LINK: http://hivinsite.ucsf.edu/social/nih_reports/2098.22a4.html

How HIV Causes AIDS
National Institute of Allergy and Infectious Diseases (NIAID) Fact Sheet
An important focus of the National Institute of Allergy and Infectious Diseases (NIAID) is research devoted to the pathogenesis of human immunodeficiency virus (HIV) disease -- the complex mechanisms that result in the destruction of the immune system of an HIV-infected person. A detailed understanding of HIV and how it establishes infection and causes the acquired immunodeficiency syndrome (AIDS) is crucial to identifying and developing effective drugs and vaccines to fight HIV and AIDS. This fact sheet summarizes what scientists are learning about this process and provides a brief glossary of terms.

Overview
HIV disease is characterized by a gradual deterioration of immune function. Most notably, crucial immune cells called CD4+ T cells are disabled and killed during the typical course of infection. These cells, sometimes called "T-helper cells," play a central role in the immune response, signalling other cells in the immune system to perform their special functions.
A healthy, uninfected person usually has 800 to 1,200 CD4+ T cells per cubic millimeter (mm) of blood. During HIV infection, the number of these cells in a person's blood progressively declines. When a person's CD4+ T cell count falls below 200/mm, he or she becomes particularly vulnerable to the opportunistic infections and cancers that typify AIDS, the end stage of HIV disease. People with AIDS often suffer infections of the intestinal tract, lungs, brain, eyes and other organs, as well as debilitating weight loss, diarrhea, neurologic conditions and cancers such as Kaposi's sarcoma and lymphomas.
Most scientists think that HIV causes AIDS by directly killing CD4+ T cells and by triggering other events that weaken a person's immune function. For example, the network of signalling molecules that normally regulates a person's immune response is disrupted during HIV disease, impairing a person's ability to fight other infections. The HIV-mediated destruction of the lymph nodes and related immunologic organs also plays a major role in causing the immunosuppression seen in people with AIDS.

Scope of the HIV Epidemic
Although HIV was first identified in 1983, studies of previously stored blood samples indicate that the virus entered the U.S. population sometime in the late 1970s. In the United States, 513,486 cases of people with AIDS had been reported to the Centers for Disease Control and Prevention (CDC) as of Dec. 31, 1995. Among these individuals, 319,849 had died by the end of 1995. AIDS is now the leading killer of people aged 25 to 44 in this country.
Worldwide, an estimated 27.9 million people had become HIV-infected through mid-1996, and 7.7 million had developed AIDS, according to the World Health Organization (WHO). Various projections indicate that, by the year 2000, between 40 and 110 million people worldwide will be HIV-infected.

HIV is a Retrovirus
HIV belongs to a class of viruses called retroviruses, which have genes composed of ribonucleic acid (RNA) molecules. The genes of humans and most other organisms are made of a related molecule, deoxyribonucleic acid (DNA).
Like all viruses, HIV can replicate only inside cells, commandeering the cell's machinery to reproduce. However, only HIV and other retroviruses, once inside a cell, use an enzyme called reverse transcriptase to convert their RNA into DNA, which can be incorporated into the host cell's genes.
Slow viruses. HIV belongs to a subgroup of retroviruses known as lentiviruses, or "slow" viruses. The course of infection with these viruses is characterized by a long interval between initial infection and the onset of serious symptoms.
Other lentiviruses infect nonhuman species. For example, the feline immunodeficiency virus (FIV) infects cats and the simian immunodeficiency virus (SIV) infects monkeys and other nonhuman primates. Like HIV in humans, these animal viruses primarily infect immune system cells, often causing immunodeficiency and AIDS-like symptoms. Scientists use these and other viruses and their animal hosts as models of HIV disease.

Organization of the HIV-1 Virion
Structure of HIV
The viral envelope. HIV has a diameter of 1/10,000 of a millimeter and is spherical in shape. The outer coat of the virus, known as the viral envelope, is composed of two layers of fatty molecules called lipids, taken from the membrane of a human cell when a newly formed virus particle buds from the cell.
Embedded in the viral envelope are proteins from the host cell, as well as 72 copies (on average) of a complex HIV protein that protrudes from the envelope surface. This protein, known as Env, consists of a cap made of three or four molecules called glycoprotein (gp)120, and a stem consisting of three or four gp41 molecules that anchor the structure in the viral envelope. Much of the research to develop a vaccine against HIV has focused on these envelope proteins.
The viral core. Within the envelope of a mature HIV particle is a bullet-shaped core or capsid, made of 2000 copies of another viral protein, p24. The capsid surrounds two single strands of HIV RNA, each of which has a copy of the virus's nine genes. Three of these, gag, pol and env, contain information needed to make structural proteins for new virus particles. The env gene, for example, codes for a protein called gp160 that is broken down by a viral enzyme to form gp120 and gp41, the components of Env.
Three regulatory genes, tat, rev and nef, and three auxiliary genes, vif, vpr and vpu, contain information necessary for the production of proteins that control the ability of HIV to infect a cell, produce new copies of virus or cause disease. The protein encoded by nef, for instance, appears necessary for the virus to replicate efficiently, and the vpu-encoded protein influences the release of new virus particles from infected cells.
The ends of each strand of HIV RNA contain an RNA sequence called the long terminal repeat (LTR). Regions in the LTR act as switches to control production of new viruses and can be triggered by proteins from either HIV or the host cell.
The core of HIV also includes a protein called p7, the HIV nucleocapsid protein; and three enzymes that carry out later steps in the virus's life cycle: reverse transcriptase, integrase and protease. Another HIV protein called p17, or the HIV matrix protein, lies between the viral core and the viral envelope.

Life Cyle of HIV
Steps in Viral Replication

• Attachment/Entry
• Reverse Transcription and DNA Synthesis
• Transport to Nucleus
• Integration
• Viral Transcription
• Viral Protein Synthesis
• Assembly of Virus
• Release of Virus
• Maturation

Course of HIV Infection
Among patients enrolled in large epidemiologic studies in western countries, the median time from infection with HIV to the development of AIDS-related symptoms has been approximately 10 years. However, researchers have observed a wide variation in disease progression. Approximately 10 percent of HIV-infected people in these studies have progressed to AIDS within the first two to three years following infection, while 5 to 10 percent of individuals in the studies have stable CD4+ T cell counts and no symptoms even after 12 or more years.
Factors such as age or genetic differences among individuals, the level of virulence of an individual strain of virus, and co-infection with other microbes may influence the rate and severity of disease progression.
Viral burden predicts disease progression. Recent studies show that people with high levels of HIV in their bloodstream are more likely to develop new AIDS-related symptoms or to die than individuals with lower levels of virus. New anti-HIV drug combinations that reduce a person's "viral burden" to very low levels may delay the progression of HIV disease, but it remains to be seen if these drugs will have a prolonged benefit. Other drugs that fight the infections associated with AIDS have improved and prolonged the lives of HIV-infected people by preventing or treating conditions such as Pneumocystis carinii pneumonia.

Transmission of HIV
Among adults, HIV is spread most commonly during sexual intercourse with an infected partner. During sex, the virus can enter the body through the mucosal linings of the vagina, vulva, penis, rectum or, very rarely, via the mouth. The likelihood of transmission is increased by factors that may damage these linings, especially other sexually transmitted diseases that cause ulcers or inflammation.
Research suggests that immune system cells called dendritic cells, which reside in the mucosa, may begin the infection process after sexual exposure by binding to and carrying the virus from the site of infection to the lymph nodes where other immune system cells become infected.
HIV also can be transmitted by contact with infected blood, most often by the sharing of drug needles or syringes contaminated with minute quantities of blood containing the virus. The risk of acquiring HIV from blood transfusions is now extremely small in the United States, as all blood products in this country are screened routinely for evidence of the virus.
Almost all HIV-infected children acquire the virus from their mothers before or during birth. In the United States, approximately 25 percent of pregnant HIV-infected women not receiving antiretroviral therapy have passed on the virus to their babies. NIAID-sponsored researchers have shown that a specific regimen of the drug zidovudine (AZT) can reduce the risk of transmission of HIV from mother to baby by two-thirds.
The virus also may be transmitted from a nursing HIV-infected mother to her infant.

Early Events in HIV Infection
Once it enters the body, HIV infects a large number of CD4+ cells and replicates rapidly. During this acute or primary phase of infection, the blood contains many viral particles that spread throughout the body, seeding various organs, particularly the lymphoid organs. Lymphoid organs include the lymph nodes, spleen, tonsils and adenoids.
During the acute phase of infection, the number of CD4+ T cells in the bloodstream decreases by 20 to 40 percent. Scientists do not yet know whether these cells are killed by HIV or if they leave the blood and go to the lymphoid organs in preparation to mount an immune response.
Two to four weeks after exposure to the virus, up to 70 percent of HIV-infected persons suffer flu-like symptoms related to the acute infection. The patient's immune system fights back with killer T cells (CD8+ T cells) and B-cell-produced antibodies, which dramatically reduce HIV levels. A patient's CD4+ T cell count may rebound to 80 to 90 percent of its original level. A person then may remain free of HIV-related symptoms for years despite continuous replication of HIV in the lymphoid organs seeded during the acute phase of infection.
One reason HIV is unique is that despite the body's aggressive immune responses, which are sufficient to clear most viral infections, some HIV invariably escapes. One explanation is that the immune system's best soldiers in the fight against HIV -- certain subsets of killer T cells -- multiply rapidly following initial HIV infection and kill many HIV-infected cells, but then appear to exhaust themselves and disappear, allowing HIV to escape and continue replication. Additionally, in the few weeks that they are detectable, these specific cells appear to accumulate in the bloodstream rather than in the lymph nodes, where most HIV is sequestered.

HIV is Active in the Lymph Nodes
Although HIV-infected individuals often exhibit an extended period of clinical latency with little evidence of disease, the virus is never truly latent. NIAID researchers have shown that even early in disease, HIV actively replicates within the lymph nodes and related organs, where large amounts of virus become trapped in networks of specialized cells with long, tentacle-like extensions. These cells are called follicular dendritic cells (FDCs).
FDCs are located in hot spots of immune activity called germinal centers. They act like flypaper, trapping invading pathogens (including HIV) and holding them until B cells come along to initiate an immune response.
Close on the heels of B cells are CD4+ T cells, which rush into the germinal centers to help B cells fight the invaders. CD4+ T cells, the primary targets of HIV, probably become infected in large numbers as they encounter HIV trapped on FDCs. Research suggests that HIV trapped on FDCs remains infectious, even when coated with antibodies.
Once infected, CD4+ T cells may leave the germinal center and infect other CD4+ cells that congregate in the region of the lymph node surrounding the germinal center.
Over a period of years, even when little virus is readily detectable in the blood, significant amounts of virus accumulate in the germinal centers, both within infected cells and bound to FDCs. In and around the germinal centers, numerous CD4+ T cells are probably activated by the increased production of cytokines such as TNF-alpha and IL-6, possibly secreted by B cells. Activation allows uninfected cells to be more easily infected and increases replication of HIV in already infected cells.
While greater quantities of certain cytokines such as TNF-alpha and IL-6 are secreted during HIV infection, others with key roles in the regulation of normal immune function may be secreted in decreased amounts. For example, CD4+ T cells may lose their capacity to produce interleukin 2 (IL-2), a cytokine that enhances the growth of other T cells and helps to stimulate other cells' response to invaders. Infected cells also have low levels of receptors for IL-2, which may reduce their ability to respond to signals from other cells.
Breakdown of FDC networks. Ultimately, accumulated HIV overwhelms the FDC networks. As these networks break down, their trapping capacity is impaired, and large quantities of virus enter the bloodstream.
Although it remains unclear why FDCs die and the FDC networks dissolve, some scientists think that this process may be as important in HIV pathogenesis as the loss of CD4+ T cells. The destruction of the lymph node structure seen late in HIV disease may preclude a successful immune response against not only HIV but other pathogens as well. This devastation heralds the onset of the opportunistic infections and cancers that characterize AIDS.

