Antiretroviral Therapies  




Antiretroviral Therapies


Understanding the specific steps in the HIV replication cycle is critical in order for scientists to develop drugs that attack vulnerable stages within the cycle. HIV belongs to a unique group of viruses known as retroviruses, so named because these viruses reverse the usual flow of genetic information within an infected cell. Most viruses store their genetic material in deoxyribonucleic acid (DNA), the double-helix structure that makes up genes. When a virus infects a cell, the viral DNA forms the template for the creation of messenger RNA, a type of ribonucleic acid. This messenger RNA directs the formation of specific proteins, and these proteins, in turn, build new virus particles (see Genetics). In HIV, however, genetic material is stored in two single-stranded RNA molecules. When HIV infects a cell, an enzyme called reverse transcriptase copies the genetic instructions in the virusís RNA and moves it into the DNA. This movement of genetic information from RNA to DNA is the opposite of that which occurs in most cells during protein synthesis.


Another HIV enzyme, called integrase, helps the newly formed viral DNA to become part of the structure of the infected cellís DNA. The viral DNA then forces the infected cell to manufacture HIV particles. A third HIV enzyme, called protease, packages these HIV particles into a complete and functional HIV virus. Over the last decade researchers have created a variety of drugs that block the action of some of the enzymes used in HIV replication. The main classes of drugs used against HIV are nucleoside analogues, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, and fusion inhibitors.


Nucleoside analogues impede the action of reverse transcriptase, the HIV enzyme that converts the virusís genetic material into DNA. During this conversion process, these drugs incorporate themselves into the structure of the viral DNA, rendering the DNA useless and preventing it from instructing the infected cell to make additional HIV. The nucleoside analogue known as azidothymidine (AZT), which became available in 1987, was the first drug approved by the United States Food and Drug Administration (FDA) to treat AIDS. AZT slows HIV growth in the body, permitting an increase in the number of CD4 cells, which boosts the immune system. AZT also prevents transmission of HIV from an infected mother to her newborn. Since the introduction of AZT, additional nucleoside analogues have been developed, including didanosine (sold under the trade name Videx), zalcitabine (HIVID), stavudine (Zerit), lamivudine (Epivir), and abacavir (Ziagen). These drugs are not particularly powerful when used alone, and often their benefits last for only 6 to 12 months. But when nucleoside analogues are used in combination with each other, they provide longer-lasting and more effective results.


Non-nucleoside reverse transcriptase inhibitors (NNRTIs), introduced in 1996, use a different mechanism to block reverse transcriptase. These drugs bind directly to reverse transcriptase, preventing the enzyme from converting RNA to DNA. Three NNRTIs are available: nevirapine (Viramune), delavirdine (Rescriptor), and efavirenz (Sustiva). NNRTIs work best when used in combination with nucleoside analogues.


The third group of antiviral drugs, called protease inhibitors, cripples protease, the enzyme vital to the formation of new HIV. When these drugs block protease, defective HIV forms that is unable to infect new cells. Protease inhibitors are more powerful than nucleosides and NNRTIs, producing dramatic decreases in HIV levels in the blood. This reduced viral load, in turn, enables CD4 cell levels to skyrocket. The first protease inhibitor, saquinavir (Invirase), was approved in 1995. Since then other protease inhibitors have been approved, including ritonavir (Norvir), indinavir (Crixivan), nelfinavir (Viracept), and amprenavir (Agenerase).


A new class of drugs, known as fusion inhibitors, became available in 2003 when the FDA approved the use of enfuvirtide, sold under the brand name Fuzeon. Fusion inhibitors prevent the binding or fusion of HIV to CD4 cells. When used with other antiretroviral medicines, fusion inhibitors can reduce the amount of HIV in the blood and increase the number of CD4 cells.


 Drug Resistance


Clinical studies of treatment with antiretroviral drugs immediately showed that their benefits are short-lived when a single drug is used alone. This short-term effectiveness results when HIV mutates, or changes its genetic structure, becoming resistant to the drug. The genetic material in HIV provides instructions for the manufacture of critical enzymes needed to replicate the virus. Scientists design current antiretroviral drugs to impede the activity of these enzymes. If the virus mutates, the structure of the virusís enzymes changes. Drugs no longer work against the enzymes, making the drugs ineffective against viral infection.


