Diseases of the Immune System

Read about HIV infection, AIDS, Chronic Fatigue Syndrome and Primary Immunodeficiency Diseases.

AIDS and the Immune System

STATEMENT OF
JOHN Y. KILLEN, M.D.
DIRECTOR
DIVISION OF ACQUIRED IMMUNODEFICIENCY SYNDROME
NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
NATIONAL INSTITUTES OF HEALTH
BEFORE THE
COMMITTEE ON GOVERNMENT REFORM
UNITED STATES HOUSE OF REPRESENTATIVES
JULY 22, 1999

Mr. Chairman and Members of the Committee, I am pleased to appear before you today to discuss the human immunodeficiency virus (HIV) epidemic, recent developments in HIV research, and the many challenges that remain in the fight against HIV and the acquired immunodeficiency syndrome (AIDS).

The Scope of the Epidemic

AIDS was recognized eighteen years ago this summer, and continues to exact an enormous toll throughout the world, in both human and economic terms. In the United States, the rate of new HIV infections—approximately 40,000 per year—remains unacceptably high, despite an encouraging downturn in new AIDS cases and AIDS-related deaths.

In the developing world, the HIV/AIDS epidemic continues to accelerate, notably in sub-Saharan Africa, southeast Asia and on the Indian sub-continent. There are also signs of expanding epidemics in Russia and other New Independent States of the former Soviet Union. As of the end of 1998, more than 33 million people worldwide were living with HIV/AIDS, according to estimates by the Joint United Nations Programme on HIV/AIDS (UNAIDS). An estimated 5.8 million new HIV infections occurred worldwide during 1998—approximately 16,000 new infections each day. More than 95 percent of these new infections occurred in developing countries. Alarmingly, in 27 developing countries, HIV prevalence more than doubled between 1995 and 1997. In 1998, HIV/AIDS was the fourth leading cause of mortality worldwide, resulting in an estimated 2.3 million deaths.

Beyond the human tragedy of HIV/AIDS, the economic costs of the epidemic are staggering, posing a significant impediment to the growth and stability of many countries where the epidemic is decimating a limited pool of skilled workers and managers as well as young people at the peak of their productive years. According to UNAIDS, life expectancy in the nine countries in Africa with the highest HIV prevalence rates will, for the first time in many years, decline an average of 17 years by 2015 due to HIV/AIDS.

Clearly, HIV remains one of the greatest threats to global health, and requires a sustained commitment by the various partners in AIDS research and prevention: U.S. and foreign government agencies, UNAIDS, non-governmental and philanthropic organizations, academia, industry, and the activist community. This week Vice President Gore reinforced the Administration’s commitment to combating AIDS worldwide by announcing a proposal to spend an additional $100 million in FY 2000 on prevention and treatment strategies, community-based care and assistance for children orphaned by AIDS.

Today, I will focus on NIH’s role in the development of treatment and prevention strategies for HIV/AIDS.

Antiretroviral Therapies

As noted above, new AIDS diagnoses and deaths have dropped significantly in the United States in the past two years, and the same is true in other developed countries. These trends are probably due to several factors, particularly the increased use of potent, albeit expensive, combinations of HIV drugs. Sixteen antiretroviral drugs are now licensed in the United States, and several new agents are in various stages of clinical testing. Consensus guidelines have been developed for the use of anti-HIV medications that, when appropriately applied, have greatly improved the prognosis for HIV-infected individuals.

Unfortunately, many HIV-infected individuals have not responded adequately to the medications, cannot tolerate their toxicities, or have difficulty adhering to complex dosing schedules and substantial pill burdens. In addition, the ability of HIV to mutate and become resistant to the current drugs is a persistent threat. Although there is evidence of immune system reconstitution in certain patients who receive combination antiretroviral therapy, the goals of completely “rebuilding” the immune system or eradicating the virus from the body appear unlikely with current approaches to treatment.

For these reasons, the development of the next generation of therapies remains a priority. Currently, all licensed antiretroviral medications are directed at one of two viral enzymes, but many new strategies are being pursued, including drugs that prevent the virus from entering a cell and approaches to boosting an infected person’s immune response.

HIV Prevention

In developing countries where per capita health care spending may be only a few dollars per year, use of antiretroviral drugs is, in most cases, not feasible. Most developing nations lack the financial resources and health care delivery infrastructure necessary to support their appropriate use. Therefore, the identification of effective, low-cost tools for preventing HIV infection is crucial to slowing the epidemic.

Researchers have shown that many approaches to HIV prevention can reduce the number of new infections, including: education and behavior modification, the social marketing and provision of condoms, treatment of other sexually transmitted diseases and the use of antiretroviral drugs to prevent the transmission of virus from mother to infant. NIH has been pursuing these approaches to prevention both domestically and internationally through the HIV Network for Prevention Trials (referred to as HIVNET), and will continue to do so through a follow-on initiative, the NIAID Prevention Trial Network.

Prevention of Mother-to-infant transmission

In early 1994, the NIH-funded clinical trial known as ACTG 076 showed that mother-to-infant transmission rates could be reduced by as much as two-thirds by treating HIV-infected pregnant women and their newborn babies with an intensive regimen of AZT (zidovudine). Unfortunately, cost and many logistical issues preclude the widespread application of the ACTG 076 regimen in the developing world.