Role of CD8+ T Cells
CD8+ T cells are important in the immune response to HIV during the acute infection and the clinically latent stage of disease. These cells attack and kill infected cells that are producing virus.
CD8+ T cells also appear to secrete soluble factors that suppress HIV replication. Three of these molecules -- RANTES, MIP-1alpha and MIP-1beta -- apparently block HIV replication by occupying receptors necessary for the entry of certain strains of HIV into their target cells. Researchers have hypothesized that an abundance of RANTES, MIP-1alpha or MIP-1beta, or a relative lack of receptors for these molecules, may help explain why some individuals have not become infected with HIV, despite repeated exposure to the virus.
CD8+ T cells probably also secrete other soluble factors -- as yet unidentified -- that suppress HIV replication.
Rapid Replication and Mutation of HIV
HIV replicates rapidly; several billion new virus particles may be produced every day. In addition, the HIV reverse transcriptase enzyme makes many mistakes while making DNA copies from HIV RNA. As a consequence, many variants of HIV develop in an individual, some of which may escape destruction by antibodies or killer T cells. Additionally, HIV can recombine with itself to produce a wide range of variants or strains.
During the course of HIV disease, viral strains emerge in an infected individual that differ widely in their ability to infect and kill different cell types, as well as in their rate of replication. Scientists are investigating why strains of HIV from patients with advanced disease appear to be more virulent and infect more cell types than strains obtained earlier from the same individual.
Theories of Immune System Cell Loss in HIV Infection
Researchers around the world are studying how HIV destroys or disables CD4+ T cells, and many think that a number of mechanisms may occur simultaneously in an HIV-infected individual. Recent data suggest that billions of CD4+ T cells may be destroyed every day, eventually overwhelming the immune system's regenerative capacity.
Direct cell killing. Infected CD4+ T cells may be killed directly when large amounts of virus are produced and bud off from the cell surface, disrupting the cell membrane, or when viral proteins and nucleic acids collect inside the cell, interfering with cellular machinery.
Syncytia formation. Infected cells also may fuse with nearby uninfected cells, forming balloon-like giant cells called syncytia. In test-tube experiments at NIAID and elsewhere, these giant cells have been associated with the death of uninfected cells. The presence of so-called syncytia-inducing variants of HIV has been correlated with rapid disease progression in HIV-infected individuals.
Apoptosis. Infected CD4+ T cells may be killed when cellular regulation is distorted by HIV proteins, probably leading to their suicide by a process known as programmed cell death or apoptosis. Recent reports indicate that apoptosis occurs to a greater extent in HIV-infected individuals, both in the bloodstream and lymph nodes.
Uninfected cells also may undergo apoptosis. Normally, when CD4+ T cells mature in the thymus gland, a small proportion of these cells are unable to distinguish self from non-self. Because these cells would otherwise attack the body's own tissues, they receive a biochemical signal from other cells that results in apoptosis. Investigators have shown in cell cultures that gp120 alone or bound to gp120 antibodies sends a similar but inappropriate signal to CD4+ T cells causing them to die even if not infected by HIV.
Innocent bystanders. Uninfected cells may die in an innocent bystander scenario: HIV particles may bind to the cell surface, giving them the appearance of an infected cell and marking them for destruction by killer T cells.
Killer T cells also may mistakenly destroy uninfected CD4+ T cells that have consumed HIV particles and that display HIV fragments on their surfaces. Alternatively, because HIV envelope proteins bear some resemblance to certain molecules that may appear on CD4+ T cells, the body's immune responses may mistakenly damage such cells as well.
Anergy. Researchers have shown in cell cultures that CD4+ T cells can be turned off by a signal from HIV that leaves them unable to respond to further immune stimulation. This inactivated state is known as anergy.
Superantigens. Other investigators have proposed that a molecule known as a superantigen, either made by HIV or an unrelated agent, may stimulate massive quantities of CD4+ T cells at once, rendering them highly susceptible to HIV infection and subsequent cell death.
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Damage to Precursor Cells. Studies suggest that HIV also destroys precursor cells that mature to have special immune functions, as well as the parts of the bone marrow and the thymus needed for the development of such cells. These organs probably lose the ability to regenerate, further compounding the suppression of the immune system.
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Central Nervous System Damage
Although monocytes and macrophages can be infected by HIV, they appear to be relatively resistant to killing. However, these cells travel throughout the body and carry HIV to various organs, especially the lungs and brain. People infected with HIV often experience abnormalities in the central nervous system. Neurologic manifestations of HIV disease, seen in 40 to 50 percent of HIV-infected people, are the subject of many research projects. Investigators have hypothesized that an accumulation of HIV in brain and nerve cells, or the inappropriate release of cytokines or toxic byproducts by these cells, may be to blame.
Role of Immune Activation in HIV Disease
During a normal immune response, many components of the immune system are mobilized to fight an invader. CD4+ T cells, for instance, may quickly proliferate and increase their cytokine secretion, thereby signalling other cells to perform their special functions. Scavenger cells called macrophages may double in size and develop numerous organelles, including lysosomes that contain digestive enzymes used to process ingested pathogens. Once the immune system clears the foreign antigen, it returns to a relative state of quiescence.
During HIV infection, however, the immune system may be chronically activated, with negative consequences. As noted above, HIV replication and spread are much more efficient in activated CD4+ cells. Chronic immune system activation during HIV disease may also result in a massive stimulation of a person's B cells, impairing the ability of these cells to make antibodies against other pathogens.
Chronic immune activation also can result in apoptosis, and an increased production of cytokines that may not only increase HIV replication but also have other deleterious effects. Increased levels of TNF-alpha, for example, may be at least partly responsible for the severe weight loss or wasting syndrome seen in many HIV-infected individuals.
The persistence of HIV and HIV replication probably plays an important role in the chronic state of immune activation seen in HIV-infected people. In addition, researchers have shown that infections with other organisms activate immune system cells and increase production of the virus in HIV-infected people. Chronic immune activation due to persistent infections, or the cumulative effects of multiple episodes of immune activation and bursts of virus production, likely contribute to the progression of HIV disease.
NIAID Research on the Pathogenesis of AIDS
NIAID-supported scientists conduct HIV pathogenesis research in laboratories on the campus of the National Institutes of Health (NIH) in Bethesda, Md., at the Institute's Rocky Mountain Laboratories in Hamilton, Mont., and at universities and medical centers in the United States and abroad.
An NIAID-supported collaborative center of the World Health Organization, known as the NIH AIDS Research and Reference Reagent Program, provides AIDS-related research materials free to qualified researchers around the world.
In addition, the Institute convenes groups of investigators and advisory committees to exchange scientific information, clarify research priorities and bring research needs and opportunities to the attention of the scientific community.
The NIAID HIV/AIDS Research Agenda and fact sheets on NIAID HIV/AIDS vaccine research, clinical trials for AIDS therapies and vaccines, and AIDS-related opportunistic infections are available from the NIAID Office of Communications. To receive free copies, call (301) 496-5717, Monday through Friday, 8:30 a.m. to 5:00 p.m. Eastern Time. These materials also are available via the NIAID home page on the Internet at http://www.niaid.nih.gov.
NIAID, a component of the National Institutes of Health, supports research on AIDS, tuberculosis and other infectious diseases, as well as allergies and immunology. NIH is an agency of the U.S. Public Health Service, U.S. Department of Health and Human Services.

Glossary
Apoptosis: Cellular suicide, also known as programmed cell death. HIV may induce apoptosis in both infected and uninfected immune system cells.
B cells: White blood cells of the immune system that produce infection-fighting proteins called antibodies.
CD4+ T cells: White blood cells that orchestrate the immune response, signalling other cells in the immune system to perform their special functions. Also known as T helper cells, these cells are killed or disabled during HIV infection.
CD8+ T cells: White blood cells that kill cells infected with HIV or other viruses, or transformed by cancer. These cells also secrete soluble molecules that may suppress HIV without killing infected cells directly.
Cytokines: Proteins used for communication by cells of the immune system. Central to the normal regulation of the immune response.
Cytoplasm: The living matter within a cell.
Dendritic cells: Immune system cells with long, tentacle-like branches. Some of these are specialized cells at the mucosa that may bind to HIV following sexual exposure and carry the virus from the site of infection to the lymph nodes. See also follicular dendritic cells.
Enzyme: A protein that accelerates a specific chemical reaction without altering itself.
Follicular dendritic cells (FDCs): Cells found in the germinal centers (B cell areas) of lymphoid organs. FDCs have thread-like tentacles that form a web-like network to trap invaders and present them to B cells, which then make antibodies to attack the invaders.
Germinal centers: Structures within lymphoid tissues that contain FDCs and B cells, and in which immune responses are initiated.
gp41: Glycoprotein 41, a protein embedded in the outer envelope of HIV. Plays a key role in HIV's infection of CD4+ T cells by facilitating the fusion of the viral and cell membranes.
gp120: Glycoprotein 120, a protein that protrudes from the surface of HIV and binds to CD4+ T cells.
gp160: Glycoprotein 160, an HIV precursor protein that is cleaved by the HIV protease enzyme into gp41 and gp120.
Integrase: An HIV enzyme used by the virus to integrate its genetic material into the host cell's DNA.
Kaposi's sarcoma: A type of cancer characterized by abnormal growths of blood vessels that develop into purplish or brown lesions.
Killer T cells: See CD8+ T cells.
Lentivirus: "Slow" virus characterized by a long interval between infection and the onset of symptoms. HIV is a lentivirus as is the simian immunodeficiency virus (SIV), which infects nonhuman primates.
LTR: Long terminal repeat, the RNA sequences repeated at both ends of HIV's genetic material. These regulatory switches may help control viral transcription.
Lymphoid organs: Include tonsils, adenoids, lymph nodes, spleen and other tissues. Act as the body's filtering system, trapping invaders and presenting them to squadrons of immune cells that congregate there.
Macrophage: A large immune system cell that devours invading pathogens and other intruders. Stimulates other immune system cells by presenting them with small pieces of the invaders.
Monocyte: A circulating white blood cell that develops into a macrophage when it enters tissues.
Opportunistic infection: An illness caused by an organism that usually does not cause disease in a person with a normal immune system. People with advanced HIV infection suffer opportunistic infections of the lungs, brain, eyes and other organs.
Pathogenesis: The production or development of a disease. May be influenced by many factors, including the infecting microbe and the host's immune response.
Protease: An HIV enzyme used to cut large HIV proteins into smaller ones needed for the assembly of an infectious virus particle.
Provirus: DNA of a virus, such as HIV, that has been integrated into the genes of a host cell.
Retrovirus: HIV and other viruses that carry their genetic material in the form of RNA and that have the enzyme reverse transcriptase.
Reverse transcriptase: The enzyme produced by HIV and other retroviruses that allows them to synthesize DNA from their RNA.
Syncytia: Giant cells formed by the fusion of other cells.
Prepared by:
Office of Communications
National Institute of Allergy and Infectious Diseases
National Institutes of Health
Bethesda, MD 20892
Public Health Service
U.S. Department of Health and Human Services

