Not long after the introduction of highly active antiretroviral therapy (HAART) and the subsequent dramatic decreases in AIDS death rates, clinicians and patients alike became very interested in stopping HIV therapy. Once the notion of viral eradication under HAART was deemed impossible and the specter of viral drug resistance to potent HIV therapy was confirmed, our therapeutic paradigm for HAART changed. We realized that, depending on a patient's disease status, HIV drugs may be less like the lifelong, uninterrupted therapy we were first told about and more like a precious resource that must be used wisely to attain maximum benefit. Unfortunately, drug toxicities complicated the HIV therapy equation even more.
The widespread use of highly active antiretroviral therapy (HAART) has had a significant impact on HIV by reducing mortality and morbidity. Unfortunately, long-term use of antiretroviral treatment is associated with several limitations and drawbacks. Currently available antiretrovirals are unable to completely eradicate the HIV infection, and infectious virus continues to reside and to replicate latently in reservoirs.
Dorothy E. Lewis, PhD, and Richard E. Sutton, MD, PhD
Controlled treatment interruptions seemed like a reasonable idea a few years ago. From a historical viewpoint, by 1996, the message was, "Now that we have better and more effective drug regimens, we might actually be able to rid the body of HIV." Several years later, the hope (or hype) was gone and a new challenge arose. Remember, this is HIV—there is always a new challenge. The newer drugs contained HIV better, but they came with new or more blatant clinical side effects such as problems with fat redistribution or worse. Not to mention the long-term expense of the medications.
"Long-term non-progressors have a strong cellular anti-HIV immune response." Thus starts many a review article on HIV immunology. And many readers therefore conclude, "After induction of a strong anti-HIV immune response, an ordinary patient with HIV infection will be transformed into a long-term non-progressor."
Joel was born in Harlingen, Texas, on January 29, 1953. Throughout his life, he was admired for his amazing combination of intellect, compassion, and achievement. Joel graduated from Rice University cum laude in 1976 and Columbia University School of Law in 1977.
This year has been busy in the fight against HIV. Several new HIV drugs were approved (Fuzeon, Reyataz, Lexiva, and Emtriva). While some of these offer people with HIV new ways to combat the virus, others offer modest advantages like improved convenience or fewer/different side effects. Surprisingly, the biggest overall challenge to people living with HIV this year has not necessarily been the virus, but the cuts in dollars for research and medication assistance programs.
Justifiable transplantation: In the past, organ transplantation usually has not been recommended in HIV+ people because of the fear that the transplant surgery and necessary immune-suppressive drugs would cause HIV disease to get worse. Also, there were concerns that HIV+ patients would not live long enough to justify the transplant.
We all suffer from what has become known as TMI—too much information. Our televisions, magazines, newspapers, computers, cell phones, fax machines, etc. have provided us with TMI. This includes the area of HIV treatment. One reason there is so much information is because there is a lot happening.
Last July, an Important Drug Warning was issued to healthcare providers concerning a high rate of virologic failure with a once-daily, 3-drug combination of Viread, Epivir, and Ziagen. Data from study ESS30009, which compared Sustiva versus Viread in combination with once-daily Ziagen/Epivir, revealed poor performance in patients taking Viread plus Ziagen/Epivir arm. Data from a pilot study presented at the 2nd IAS Conference in Paris also indicated a high rate of failure (inability to lower and keep viral load undetectable) with this combination.
Cancer has been associated with AIDS before the human immunodeficiency virus was even identified. The telltale purple-brown lesions of Kaposi's sarcoma (KS) were one of the characteristic signs of an epidemic coming into its own. In the very early days of AIDS, many patients with nowhere to turn were being referred to cancer centers for care only to find out that (as with the rest of the general medical community) there was great fear, and many clinicians were reluctant to go anywhere near them. As an understanding of HIV and AIDS grew, so did the realization that a weakened immune system allowed opportunistic infections to take over, eventually leading to death.
Cancer is a significant cause of mortality and morbidity in people infected with HIV; in fact 30% to 40% will develop a malignancy during their lifetime. The majority of cancers affecting HIV-positive people are those established as AIDS-defining: Kaposi's sarcoma, non-Hodgkin's lymphoma, and invasive cervical cancer. However, other types of cancer also appear to be more common among those infected with HIV.
Common sense tells us that viruses should be cleared from our bodies just like any other invading pathogen. However, many are not cleared entirely and are able to persist by establishing latent infection. In many cases, virus-host interactions have evolved over the millennia such that viruses reproduce, remain viable, and are transmitted, while host immune systems can contain infections and prevent severe illness or death. Examples of such viruses include herpesviruses and papillomaviruses.
Immunodeficiency (whether congenital, iatrogenic, or caused by infection) increases the risk of some types of cancer, especially malignancies etiologically linked to DNA tumor viruses, such as herpesviruses and polyomavirus.
Individuals with HIV infection and cancer are faced with two complex life-threatening diseases. Treatment of such complex illnesses is more straight-forward for the clinician when adequate evidence-based clinical guidelines are available. However, for many patients with AIDS-related (or "AIDS-defining") malignancies, there are no such guidelines and there is in fact little actual clinical science upon which to base dogmatic recommendations.
Research on AIDS-associated malignancies has focused on the interplay of immunity and viral infections and has increased our understanding of cancer pathogenesis. But what have we learned, and how can we build upon our knowledge to develop improved preventive and therapeutic interventions? This article outlines resources available from the National Cancer Institute (NCI) to stimulate research and to increase our knowledge of the underlying pathophysiology of HIV/AIDS-associated malignancies and the development of more effective interventions.
