Treatment of HIV Infection

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

The discovery and development of new therapeutic strategies against HIV is a high priority 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 disease. 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/AIDS

Currently, there are 30 antiretroviral drugs approved by the Food and Drug Administration to treat people infected with HIV. These drugs fall into four major classes.

1. Reverse transcriptase (RT) inhibitors interfere with the critical step during the HIV life cycle known as reverse transcription. During this step, RT, an HIV enzyme, converts HIV RNA to HIV DNA. There are two main types of RT inhibitors.
* 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.
* Non-nucleoside RT inhibitors bind to RT, interfering with its ability to convert the HIV RNA into HIV DNA.
2. Protease inhibitors interfere with the protease enzyme that HIV uses to produce infectious viral particles.
3. Entry and fusion inhibitors interfere with the virus' ability to fuse with the cellular membrane, thereby blocking entry into the host cell.
4. Integrase inhibitors block integrase, the enzyme HIV uses to integrate genetic material of the virus into its target host cell.
5. Multidrug combination products combine drugs from more than one class into a single product.

Currently available drugs do not cure HIV infection or AIDS. They can suppress the virus, even to undetectable levels, but they cannot eliminate HIV from the body. Hence, people with HIV need to continuously take antiretroviral drugs.

Highly Active Antiretroviral Therapy (HAART) Counters Drug Resistance


As HIV reproduces itself, variants of the virus emerge, including some that are resistant to antiretroviral drugs. Therefore, health care providers recommend that people infected with HIV take a combination of antiretroviral drugs known as highly active antiretroviral therapy, or 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 people infected with HIV are treated. HAART works by 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, and possibly the transmission of HIV/AIDS as well, 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 of an associated co-infection is hepatitis C virus infection, which can lead to liver cancer.

Potent HIV therapies such as HAART, however, have produced dramatic responses in patients. These therapies often 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 effective, thereby improving the quality and length of life for people with HIV.

Side Effects of Antiretroviral Drugs

People taking antiretroviral drugs may have low adherence to complicated drug regimens. Current recommended regimens involve taking several antiretroviral drugs each day from at least two different classes, some of which may 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 can continuously suppress the virus with few side effects. Through human clinical trials, NIAID-supported studies provide accurate and extensive information about the safety and efficacy of drug candidates and combinations, and identify potential uncommon but important toxicities of newly approved agents. Studies are also under way 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 infection 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: the AIDS Clinical Trials Group, the International Maternal Pediatric Adolescent AIDS Clinical Trials Group, and the International Network for Strategic Initiatives in Global HIV Trials.

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

* Structured treatment interruption (STI) protocols
* Use of immune-based therapies with HAART
* Studies to compare different drug dosing schedules or combinations
* 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. 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

* Entry inhibitors that interfere with HIV's ability to enter cells
* Integrase inhibitors that interfere with HIV's ability to insert its genes into a cell's normal DNA
* Assembly and budding inhibitors that interfere with the final stage of the HIV life cycle, when new virus particles are released into the bloodstream
* Cellular metabolism modulators that interfere with the cellular processes needed for HIV replication
* 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 exploring whether immune modulators help boost the immune response to the virus and may make 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.