To surmount these barriers, NIH and CDC-supported researchers have been collaborating with the health ministries and scientists of several developing countries on research to identify simpler, less costly ways to prevent mother-to-infant transmission of HIV.

Several recently reported studies, including two in Thailand and the Ivory Coast (both supported by CDC), have shown that shorter regimens of AZT can also be beneficial, reducing transmission by between 37 and 51 percent. Despite these promising advances, widespread implementation of these proven regimens in most developing countries has not occurred because of their expense and their dependence on an infrastructure of good prenatal care.

Last week NIAID and the Health Ministry of Uganda reported on the exciting results of a study in Uganda that could have profound implications for the epidemic in children worldwide. This study showed that just two doses of the antiretroviral drug nevirapine—one dose administered to the mother at the onset of labor and one to her baby shortly after birth—reduced the risk of maternal-infant transmission of HIV by nearly 50 percent when compared with a similar brief course of AZT. What makes this finding so significant for the worldwide epidemic is that nevirapine is extremely inexpensive and easy to administer; the regimen costs approximately $4 and is 70 times cheaper than the prveiously studied regimens of short course AZT.

Topical Microbicides

Other methods of preventing HIV transmission also may have an important impact on slowing the epidemic. For example, researchers are developing and testing topical microbicides, substances that a woman could use in her vagina before sex to prevent the transmission of HIV and other sexually transmitted diseases. These interventions may help empower women to protect themselves in situations where they are unable to avoid sex with partners who may be HIV-infected or to persuade their partners to use a condom. Several studies have been conducted or are underway in Africa using a variety of products.

HIV Vaccine Development

The development of a safe and effective vaccine for HIV infection remains the ultimate goal of AIDS research, and a key step toward bringing the HIV epidemic under control around the world. To hasten HIV vaccine discovery, many public and private agencies have dramatically increased the resources devoted to HIV vaccine research. For example, at NIH, HIV vaccine funding increased by 93 percent between FY 1995 and FY 1999.

As part of this expanded effort, NIH has awarded numerous grants to foster innovative research on HIV vaccines, and is invigorating and reorganizing its vaccine clinical trials effort. In addition, NIH has established the Dale and Betty Bumpers Vaccine Research Center within the NIH intramural research program to stimulate multidisciplinary vaccine research.

Since 1988 more than 3000 healthy volunteers have enrolled in 52 (50 phase I and two phase II) NIAID-supported studies involving 27 vaccines. Recent studies supported by NIH in collaboration with several vaccine manufacturers have assessed so-called “vectored vaccines”: harmless viruses (e.g. canarypox) that are genetically altered to make HIV proteins. Results have been encouraging: in phase I and phase II studies, this combination approach has appeared safe and evoked several types of immune responses that may have a role in protection from HIV.

Additional phase II trials of the combination vaccine concept will open later this year in Brazil, Haiti, and Trinidad and Tobago. These studies, as well as additional data that emerge from basic research, will provide the information to determine which products will advance into larger-scale testing. An exciting development for AIDS vaccine research was the initiation of the first AIDS vaccine study in Africa this spring. This NIH-supported phase I study, which is being conducted in Uganda, is designed to help determine whether it will be possible to design vaccines that work against more than one strain of HIV.

Meanwhile, a large-scale study of a vaccine based on the surface proteins of two HIV strains was recently undertaken in the United States by a private company—VAXGEN. An additional phase III study is being conducted by VAXGEN in collaboration with CDC in Thailand. NIH will collaborate with the company in evaluating the immunological responses to the vaccine.

Research Training

Training is a critical component of an international AIDS research and prevention program. Currently, the Fogarty International Center is working with several NIH Institutes to build HIV/AIDS research training and capacity in developing countries. Over the past decade, the AIDS International Training and Research Program, an arm of NIH’s vaccine research effort, has trained in the U.S. over 1,500 scientists from nearly 100 nations. This capacity-building effort has expanded research capabilities in a number of developing counties and has facilitated many NIH international HIV/AIDS research initiatives.

Conclusion

Two years ago, President Clinton set a national goal of having an effective HIV vaccine within 10 years. We are well positioned in our attempt to meet this goal with the extraordinary basic and applied research that is now under way. As we work to contain the global HIV/AIDS epidemic, it is essential that public and private sector partners strengthen their commitment to working together to speed HIV vaccine development, refine prevention efforts, and develop new treatments for those infected with the virus. Thank you for the opportunity to address this subcommittee.

10 Warning Signs of Primary Immunodeficiency Diseases

Today, people with primary immunodeficiency can be accurately diagnosed, and effective treatments are available to prevent or control damage to tissues and organs. Thus, it is extremely important that affected individuals are diagnosed early before such damage occurs. Diagnosis usually involves nothing more complicated than blood tests. Parents should be aware of the 10 warning signs and should speak to their physicians about the possible presence of primary immunodeficiency disease if a child shows more than one of the warning signs.

