Treatment Review #18; April 1995

There are three kinds of drugs used to treat people with HIV/AIDS: antiretroviral drugs, drugs to treat and prevent opportunistic diseases, and therapies that treat specific symptoms of AIDS, such as wasting or anemia. Antiretroviral drugs block reproduction of HIV, the virus that causes AIDS.

The HIV virus is a complicated virus, known as a retrovirus. It contains two copies of RNA, which can be thought of as a blueprint for making new viruses. It also has protein spikes called gp120 on its surface. gp120 is used by the virus to bind with a protein on immune system cells in order to permit HIV to infect those cells. The viral RNA is then injected into the cell where it is converted to DNA. DNA is the main way the body stores information to make new cells. The conversion of RNA into DNA is accomplished by an enzyme called reverse transcriptase. Available antiviral drugs all work by blocking this enzyme, and thereby preventing the virus from infecting new cells.

In clinical trials or studies to determine whether these drugs work, researchers look at three different things: how long people live while taking the drug, whether the drug can keep them from getting sick, and whether the drug can improve markers of disease and immunity in their blood. At this time there are five available drugs to treat HIV. Each drug has several names, which can be confusing. They are called AZT (Retrovir), ddI (Videx), ddC (Hivid), d4T (Zerit), and 3TC (lamivudine).

AZT

AZT is the drug most frequently used to treat HIV disease. AZT is usually given as pills, and people often take 600 mg every day. This means they will take six pills, split up into either two pills three times a day, or three pills two times a day. A new time-released version, called AZTEC, is being tested in clinical trials now. AZTEC reduces the number of pills that need to be taken.

In a study looking at the effects of the drug in very sick people over the short term, AZT appeared to delay death.

Researchers then tried to give AZT to healthier people with HIV to see if the drug would delay the development of serious AIDS-related infections. Two early studies suggested that AZT did help people maintain health. People taking AZT developed fewer infections than people who were taking the placebo. A placebo is a sugar pill used for comparison to see how well the treatment works.

However, two more recent studies have cast some doubt on the usefulness of AZT in delaying the onset of AIDS. A study by the Veterans Administration found that, while AZT could slow the rate at which HIV-infected persons got AIDS- related infections, the drug did not make people live longer than people who were taking the placebo. More recently, the Concorde Study was a large study of early treatment with AZT. It also found that, while early AZT could slightly reduce AIDS-related infections, the drug did not extend life.

People with HIV are sometimes prescribed to take several AIDS drugs at once. This is called combination therapy.

When AZT was first used to treat AIDS, people were commonly given very high doses of the drug. Side effects were common and severe, including nausea, vomiting, headache, muscle wasting and anemia. While these side effects are sometimes seen in people taking only 600mg of AZT per day, they are much less frequent, and usually less severe.

AZT is also used to treat dementia which affects some people with AIDS, and a blood disorder called thrombocytopenia, which means low levels of the cells that allow blood to clot.

Recently, an important study showed that pregnant women treated with AZT were only one-third as likely to pass HIV on to their babies as women who didn't take AZT. In another study, children taking AZT alone did not do as well as those taking a combination of AZT and ddI or ddI by itself. ddI is described below.

AZT does not work forever. HIV is capable of changing rapidly, or mutating. This allows the virus to escape the antiviral effects of AZT. Test-tube studies show that, in most people, HIV is largely resistant to AZT within six months of beginning treatment. Resistance means the virus is no longer affected by the drug. However, the usefulness of the drug in delaying disease seems to last longer than six months. Most doctors monitor their patients' blood, as well as their overall health status, to determine when AZT is no longer working.

ddI

ddI works in the same way as AZT. Early studies showed the drug raises levels of T-cells, an important type of immune cell that some researchers use to determine if a treatment is working.

A later study showed that, in people who'd never taken antiviral drugs to treat HIV, AZT was better than ddI at keeping people healthy and alive. In people who'd taken AZT for up to eight weeks, ddI was as good as AZT at keeping people alive and healthy. In people who'd taken AZT for more than sixteen weeks, ddI was better than AZT.

ddI usually comes in the form of a large, flavored tablet that can be chewed or dissolved in water, or in a powder that gets dissolved in water. Because food can slow down the body's absorption of ddI, people should not eat for one hour before taking ddI, or for two hours after. The proper dose is based on the person's body weight, and so the number of tablets taken each day may depend on the individual. Generally, people are told to take two doses, one in the morning, and one in the evening.

One possible side effect of ddI is called peripheral neuropathy. The main symptom is a painful burning sensation in the hands and feet. People taking ddI may also develop swelling of an organ called the pancreas. If pancreatitis isn't caught soon enough, it can be deadly. Careful monitoring of a specific blood enzyme called amylase can provide warning of pancreatitis. A drug called pentamidine, which is often used to prevent an AIDS-related pneumonia called PCP, can also cause pancreatitis. People taking ddI should not use pentamidine at the same time. ddI may also cause diarrhea or nausea.

ddC

ddC is another antiretroviral that works in the same way as AZT. As a single drug, ddC is less effective than AZT in delaying illness and death in people who've never taken antiviral treatment for HIV infection. In people who'd already taken AZT for a long time, ddC was about as effective as ddI in delaying illness and death.

ddC is given in the form of a tablet. People usually take three tablets per day, along with six AZT pills. It is important that people with ddC see their doctor regularly to monitor blood work for toxicity, and report immediately if they feel any signs of neuropathy.

ddC is mostly used in combination with AZT after a person has begun to show signs of immune-system damage after taking AZT for a long time. The combination of these two drugs can raise T-cells better than either drug alone, however it is not clear whether or not they can delay illness and death better than single-drug treatment. One large study suggested that combination therapy was no better than single-drug treatment at delaying illness and death, but some researchers believe that healthier people may respond better to the combination.

The main side effect of ddC treatment is peripheral neuropathy. After people stop taking ddC, their peripheral neuropathy will usually go away, but it can take weeks and even months. Also, peripheral neuropathy may continue to get worse for a little while after ddC treatment is stopped. ddC also causes pancreatitis in a very few people and, possibly, severe mouth sores.

d4T

d4T, also known as Zerit or stavudine, is similar to other approved drugs. Early studies have shown that d4T can produce small increases in T-cell levels, although no decreases in virus levels were seen.

The main side effect of d4T is peripheral neuropathy. In a large study, comparing high-dose d4T (80mg/day) to low-dose d4T (40mg/day) in people with AIDS, 21% of participants taking high-dose d4T developed peripheral neuropathy, while only 15% of those taking low-dose d4T developed neuropathy. There was no improvement in rates of disease or death on high- dose treatment as compared to low-dose treatment.

Ongoing studies are expected to produce more information about the ability of d4T to delay illness and death.

3TC

3TC, also known as lamivudine, is an experimental anti-HIV treatment that is related to other anti-HIV drugs. 3TC is available to people with AIDS who have less than 100 T-cells, or children with less than 300 T-cells, who have taken AZT, ddI, ddC and d4T. Early studies have suggested that 3TC may raise T-cell levels, and lower levels of HIV. More importantly, studies have suggested that 3TC treatment in combination with AZT may make AZT work more effectively, even in people who have already taken AZT for a long time.

3TC is given in tablets, and people may take either one tablet twice a day, or two tablets once a day. It is not yet known which dose is better. Studies are now underway to determine whether or not 3TC will delay disease and death. The drug is expected to be approved for sale within the next year.

Spencer Cox contributed this article. Spencer works at CRIA, the Community Research Initiative on AIDS, which does community-based clinical trials and information gathering studies. For more information about CRIA, call (212) 924- 3934.)

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