The AIDS Malignancy Consortium (AMC) is a National Cancer Institute (NCI)-supported clinical trials group, founded in 1995 to support innovative trials for AIDS-associated malignancies. The AMC is composed of 15 main Clinical Trials Sites and their affiliates, and an Operations and Statistical Center.
have always had a distaste for writing autobiographically when I write for this publication. It stems from a personal belief in and conviction for the so-called "scientific method"—an early indoctrination that disease could and would be conquered. AIDS has been the great curve ball. Still, in my heart I have always had this deep-seated sentiment that what HIV/AIDS research and medicine lack most is the scientific authority that comes from sufficient process and analytical thinking.
Sugar-coated HIV. That is the thought that occurred to me while putting together this issue. No, this has nothing to do with the sticky, "sugar" molecules (called "glycoproteins") on the outside of the HIV molecule. Rather, the sugar-coating I am referring to is about trying to stay positive about HIV—to convey hope and the idea that it's not all bad news.
The Annual Retrovirus Conference is the major HIV research meeting in the US. Each winter, the conference brings together several thousand healthcare providers, researchers, and community activists to review the latest developments in the field of HIV. Over 5 days, the conference covers research on experimental anti-HIV drugs, drug interactions, side effects, potential vaccines, and more.
When making presentations on HIV treatment issues, I always end with the same line: "These are the things you should know if you get hit by a bus." I realize that this may sound a bit unusual, but there's a method to my madness.
HIV superinfection: it's real. HIV-infected patients have been cautioned against unprotected sex and sharing needles because of the possibility of contracting another, possibly more aggressive, strain of HIV. But until recently, there has been no definitive proof that this could happen.
Trizivir has been marketed as a 1-pill, twice-a-day complete regimen, but this may have been premature. On March 10, 2003, a Notice to Physicians was sent out by the Division of AIDS at the National Institute of Allergy and Infectious Diseases. This notice was sent to update doctors and healthcare providers on a government study (ACTG A5095), which looked at 3 anti-HIV treatment combinations that did not include protease inhibitors.
Project LEAP (Learning, Empowerment, Advocacy and Participation) is a unique training program for HIV+ people who want to become part of the decision-making process that determines how HIV funding is spent locally.
On December 5, 2002, The Center for AIDS hosted the second Basic Science Workshop on HIV. The meeting was cosponsored by the Center for AIDS Research (CFAR) unit at Baylor College of Medicine and held at the Woodlands Resort and Conference Center just outside of Houston. Approximately 40 people attended the day-long meeting, which featured a series of slide presentations, an activism roundtable discussion, and a keynote address by Sandra Bridges, PhD, from the National Institutes of Health. The theme of the meeting was novel therapeutic interventions.
Ronald G. Collman, MD - University of Pennsylvania School of Medicine and Penn Center for AIDS Research
While HIV has subverted the chemokine receptors CCR5 and CXCR4 for its own use as an entry co-receptor, their normal functions are to transduce signals in response to extracellular ligands. Our lab is interested in understanding how HIV-1 glycoprotein 120 (gp120) may activate intracellular signals through these receptors in primary human macrophages, and how these responses may contribute to pathogenesis. Our studies demonstrate HIV-1 gp120 elicits several different types of signals in macrophages through CXCR4 and CCR5, including calcium elevations, ionic channel activation, non-receptor protein tyrosine kinase activation, and activation of MAP kinases. Receptor activation is triggered by both monomeric gp120 and whole HIV virus.
Frederick Siegal, MD - St. Vincent Catholic Medical Center
Interferon-α (IFN-α) generation by peripheral blood mononuclear cells (PBMC) responding in vitro to HSV was first found to be deficient in patients with severe ulcerative herpes simplex virus (HSV) infections early in the AIDS epidemic.
HIV-specific T cell immune responses will play an important role in any HIV vaccine paradigm. Studies in rhesus monkeys have shown that significant and persistent virus-specific T cell responses can be elicited with vaccines incorporating viral genetic sequences and that these responses are primarily mediated by CD8 T cells.
Rana A. K. Singh, PhD, and Michael A. Barry, PhD - Baylor College of Medicine and Rice University
HIV-1 is a fundamentally difficult target for vaccines because of its high mutation rate and its repertoire of immune evasion strategies. To address these difficulties, a multivalent genetic vaccine or "live genetic vaccine" was recently developed against HIV-1 using the expression library immunization (ELI) approach.
Qizhi (Cathy) Yao, MD, PhD - Baylor College of Medicine
To enhance mucosal immune responses using simian-human immunodeficiency virus-like particles (SHIV VLPs) as a mucosal HIV vaccine, we have produced phenotypically mixed, chimeric influenza HA/SHIV 89.6 VLPs and used them to immunize C57B/6J mice intranasally.
Richard E. Sutton, MD, PhD, Ayse K. Coskun, MD, and Van Nguyen - Baylor College of Medicine
A small animal model would be very valuable for HIV/AIDS vaccine testing, investigating HIV pathophysiology, and exploring anti-HIV therapeutics. Unfortunately, HIV does not replicate in mouse cells. Provision of mouse cells with human CD4, CCR5 and cyclin T1 (cycT1) has uncovered a block to HIV assembly or release. Since mouse-human cell fusions allow viral replication, mouse cells lack at least one critical factor that permits completion of the viral life cycle.
Sandra Bridges, PhD - Division of AIDS, National Institute of Allergy and Infectious Diseases
For more than 10 years, drug discovery efforts have concentrated on relatively few viral targets: reverse transcriptase (RT) and protease (PR). While viral load can be reduced by combining RT and PR inhibitors in regimens referred to as highly active antiretroviral therapy (HAART), recent studies suggest that many treatment failures occur because of the development of drug resistance and lack of adherence to complicated and often toxic regimens.
This information is designed to support, not replace, the relationship that exists between you and your doctor.