The 10 Warning Signs of Primary Immune Deficiency
(in no particular order)

1. Eight or more new ear infections within one year.
2. Two or more serious sinus infections within 1 year.
3. Two or more months on antibiotics with little effect.
4. Two or more pneumonias within 1 year.
5. Failure of an infant to gain weight or grow normally.
6. Recurrent, deep skin or organ abscesses.
7. Persistent thrush in mouth or elsewhere on skin, after age 1.
8. Need for intravenous antibiotics to clear infections.
9. Two or more deep-seated infections such as sepsis, meningitis or cellulitis.
10. A family history of primary immune deficiency.

HIV Infection and AIDS: An Overview

AIDS — acquired immunodeficiency syndrome — was first reported in the United States in 1981 and has since become a major worldwide epidemic. AIDS is caused by the human immunodeficiency virus (HIV). By killing or damaging cells of the body’s immune system, HIV progressively destroys the body’s ability to fight infections and certain cancers. People diagnosed with AIDS may get life-threatening diseases called opportunistic infections, which are caused by microbes such as viruses or bacteria that usually do not make healthy people sick.

More than 700,000 cases of AIDS have been reported in the United States since 1981, and as many as 900,000 Americans may be infected with HIV. The epidemic is growing most rapidly among minority populations and is a leading killer of African American males. According to the U.S. Centers for Disease Control and Prevention (CDC), AIDS affects six times more African Americans than whites and three times more Hispanics than whites.

Transmission

HIV is spread most commonly by having sex with an infected partner. The virus can enter the body through the lining of the vagina, vulva, penis, rectum, or mouth during sex.

HIV also is spread through contact with infected blood. Before blood was screened for evidence of HIV infection and before heat-treating techniques to destroy HIV in blood products were introduced, HIV was transmitted through transfusions of contaminated blood or blood components. Today, because of blood screening and heat treatment, the risk of getting HIV from such transfusions is extremely small.

HIV frequently is spread among injection drug users by the sharing of needles or syringes contaminated with very small quantities of blood from someone infected with the virus. It is rare, however, for a patient to give HIV to a health care worker or vice-versa by accidental sticks with contaminated needles or other medical instruments.

Women can transmit HIV to their babies during pregnancy or birth. Approximately one-quarter to one-third of all untreated pregnant women infected with HIV will pass the infection to their babies. HIV also can be spread to babies through the breast milk of mothers infected with the virus. If the mother takes the drug AZT during pregnancy, she can reduce significantly the chances that her baby will be infected with HIV. If doctors treat mothers with AZT and deliver their babies by cesarean section, the chances of the baby being infected can be reduced to a rate of 1 percent.

A study sponsored by NIAID in Uganda found a highly effective and safe drug regimen for preventing transmission of HIV from an infected mother to her newborn that is more affordable and practical than any other examined to date. Interim results from the study show that a single oral dose of the antiretroviral drug nevirapine (NVP) given to an HIV-infected woman in labor and another to her baby within three days of birth reduces the transmission rate by half compared with a similar short course of AZT.

Although researchers have detected HIV in the saliva of infected individuals, no evidence exists that the virus is spread by contact with saliva. Laboratory studies reveal that saliva has natural properties that limit the power of HIV to infect. Research studies of people infected with HIV have found no evidence that the virus is spread to others through saliva such as by kissing. No one knows, however, whether so-called “deep kissing,” involving the exchange of large amounts of saliva, or oral intercourse increase the risk of infection. Scientists also have found no evidence that HIV is spread through sweat, tears, urine, or feces.

Studies of families of HIV-infected people have shown clearly that HIV is not spread through casual contact such as the sharing of food utensils, towels and bedding, swimming pools, telephones, or toilet seats. HIV is not spread by biting insects such as mosquitoes or bedbugs.

HIV can infect anyone who practices risky behaviors such as:

• sharing drug needles or syringes, or
• having sexual contact with an infected person without using
  a condom or with someone whose HIV status is unknown.

Having a sexually transmitted disease such as syphilis, genital herpes, chlamydial infection, gonorrhea, or bacterial vaginosis appears to make people more susceptible to acquiring HIV infection during sex with infected partners.

Early Symptoms

Many people do not develop any symptoms when they first become infected with HIV. Some people, however, have a flu-like illness within a month or two after exposure to the virus. This illness may include fever, headache, tiredness, and enlarged lymph nodes (organs of the immune system easily felt in the neck and groin). These symptoms usually disappear within a week to a month and are often mistaken for those of another viral infection. During this period, people are very infectious, and HIV is present in large quantities in genital fluids.

More persistent or severe symptoms may not surface for a decade or more after HIV first enters the body in adults, or within two years in children born with HIV infection. This period of “asymptomatic” infection is highly individual. Some people may begin to have symptoms as soon as a few months, while others may be symptom-free for more than 10 years. During the asymptomatic period, however, the virus is actively multiplying, infecting, and killing cells of the immune system. HIV’s effect is seen most obviously in a decline in the blood levels of CD4+ T cells (also called T4 cells) — the immune system’s key infection fighters. At the beginning of its life in the human body, the virus disables or destroys these cells without causing symptoms.

