Important advances in understanding the biology and treatment of human immunodeficiency virus (HIV) infection have occurred during the past [two years]. As a result, new approaches to therapy have been developed that offer scientifically sound options for persons with HIV infection1 and may have implications for those who are HIV uninfected, although much is still unknown. 

After a review of the current professional literature and discussions with experts in the treatment of individuals with HIV disease, the Seattle-King County Department of Public Health' AIDS Prevention Project has developed a set of recommended messages to assist health educators and other HIV/AIDS prevention workers to deliver clear, accurate, and consistent information regarding antiretroviral therapies and their relationship to HIV/AIDS risk behavior choices. A glossary has been included to assist individuals with difficult/technical terms. 

Overview

Antiretroviral drugs effective against HIV have been used in the United States since 1985 (when studies of AZT began). These drugs block replication of HIV in several different ways and are now usually used in various combinations which have been shown to more effectively halt viral replication than treatment with only one drug (monotherapy). The objective of antiretroviral therapy is to minimize HIV's ability to make copies of itself, thereby slowing disease progression and limiting development of viral drug resistance.

Zidovudine (AZT) was the first such therapy to be approved by the Food and Drug Administration (FDA) in 1987. Zidovudine was followed by several other similar drugs, known as nucleoside analogs. Nucleoside Analogs work by inhibiting the retroviral enzyme, reverse transcriptase, which changes HIV's RNA into DNA and plays a key role in HIV's ability to reproduce itself. The other nucleoside analogs currently available are didanosine (ddI), zalcitabine (ddC), stavudine (d4T), and lamivudine (3TC).2 In the past few years, zidovudine monotherapy has been shown to be much less effective than other approaches, including: 1) didanosine monotherapy, 2) zidovudine in combination with other nucleoside analogues, and 3) zidovudine in combination with other nucleoside analogs AND a protease inhibitor. 

In 1996, three new drugs, known as protease inhibitors, were approved by the FDA for use in treating HIV disease, and, in March of 1997, a fourth protease inhibitor was approved. Unlike the nucleoside analogs, the protease inhibitors - indinavir (Crixivan), ritonavir (Norvir), saquinavir (Invirase), and nelfinavir (Viracept) -- work by inhibiting the retroviral enzyme, protease, which also plays a key role in HIV's ability to make copies of itself. Recent studies have shown these agents to be particularly effective when used in combination with nucleoside analogs. Also in 1996, another antiretroviral drug, nevirapine (Viramune), was approved by the FDA for use in the treatment of HIV/AIDS. Nevirapine is a non-nucleoside reverse transcriptase inhibitor and has the substantial advantage of once-a-day dosing. 

A new measure for antiretroviral therapy was recently introduced, known as "viral load testing." Recent studies have confirmed that "viral load" reflects the patient's response to antiretroviral therapy and predicts the course of HIV/AIDS better than other markers, including CD4 cell counts.

The increasing availability of HIV viral load testing, along with potent new antiretroviral therapeutic regimens, has created the opportunity for very early detection and treatment of HIV infection - even before seroconversion (i.e., when antibodies appear in the blood) or before symptoms develop during acute retroviral syndrome (which presents much like mononucleosis). The primary goal of early detection and treatment is to limit early viral production (and dissemination to organ systems), resulting in a lower "viral set point," the amount of virus in the blood once the virus has spread throughout the body. Presumably, a lower viral set point will lead to better health over a longer period of time for the patient. Although there is currently little clinical data on which to base therapeutic decisions, preliminary data suggest that use of aggressive combination therapies as soon as infection is detected may offer the most promising prognosis to date for HIV infection.7 

The use of these new drug combinations has been dramatically improving the health of many people with HIV/AIDS, and has helped to reduce AIDS death rates in 1996. Despite this recent good news, however, HIV and AIDS remain serious, life-threatening health problems, and there is currently no cure. Human clinical experience with these new treatment regimens is only a little over a year old. Consequently, there are still many unknowns about these therapies including their long-term effectiveness and toxicity (e.g., the effects of these drugs over time on the liver and other organ systems), the ability of patients to adhere to complex and rigorous dosing schedules (e.g., taking dozens of pills daily on a regular schedule that dictates when you can and cannot eat), and the potential for the generation (and transmission to others) of new and drug resistant strains of HIV. While these regimens in some patients can drastically reduce amounts of HIV in the blood, most (98%) of HIV is found in other human tissues (e.g., the brain) which have yet to be carefully evaluated. In addition, perhaps 1/3 of people with HIV cannot tolerate these drugs and are unable to benefit from them.