Genes mutate during the course of viral replication, so the best way to prevent mutation is to halt replication. Studies have shown that the most effective treatment to halt HIV replication employs a combination of three drugs taken togetherófor instance, a combination of two nucleoside analogues with a protease inhibitor. This regimen, called triple therapy, maximizes drug potency while reducing the chance for drug resistance. The combination of three drugs is often referred to as an AIDS cocktail. In HIV-infected patients who have undergone triple therapy, the viral loads reduced significantly, sometimes to undetectable levels. Their CD4 cell count gradually increased, and they sustained good health with no complications. With this treatment, some patients who were near death were able to return to work and normal physical activity. Triple therapy was introduced in the United States in 1996. That year AIDS deaths in the United States decreased 26 percent, the first decrease since the beginning of the epidemic. In 1997 U.S. AIDS deaths decreased by 56 percent from the year before.


Despite phenomenal success, triple therapy has some drawbacks. This multidrug therapy is quite complicated, requiring patients to take anywhere from 5 to 20 pills a day on a specific schedule. Some drugs must be taken with food, while others cannot be taken at the same time as certain other pills. Even the most organized people find it difficult to take pills correctly. Yet, just one or two lapses in treatment may cause the virus to develop resistance to the drug regimen.


Many people also find it difficult to deal with the unpleasant side effects produced by antiretroviral drugs. Common side effects include nausea, diarrhea, headache, fatigue, abdominal pain, kidney stones, anemia, and tingling or numbness in the hands and feet. Some patients may develop diabetes mellitus, while other patients develop collections of fat deposits in the abdomen or back, causing a noticeable change in body configuration. Some antiretroviral drugs produce an increase in blood fat levels, placing a patient at risk for heart attack or stroke. Some patients suffer more misery from the drug treatment than they do from the illnesses produced by HIV infection.


Perhaps the greatest drawback to triple therapy is its cost, which ranges from $10,000 to $12,000 a year. This high cost is well beyond the means of people with low incomes or those with limited health-care insurance. As a result, the most effective therapies currently available remain beyond the reach of the majority of HIV-infected people worldwide.


To decrease the toxic effects of drugs and to defer costly therapy, in 2001 United States federal health officials recommended delaying drug treatment for HIV infection in people showing no symptoms and who have been infected with HIV for more than six months. The new guidelines call for delaying treatment until an infected personís CD4 cells fall below 350 cells per microliter of blood or the HIV viral load exceeds 30,000 per microliter of blood. Evidence suggests that delaying treatment poses no harm to infected people and, in fact, benefits them by deferring the toxic side effects of the drugs.


Postexposure Prevention


Studies show that under certain circumstances, administering antiretroviral drugs within 24 hours (preferably within one to two hours) after exposure to HIV can protect a person from becoming infected with the virus. Although the effectiveness of postexposure antiretroviral therapy following sexual exposure to HIV remains uncertain, the CDC recommends that health-care personnel exposed to HIV infection from a needle stick or other accident take antiretroviral drugs.


Development of New Drugs


Scientists continue to develop more powerful HIV treatments that have fewer side effects and fewer resistance problems. Some drugs under investigation block the HIV enzyme integrase from inserting viral DNA into the infected cell. Other drugs prevent HIV from binding with a CD4 cell in the first place, thereby barring HIV entry into cells.


Some scientists focus on ways to fortify the immune system. A biological molecule called interleukin-2 shows promise in boosting the immune systemís arsenal of infection-fighting cells. Interleukin-2 stimulates the production of CD4 cells. If enough CD4 cells can be created, they may trigger other immune cell responses that can overpower HIV infection.


In other research, doctors hope to bolster the immune system with a vaccine. Most vaccines available today, including those that prevent measles or poliomyelitis, work by helping the body to create antibodies. Such vaccines mark specific infectious agents, such as the measles and polio viruses, for destruction. But many experts believe that an effective HIV vaccine will need to do more than just stimulate anti-HIV antibodies. Studies are underway to develop vaccines that also elevate the production of T cells in the immune system. Scientists hope that this dual approach will prime the immune system to attack HIV as soon as it appears in the body, perhaps containing the virus before it spreads through the body in a way that natural immune defenses cannot. The genetic variability of HIV frustrates efforts to develop a vaccine: A vaccine effective against one type of HIV may not work on a virus that has undergone genetic mutation.