As the immune system deteriorates, a variety of complications start to take over. For many people, their first sign of infection is large lymph nodes or “swollen glands” that may be enlarged for more than three months. Other symptoms often experienced months to years before the onset of AIDS include:

• lack of energy,
• weight loss,
• frequent fevers and sweats,
• persistent or frequent yeast infections (oral or vaginal),
• persistent skin rashes or flaky skin,
• pelvic inflammatory disease in women that does not respond to treatment, or
• short-term memory loss.

Some people develop frequent and severe herpes infections that cause mouth, genital, or anal sores, or a painful nerve disease called shingles. Children may grow slowly or be sick a lot.

AIDS

The term AIDS applies to the most advanced stages of HIV infection. The CDC in Atlanta, GA, develops official criteria for the definition of AIDS and is responsible for tracking the spread of AIDS in the United States.

CDC’s definition of AIDS includes all HIV-infected people who have fewer than 200 CD4+ T cells per cubic millimeter of blood. (Healthy adults usually have CD4+ T-cell counts of 1,000 or more.) In addition, the definition includes 26 clinical conditions that affect people with advanced HIV disease. Most of these conditions are opportunistic infections, which rarely cause harm in healthy people. In people with AIDS, these infections are often severe and sometimes fatal because the immune system is so ravaged by HIV that the body cannot fight off certain bacteria, viruses, fungi, parasites, and other microbes.

Opportunistic infections common in people with AIDS cause symptoms such as:

• coughing and shortness of breath,
• seizures and lack of coordination,
• difficult or painful swallowing,
• mental symptoms such as confusion and forgetfulnesss,
• severe and persistent diarrhea,
• fever,
• vision loss,
• nausea, abdominal cramps, and vomiting,
• weight loss and extreme fatigue,
• severe headaches, and
• coma.

Although children with AIDS may get the same opportunistic infections as adults with the disease, they also experience severe forms of the bacterial infections which all children may get, such as conjunctivitis (pink eye), ear infections, and tonsillitis.

People with AIDS are particularly prone to developing various cancers, especially those caused by viruses such as Kaposi’s sarcoma and cervical cancer, or cancers of the immune system known as lymphomas. These cancers are usually more aggressive and difficult to treat in people with AIDS. Signs of Kaposi’s sarcoma in light-skinned people are round brown, reddish, or purple spots that develop in the skin or in the mouth. In dark-skinned people, the spots are more pigmented.

During the course of HIV infection, most people experience a gradual decline in the number of CD4+ T cells, although some may have abrupt and dramatic drops in their CD4+ T-cell counts. A person with CD4+ T cells above 200 may experience some of the early symptoms of HIV disease. Others may have no symptoms even though their CD4+ T-cell count is below 200.

Many people are so debilitated by the symptoms of AIDS that they cannot hold steady employment or do household chores. Other people with AIDS may experience phases of intense life-threatening illness followed by phases in which they function normally.

A small number of people (fewer than 50) initially infected with HIV 10 or more years ago have not developed symptoms of AIDS. Scientists are trying to determine what factors may account for their lack of progression to AIDS, such as particular characteristics of their immune systems or whether they were infected with a less aggressive strain of the virus, or if their genes may protect them from the effects of HIV. Scientists hope that understanding the body’s natural method of control may lead to ideas for protective HIV vaccines and use of vaccines to prevent the disease from progressing.

Diagnosis

Because early HIV infection often causes no symptoms, a doctor or other health care worker usually can diagnose it by testing a person’s blood for the presence of antibodies (disease-fighting proteins) to HIV. HIV antibodies generally do not reach levels in the blood which the doctor can see until one to three months following infection, and it may take the antibodies as long as six months to be produced in quantities large enough to show up in standard blood tests.

People exposed to the virus should get an HIV test as soon as they are likely to develop antibodies to the virus. By getting tested early, they can get the right treatment at a time when their immune systems are most able to combat HIV and thus prevent the emergence of certain opportunistic infections (see Treatment below). Early testing also alerts HIV-infected people to avoid high-risk behaviors that could spread the virus to others.

Most doctors’ offices or health clinics can do HIV testing and will usually offer counseling to the patient at the same time. Of course, individuals can be tested anonymously at many sites if they are concerned about confidentiality.

Doctors diagnose HIV infection by using two different types of antibody tests, ELISA and Western Blot. If a person is highly likely to be infected with HIV and yet both tests are negative, a doctor may look for HIV itself in the blood. The person also may be told to repeat antibody testing at a later date, when antibodies to HIV are more likely to have developed.

Babies born to mothers infected with HIV may or may not be infected with the virus, but all carry their mothers’ antibodies to HIV for several months. If these babies lack symptoms, a definitive diagnosis of HIV infection using standard antibody tests cannot be made until after 15 months of age. By then, babies are unlikely to still carry their mothers’ antibodies and will have produced their own, if they are infected. New technologies to detect HIV itself are being used to more accurately determine HIV infection in infants between ages 3 months and 15 months. A number of blood tests are being evaluated to determine if they can diagnose HIV infection in babies younger than 3 months.

