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Treatment of HIV Infection

National Institutes of Health

Treatment of HIV Infection

In the early 1980s when the epidemic began, AIDS (acquired immunodeficiency disease) patients were not likely to live longer than a few years. With the development of safe and effective drugs, however, people infected with HIV (human immunodeficiency virus) now have longer and healthier lives.

The discovery and development of new therapeutic strategies against HIV is one of the highest priorities for the National Institute of Allergy and Infectious Diseases (NIAID). Research supported by NIAID has already greatly advanced our understanding of HIV and how it causes AIDS. This knowledge provides the foundation for NIAID’s HIV/AIDS research effort and continues to support studies designed to further extend and improve the quality of life of those infected with HIV.

DRUGS FOR HIV INFECTION

Currently, there are 26 antiretroviral drugs approved by the Food and Drug Administration to treat individuals infected with HIV. These drugs fall into three major classes.

  1. Reverse transcriptase (RT) inhibitors interfere with the critical step during the HIV life cycle known as reverse transcription. During this step, reverse transcriptase, an HIV enzyme, converts HIV RNA to HIV DNA. There are two main types of RT inhibitors. (1) Nucleoside/nucleotide RT inhibitors are faulty DNA building blocks. When these faulty pieces are incorporated into the HIV DNA (during the process when the HIV RNA is converted to HIV DNA), the DNA chain cannot be completed, thereby blocking HIV from replicating in a cell. (2) Non-nucleoside RT inhibitors bind to reverse transcriptase, interfering with its ability to convert the HIV RNA into HIV DNA.
  2. Protease inhibitors (PI) interfere with the protease enzyme that HIV uses to produce infectious viral particles.
  3. Fusion inhibitors interfere with the virus’ ability to fuse with the cellular membrane, thereby blocking entry into the host cell.

Drugs Approved for HIV Infection

Nucleoside/Nucleotide RT Inhibitors: Retrovir (zidovudine, AZT); Videx (didanosine, ddI); Hivid (zalcitabine, ddC); Zerit (stavudine, d4T); Epivir (lamivudine, 3TC); Combivir (AZT and 3TC); Ziagen (abacavir); Trizivir (AZT + 3TC + abacavir); Viread (tenofovir); Emtriva (emtricitabine); Epzicom (abacavir/ lamivudine); Truvada (tenofovir/emtricitabine).

Non-nucleoside RT Inhibitors: Viramune (Nevirapine); Rescriptor (delavirdine); Sustiva (efavirenz).

Protease Inhibitors: Invirase (saquinavir-HGC); Norvir (ritonavir); Crixivan (indinavir); Viracept (nelfinavir); Fortovase (saquinavir-SGC); Agenerase (amprenavir); Kaletra (lopinavir and ritonavir); Lexiva (fosamprenavir); Aptivus (tipranavir); Reyataz (atazanavir).

Fusion Inhibitors: Fuzeon (enfuvirtide).

NO CURE FOR HIV/AIDS

Currently available drugs do not cure HIV infection or AIDS. They can suppress the virus, even to undetectable levels, but are unable to completely eliminate HIV from the body. Hence, infected patients still need to take antiretroviral drugs.

HIGHLY ACTIVE ANTIRETROVIRAL THERAPY (HAART) COUNTERS DRUG RESISTANCE

As HIV reproduces itself, different strains of the virus emerge, some that are resistant to antiretroviral drugs. Therefore, doctors recommend patients infected with HIV take a combination of antiretroviral drugs known as HAART. This strategy, which typically combines drugs from at least two different classes of antiretroviral drugs, has been shown to effectively suppress the virus when used properly. Developed by NIAID-supported researchers, HAART has revolutionalized how we treat people infected with HIV by successfully suppressing the virus and decreasing the rate of opportunistic infections.

HIV TRANSMISSION AND ANTIRETROVIRAL DRUGS

Although the use of HAART has greatly reduced the number of deaths due to HIV/AIDS, this powerful combination of drugs cannot suppress the virus completely. Therefore, people infected with HIV who take antiretroviral drugs can still transmit HIV to others through unprotected sex and needle sharing.

ANTIRETROVIRAL DRUG EFFECTS ON OPPORTUNISTIC INFECTIONS AND AIDS-ASSOCIATED CO-INFECTIONS

People infected with HIV have impaired immune systems that can leave them susceptible to opportunistic infections (OIs) and AIDS-associated co-infections, caused by a wide range of microorganisms such as protozoa, viruses, fungi, and bacteria. One example is hepatitis C virus (HCV) infection which can lead to liver cancer.

Potent HIV therapies such as HAART, however, have produced dramatic responses in patients by suppressing HIV and slowing the progression of OIs and AIDS-associated co-infections. These therapies allow the immune system to recover, sustain, and protect the body from other infections. Hence, antiretroviral drugs provide a way for the immune system to remain intact and effective, thereby improve the quality and duration of life for people with HIV.