The costs associated with these new therapy regimens can be another barrier to their use. The total annual cost of combination therapy plus the associated monitoring of treatment effects/benefits is estimated to be well over $10,000 per year.8 For those without insurance that covers payment of these drugs and tests, obtaining them consistently over time may be difficult. 

Finally, there is currently no "morning after pill" for HIV infection; however, study of a proposed "morning after" treatment regimen is scheduled to begin in San Francisco during Spring of 1997. The idea of treatment directly after exposure to HIV is to snuff out early HIV infection before it can take hold. For several years, prevention therapies have been recommended and carried out for health care workers who were accidentally stuck by needles contaminated with HIV. Within 1-4 hours of exposure, health care workers have been offered a 30 day supply of AZT which, in a study conducted by the Centers for Disease Control, has been shown to reduce risk of HIV infection by two-thirds among study participants; other studies show an even higher protection rate.9 Perhaps a similar regimen will prove effective at preventing HIV infections among those exposed in isolated incidents of unsafe sex or because of a broken condom. 

New therapies for HIV/AIDS

1. While progress is being made in the fight against HIV and AIDS, there is still no cure , nor is there yet a vaccine to prevent infection with HIV. Those without HIV infection should not drop their guard against this life-threatening agent. Everyone ought to do everything possible to avoid and prevent HIV infection (e.g., abstain from unprotected sex and injection drug-use, use condoms consistently and correctly). Prevention is still much better than treatment. 
2. All people at risk for acquiring HIV infection should get tested regularly (every 3 - 6 months) for HIV-antibodies, so that those infected with HIV may be evaluated and treated at the earliest possible opportunity. The early identification and prompt treatment of HIV infection can delay disease progression, prolong life, and improve quality of life for people living with HIV/AIDS. 
3. Even though there are still many unknowns, the use of protease inhibitors in combination with other antiretroviral drugs is dramatically improving the health and quality of life for many people with HIV/AIDS. At the earliest opportunity, all people living with HIV/AIDS must obtain evaluation and explore care options with knowledgeable health providers who can prescribe antiretroviral therapies. 
4. Potent new drugs, known as protease inhibitors, have recently become available for use in treating HIV/AIDS. Protease inhibitors reduce the amount of HIV in someone's bloodstream by interfering with the enzyme, protease, which plays a key role in HIV's ability to make copies of itself. Other antiretroviral drugs (e.g., AZT, 3TC, nevirapine) work by interfering with another enzyme, reverse transcriptase, which also plays a key role in HIV's ability to reproduce. Protease inhibitors are only to be used in combination with other antiretroviral drugs in order to limit development of viral resistance. 
5. While the new and more powerful treatment regimens for HIV/AIDS appear to be successful, study of these drug combinations has been conducted in humans only since the mid-1990s, and there are still many unknowns and concerns including:
   • how long these treatment regimens will remain effective. 
   • the long-term side effects to taking these drugs (e.g., could they cause cancer or have other debilitating consequences?). 
   • how effective these treatment regimens are at reducing HIV in tissue other than blood; while these therapies can reduce the amount of HIV in the bloodstream, most (98%) of HIV is found in other human tissue (e.g., brain, lymph nodes, spleen) which have yet to be carefully evaluated. 
   • how easily someone could transmit drug-resistant HIV to sex or needle-sharing partners - even if that partner is also infected with HIV; it is currently unknown how infectious someone is while taking these drug regimens. 
   • up to 1/3 of HIV infected people cannot tolerate these drugs and are unable to benefit from them. 
   • the high cost of these therapies and associated monitoring tests (probably >$10,000 per year). 