Treatment

When AIDS first surfaced in the United States, no medicines were available to combat the underlying immune deficiency and few treatments existed for the opportunistic diseases that resulted. Over the past 10 years, however, researchers have developed drugs to fight both HIV infection and its associated infections and cancers.

The Food and Drug Administration has approved a number of drugs for treating HIV infection. The first group of drugs used to treat HIV infection, called nucleoside reverse transcriptase (RT) inhibitors, interrupts an early stage of the virus making copies of itself. Included in this class of drugs (called nucleoside analogs) are AZT (also known as zidovudine or ZDV), ddC (zalcitabine), ddI (dideoxyinosine), d4T (stavudine), and 3TC (lamivudine). These drugs may slow the spread of HIV in the body and delay the onset of opportunistic infections.

Non-nucleoside reverse transcriptase inhibitors (NNRTIs), such as delvaridine (Rescriptor) and nevirapine (Viramune), are also available for use in combination with other antiretroviral drugs.

More recently, a second class of drugs has been approved for treating HIV infection. These drugs, called protease inhibitors, interrupt virus replication at a later step in its life cycle. They include ritonavir (Norvir), saquinivir (Invirase), indinavir (Crixivan), amprenivir (Agenerase), and nelfinavir (Viracept). Because HIV can become resistant to both classes of drugs, combination treatment using both is necessary to effectively suppress the virus.

Currently available antiretroviral drugs do not cure people of HIV infection or AIDS, however, and they all have side effects that can be severe. Some of the nucleoside RT inhibitors may cause a depletion of red or white blood cells, especially when taken in the later stages of the disease. Some may also cause an inflammation of the pancreas and painful nerve damage. Other complications, including lactic acidosis and severe hepatomegaly (enlarged liver) with steatosis (fatty liver) that may result in liver failure and death, have also been reported with the use of antiretroviral nucleoside analogs alone or in combination, including AZT, ddI, ddC, 3TC, and abacavir.

The most common side effects associated with protease inhibitors include nausea, diarrhea, and other gastrointestinal symptoms. In addition, protease inhibitors can interact with other drugs resulting in serious side effects.

Researchers have credited highly active antiretroviral therapy, or HAART, as being a major factor in reducing the number of deaths from AIDS in this country by 47 percent in 1997. HAART is a combination of several drugs to treat patients. These drugs include reverse transcriptase inhibitors and protease inhibitors. Patients who are newly infected with HIV as well as AIDS patients can take the combination.

HAART is not a cure. The health of HIV and AIDS patients has benefited dramatically by combining protease inhibitors with other AIDS drugs, but there are drawbacks. Also, though HIV may not be found in the patients successfully treated with HAART, researchers know that it is still present, lurking in hiding places such as the lymph nodes, the brain, testes, and the retina of the eye.

A number of drugs are available to help treat opportunistic infections to which people with HIV are especially prone. These drugs include foscarnet and ganciclovir, used to treat cytomegalovirus eye infections, fluconazole to treat yeast and other fungal infections, and trimethoprim/sulfamethoxazole (TMP/SMX) or pentamidine to treat Pneumocystis carinii pneumonia (PCP).

In addition to antiretroviral therapy, adults with HIV whose CD4+ T-cell counts drop below 200 are given treatment to prevent the occurrence of PCP, which is one of the most common and deadly opportunistic infections associated with HIV. Children are given PCP preventive therapy when their CD4+ T-cell counts drop to levels considered below normal for their age group. Regardless of their CD4+ T-cell counts, HIV-infected children and adults who have survived an episode of PCP are given drugs for the rest of their lives to prevent a recurrence of the pneumonia.

HIV-infected individuals who develop Kaposi’s sarcoma or other cancers are treated with radiation, chemotherapy or injections of alpha interferon, a genetically engineered naturally occurring protein.

Prevention

Because no vaccine for HIV is available, the only way to prevent infection by the virus is to avoid behaviors that put a person at risk of infection, such as sharing needles and having unprotected sex.

Many people infected with HIV have no symptoms. Therefore, there is no way of knowing with certainty whether a sexual partner is infected unless he or she has repeatedly tested negative for the virus — and has not engaged in any risky behavior.

People should either abstain from having sex or or use latex condoms, which may offer partial protection, during oral, anal, or vaginal sex. Only condoms made of latex should be used, and water-based lubricants should be used with latex condoms.

Although some laboratory evidence shows that spermicides can kill HIV, researchers have not found that these products can prevent a person from getting HIV.

The risk of HIV transmission from a pregnant woman to her baby is significantly reduced if she takes AZT during pregnancy, labor and delivery, and her baby takes it for the first six weeks of life.

Research

NIAID-supported investigators are conducting an abundance of research on HIV infection, including the development and testing of HIV vaccines and new therapies for the disease and some of its associated conditions. Twenty-eight HIV vaccines are being tested in people, and many drugs for HIV infection or AIDS-associated opportunistic infections are either being developed or being tested. Researchers also are investigating exactly how HIV damages the immune system. This research is suggesting new and more effective targets for drugs and vaccines. NIAID-supported investigators also continue to trace how the disease progresses in different people.