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(UPDATED Feb 12, 2000)
LINK: http://hivinsite.ucsf.edu/medical/iasusa/2098.3278.html

Improving the Management of HIV Disease

International AIDS Society-USA
Volume 5, Issue 1: June 1997.
Contents | Editorial Board | This Issue's Symposia Chairpersons | International AIDS Society-USA Board of Directors
Table of Contents:
HIV Pathogenesis
Susceptibility to Infection
Disease Progression
CD4+ Lymphocyte Dynamics
Naive and Memory Cell Cynamics
Polymerase Chain Reaction (PCR) Studies of T-cell Receptor Families
Summary
Suggested Readings
Viral Load in Clinical Trials
The Use of Viral Load Measurements as Prognostic and Therapeutics Markers
Clinical Use of Viral Load Measurements
Evaluating Virologic Response Data from Clinical Trials
Conclusion
Suggested Readings
Table 1. Decimal, Exponent, and Logarithms
Table 2. Questions to Consider in Evaluating Virologic Response Data From Clinical Trials of Antiretroviral Therapy
Adherence: The Achilles' Heel of Highly Active Antiretroviral Therapy
Efficacy vs. Effectiveness
Adherence to Treatment Regimens
Determinants of Adherence
Measuring Adherence
Interventions to Improve Adherence
Conclusion
Suggested Readings
Table 1. Factors That Affect Adherence
Table 2. Interventions to Enhance Adherence
Pain Management in HIV Disease
Pain Syndromes in HIV Disease
Strategies for Managing Pain in HIV Disease
Undertreatment of Pain in HIV Disease
Summary
Suggested Readings
Table 1. Causes of Pain Syndromes in Persons With HIV Disease and AIDs
Table 2. An Approach to Pain Management
Table 3. Analgesics for Managing Pain in HIV Disease and AIDS
Table 4. Psychotropic Adjuvant Analgesic Drugs
 

Editorial Board:
Editor in Chief
Douglas D. Richman, MD
Editorial Board
Paul A. Volberding, MD
Margaret A. Fischl, MD
Harold A. Kessler, MD
Michael S. Saag, MD
Robert T. Schooley, MD
Guest Editor: John P. Phair, MD

This Issue's Symposia Chairpersons:
Michael S. Saag, MD, University of Alabama at Birmingham
Melanie A. Thompson, MD, AIDS Research Consortium of Atlanta
Ronald T. Mitsuyasu, MD, University of California, Los Angeles
Paul A. Volberding, MD, University of California, San Francisco
Gerald H. Friedland, MD, Yale University School of Medicine
Paul A. Volberding, MD, University of California, San Francisco
Improving the Managment of HIV Disease is produced by the International AIDS Society-USA (IAS-USA). The views and opinions expressed in this publication are those of the conference participants and authors and do not necessarily reflect the views or recommendations of the IAS-USA, the conference joint sponsors, or the commercial companies providing unresitricted grant support. Unrestricted educational grant support for this publication was received from several commercial companies. All symposia faculty and publication contributors have provided disclosures of financial interests, and this information is available from IAS-USA by request. This publication may contain contain information about the investigational uses of drugs or products that are not approved by the U.S. Food and Drug Administration. Please consult full prescribing information before using any medications or product mentioned in this publication.
©International AIDS Society-USA
353 Kearny Street
San Francisco, CA 94108
Phone: 415-675-7430 Fax: 415-675-7438
email: IASUSA1@aol.com
Printed in USA
June 1997

International AIDS Society-USA Board of Directors

Paul A. Volberding, MD
Professor of Medicine
University of California San Francisco
San Francisco, California
Margaret A. Fischl, MD
Professor of Medicine
University of Miami School of Medicine
Miami, Florida

Michael S. Saag, MD
Associate Professor of Medicine
University of Alabama
at Birmingham
Birmingham, Alabama

Constance A. Benson, MD
Associate Professor of Medicine
Rush Medical College
Chicago, Illinois

Harold A. Kessler, MD
Professor of Medicine and Immunology/
Microbiology
Rush Medical College
Chicago, Illinois
Robert T. Schooley, MD
Professor of Medicine
University of Colorado School of Medicine
Denver, Colorado

Peter C. Cassat, JD
Associate General Counsel
U.S. News & World Report
Washington, DC

Douglas D. Richman, MD
Professor of Pathology and Medicine
University of California San Diego
and San Diego Veterans Affairs Medical Center
San Diego, California
Donna M. Jacobsen
Executive Director
International AIDS Society-USA
San Francisco, California
 

HIV PATHOGENESIS
HIV pathogenesis was discussed at the Los Angeles and Atlanta courses by H. Clifford Lane, MD, from the National Institutes of Health, Bethesda, Maryland.
Recent studies in viral dynamics, host immune response, and the regenerative ability of the immune system have yielded a substantial amount of information on pathogenesis of HIV infection. Studies of HIV replication and survival dynamics, detailed investigation of the architecture of lymphoid tissue in infection, and studies of CD4+ lymphocyte dynamics have demonstrated that HIV infection is a dynamic process of continuous viral replication (see accompanying article). Disparate lines of investigation have merged in the discovery of coreceptors to HIV and research has characterized a progressive decrease in the size and diversity of the CD4+ lymphocyte pool.

Susceptibility to Infection
The identification of factors that may influence susceptibility to infection upon exposure is the subject of much ongoing research. Building on the early work of Gallo et al on chemokines as anti-HIV factors and of Berger et al on a coreceptor with CD4 that mediated fusion, fusin was identified as a coreceptor for viral entry for the T-celltropic (syncytium inducing [SI]) isolates of HIV and of the b-chemokine receptor CCR5 as the coreceptor for the primary isolates of the macrophage-tropic (non-SI) phenotype isolates of HIV. In a study by Berger et al, CD4+ cells transfected with fusin are easily infected with the T-celltropic isolates of HIV-1 (LAY, HTLV-IIIB and RF), however, these cells lines could not be infected with macrophage-tropic isolates. Similarly, if CD4+ cells are transfected with CCR5, they can be easily infected with macrophage-tropic strains but not T-cell-tropic strains. The chemokine receptors are 7-transmembrane, G-protein coupled receptors. CCR5 is the physiological receptor for the cysteine-cysteine (CC) linked b-chemokines, RANTES, MIP-la and MIP-1b. Fusin is the receptor to SDF1, a CXC chemokine (see Figure 1).
Since macrophage-tropic isolates are the more prevalent isolates in patients, it may be possible to use a congener of the ligand as a therapeutic agent.
The identification of coreceptors in part explains why some people, despite multiple high-risk behaviors, do not become infected with HIV. Genotypic analyses identified that some of these high-risk uninfected individuals are homozygous for deleted alleles of the CCR5 gene. The frequency of this mutation, a 32 base-pair deletion, is estimated at 11% in the Caucasian population and 1.7% in the African-American population. The homozygous genotype appears to confer resistance to HIV-1 infection. In a cohort of 1343 HIV-positive and 612 HIV-negative patients, none of the HIV-positive patients were homozygous for the D32 CCR5 mutation compared with 3% of the HIV-negative patients.
The heterozygous genotype does not appear to have an effect on resistance to infection; several studies have shown a consistent, but minor difference in the rate of disease progression between patients with the heterozygous D32 mutation and those with no mutation.

Disease Progression
The strength of the immune response to acute HIV infection appears to have a long-term impact on the course of the disease. Those patients who are able to control the virus well, as evidenced by low plasma HIV RNA levels and diverse T-cell responses, advance to clinical disease much more slowly than do those with high plasma HIV RNA levels (eg, >100,000 copies/mL) and a more restricted immune response. Nevertheless, the majority of patients eventually exhibit disease progression. A small proportion of patients— estimated by Dr. Lane at probably less than 5%—do not appear to progress. "Longterm nonprogressors" have been the focus of much recent study that has attempted to characterize the immune effector mechanisms of such an apparently potent and enduring response to infection.
Much of the work done in the area of nonprogression has been descriptive and has thus far failed to adequately characterize the mechanisms underlying the phenomenon. In general, those persons categorized as long-term nonprogressors have lower levels of plasma HIV RNA and broader T-cell immune responses, ie, more CD8+ T-cell clones, than do persons who progress more rapidly. In fact, long-term nonprogressors do not constitute a discrete subset of patients; Dr. Lane maintained that it is more likely that "nonprogression" is part of a continuum of responses ranging from very rapid to very slow progression. He cited data from a study in Multicenter AIDS Cohort Study (MACS) patients that showed that those who maintained relatively stable CD4+ cell counts over the first several years of HIV disease still exhibited a characteristic decline in counts in subsequent years. In that study, a cohort of 56 patients who had been identified as longterm nonprogressors on the basis of follow-up over the first 7 years, during which they exhibited a mean CD4+ Iymphocyte count increase of 18 cells/mL per year, were found to have a mean decrease of 67 cells/mL per year over the following 5 years—a rate of decline comparable to that observed in patients exhibiting a more typical infection course.

CD4+ Lymphocyte Dynamics
Studies of CD4+ Iymphocyte dynamics in HIV infection have shown that the immune system is in a state of constant turnover far greater than under normal conditions. This phenomenon is readily demonstrated by the rapid increases in CD4+ cell counts following initiation of effective antiretroviral therapy and by measuring the fractions of CD4+ cells that are in the S phase (actively preparing to divide) at any given time. Despite the increased production of CD4+ cells during HIV infection, there is a steady decline in the number of CD4+ cells over time. Along with this quantitative change, there are qualitative changes that have profound implications for treatment. Studies of changes in "naive" and "memory" CD4+ Iymphocyte populations, analyses of the survival and distribution of genetically marked CD4+ Iymphocytes, and analyses of specificity-mapping of the CD4+ Iymphocyte receptor repertoire all support the conclusions that (1) elements of the T-cell repertoire are lost during progressive infection, and (2) increases in cell counts observed during treatment represent expansion of the remaining elements of the repertoire rather than addition of new or reacquisition of lost elements.