SIDE EFFECTS AS BARRIERS TO ANTIRETROVIRAL DRUG USE

People taking antiretroviral drugs often have low adherence to complicated drug regimens. The current recommended regimen involves taking several antiretroviral drugs each day from at least two different classes, some of which may require fasting and cause unpleasant side effects such as nausea and vomiting. In addition, antiretroviral drugs may cause more serious medical problems, including metabolic changes such as abnormal fat distribution, abnormal lipid and glucose metabolism, and bone loss. Therefore, NIAID is investigating simpler, less toxic, and more effective drug regimens.

DEVELOPMENT OF NEW SAFE AND EFFECTIVE ANTIRETROVIRAL DRUGS

NIAID supports the development and testing of new therapeutic agents, classes, and combinations of antiretroviral drugs that will be able to continuously suppress the virus with few side effects. Through clinical trials involving volunteers, NIAID-supported studies will provide accurate and extensive information about the safety and efficacy of the new drug candidates and combinations, and will identify potential uncommon, but important, toxicities of newly approved agents. Studies are also underway to assess rare toxicities of older approved agents, especially as a result of long-term use.

Through the Multicenter AIDS Cohort Study and Women’s Interagency HIV Study, NIAID supports long-term studies of HIV disease and its treatment in both men and women. Since their inception, these cohort studies have enrolled and collected data from more than 10,000 people. In addition, NIAID supports treatment studies conducted through three HIV/AIDS clinical trials networks: Adult AIDS Clinical Trials Groups, Pediatric AIDS Clinical Trials Groups, and the Terry Beirn Community Programs for Clinical Research on AIDS.

To expand upon and better coordinate the global HIV/AIDS research activities, NIAID is restructuring all of its HIV clinical trials research networks to increase collaboration, efficiency, harmonization, and flexibility. This new structure is designed to encourage greater integration of vaccine, prevention, and treatment research; to improve upon research efforts; and to address high priority research questions, particularly in resource-limited settings where AIDS is most devastating. For more information about HIV/AIDS drugs and treatment trials, please visit the AIDS_info_ web site at www.aidsinfo.nih.gov.

NIAID RESEARCH ON THE COMPLICATIONS OF ANTIRETROVIRAL DRUGS

NIAID supports studies aimed at understanding the side effects of antiretroviral drugs as well as strategies to reduce exposure to potentially toxic drug regimens, such as

  1. Structured treatment interruption (STI) protocols
  2. Use of immune-based therapies with HAART
  3. Studies to compare different dosing schedules
  4. Studies to compare early versus delayed treatment

NIAID also supports projects evaluating regimens containing agents associated with toxicities. For example, NIAID-funded researchers are conducting studies to evaluate treatments for several drug-associated metabolic complications, including fat redistribution, lipid and glucose abnormalities, and bone loss. In addition, researchers are studying the long-term metabolic effects of various antiretroviral regimens in pregnant women and their infants and in HIV-infected children and adolescents.

DOWN THE ROAD: NEW DRUGS IN THE PIPELINE

The Pharmaceutical Research and Manufacturers Association of America maintains a database of new drugs in development to treat HIV infection (www.newmeds.phrma.org). They include new protease inhibitors and more potent, less toxic RT inhibitors, as well as other drugs that interfere with entirely different steps in the virus’ lifecycle. These new categories of drugs include

  1. Entry inhibitors that interfere with HIV’s ability to enter cells
  2. Integrase inhibitors that interfere with HIV’s ability to insert its genes into a cell’s normal DNA
  3. Assembly and budding inhibitors that interfere with the final stage of the HIV life cycle, when new virus particles are released into the bloodstream
  4. Cellular metabolism modulators that interfere with the cellular processes needed for HIV replication
  5. Gene therapy that uses modified genes inserted directly into cells to suppress HIV replication. These cells are designed to produce T cells that are genetically resistant to HIV infection.

In addition, scientists are learning how immune modulators help boost the immune response to the virus and may make the existing anti-HIV drugs more effective. Therapeutic vaccines also are being evaluated for this purpose and could help reduce the number of anti-HIV drugs needed or the duration of treatment.

MORE INFORMATION

AIDSinfo P.O. Box 6303 Rockville, MD 20849-6303 1-800-HIV-0440 (1-800-448-0440) or 301-519-0459 1-888-480-3739 (TTY/TDD) Monday to Friday, 12:00 p.m. to 5:00 p.m. Eastern Time http://aidsinfo.nih.gov

AIDSinfo is a comprehensive resource for up-to-date information on government and industry sponsored HIV/AIDS treatment and prevention clinical trials. AIDSinfo also maintains the most current, federally approved guidelines for treating and preventing HIV/AIDS in adults and children, for treating and preventing AIDS-related illnesses, managing occupational exposure to HIV, and for preventing HIV transmission from mother-to-child during pregnancy. AIDSinfo is sponsored by the NIH Office of AIDS Research, NIAID, National Library of Medicine, Centers for Disease Control and Prevention, Health Resources and Service Administration, and Centers for Medicare and Medicaid Services.

Food and Drug Administration 5600 Fishers Lane Rockville, MD 20857-0001 1-888-INFO-FDA (1-888-463-6332) http://www.fda.gov

originally published in April 2006


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