Glossary

Acute HIV Infection: Once HIV enters the body, it 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 themselves in various organs, particularly the lymphoid tissue. During this phase of HIV infection, individuals are highly infectious. 

Also known as "primary HIV infection." See also "Acute Retroviral Syndrome" and "Seroconversion." 

Acute Retroviral Syndrome: A collection of symptoms associated with Acute HIV infection. The acute HIV infection often passes unrecognized, but may express itself as a mononucleosis-like syndrome within 2 weeks - 3 months of infection.4 Symptoms can include persistent fatigue, swollen lymph nodes, and high fevers. Seroconversion usually occurs shortly after this syndrome. During this phase of HIV infection, individuals are highly infectious. See also "Acute HIV Infection" and "Seroconversion." 

AIDS: Acquired Immune Deficiency Syndrome (AIDS) is advanced infection with HIV, marked either by opportunistic infections that do not occur in people with healthy immune systems AND/OR by a decrease in CD4 cells below the level of 200 copies per microliter of blood.3 

Antiretroviral therapy: Drugs used, usually in combination with other antiretroviral drugs, against retroviruses such as HIV.4 

CD4 cells: White blood cells that help orchestrate the body's infection-fighting cells. They are named after the CD4 molecules they carry on their surface3 and are HIV's preferred target in the blood stream.4 

Also called "T helper cells." 

CD4 cell count: The number of CD4 cells in a tiny drop of blood (a microliter, or about 1/500 of a teaspoon). Because HIV attacks CD4 cells, their number falls as the infection gets more serious.3 

Also called "T cell count" or "T count." 

DNA (deoxyribonucleic acid):A large nucleic acid molecule, found principally in the chromosomes of the nucleus of a cell, that is the carrier of genetic information.6 When HIV infects a cell, its enzyme, reverse transcriptase, changes HIV's RNA into DNA. 

Enzyme: A kind of protein that facilitates chemical changes inside cells.3 Enzymes act like catalysts. 

HIV: The human immunodeficiency virus (HIV), a retrovirus, attacks infection-fighting blood cells (CD4 cells) and other cells,3 usually causing the immune system to break down and allowing certain opportunistic infections to attack the body. In other words, HIV causes AIDS. 

Immune System: The complex network of organs and cells in the body that recognizes and fights off infections and other "foreign invaders,"3 neutralizes them, and recalls the response later when confronted with the same challenge.4 The immune system is not completely effective at fighting off HIV. 

Monotherapy: Treatment with only one drug. 

Non-nucleoside Reverse Transcriptase Inhibitor: A substance/drug (e.g., nevirapine), not like an RNA or DNA building block, which nevertheless inhibits the reverse transcriptase enzyme and interferes with viral replication. 

Nucleoside Analog: A general type of antiretroviral drug (i.e., AZT, ddI, ddC, 3TC, and d4T) which resemble some of the building blocks needed to make RNA and DNA. They work by interfering with the reverse transcriptase enzyme and, thus, interrupting HIV's replication process. 

Opportunistic Infections: An illness caused by an organism that usually does not cause disease with a normally functioning immune system. People with advanced HIV infection (AIDS) suffer opportunistic infections of the lungs, brain, eyes, and other organs.4 

Primary HIV Infection: See "Acute HIV Infection" and "Acute Retroviral Syndrome." 