Naive and Memory Cell Dynamics
Antigen specificity of CD4+ lymphocytes is conferred by expression of a/b heterodimers on the cell surface—the T-cell receptors. CD4+ Iymphocytes can be phenotypically characterized as "naive" or "memory" on the basis of CD45R isoform expression: those cells that have a high molecular-weight isoform (CD45RA) are termed naive, while those with a low molecular-weight isoform (CD45RO) are referred to as memory cells. Naive CD4+ T Iymphocytes have a long half-life (>10 years), do not exhibit effecter functions, and express L-selectin, an adhesion molecule that facilitates binding to the lymph node high endothelial venules. The memory T cells have a shorter half-life (1 year), exhibit effecter functions, and express adhesion molecules that facilitate binding to tissues (LFA-1,3 and a4, a5, a6, and b1 integrins).
When T cells exit the ***** thymus, they all bear the high molecular-weight isoform. Through selection processes in the thymus, each cell is "programmed" to respond to a specific potential antigen. Thus, although each cell has a unique specificity, the total cell population produced represents a possible response to an enormous number of different potential antigens. As the cells encounter the antigen for which they are specific (eg, in early life), the CD45 gene undergoes differential splicing in such a way that the low molecular-weight isoform comes out on the cell surface, with clonal expansion of the memory cell. In any individual, the total T-cell population comprises naive cells and memory cells, with the character of the overall system gradually reflecting the specific antigenic environment of that individual. These phenotypes, however, are not stable: naive cells can become memory cells after they encounter their specific antigen, and memory cells can revert to naive cells if they do not encounter antigen.
In initial studies in AIDS patients, a loss of ability to respond to recall antigen was observed, suggesting that memory cells were selectively lost. However, it subsequently has been demonstrated that the proportion of naive CD4+ cells declines as overall CD4+ counts decline (Figure 2); it has been postulated that only memory cells remain by the end stages of HIV infection. Dr. Lane noted that this phenomenon is similar to what is observed in normal aging, suggesting that HIV infection might be likened to an accelerated immune senescence.
With the use of the CD45 marker, characteristics of the CD4+ cells produced during treatment-related increases in cell counts have been examined. Patients who have both naive and memory cells when treatment is initiated exhibit increases in both cell types, whereas those who have lost naive cells exhibit increases only in memory cells despite the fact that the magnitudes of overall increases in CD4+ counts can be identical. The finding that some patients exhibit an increase in naivecell populations suggested that new cells may be entering the system from the thymus, and thus that the system might be able to regain elements of the repertoire deleted through quantitative loss.
However, a number of findings suggest that in fact this is not the case*****. High resolution CT scanning of the thymus during treatment-associated increases in CD4+ cell counts has shown increases in both naive- and memory-cell populations despite involution of the thymus. In one example presented by Dr. Lane, an increase in CD4+ cell counts from approximately 50/pL to more than 500/mL was not accompanied by thymic hyperplasia or other evidence that the cells originated from the thymus ( Figure 3). Labeling of existing cells with a genetic marker has shown that the proportion of marked cells remains constant throughout the expansion of the population, indicating that the increase in cell numbers can be explained by expansion of existing circulating cells, not entry of new cells from the thymus*****.

Polymerase Chain Reaction (PCR) Studies of T-cell Receptor Families
Other data demonstrating that loss of elements of the T-cell repertoire occurs during HIV infection come from PCR studies of T-cell receptor repertoires. A number of different subsets of T cells are produced by rearrangement of the T-cell receptor gene after stem cells enter the thymus. Some of these subsets can be recognized by distinctive T-cell receptor variable region b (Vb) chains. A total of 24 different types of Vb chains has been identified, each of which gives rise to T-cell receptors of 8 different sizes, producing a total of 192 different T-cell receptor families. Selective PCR amplification of the Vb chains allows mapping of the distribution of the different T-cell receptor types.Figure 4 shows the results of such studies in syngeneic twins discordant for HIV infection. Such results indicate that HIV infection is associated with a severe disruption of CD4+ lymphocyte repertoire. This disruption does not appear to be reversed, at least over the short term, by effective antiretroviral treatment. Figure 5 shows the distribution of receptor families for 3 Vb chains before and after treatment with a protease inhibitor and interleukin-2, which resulted in an increase in CD4+ cell counts from 238/mL to 1102/mL.
The determinants of the quality of the CD4+ lymphocyte pool in the context of HIV infection can be understood schematically (see Figure 6). Cells leave the pool both through death as part of the natural remodeling of the immune system and through HIV-induced death. Cells can enter the pool by *****stem-cell differentiation and processing in the thymus in early life or by somatic cell division. In adults, regardless of whether HIV infection is present, the entry of new cells appears to play little, if any, role; the division of cells already existing in the pool accounts for all replenishment of cells lost through natural or other death. Thus, it appears that if diversity within the existing pool is lost in the adult, it is not likely to be replaced, at least during the short term. According to Dr.. Lane, the T cells of the immune system can be viewed as the tiles in a game of Scrabble. In the normal aging process, a memory pool is generated of the letters that are commonly needed; the crucial part of the immune system resides in the memory pool. Some of the naive pool is retained, analogous to the letters that are not used as often. As HIV progresses, there are fewer letters and fewer different letters. As Dr.. Lane noted, it is still possible to communicate with these fewer letters, but far more difficult.

Summary
Current understanding of viral and immune system dynamics can be summarized as follows: (1) HIV infection is characterized by ongoing viral replication that leads to progressive depletion of CD4+ lymphocytes with preferential loss of "naive" cells. (2) This viral replication is Dr.iven by the number of productively infected cells and is associated with an increased turnover of CD4+ lymphocyte. (3) As the CD4+ lymphocyte pool is quantitatively reduced, there is a progressive and irreversible loss in immunologic diversity. Dr. Lane emphasized that these data all point to the importance of early therapeutic intervention in patients with HIV infection.

H. Clifford Lane is Clinical Director at the National Institute of Allergy and Infectious Diseases, National Institutes of Health, in Bethesda, Maryland.
 

Suggested Readings

Chou CC, Gudeman V, O'Rourke S. et al. Phenotypically defined memory CD4+ cells are not selectively decreased in chronic HIV disease. J Acquir Immune Defic Syndr.1994;7:665-675.
Cocchi F. DeVico AL, Garzino-Demo A, et al. Identification of RANTES, MIP-1a and MIP-1b as the major HlV-suppressive factors produced by CD8+ T cells. Science.1995;270:1811-1815.
Embretson J. Zupancic M, Ribas JL, et al. Massive covert infection of helper T lymphocytes and macrophages by HIV during the incubation period of AIDS. Nature.1993;362:359-362.
Graziosi C, Pantaleo G. Gantt KR, et al. Lack of evidence for the dichotomy of TH1 and TH2 predominance in HlV-infected individuals. Science.1994;265:248-252.
Roederer M, Dubs JG, Anderson MT, et al. CD8 naive T-cell counts decrease progressively in HlV-infected adults. J Clin Invest.1995;95:2061-2066.
Rowland-Jones S. Sutton J. Ariyoshi K, et al. HlV-specific cytotoxic T cells in HlV-exposed but uninfected Gambian women. Nat Med.1995;1:59-64.
 

VIRAL LOAD IN CLINICAL TRIALS

Recent findings on plasma viral load and the practical aspects of using viral load data in the clinical setting were discussed at the Los Angeles course by Steven A. Miles, MD, from the University of California Los Angeles

The Use of Viral Load Measurements as Prognostic and Therapeutic Markers

In the last year, the use of viral load assays to measure HIV RNA in plasma has become recognized as an essential part of clinical management for patients with HIV disease. One viral load test, a quantitative reverse transcriptase polymerase chain reaction (RT PCR) test can dependably detect 500 or more copies of HIV RNA/mL of plasma and has been approved by the FDA for diagnostic and prognostic use. Two other tests, branch DNA (bDNA) and nucleic acid sequence based amplification assay (NASBA) have comparable sensitivities but are not yet FDA-approved.
Several studies have now demonstrated the correlation between higher viral load and more-rapid disease progression and death in HIV-infected adults and children. The risk of progression and death grows steadily with increasing viral load. Plasma HIV RNA levels and CD4+ cell counts are independent markers of disease progression, and they should be used in conjunction to monitor disease status and manage antiretroviral therapy.
Ongoing investigations have clarified the prognostic value of viral load measurements in early disease. In a prospective longitudinal study of 74 patients with primary and very early infection, median plasma HIV RNA levels were 235,000 copies/mL at 30 days and 46,000, 52,000, 36,000, and 19,000 copies/mL at 60, 90, 120, and 180 days, respectively. Considerable intersubject variation was observed at all time points. In patients from whom samples were obtained within 6 months of seroconversion, clinical and immunologic progression was not related to the plasma HIV RNA level. After approximately 6 months a steady state "set point" appears to be established. In one study, the plasma HIV RNA level at the post-seroconversion set point level (>6 months after seroconversion) was highly predictive of clinical progression and was related to the risk of death.
Viral load measurements are also valuable in measuring the kinetics of viral and T-cell replication in response to antiretroviral therapy. There is a two-phase viral decay slope, with a 90% to 99% reduction in plasma viral load in the first two weeks of therapy, and a slower second-phase decline to undetectable levels over the next 12 to 24 weeks. This second phase reflects the slower clearance of chronically infected T cells or macrophages.
With potent combination therapies, many patients achieve a level of plasma viral RNA below the limit of detection of the available assays. Newer generation bDNA and RT PCR research assays, which can detect as little as 20 to 50 copies of HIV RNA/mL of plasma have confirmed that "undetectable" does not necessarily indicate "no viral replication." Further, while the virus may be undetectable in the plasma, it may be present in the central nervous system, the lymph nodes, the bone marrow, and other body compartments.
The limits of currently available assays in detecting low levels of plasma HIV RNA complicates the ability to completely assess the effectiveness of antiretroviral regimens and to identify initial failure. The "duration of maximal viral suppression," a term borrowed from oncology, is defined as the time between the trough value for the plasma HIV RNA level and two subsequent values (measured at least four weeks apart) that are at least 0.3 log greater than the trough value. In the studies of ritonavir, the durability of the HIV RNA level response was predicted by the trough value, not by the magnitude or rate of the plasma HIV RNA decline. Thus, with the protease inhibitors, the minimum plasma HIV RNA value achieved with therapy may serve as a prognostic indicator for time to eventual viral rebound.
Clearly, viral load assays are important and powerful tools, but many questions remain about optimal clinical use. Understanding the value and limitations of the assays will help to avoid premature discontinuation of still-effective antiretroviral regimens. Familiarity with logarithms, knowledge of factors that effect plasma viral load, and the ability to assess clinical trial data critically all contribute to optimal use of these assays.

Clinical Use of Viral Load Measurements

Interpreting Logarithmic Data
Several general strategies can simplify the use of viral load data. Table l lists decimal numbers, the exponential forms, and the logarithmic equivalents. To calculate a l-log increase or decrease, add or remove, respectively, the last digit (eg, 1-log decrease from a value of 10,000 is a decrease to 1000). To determine if two plasma HIV RNA values are significantly different, calculate whether there is a threefold difference between them (eg, 150copies/mL to 50 copies/mL represents a significant decline). While these strategies may help in comparing serial viral load measurements, it is important to emphasize that the target viral load value is unequivocally zero.
Factors That Influence Viral Load Measurements
A number of immunologic stimuli, including secondary viral infections such as reactivation of herpes simplex virus; opportunistic infections; influenza; and vaccinations may increase viral load and confound viral load measurements. Suppressing opportunistic or other infections, with the resulting decline in cytokine levels, decreases plasma HIV RNA levels. Other factors that are known to increase viral replication are blood transfusions and poor patient adherence to the drug regimen. One plasma HIV RNA value at any given point in time is difficult to interpret; the ability to assess a patient's response to a drug regimen requires multiple sequential measurements. According to Dr. Miles, if a laboratory value indicates increased viral replication, particularly a modest increase of 0.5 to 0.7 log, it is important to consider laboratory error, a transient intervening influence such as a secondary infection, and poor patient adherence before changing the antiretroviral regimen.
One common clinical question is the value of influenza vaccine for patients with HIV. According to Dr. Miles, while the vaccine is likely to increase HIV replication, an episode of influenza is likely to cause a greater increase. Thus, if a patient is likely to be exposed to influenza, the vaccine is recommended.