Scientists are investigating and testing chemical barriers, such as topical microbicides, that people can use in the vagina or in the rectum during sex to prevent HIV transmission. They also are looking at other ways to prevent transmission such as controlling sexually transmitted diseases and modifying people’s behavior as well as ways to prevent transmission from mother to child.

Resources

For information about Food and Drug Administration-approved HIV-related clinical trials being conducted throughout the United States, call the AIDS Clinical Trials Information Service:

1-800-TRIALS-A
(1-800-874-2572)
1-800-243-7012 (TDD/Deaf Access)
For federally approved treatment guidelines on HIV/AIDS, call the HIV/AIDS Treatment Information Service:

1-800-HIV-0440
(1-800-448-0440)
1-800-243-7012 (TDD/Deaf Access)
Both services operate from 9 a.m. to 7 p.m. Eastern Time, Monday through Friday. Spanish-speaking specialists are available.

To obtain information specifically about clinical trials conducted by the NIAID Intramural AIDS Research Program, call 1-800-243-7644.

To obtain materials for adolescents with HIV, or more information about adolescents and HIV, contact the National Prevention Information Network at 1-800-458-5231 or 1-800-243-7012 (TDD/Deaf Access).

NIAID Public-Private Partnerships Seek to Develop HIV-AIDS Vaccine

The National Institute of Allergy and Infectious Diseases (NIAID) announced today four novel public-private partnerships to accelerate development of promising HIV/AIDS vaccines for use around the world. The new partnerships, called HIV Vaccine Design and Development Teams (HVDDT), tap the different skills and talents of private industry and academic research centers, and provide incentive to move strong HIV/AIDS vaccine candidates out of the laboratory and into human testing. NIAID has committed to spend approximately $70 million over the next five years on the four HVDDT contracts that have been awarded.

The HVDDT program responds directly to President Clinton’s call to increase public-private cooperation in developing vaccines against globally important diseases such as AIDS, tuberculosis and malaria.

“Many vaccines in use today resulted from both government-sponsored and private research,” explains Anthony S. Fauci, M.D., director of NIAID. “The HVDDT program is a unique addition to this model that encourages the private sector to increase their AIDS vaccine efforts while allowing NIAID to work closely with its partners throughout the development process.”

Designing and testing vaccines for diseases like AIDS is an expensive and scientifically complex undertaking with no guarantees of success and little likelihood of significant profit. “The HVDDT program encourages pharmaceutical companies to invest more in AIDS vaccine research by partially offsetting their financial risk. In essence, HVDDT contracts ‘prime the pump’ to get the vaccine-production engine running, including vaccine candidates for HIV subtypes that circulate in developing countries,” explains Peggy Johnston, Ph.D., assistant director for AIDS vaccines at NIAID.

HVDDT awards are incentive-based contracts aimed at vaccine candidates in the middle of the development pipeline — those not yet in clinical testing. Applicants were required to describe a clear development plan, including timelines to indicate when different phases would be completed. Funding will be provided in increments as these preset milestones are reached. “This goal-based incentive structure helps ensure continuous progress toward a testable vaccine while at the same time rewarding companies for research accomplishments made along the way,” states Dr. Johnston.

Each of the initial HVDDT contracts proposes using a DNA-based HIV vaccine for the initial immunization. The proposals differ in the unique properties of the DNA, the specific immune response that is targeted, the delivery system used, and the manner of boosting the initial vaccine. Each of the proposed vaccines contains the genetic information to make specific HIV proteins, either from the outer viral envelope or the internal viral core, to induce an immune response. The vaccines do not contain enough genetic information to construct a complete virus, and therefore will pose no threat of HIV infection to study participants. The four research organizations that have received an award and a summary of their proposed projects are listed below.

**Advanced BioScience Laboratories, Inc. (ABL), Kensington, MD**

Under the direction of Phillip Markham, Ph.D., researchers from ABL and the University of Massachusetts Medical School will develop and test a DNA vaccine containing genes for envelope proteins from HIV strains isolated around the world. Study participants will receive non-DNA booster vaccines consisting of engineered, or recombinant, HIV proteins. The researchers will explore ways to enhance the antibody response to this vaccine and hope that this combination will provide broad immunity against the different subtypes of the virus found worldwide. ABL is an affiliate of Organon Teknika Corporation in Durham, NC.

**Chiron Corporation, Emeryville, CA**

Susan Barnett, Ph.D., and colleagues at Chiron will produce a DNA vaccine candidate based on a common U.S. HIV subtype called clade B. They will also work on a vaccine based on a clade C virus, the most common HIV subtype in sub-Saharan Africa and India. The vaccines, consisting of HIV envelope and core protein genes, are designed to stimulate antibodies and T cells that attack the virus and virus-infected cells, respectively. The DNA vaccine will be followed by a booster vaccine consisting of alphavirus particles, which serve as novel delivery vehicles to ferry a recombinant HIV protein to certain immune cells. By slightly changing the genetic code of the vaccine’s DNA, Chiron scientists hope to improve the ability of the body to decode the genetic instructions once the vaccine is administered. The investigators will also study different ways to enhance the immune response to the DNA vaccine.