Protease: An enzyme which cuts ribbons of newly fabricated HIV in order to make viral particles. To make new copies of itself inside infected cells, HIV depends on several enzymes. All of these enzymes have specific jobs in the HIV replication process. Protease is one of HIV's enzymes, and it is required to continue the process of HIV infection. Its job comes near the end of HIV replication. By then, HIV has already entered the cell's nucleus and has made long chains of proteins and enzymes that will form many new copies of HIV. But before they can produce working viral particles, the long chains have to be cut into smaller pieces. The HIV protease enzyme is like a "chemical scissors" because it cuts the long chain into shorter pieces.5 

Protease Inhibitors: Protease inhibitors are drugs that resemble pieces of the protein chain that protease normally cuts. By "gumming up" the protease "scissors," HIV protease inhibitors prevent protease from cutting long chains of proteins and enzymes into shorter pieces that HIV needs to make new copies of itself.5 

Retrovirus: HIV and other viruses that carry their genetic material in the form of RNA and have the enzyme called reverse transcriptase are retroviruses. Like all viruses, HIV can replicate only inside cells, commandeering the cell's machinery to reproduce. Like other retroviruses, HIV uses the enzyme called reverse transcriptase to convert its RNA into DNA, which is then integrated into the host cell's DNA.4 

Reverse Transcriptase: A retroviral enzyme that lets HIV's genetic message get inside the genetic machinery of infected cells.3 To make new copies of itself inside infected cells, HIV depends on several enzymes. All of these enzymes have specific jobs in the HIV replication process.5 Reverse transcriptase is one of HIV's enzymes. Its job comes near the beginning of HIV replication. It converts HIV's RNA into DNA, the form in which a cell carries its genes.4 

Reverse Transcriptase Inhibitors:Reverse transcriptase inhibitors are drugs that stop the enzyme, reverse transcriptase, from doing its job efficiently.3 

RNA (ribonucleic acid): A nucleic acid, found in both the nucleus and cytoplasm of cells, that transmits genetic instructions from the nucleus to the cytoplasm.6 RNA is the genetic material carried by HIV and other retroviruses.4 

Seroconversion: The development of antibodies to a particular antigen. When people develop antibodies to HIV, they "seroconvert" from antibody-negative to antibody-positive.4 Seroconversion usually occurs shortly after the acute retroviral syndrome. During this phase of HIV infection, individuals are highly infectious. 

T cells/T helper cells: See "CD4 cells." 

Viral Load: The amount of detectable free virus, specifically HIV, found in the blood (or other tissue) of HIV infected people. Lower viral loads mean lower amounts of viruses in an individual's blood AND, consequently, less potential for morbidity associated with HIV infection. Viral load testing has become a standard of HIV treatment monitoring. 

(For more information on viral load testing, see: SKCDPH HIV-Infogram: Viral Load Testing - 9/20/96)

Viral resistance: When subjected to certain conditions (e.g., drug therapy), HIV has the ability to change its chemical (or genetic) structure so that it resists the effects of those conditions. In other words, HIV adapts, when exposed to drugs, in such a way as to make it resistant to the effects of those drugs. 

> References

• Carpenter, CCJ et al. Consensus Statement: Antiretroviral therapy for HIV Infection in 1996, Recommendations of an International Panel (July 10, 1996) JAMA, 276 2:146-154 
• Protease Inhibitors for HIV Infection (15 June 1996) Annals of Internal Medicine, 124, 12:1086-1088 [editorial] 
• Protease Inhibitor Word List (accessed February 28, 1997) http://www.iapac.org/consumer/wordlist.html#reverstrans 
• Glossary, JAMA HIV/AIDS Information Center (accessed February 28, 1997) http://www.ama-assn.org/special/hiv/glossary/gloss-ei.htm 
• Markowitz, M. Protease Inhibitors: What They Are, How They Work, When to Use Them (1996) [booklet] 
• Mosby's Medical, Nursing, & Allied Health Dictionary, Fourth Edition (1994) Mosby -- Year Book Inc. 
• Cotton, DJ [editor] Primary HIV Infection and the Acute Retroviral Syndrome, The Urgent Need for Recognition (March 1997) AIDS Clinical Care, 9 3:22-28 
• Deek, SG; Smith, M; Holodniy, M; Kahn, JO. HIV-1 Protease Inhibitors (January 8, 1997) JAMA, 277, 2:145-153 
• Russell, S. Tantalizing HIV Study to Probe Prospect of 'Morning-After' Pill (March 4, 1997) San Francisco Chronicle [online, accessed March 5, 1997]