Evaluating Virologic Response Data From Clinical Trials
Interpreting virologic response data from clinical trials of antiretroviral therapy is challenging due to the number of factors that can be incorporated into, or not be included in, any particular analysis. According to Dr Miles, four pieces of information are critical: l) the sensitivity of the assay (eg, what is the limit of detection of the method used); 2) the pretreatment viral load; 3) the median decrease in plasma HIV RNA; and 4) the number of patients at each measurement interval (see Table 2).

Conclusions

New generations of viral load tests with greater sensitivity will enable providers and patients to more accurately assess the viral burden and the potency of various antiretroviral therapies. In the near future, proviral DNA assays, which can determine the level of integrative virus, may be used for viral testing in patients with undetectable levels of plasma HIV RNA. At present, however, the available assays provide invaluable markers of disease progression and response to antiretroviral therapy.

Steven A. Miles is Associate Professor of Medicine at the University of California Los Angeles and the UCLA Center for Clinical AIDS Research and Education (CARE Center)
 

Suggested Readings

Brown TM, Steketee RW, Abrams EJ, et al. Early diagnosis of perinatal HIV infection comparing DNA-polymerase chain reaction and plasma viral amplification. Presented at the XI International Conference on AIDS; July 7-11, 1996; Vancouver, BC, Canada. AbstractTu.B. 2374.
Busch M, Schumacher RT, Stramer S. et al. Consistent sequential detection of RNA, antigen and antibody in early HIV infection: assessment of the window period. Presented at the XI International Conference on AIDS; JuIy 7-11, 1996; Vancouver, BC, Canada. Abstract Tu.A. 153.
Cavert W, Staskus K, Zupancic M, et al. Quantitative in situ hybridization (ISH) measurement of HIV-1 RNA clearance kinetics from Iymphoid tissue (LT) cellular compartments during triple-drug therapy. Presented at the 4th Conference on Retroviruses and Opportunistic Infections; January 22-26, 1997; Washington, DC. Abstract LB9.
Hubert JB, Meyer L, Dussaix E, et al and the SEROCO Study Group. Prognostic value of early HIV-1 RNA levels on disease progression in 363 patients with a known date of infection. Presented at the 4th International AIDS Society-USA Conference on Retroviruses and Opportunistic Infections; January 22-26,1997; Washington, DC. Abstract 478.
Kempf D, Mona A, Sun E, et al. The duration of viral suppression is predicted by viral load during protease inhibitor therapy. Presented at the 4th Conference on Retroviruses and Opportunistic Infections; January 22-26,1997; Washington, DC. Abstract 603.
Kotler DP, Shimada T. Clayton E Effect of combination antiretroviral therapy upon mucosal viral RNA burden and apoptosis. Presented at the 4th Conference on Retroviruses and Opportunistic Infections;January22-26,1997;Washington, DC. AbstractLB11.
Lederman M, Connick E, Landay A, et al. Partial immune reconstitution after 12 weeks of HMRT (AZT, 3TC, ritonavir): preliminary results of ACTG 315. Presented at the 4th Conference on Retroviruses and Opportunistic Infections; January 22-26,1997; Washington, DC. Abstract LB13.
Mellors JW. The contribution of viral load measurements. Presented at the Xl International Conference on AIDS; July 7-11,1996; Vancouver, BC, Canada. Abstract Mo.B.533.
Mellors JW, Kingsley LA, Rinaldo CR, et al. Quantitation of HIV-1 RNA in plasma predicts outcome after seroconversion. Ann Intern Med.1995;122:573-597.
Mellors JW, Rinaldo CR, Gupta P. et al. Prognosis in HIV-1 infection predicted by the quantity of virus in plasma. Science. 1996; 272:1167-1170.
Schacker T. Hughes J. Shea T. et al. Viral load in acute and very early HIV infection does not correlate with disease progression. Presented at the 4th Conference on Retroviruses and Opportunistic Infections; January 22-26,1997; Washington, DC. Abstract 475.
Wei X, Ghosh SK, Taylor ME, et al. Viral dynamics in human immunodeficiencyvirustype-1 infection. Nature 1995;373:117-122.
Weverling GH, Keet IPM, de Jong MD, et al. HIV-1 RNA level is set early in the HIV infection and predicts clinical outcome. Presented at the Xl International Conference on AIDS, July 7-11,1996, Vancouver, BC, Canada. Abstract Th.B.4330.
Table 1. Decimal, Exponent and Logarithms

Decimal Number
Exponential Form
Log10

100,000,000
108
8

10,000,000
107
7

1,000,000
106
6

100,000
105
5

10,000
104
4

1,000
103
3

100
102
2

Each number is a tenfold change from the previous

Table 2. Questions to Consider in Evaluating Virologic Response Data From Clinical Trials of Antiretroviral Therapy
What is the sensitivity of the assay used?
What is the baseline (pretreatment) viral load of the population?
What is the mean change in the plasma HIV RNA level?
How many patients were evaluated at each observation interval?
What is the maximum response that could be achieved?
How many patients achieved the maximum response?
What was the HIV disease stage and prior drug history of the population?
 

ADHERENCE: THE ACHILLES' HEEL OF HIGHLY ACTIVE ANTIRETROVIRAL THERAPY
At the recent New York course, Gerald H. Friedland, MD, from the Yale University School of Medicine in New Haven, Connecticut, discussed adherence as a key factor in extending the benefits observed with aggressive combination therapy in clinical trials to the practice setting.
Advances in HIV pathogenesis and viral dynamics, and the availability of viral load assays and potent antiretroviral drug regimens have provided new opportunities to treat patients with HIV disease. Combined aggressive antiretroviral therapy has enormous potential to delay disease progression and death. However, achieving this potential in the practice setting involves addressing the complex behavioral issue of compliance/adherence. Despite different connotations, the terms "compliance" and"adherence" are currently used interchangeably. Adherence is perhaps the more accurate term in that it indicates patient choice in medication taking, but compliance is in more common usage.

Efficacy vs Effectiveness

The term efficacy is used to characterize the definable benefits from a drug or a combination of drugs; measures of efficacy are specific, clearly defined, and usually derived from a controlled clinical trial. Effectiveness, however, refers to how a drug or combination of drugs works in the real world. For many reasons, including methodological issues, wide variations in responses to drug, pharmacologic variability, and the influence of licensing and regulatory goals on the structure of clinical trials, information derived from clinical trials may not necessarily translate well to clinical practice.
Clinical trials are designed to enroll highly-selected populations and the findings are often difficult to generalize to the larger, more diverse patient population in clinical practice. Patients with medical issues such as liver function abnormalities, renal failure, alcoholism, and substance abuse, while common in clinical practice, are excluded from most drug trials. In part due to the maturity of the HIV epidemic, patients presenting in the clinical setting are often heavily pretreated, and have advanced disease. In addition, the behavioral characteristics of patients who enroll in clinical trials differ from those of patients who do not. In a study conducted by Ethier and colleagues at Yale, investigators assessed characteristics of patients in clinical trials, those interested in participating in clinical trials, and those declining participation. Patients choosing to enroll in clinical trials were more likely to be able to keep track of time, to be able to adapt their lifestyle to treatment regimens, and to believe that the value of the drug outweighed the inconvenience of the number of pills involved, and were less fearful of potential of side effects.

Adherence to Treatment Regimens

Studies in the disease areas of hypertension, epilepsy, tuberculosis, and in the geriatric population have demonstrated 1) adherence to drug regimens is poor across populations and diseases; 2) providers cannot predict who will or will not adhere to drug regimens; and 3) providers consistently overestimate patients' adherence to recommended drug regimens.
Clearly, the degree of adherence to therapy effects treatment outcome; low adherence reduces both efficacy and toxicity. Importantly, in the field of HIV disease poor adherence promotes the opportunity for the development of viral resistance. If a patient takes very little or no drug, the likelihood of resistance is relatively low because there is little or no pressure to select a resistant mutant. In theory, if adherence is complete (100%) with potent combination therapy, viral replication will most likely be halted and resistant viral mutants are unlikely. However, in patients who intermittently or irregularly take drugs (the majority of patients in clinical practice setting), the likelihood of selection of mutants that are resistant to the drug(s) increases, a consequence of both continuing viral replication and selective automicrobial pressure.

Determinants of Adherence

As shown in Table 1, adherence to medication has multiple, overlapping determinants. In terms of patient characteristics, social support is probably the most important factor. The literature on adherence strongly and consistently demonstrates that adherence cannot be predicted based solely on age, race, sex, or educational status. Addressing individual health beliefs, and understanding the individuals risk-benefit equation is a key in influencing adherence. Aspects of the patient provider relationship, including trust, consistency, and continued interaction are also important determinants of adherence. In a study by Altice and colleagues conducted among prison inmates with HIV disease, a scale designed to measure trust in physician was used to demonstrate that increased trust was associated with both increased acceptance of and adherence to antiretroviral medication. Characteristics of the treatment regimen also predict adherence. Increasing number of pills, frequency of dosing, duration of therapy, and frequency of side effects all decrease the likelihood of adherence.

Measuring Adherence
Four methods are commonly used to measure adherence: self-report (questionnaire/interviews/diary), pill count, drug assay, and electronic monitoring. Pill counts have been used extensively but are not believed to be accurate; patients may empty the pill box, or take all of the remaining pills before their clinic visit. The accuracy of drug assays depends in part on the half-life of the drug; longer-acting indicators have been used, but testing will show only past ingestion and not frequency or dosing interval.
The Medication Event Monitoring System (MEMS) provides a computer chip in the cap of the medicinal bottle; information is recorded each time the bottle is opened. Figure 1 is an example of MEMS data, and shows the wide variation in adherence patterns for four patients given didanosine therapy. Data from the MEMS allows calculation of 1) the adherence rate, or percentage of pills taken; 2) prescribed frequency; and 3) prescribed interval. A small study of adherence in patients taking antiretroviral therapy revealed that while the overall adherence rate (fraction of doses taken) was 82% to 86%, more detailed measures of the fraction of doses taken at the prescribed daily interval (55%-76%) and fraction of doses taken at the prescribed dosing interval (27%) were lower.

Interventions to Improve Adherence

Table 2 lists strategies for improving adherence to drug therapy. As noted earlier, social and technical support from partners, family members, and health care providers are important elements for enhancing adherence.