**University of New South Wales, Australia**

David Cooper, M.D., will lead a consortium of Australian universities and research organizations in producing a DNA vaccine that contains HIV genes as well as specific stretches of DNA that directly stimulate immune responses. The vaccination boost will contain HIV genes contained in a viral (fowlpox) delivery system that also contains immunity-enhancing genes. This vaccine is designed to stimulate both antibody and T-cell responses and to generate active immunity at mucosal surfaces, the first site of viral assault during most HIV infections.

**Wyeth Lederle Vaccines and Nutrition, Pearl River, NY**

Wyeth Lederle’s John Eldridge, Ph.D., will direct an effort with academic researchers at the University of Pennsylvania and Duke University to produce a DNA vaccine containing immunity-stimulating genes in addition to the HIV genes. The initial DNA vaccination will be boosted by a candidate vaccine consisting of multiple protein fragments, or peptides, that trigger anti-HIV responses. The goal of this approach is to produce a vaccine that strongly stimulates HIV-specific immune responses in very diverse human populations.

The HVDDT awards are part of NIAID’s expanded commitment to develop an HIV vaccine, and the contracts complement other currently supported HIV vaccine research and development programs. The Innovation Grant Program (IGP) supports novel, high-risk, and exploratory studies in AIDS vaccine-related research. The HIV Vaccine Research and Design Program (HIVRAD) supports studies emphasizing targeted AIDS vaccine research and development and is designed for vaccine concepts that have already generated significant preliminary data. The Integrated Preclinical/Clinical AIDS Vaccine Development Program (IPCAVD) supports grants designed to move promising HIV vaccine candidates into preliminary human studies. IPCAVD awards are not milestone-driven, however, because they support vaccine development at an earlier stage than the HVDDT contracts, where timelines are more difficult to predict. NIAID also supports HIV vaccine development through its Vaccine Development Resources program, which assists AIDS researchers by manufacturing pilot lots of vaccine for testing, conducting preliminary safety and efficacy evaluations, and preparing submissions to the Food and Drug Administration for trials in humans. More recently, NIAID announced the funding of the HIV Vaccine Trials Network (HVTN), a global network of clinical sites, which will conduct all phases of clinical trials of candidate HIV vaccines.

NIAID is a component of the National Institutes of Health (NIH). NIAID conducts and supports research to prevent, diagnose and treat illness such as HIV disease and other sexually transmitted diseases, tuberculosis, malaria, asthma and allergies. NIH is an agency of the U.S. Department of Health and Human Services.

For more information on NIAID’s AIDS vaccine research program, please visit http://www.niaid.nih.gov/daids/vaccine/. Press releases, publications and other NIAID-related materials are available on the NIAID Web site at http://www.niaid.nih.gov

What Is Chronic Fatigue Syndrome?

We all get tired. Many of us at times have felt depressed. But the mystery known as chronic fatigue syndrome (CFS) is not like the normal ups and downs we experience in everyday life. The early sign of this illness is a strong and noticeable fatigue that comes on suddenly and often comes and goes or never stops. You feel too tired to do normal activities or are easily exhausted with no apparent reason. Unlike the mind fog of a serious hangover, to which researchers have compared CFS, the profound weakness of CFS does not go away with a few good nights of sleep. Instead, it slyly steals your energy and vigor over months and sometimes years.

How CFS Begins and Its Symptoms
For many people, CFS begins after a bout with a cold, bronchitis, hepatitis, or an intestinal bug. For some, it follows a bout of infectious mononucleosis, or mono, which temporarily saps the energy of many teenagers and young adults. Often, people say that their illnesses started during a period of high stress. In others, CFS develops more gradually, with no clear illness or other event starting it.

Unlike flu symptoms, which usually go away in a few days or weeks, CFS symptoms either hang on or come and go frequently for more than six months. CFS symptoms include:

• Headache
• Tender lymph nodes
• Fatigue and weakness
• Muscle and joint aches
• Inability to concentrate

Who Gets CFS?
CFS was once stereotyped as a new “yuppie flu” because those who sought help for and caused scientific interest in CFS in the early 1980s were mainly well-educated, well-off women in their thirties and forties. Similar illnesses, known by different names, however, date back at least to the late 1800s. The modern stereotype arose. Since then, doctors have seen the syndrome in people of all ages, races, and social and economic classes from several countries around the world.

Still, CFS is diagnosed two to four times more often in women than in men, possibly because of biological, psychological, and social influences. For example,

• CFS may have a gender difference similar to diseases such as systemic lupus erythematosus and multiple sclerosis, which affect more women than men.
• Women may be more likely than men to talk with their doctors about CFS-like symptoms.
• Some members of the medical community and the public do not know about or are skeptical of the syndrome.
• An increasingly diverse patient group will likely emerge as more doctors see CFS as a real disorder.

How Many People Have It?
Because there is no specific laboratory test or clinical sign for CFS, no one knows how many people this illness affects. CDC estimates, however, that as many as 500,000 people in the United States have a CFS-like condition.

