored in 2006 with the first NIH World AIDS Day Award (Figure 2).

This combination drug therapy, the backbone of HAART revolutionized the treatment of HIV patients.

The first-generation protease inhibitors, while effective, had significant side effects and required high doses to be effective. Moreover, the development of resistance has been a vexing problem. Therefore, a number of scientists (including Mitsuya) and pharmaceutical companies have been looking into the development of improved, second-generation protease inhibitors. Darunavir, developed by Mitsuya and collaborators and approved by the U.S. Food and Drug Administration in 2006, is one such drug. Darunavir has the advantage of retaining its activity even in patients who have become resistant to other inhibitors.

For several years, my colleague David Davis, Ph.D., and I have been studying the possibility of inhibiting HIV protease by a new mechanism: by blocking the linkage of its two monomers into an active dimer. Working with the two of us, Mitsuya recently found that in addition to blocking the enzyme’s active site, darunavir does just this, making the drug quite different from other approved HIV protease inhibitors. This observation was highlighted as one of CCR’s major scientific advances of 2007 (see "Multiple Strategies for Attacking HIV").