Conclusion

Impressive gains have been made in the ability of antiretroviral therapy to suppress viral replication and delay disease progression in patients with HIV. However, given the current recommendations to use highly aggressive combination therapy, drug options remain limited. In order to replicate the findings observed in clinical trials of these combinations, and to maximize the potential of each drug, targeted efforts to increase adherence in the real world clinical setting are essential.

Gerald H. Friedland, MD, is Professor of Medicine, Epidemiology and Public Health at the Yale University School of Medicine, and Director of the AIDS Program at Yale New Haven Hospital in New Haven, Connecticut.
 

Suggested Readings

Altice FL, Mostashari F. Thompson AS, Friedland GH. Perceptions, acceptance and adherence to antiretrovirals among prisoners. Presented at the 4th Conference on Retroviruses and Opportunistic Infections; January 22-26,1997; Washington, DC. Abstract 253.
Besch CL. Compliance in clinical trials. AIDS1995;9:1-10.
Blatschke T. Non-compliance and resistance to protease inhibitors. Presented at the 4th Conference on Retroviruses and Opportunistic Infections; January 22-26,1997; Washington, DC. Abstract S43.
Cotton D, Finkelstein D, He W. Feinberg J. Determinants of accrual of women to a large multicenter clinical trials program of human immunodeficiency virus infection. The AIDS Clinical Trials Group. J AIDS1993;6:1322-1328.
Cramer JA, Mattson RH, Prevey ML, et al. How often is medication taken as prescribed? A novel assessment technique. JAMA.1989;261 :3273-3277.
Craven DE, Liebman HA, Fuller J. et al. AIDS in intravenous drug users: Issues related to enrollment to clinical trials. J AIDS1990;S3 :45-50.
El-Sadr W. Capps I. The challenge of minority recruitment in clinical trials. JAMA1992;267:954-957.
Epstein LH. The direct effects of compliance on health outcome. Health Psychol1984;3 :385-393.
Ethier K, Rodriquez M, Fox-Tierney R. Martin C, Friedland GH, Ickovics J. Recruitment in AIDS Clinical Trials: (Submitted).
Griffith S. A review of the factors associated with patient compliance and the taking of prescribed medicines. Br J Gen Pract 1990;40:114-116.
Haynes RB, Taylor DW, Sackett DL. Compliance in Health Care. Baltimore, MD: Johns Hopkins University Press, 1979.
Horwitz Rl, Horwitz SM. Adherence to treatment and health outcomes. Arch Intern Med1993:153:1863-1868.
Sackett DL, Snow JC. The magnitude of compliance and noncompliance. In: Haynes RB, Taylor DW, Sackett DL, eds. Compliance in Health Care. Baltimore, MD: Johns Hopkins University Press, 1979.
Samet JH, et al. Compliance with zidovudine therapy in patients infected with human immunodeficiency virus, type 1: A crosssectional study in a municipal hospital clinic. Am J Med.1992:495-501.
Selwyn, PA. HIV therapy in the real world. Editorial Comment. AIDS1996;10;1591 -1593.
Urquhart J. Compliance and clinical trials. Lancet1991;337:1224-1225.
Urquhart J. Role of patient compliance in clinical pharmacokinetics: A review of recent research. Clin Pharmacokinet1994;27:202-215.
Wright EC. Non-compliance-or how many aunts has Matilda? Lancet1993;342:909-913.

Table 1. Factors That Affect Adherence,
Patient Characteristics
Knowledge
Social support
Beliefs
Trust in Provider
Demographic characteristics
Treatment Regimen
Number of medications
Frequency of dosing
Complexity
Duration
Side Effects
Degree of behavioral change required
Patient-provider relationship
Trust
Consistency
Level of supervision
Simiilar demographics characteristics

Table 2. Interventions to Enhance Adherence
 

Provide peer education and support

Use existing lifestyles

Involve family members and partners

Pay attention to food/no food requirements

Provide substance abuse treatment

Avoid unnecessary medications

Provide financial support/ensure drug availability

Simplify regimens (bid vs tid)

Build trust and offer consistency

Monitor and mange side effects proactively

Provide appropriate and persistent information
and reinforcement

Involve nonphysician providers

Do medication checks

Eleicit health beliefs

Link adherence to treatment goals
(ie, viral load)

Use modified directly observed therapy (DOT)
 
 

PAIN MANAGEMENT IN HIV DISEASE

Pain is common in persons with advanced HIV disease. It has many causes and presentations. Many physicians may tend to minimize the pain that HIV-infected patients experience. The management of pain in HIV disease was discussed by William Breitbart, MD, in New York and by Mathew Lefkowitz, MD, in Los Angeles. In their presentations Drs. Breitbart and Lefkowitz emphasized that pain in HIV disease is often undertreated and reviewed the extensive HlV-related pain syndromes, the existing guidelines for assessing and managing this pain, and the analgesic and other agents that are available for treating it.
Pain is highly prevalent and dramatically undertreated in patients with HIV disease. The prevalence increases as the disease progresses; data from various studies indicate that clinically significant pain occurs in approximately 25% of patients with early HIV disease, in 50% of ambulatory patients with AIDS, and in 90% or more of patients in hospice and palliative care units. With an intensity comparable to that of cancer pain, HIV-related pain is associated with significant psychological, functional, and physical morbidity.

Pain Syndromes in HIV Disease

The pain associated with HIV disease is diverse in its presentations and causes: more than 100 distinct syndromes have been described in patients with HIV disease. Approximately 50% of these syndromes are related directly to the HIV infection or the associated opportunistic infections and neoplasms, approximately 30% are due to anti-HIV therapies or diagnostic procedures, and approximately 20% are not related to either HIV infection or the associated therapies (Table 1). The most common pain syndromes reported by patients with HIV disease are abdominal pain, peripheral neuropathy, oropharyngeal pain, headache, arthralgias and myalgias, painful dermatologic conditions, and back pain. In addition, there are painful gynecologic and pelvic syndromes that are unique to women with HIV disease.
Typically, two or three different pain syndromes are occurring simultaneously in patients with HIV-related pain. Approximately 40% of the pain syndromes in patients with HIV disease have neuropathic origins, resulting from damage to the peripheral nervous system. The remaining 60% of the pain syndromes are somatic or visceral in origin, resulting from damage to the skin, muscles, and soft tissue and from processes that involve the visceral organs of the abdomen.

Strategies for Managing Pain in HIV Disease

In developing an approach to managing pain it is important that clinicians understand that HIV-related pain, like cancer pain and other chronic pain, is multidimensional. More than just the physical phenomenon, the experience of pain includes cognitive aspects, such as the meaning of pain; emotional aspects, such as fear, anxiety, and depression; and socioenvironmental factors, such as social support, financial stability, and issues related to substance abuse. The psychosocial components of pain may be more pronounced in patients with HIV disease. One study by Breitbart and colleagues found significantly higher rates of depression, overall psychological distress, hopelessness, and suicidal ideation in patients with AIDS-related pain than in patients with pain that was related to other diseases. Patients with AIDS-related pain in this study who interpreted new occurrences of pain as progression of their HIV disease reported significantly greater pain intensity than those who saw no connection between their pain and progression of their disease.
An optimal approach to pain management is multidisciplinary, and includes pharmacologic therapy, cognitive/behavioral interventions, and psychosocial therapy (Table 2). Given limited resources, however, analgesic therapy can achieve adequate pain relief in only 80% to 85% of patients with HIV-related pain. This summary focuses on the pharmacologic management of pain.
Analgesic Therapy for Pain
Appropriate analgesic drugs can be selected with the aid of tools like the World Health Organization (WHO) Analgesic Ladder ( Figure 1), which is based on principles developed over the last two decades for managing cancer pain. In the WHO Analgesic Ladder the assessment is based on the intensity and type of the pain. Intensity is typically assessed on a 1-to-10 scale. Treating patients with mild pain (1-3 score) would begin at the bottom of the ladder, with a nonopioid drug such as acetaminophen or a nonsteroidal antiinflammatory drug (NSAID). Persistent or increasing pain or an initial presentation with moderate pain (4-7 score) would call for the use of a weak opioid (such as codeine, hydrocodone, or oxycodone) together with a nonopioid. If the pain persists or increases, or a patient presents with severe pain (8-10 score), the use of strong opioids (such as morphine or methadone) is appropriate. Adjuvant drugs may be added at any level of the ladder. Data on specific analgesic and adjuvant drugs are provided in Tables 3 and 4.
Nonopioid Analgesics
Nonsteroidal anti-inflammatory drugs are effective in the treatment of mild to moderate pain, particularly nociceptive pain, or pain secondary to tissue inflammation or trauma. Toxicity is the limiting factor with NSAIDs. In addition, caution is required in giving NSAIDs, which are highly plasma protein-bound, to patients with advanced HIV disease. The incidence of toxic effects, including blood dyscrasias, increases in bleeding time, gastric damage, renal effects, and hepatic reactions, may be higher in patients with hypoproteinemia that is due to wasting. Acetaminophen is not as effective in HIV-related pain, and toxic effects occur at doses greater than 1000 mg q4h.
Opioid Analgesics
Opioid drugs are the basis for managing moderate to severe pain, and can be categorized as short-acting and long-acting. The dose and the schedule of administration depend on a number of factors, including the severity and type (nociceptive or neuropathic) of the pain, side effects, and individual patient tolerance.
Within the category of short-acting opioids, the weaker agents include hydrocodone and codeine. Codeine is commonly prescribed, but it has only a weak analgesic effect and is associated with constipation. Propoxyphene and opioid agonists/antagonists are not recommended. The stronger, short-acting opioids include morphine, oxycodone, and methadone. Methadone is an inexpensive alternative, with high bioavailability and a variable duration of analgesia. Meperidine is associated with a higher incidence of side effects, and may cause central nervous system (CNS) excitation, seizures, tremor, and multifocal myoclonus.
Patients who are taking 5 to 10 doses of short-acting opioids a day may have to be shifted to long-acting opioids, such as sustained-release morphine or sustainedrelease oxycodone, which provide analgesia for 8 to 12 hours. These drugs provide more-constant serum levels and facilitate convenient dosing and administration, which result in substantial psychological benefits. Sustained-release morphine sulfate is administered on a ql2h schedule, but more-frequent dosing may be required in patients with AIDS because of their increased metabolic rate and the drug's variability in absorption. Peak plasma concentrations are achieved in approximately 4 hours and steady-state levels in 1 to 2 days. In patients with a daily morphine requirement of less than 120 ma, sustainedrelease morphine sulfate should be initiated at a dose of 30 mg ql2h. There is no evidence of drug accumulation, and the side effects are comparable to those with the immediate-release formulation.
The fentanyl transdermal system, which provides analgesia for up to 72 hours, is an alternative in patients who may not be able to tolerate additional oral medications. Fentanyl is effective for both nociceptive and neuropathic pain that cannot be managed with an acetaminophen/opioid combination, NSAIDs, or short-acting opioids in prn doses. Delivered through a microporous membrane, a fixed amount of fentanyl is absorbed into the skin, creating a reservoir that is available for systemic circulation. Because analgesic levels of the drug are not reached until 12 hours after the patch has been applied, and because the dose cannot be adjusted immediately, it is important to provide patients with shortacting opioids for breakthrough pain. A number of factors, including high fever, broken skin beneath the patch, and low body fat, increase the rate of reservoir depletion and limit the duration of analgesia.
Adjuvant Drugs
At each step in the analgesic ladder the use of adjuvant drugs is an option; some selected drugs are listed in Table 4. The adjuvant drugs include antidepressants and anticonvulsants, which are used primarily in treating neuropathic pain, and various other drugs that are used to prevent or counteract the side effects of opioid drugs.
The antidepressants potentiate the analgesic effects of opioid drugs and also have an independent analgesic effect. These agents function by altering the level of neurotransmitters, such as serotonin and norepinephrine, in the central nervous system and through direct effects on damaged nerves, eg, by decreasing the paroxysmal discharges of damaged nerves and decreasing the sensitivity of adrenergic receptors on budding nerve sprouts. The tricyclic agents have been studied most extensively for pain relief, and are first-line therapy for burning, tingling, and numbing neuropathic pain. The onset of their analgesic effect is approximately 3 days, with peak effects occurring within 2 to 6 weeks. Of the tricyclic antidepressants, amitriptyline is the gold standard of analgesic antidepressants. Of the newest serotonin specific reuptake inhibitors (SSRIs), only paroxetine appears to have analgesic effects in a neuropathic pain model, although other SSRIs may be helpful in headache and back pain. Patients should be counseled when antidepressants are initiated that a serial trial of a variety of drugs may be necessary to determine which is the most effective. Greater caution is required when these drugs are used in patients with HIV dementia or other CNS complications, cardiac arrhythmias, or hepatic dysfunction.
The anticonvulsants, including carbamazepine, valproic acid, phenytoin, gabapentin, and clonazepam, are first-line therapy for electric, shooting, and intermittent neuropathic pain. These drugs are also used for neuropathic pain that is refractory to antidepressants. Their potential adverse effects necessitate close clinical and laboratory monitoring, including serum drug levels.
In addition, mexilitene blocks sodium and potassium channels and may play a role in treating refractory neuropathic pain. Corticosteroids stabilize neuronal membranes and reduce the swelling around tumors. The short-term use of corticosteroids may increase patients' appetite and weight gain and improve their mood, but side effects of these drugs prohibit their long-term use.
Adjuvant Drugs to Counteract Opioid
Side Effects
An additional category of different types of adjuvant drugs includes laxatives, antiemetics, antihistamines, psychostimulants to counteract sedation, and neuroleptics to counteract hallucinations.