What Causes CFS?
While no one knows what causes CFS, for more than a century, doctors have reported seeing illnesses similar to it. In the l860s, Dr. George Beard named the syndrome neurasthenia because he thought it was a nervous disorder with weakness and fatigue. Since then, health experts have suggested other explanations for this baffling illness:

• Iron-poor blood (anemia),
• Low blood sugar (hypoglycemia),
• Environmental allergy, or
• A body wide yeast infection (candidiasis).

In the mid-1980s, the illness became labeled “chronic EBV” when laboratory clues led scientists to wonder whether the Epstein-Barr virus (EBV) might be causing this group of symptoms. New evidence soon cast doubt on the theory that EBV could be the only thing causing CFS. High levels of EBV antibodies (disease-fighting proteins) have now been found in some healthy people as well as in some people with CFS. Likewise, some people who don’t have EBV antibodies, and who thus have never been infected with the virus, can show CFS symptoms.

How Is CFS Diagnosed?
Doctors find it difficult to diagnose CFS because it has the same symptoms as many other diseases. When talking with and examining you, your doctor must first rule out diseases that look similar, such as multiple sclerosis and systemic lupus erythematosus in which symptoms can take years to develop. In follow-up visits, you and your doctor need to be alert to any new cues or symptoms that might show that the problem is something other than CFS.

When other diseases are ruled out and if your illness meets other criteria as well, your doctor can diagnose you with CFS (see The CFS Case Definition).

The CFS Case Definition
The EBV work sparked new interest in the syndrome among a small group of medical researchers. They realized they needed a standard way to describe CFS so that they could more easily compare research results.

In the late 1980s, CDC brought together a group of CFS experts to tackle this problem. Based on the best information available at the time, this group published in the March 1988 issue of the scientific journal, Annals of Internal Medicine, strict symptom and physical criteria – the first case definition – by which scientists could evaluate CFS study patients.

Not knowing the cause or a specific sign for the disease, the group agreed to call the illness “chronic fatigue syndrome” after its primary symptom. “Syndrome” means a group of symptoms that occur together but can result from different causes. (Today, CFS also is known as myalgic encephalomyelitis, postviral fatigue syndrome, and chronic fatigue and immune dysfunction syndrome.)

After using this definition for several years, CFS researchers realized some criteria were unclear or redundant. An international group of CFS experts reviewed the criteria for CDC, which led to the first changes in the case definition. This new definition was published in the same journal in December 1994.

Besides revising the CFS case criteria – which reduced the required minimum number of symptoms to four out of a list of eight possible symptoms – the newer report also proposed a conceptual outline for studying the syndrome. This outline recognizes CFS as part of a range of illnesses that have fatigue as a major symptom. Although primarily intended for researchers, these guidelines should help doctors better diagnose CFS.

How Can I Cope With and Manage the Illness?
There is no effective treatment for CFS. Even though there is no specific treatment for CFS itself, you may find it quite helpful to treat your symptoms. Nonsteroidal anti-inflammatory drugs, such as ibuprofen, may help get rid of any body aches or fever, and nonsedating antihistamines may help relieve any prominent allergic symptoms, such as runny nose.

Learning how to manage your fatigue may help you improve the level at which you can function and your quality of life despite your symptoms. A rehabilitation medicine specialist can evaluate and teach you how to plan activities to take advantage of times when you usually feel better.

The lack of any proven effective treatment can be frustrating to both you and your doctors. If you have CFS, health experts recommend that you try to maintain good health by:

• Eating a balanced diet and getting adequate rest.
• Exercising regularly but without causing more fatigue.
• Pacing yourself – physically, emotionally, and intellectually – since too much stress can aggravate your symptoms.

The course of CFS varies from patient to patient. For most people, CFS symptoms plateau early in the course of illness and thereafter wax and wane. Some people get better completely, but it is not clear how frequently this happens. Emotional support and counseling can help you and your loved ones cope with the uncertain outlook and the ups and downs of this illness.

Although new studies seem to show that cognitive behavioral therapy and graduated exercise programs can greatly help many. Others are helped by antidepressants.

Because well-designed clinical studies have found that patients with fibromyalgia (an illness similar to CFS) benefit from low-dose tricyclic antidepressants, doctors often prescribe these drugs for people with CFS with generally positive results. Some researchers believe that these drugs improve the quality of sleep. Patients also have benefited from other kinds of antidepressants, including the newer serotonin reuptake inhibitors. Therapeutic doses of antidepressants often increase fatigue in CFS, so doctors may have to increase the dosage very slowly, or prescribe more active antidepressants. In addition, some people with CFS benefit from the benzodiazepines, a class of drugs used to treat acute anxiety and sleep problems. Patients often try more than one drug before finding one that works and can be tolerated.

Conclusion
CFS seems to involve interactions between the immune and central nervous systems, interactions about which scientists know relatively little. Scientists’ concerted efforts to penetrate the complex nervous system and immune system events in CFS have created a challenging new concept of the pathology of this and other illnesses.

For More Information About CFS, Contact: Centers for Disease Control and Prevention
1500 Clifton Road NE
Atlanta, GA 30333
1-800-232-3228
www.cdc.gov/ncidod/diseases/cfs/facts.htm