Undertreatment of Pain in HIV Disease

Pain is significantly undertreated in HIV disease. Dr Breitbart and his colleagues recently examined the use of analgesics in 550 ambulatory patients with AIDS in New York City. Of 114 patients who reported severe pain (a score of 8 to 10 on the rating scale of 1 to 10) more than 25% were taking no analgesics, 40% were taking an NSAID, and 6% were taking a strong opioid. On the basis of the guidelines in the WHO Analgesic Ladder, a strong or long-acting opioid should be considered in all patients who report pain of this intensity.
Using the pain-management index, a measure for comparing the potency of the analgesics prescribed with the intensity of the pain reported, Breitbart and colleagues were able to compare the pain management used in patients with HIV disease with that used in patients with cancer. According to this pain-management index, only 15% of the 235 patients with HIV disease who reported pain were being given adequate analgesic therapy. The factors that predicted undertreatment in the subset of patients with AIDS were female sex, lower educational levels, injection drug use as a risk factor for HIV infection, greater levels of pain intensity, and patient-related barriers such as being reluctant to complain about pain so as to avoid being labeled a problem patient and to avoid deflecting the focus of treatment from the life-threatening aspects of the disease. Cleeland and colleagues used the same index to evaluate the management of cancer-related pain in 597 patients in Eastern Cooperative Oncology Group studies. In contrast to what Breitbart and colleagues found, 58% of the patients in this analysis were being given adequate analgesic therapy.
Physicians may be reluctant to prescribe opioid drugs for patients with moderate or severe pain for many reasons; some major ones being the physicians' relative lack of knowledge about pain management, lack of ability to assess pain objectively, and fear of contributing to drug abuse or causing readdiction in patients with a history of substance abuse. Not only is the prevalence of HIV-related pain somewhat higher in women, but these women are also twice as likely to be undertreated as are men. Women may have a higher tolerance to pain and may also be more likely to deny the symptom. Problems with communication may complicate effective pain management in children with HIV disease and in patients with HIV-related dementia.
The reluctance of physicians to prescribe opioid medications is a particular obstacle to effective pain management in patients with a history of substance abuse, particularly injection drug use. Patients with a history of injection drug use are the most rapidly growing segment of the population living with HIV disease; the overt and covert issues associated with pain management in this population have to be addressed. The label "substance abuser" may be misleading; it is important to differentiate between patients who are actively using drugs, those who are in methadone maintenance programs, and those who are in recovery. It is also important to distinguish between drug tolerance, physical dependence, psychological addiction, and drug abuse.
There is a tendency to distrust reports of pain from patients with a history of substance abuse. However, one study by Breitbart and colleagues that compared the experience of pain in 138 patients with a history of injection drug use with that in 112 patients with no history of injection drug use or substance abuse, found no significant differences in pain prevalence, intensity, or relief or pain-related functional interference in the two groups.
The need for pain medication in patients with a history of injection drug use who are in methadone maintenance programs is a separate issue from their need for methadone on a daily basis to prevent drug withdrawal. With a long plasma half-life, 36 to 72 hours, methadone binds to opioid receptors to prevent withdrawal and drug craving. The duration of analgesia in patients given methadone 40 to 100 mg/d is approximately 6 hours. Tolerance to the analgesic effect of opioids develops in patients who have been in methadone maintenance therapy for a long time. Two options for managing pain in patients in methadone maintenance therapy are increasing the daily dose of methadone and giving it on a q6h or a qid basis, or adding a long-acting opioid. Methadone is the less expensive alternative, but access to the drug may be limited.
Pain medications are, in fact, abused. However, clinicians have an obligation to treat pain in all patients and all reports of pain should be accepted and respected. The potential for abuse with opioids may be minimized by establishing clear goals, conditions, limits, and consequences of abuse. Written contracts with certain patients may be useful. It is also important to establish that there will be but one prescriber and to be alert to behaviors that point to drug abuse. A multidimensional approach to pain management that incorporates pharmacologic, psychosocial, and other interventions may also reduce the potential for abuse.

Summary

Effective pain management improves the quality of life in persons with HIV disease considerably. Yet, despite a great number of effective agents and proven guidelines for using them, pain is significantly undertreated in this population, especially in women and persons with a history of substance abuse. Pain is a complex, subjective, and multidimensional experience; optimal management of pain requires individual treatment plans that address the physical, psychological, and social components of the pain. Nursing organizations and hospices have advanced the practice of pain management in HIV disease, but, among many physicians, a relative lack of information on pain anagement strategies and a resistance to prescribing opioid drugs remain key clinical obstacles.

Dr Breitbart is Associate Attending Psychiatrist at Memorial S/oan-Kettering Cancer Center, in New York City. Dr Breilbart's work is supported by the Faculty Scholars Program, Project on Death in America, the Emily Davie and Joseph S. Cornfeld Foundation, NCI Grant # IR25CA57790 and NIMH Grant # MH4903.
Dr Lefkowitz is Clinical Associate Professor of Anesthesiology at the State University of New York Health Sciences Center, in Brooklyn.

Suggested Readings

Anand A, Carmosino L, Watt, AK. Evaluation of recalcitrant pain in HlV-infected hospitalized patients. J AIDS. 1994;7:52-56.
Breitbart W. McDonald MV, Rosenfeld B. et al. Pain in ambulatory AIDS patients. I: Pain characteristics and medical correlates. Pain. 1996;68:315-321.
Breitbart W. Rosenfeld BD, Passik SD, et al. The undertreatment of pain in ambulatoryAIDS patients. Pain. 1996;65:243-249.
Breitbart W. Pharmacotherapy of pain in AIDS. In: Wormser GP, ed. A Clinical Guide to AlDS and HIV. Philadelphia, PA: Lippincott-Raven Publishers, 1996;359-378.
Carr DB, Dubois M, Luu M, Shepard KV. Pharmacotherapy of pain in HIV/AIDS. In: Carr DB, ed. Pain in HIV/AIDS: Proceedings of a workshop convened by France- U.S.A. Pain Association. Washington, DC: France-U.S.A. Pain Association, 1994;18-28.
Lebovits AK, Lefkowitz M, McCarthy D, et al. The prevalence and management of pain in patients with AIDS. A review of 134 cases.
Lipton RB, Feraru ER, Weiss G, et al. Headache in HIV-1 related disorders. Headache. 1991 ;31 :518-522.
McCormack J P, L i R, Zarowny D, Si nger J. I nadequate reatment of pain in ambulatory HIV patients. ClinJ Pain. 1993;9:279-283.
O'Neill WM, Sherrard JS. Pain in human immunodeficiency virus disease: a review. Pain. 1993;54:3-14.
Rosenfeld B, Breitbart W, McDonald MV, et al. Pain in ambulatory AIDS patients. Il: Impact of pain on psychological functioning and quality of life. Pain. 1996;68:323-328.
Simpson DM, Wolfe DE. Neuromuscular complication of HIV infection and its treatment. AIDS. 1991 ;5:917-926.
Singer EJ, Zorilla C, Feby-Chandon B, et al. Painful symptoms reported for ambulatory HlV-infected men in a longitudinal study. Pain. 1993;54:15-19.

Table 1. Causes of Pain Syndromes in Persons with HIV Disease and AIDS
Syndromes related to HIV disease or the consequences of immunosuppression
HIV neuropathy
HIV myelopathy
Kaposi's sarcoma
Secondary infections (intestinal, dermatologic)
Organomegaly
Arthritis, vaculitis
Myopathy, myositis
Therapy or diagnostic procedures that may cause pain syndromes
Antiretrovirals, antivirals
Antimycobacterials, PCP prophylaxis
Chemotheraly (eg. vincristine)
Radiation, surgery
Procedures (eg. bronchoscopy, biiopsies)
Syndromes unrealated to HIV or therapy
Intervertebral disc disease
Headaches

Table 2. An Approach to Pain Managment
Take comprehensive history and perform thorough physical examination
Medication history
Substance use/abuse history
Neurologic and psychologic assessments
Localize and characterize the print
Be aware of multifaceted etiology
Rule out infections and malignancies
Treat medical and psychological causes of pain
Use pain consultants as needed

Table 3. Analgesics for Managing Pain in HIV Disease and AIDS
Analgesic
Route
Dose (mg)
Duration (h)
Plasma half life (h)
Comments

NSAIDS

Aspirin
po
650
4-6
4-6
The standard for comparison among nonopioid analgesics

Ibuprofen
po
400-600
---
---
Like aspirin, can inhibit platelet function

Choline magnesium
po
700-500
---
---
Essentially no hematologic or gastrointestinal side effects

Short-acting opoids

Codeine
po
32-65
3-4
---
Metabolized to morphine; often used to suppress cough in patients at risk for pulmonary bleeding

Oxycodone
po
5-10
3-4
---
Available as a single drug and in combination with aspirin or acetaminophen

Propoxyphene
po
65-130
4-6
---
Toxic metabolite nonpropoxy accumulates with repeated dosing

Long-acting opoids
 

Morphine, sustained release
po
90-120
8-12
---
Now available in long-acting sustained-release forms

Oxycodone, sustained release
po
20-40
8-12
2-3
In combination with aspirin or acetaminophen it is considered a weaker opoid; as a single drug it is comprable to the stong opioids, like morphine

Fentanyl system
transdermal
.025
48-72
2-3
Transdermal patch is convenient, bypassing GI analgesia until depot is formed; not suitable for rapid titration
 

Table 4. Psychotropic Adjuvant Analgesic Drugs

Drug
Approximate daily dose (mg)
Route

Tricyclic antidepressants

Amitriptyline
10-150
po, IM

Nortriptyline
10-150
po

Imipramine
15.5-150
po, IM

Desipramine
10-150
po

Clomipramine
10-150
po

Doxepin
12-150
po, IM

Heterocyclic and noncylcic
antidepressants

Trazodone
125-300
po

Maprotiline
50-300
po

Serotonin reuptake
inhibitors

Fluoxetine
20-80
po

Sertaline
50-200
po

Newer agents

Nefazodone
100-500
po

Venlafaxine
75-300
po

Psychostimulants

Methylphenidate
2.5-20 bid
po

Dextroamphetamine
2.5-20 bid
po

Pemoline
13.75-75 bid
po

Phenothiazines

Fluphenazine
1-3
po, IM

Methotrimeprazine
10-20 q6h
IM, IV

Butyrophenones

Haloperidol
1-3
po, IV

Pimozide
2-6 bid
po

Antihistamines

Hydroxyzine
50 q 4h or q6h
po

Corticosteroids

Dexamethasone
4-16
po, IV

Benzodiazapines

Alparazolam
0.25-2 tid
po

Clonazepan
0.5-4 bid
po

--
*****

(UPDATED Feb 12, 2000)

LINK:
http://hivinsite.ucsf.edu/topics/basic_science_pathogenesis/2098.4084.html

Molecular Insights into HIV Pathogenesis
Recent Studies of T Cell Kinetics: What Do They Mean?
Marc Hellerstein, MD, PhD
Associate Professor of Medicine
University of California, San Francisco
Progressive depletion of CD4+ T cells is a defining feature of HIV disease. The reason why T cell counts drop has remained uncertain, however. This central question, along with the related question of how highly active antiretroviral therapy (HAART) increases CD4 counts, was the subject of our recent study published in Nature Medicine (Vol. 5:83-89, January 1999).
T cells, like all tissues in the body, do not exist in a static condition; there are always some new cells being produced to replace cells that have died or been removed. This process of replacement is also called turnover. The question in relation to HIV disease is therefore, does the virus accelerate the destruction of T cells, impair their production, or both? Similarly, does HAART reduce T cell destruction, increase production, do both, or do something else (e.g., simply change their distribution between tissue and blood)?
The reason that this basic question had not previously been answered was technical: there was no technique available for accurately measuring the rates of production and destruction of T cells that could be used in humans. In fact, the normal rates of T cell production and the normal survival time (half-life) of T cells in healthy, HIV-uninfected people were not known.
Papers using indirect methods to address this issue had been published, but the results have been contradictory. David Ho's group and George Shaw's group measured the rate at which blood CD4 counts increased after starting HAART, as a strategy for estimating T cell turnover prior to therapy. The assumption here was that HAART stopped all death of CD4 T cells, so that the accumulation of cells was identical to their production rate. This is analogous to a sink where the drain has been plugged: the rate at which the water level rises reveals the flow rate into the sink from the tap. This assumption that all T cell death stops in HAART is unlikely to be correct, however, since HIV-uninfected people normally exhibit T cell turnover. Another assumption was that HAART has no effect on T cell production, so that the post-HAART production rate represents the pre-therapy rate. This is unproven - indeed, this could be precisely how antiviral therapy works. Also, it had to be assumed that the higher counts reflected new cells, not just redistribution of already existing cells from tissues into blood, which could not be excluded by this method. Finally, no one really knew what a normal T cell turnover rate should be, for comparison. Whether the CD4 accumulation rates after HAART represented high, normal or low turnover could not therefore be stated with certainty.
Subsequent studies using other indirect methods added to the uncertainty. Some reports, such as the work from Frank Miedema's group measuring the rate at which T cell chromosome tips (telomeres) shortened, found no evidence for high turnover of CD4+ T cells in HIV-infected humans.
We were able to work on this question because of technical advances. About two years ago, my laboratory developed a new method for measuring the production and destruction rates of cells that did not involve radioactivity or other toxic agents, and therefore could be used safely in people. This method involves stable (non-radioactive) isotope tagging of newly synthesized DNA followed by detection using mass spectrometry. Then, last year Mike McCune's laboratory developed techniques for isolating sufficient numbers of purified T cell subpopulations (such as CD4+ and CD8+ T cells) from blood, using fluorescent activated cells sorting (FACS), to measure turnover by mass spectrometry. These two technical developments allowed us to measure human T cell production and survival directly in people, for the first time.
We compared three groups in our study: healthy HIV-uninfected controls, people with advanced HIV infection who were taking no antiretroviral therapy (average CD4 count 342/µL, viral load 94,000), and previously untreated patients who had been started on a HAART regimen that included ritonavir/saquinavir exactly 12 weeks before (pre-HAART CD4 counts 184/µL; post-HAART 358/µL, all with undetectable viral load on HAART). The HAART group had reached a stable, though higher, CD4 count when we studied them at 12 weeks of therapy. All subjects received the stable isotope label intravenously for two days (48 hr). Blood T cells were then isolated. Labeling of T cell DNA was measured over the subsequent two weeks.
This technique allows two parameters to be characterized: (1) the fraction of newly produced T cells present and (2) the total number of T cells that were newly produced. Because T cell counts were at a steady-state in all the groups, each new cell made must be balanced by the loss of another cell (i.e., new produced cells replaced dying cells). The first parameter therefore tells us not only the fraction of cells being produced but also the fraction of the T cell population that was dying per day - the average survival time. The second parameter tells us the total output of T cells into the bloodstream - the production capacity of T cell generating systems being expressed. Thus, our study, which represents a classic kinetic analysis using an endogenous labeling approach, could distinguish specifically between effects on the production (input) and destruction (outflow) sides of the T cell kinetic equation.
We found, first of all, that in normal healthy people, about ten new CD4+ T cells enter the bloodstream daily and the survival time (half-life) of CD4+ T cells is about three months (87 days). In untreated HIV disease, the survival time of CD4 cells was shorter (half-life about 24 days) and there was no compensatory increase in total CD4 production (nine new blood CD4 cells produced per day). Based on studies in animals, when T cell counts are made low, the system normally responds by increasing T cell production dramatically; but this was not observed in these lymphopenic HIV-infected subjects.
So, our first conclusion was that the low CD4 counts in advanced HIV disease are due to both a shortened survival time and a failure of the system to compensate by increasing CD4 T cell production.
In HIV-infected subjects after short-term (12 weeks) HAART, T cell kinetics were very different. The total CD4 production rate was higher (18 new cells produced per day) than in untreated patients and the sum of CD4+ plus CD8+ production rates was increased even more (to 71 cells/day) from 34 in untreated HIV). Responses in individual subjects showed considerable variability, however, and there was a strong correlation between the rate of CD4+ T cell production and the CD4 count that was attained on HAART. These findings indicate that HAART improved the capacity to make new T cells (both CD4+ and CD8+), at least in those subjects who responded clinically by increasing their CD4 counts.
What effect did HAART have on the shortened survival of T cells observed in untreated patients? This was perhaps the most unexpected finding: the survival of CD4+ and CD8+ T cells was even shorter, not longer, on HAART (half-lives of 14 days for both CD4+ and CD8+ cells). We believe that this reflects non-HIV-mediated cell death related to the activation of T cell proliferation - also termed activation-induced cell death (AICD). The phenomenon of AICD is well described in many other immunologic settings, but we can only speculate that AICD is the explanation here for shorter half-lives of T cells on HAART. The fact that survival was shorter for both CD4+ and CD8+ T cells supports the conclusion that it reflects non-HIV-mediated cell death.
The kinetic results are nevertheless clear, regardless of the biological explanation: the basis for higher CD4 counts after short-term HAART was a greater production rate, not a longer half-life, of circulating CD4+ T cells. HAART therefore opened the T cell "tap" into the bloodstream rather than closing the T cell "drain" from the bloodstream.
What are the implications of this study, and what questions were not answered?
Some firm conclusions can be drawn from these results:
CD4 lymphopenia in advanced HIV infection is due to both a shortened survival time and a failure to increase the production of circulating CD4+ T cells.
The increase in CD4 counts after short-term HAART is not due to simple redistribution of T cells from tissue into blood (there were more newly produced cells present).
The increase in CD4 counts after short-term HAART was related to higher production rate (greater inflow of new cells into the bloodstream), not longer survival of cells in the bloodstream.
Thus, these results make the (optimistic) suggestion that T cell producing systems are impaired but not irreversibly damaged or exhausted in advanced HIV disease. If HIV itself suppresses T cell generation (e.g., in the thymus ***** or peripheral lymphoid tissues) this is a very different scenario than if the system were terminally damaged or "burned out," due to a long-standing strain on proliferative reserves.
This model, if it proves true, would have some therapeutic implications. Adjunctive immunostimulatory therapies might prove effective in addition to antiretroviral therapy, if T cell production capacity is a key factor determining CD4 counts. Patients may also differ in their ability to produce new T cells; kinetic measurements may identify those individuals with T cell production that is HAART-unresponsive and might help select the patients who are most likely to benefit from adjunctive therapies. Preservation of T cell proliferative reserve might be a goal in its own right that will need to be considered in designing therapeutic strategies in the future.
It is important to emphasize that there remain several basic questions that were not resolved by our study. Because we only measured T cell kinetics in the bloodstream in this first study, we can draw no conclusions yet about what was occurring in the tissues. We can not exclude the possibility, for example, that newly produced T cells were being killed by HIV in the tissues prior to antiretroviral therapy and were allowed to escape into the bloodstream in the patients on HAART. The underlying reason why more newly produced T cells enter the bloodstream on HAART therefore needs to be determined. This can be done by comparing labeling in tissue biopsy samples to blood; we have begun to perform these studies (and are presently looking to enroll antiretroviral naïve or recently started HAART subjects for such studies).
Our study also did not characterize T cell kinetics in various other phases of the natural history of HIV disease or the response to HAART. T cell production or survival might be very different in early HIV infection, for example, or after long-term HAART. These questions can be addressed using the same techniques, however.
Also, we did not show where the new T cells came from. Were they "naïve" cells from the thymus or "memory" cells from the peripheral lymphoid tissues? Studies isolating "naïve" and "memory" T cells are in progress to address this question.
In summary, measurement of T cell kinetics has already revealed some interesting features about HIV infection and antiretroviral therapy, but much remains to be done. (*****LG Comment: However, studies conducted since this publication, indicate critical data related to this subject)