Treatment Review; Double Issue #26 & #27 November 1997

After many years of research, scientists now have a much clearer idea of how HIV causes illness. Once a person is infected, the HIV virus uses the cells of the human immune system to make more HIV. The immune system is the body's defense against disease. Immune system cells that get infected by HIV die, and new cells are made to replace them. These new cells also become targets for infection by HIV. The hardest hit cells are known as T4 cells. T4 cells are important in directing the day-to-day work of the immune system. Over time, people with HIV lose T4 cells and become at risk for serious illnesses called opportunistic infections.

Studies have shown HIV produces a great number, perhaps billions, of new viruses in the body every day. The immune system responds by producing many new T4 cells to try and fight HIV and clear it from the body. The immune system is strong enough to keep HIV from causing serious damage for some time. It usually takes 3 - 20 years before serious immune system damage occurs. Without any treatment, the average time from when someone gets infected with HIV to when they are diagnosed with the immune deficiency called AIDS is around 10 years. The new guidelines provide information on how anti-HIV drugs can help control HIV in the body. Many studies have now shown that lowering the amount of HIV in the body can improve health and prevent damage to the immune system. This new understanding of HIV disease, along with the development of better anti-HIV drugs, means that people living with HIV have a much better chance of staying healthy. But because there are a limited number of treatments, it is important to use them carefully to get the most benefit.

When Should You Start Anti-HIV Treatment?

This is still a very difficult question to answer. No study has been done specifically to work out when is the best time to start anti-HIV treatment. Studies of anti-HIV drugs show that they can help people with AIDS live longer. Other studies have found some benefit to anti-HIV treatment if you have under 500 T4 cells, and very clear benefits if you have under 350 T4 cells.

The most definite recommendation the guidelines make is that if you have AIDS or symptoms of HIV disease you should start anti-HIV treatment. Symptoms of HIV disease can include unexplained fever, night sweats, shingles, weight loss and a fungal infection called thrush.

If you have don't have AIDS or symptoms of HIV disease, blood tests need to be done to see if you are at risk of getting sick. The two most important blood tests are the viral load tests and the T4 cell count (See below). Information about the T4 cell count and viral load are used together to get an idea of your risk of disease progression. If your risk of disease progression is low you may benefit from waiting to start treatment. New and better treatments may come along that are not yet available. Waiting might also allow time for new information to come out about the long-term effects of the currently available anti-HIV drugs.

Another consideration is that currently available anti-HIV drug combinations can be very complicated to take. Different drugs have to be taken on different schedules, some with food and some without. Because the goal is to try and keep high enough levels of the drugs in your body to stop HIV, taking the drugs on schedule and at the right dose (often called adherence) is very important. One of the factors to consider before starting treatment is whether you are ready to deal with a complicated drug schedule.

Some doctors caution against waiting too long to start treatment because HIV may be causing ongoing damage to the immune system. More studies should help work out if early anti-HIV treatment can benefit people with a very low risk of disease progression.

Viral Load Tests and T4 Cell Counts

An important new test called the viral load test is one of the tests used to help work out if you should start anti-HIV treatment. The viral load test measures the amount of HIV in a blood sample. The result is given as the number of copies of HIV that were found, and this is called the viral load. The T4 cell count is the other important blood test used in making treatment decisions. The T4 cell count gives an idea of the health of the immune system. A normal T4 cell count can be anywhere from 400-1200. When the T4 cell count goes below 200, there is a risk of serious illness. For specific recommendations on how often viral load tests and T4 cell counts should be done, see page 7.

Several studies have found that the viral load is closely linked to the risk of disease progression and illness. In one large study, a person who started with T4 cells between 350 and 500 and a viral load of less than 14,000 had a very low risk of disease progression over the next three years. Their risk of progressing to a diagnosis of AIDS within three years was about 5% or a 1 in 20 chance.

A person who started the same study with a T4 cell count in the same range (350-500) but a viral load of over 110,000 had a much greater risk of disease progression. Their risk of progressing to a diagnosis of AIDS within three years was close to 50% or a 1 in 2 chance.

The Ideal Goal of Anti-HIV Treatment

The new guidelines say that the ideal goal of anti-HIV treatment is to reduce the amount of HIV in the body as much as possible for as long as possible. Viral load tests are also used to measure how well anti-HIV treatments are lowering the amount of HIV in the body.

Anti-HIV treatments should also have a good effect on your T4 cell count and any symptoms of HIV disease. If the viral load is undetectable but the T4 cell count is going down or symptoms are occuring, the guidelines recommend that a change in anti-HIV treatments be considered.

Viral Load Test Results

Viral load tests are not perfect - they usually can't find less than 400 copies of HIV in a blood sample so any number less than 400 is called undetectable. Some laboratories can measure down to 200 copies, and some only down to 500, so you need to check with your doctor to find out what amount of HIV is undetectable for the viral load test you are using. Undetectable means the amount of HIV in the blood sample is too low to be measured, but it doesn't mean that there is no HIV there at all. The guidelines say that, for now, undetectable viral load is the ideal goal of anti-HIV treatment.

Viral load tests can also give slightly different results if you do them twice using the same blood sample. A viral load test done twice on the same blood sample might give one result of 5,000 and then a second result of 10,000. Since it is the same blood sample, you know that the amount of HIV has not changed. The problem is that the test isn't perfect and only gives a rough idea of how much HIV is in the blood sample.

The important thing to know is that anything less than a three-fold (3x) change in viral load may just be variation or error in the test results. For example: a change in viral load from 5,000 to 10,000 is only a two-fold (2x) change and it could just be an error in the test. A change in viral load from 5,000 to 15,000 is a three-fold change and probably means that the viral load is increasing. Any change in viral load of three-fold or more should be confirmed by doing another viral load test.

Viral load tests should not be done during an active infection or after receiving a vaccination. Both infections and vaccinations can cause a temporary increase in HIV viral load that may last several weeks.

What Anti-HIV Drugs Should You Start With?

If you're starting treatment for the first time, combinations of three anti-HIV drugs offer the best chance of lowering viral load to undetectable levels. The guidelines recommend very strongly that all of the anti-HIV drugs be started at the same time.

The guidelines recommend that you use two drugs from the nucleoside analog reverse transcriptase inhibitor class or NRTIs - AZT (trade name Retrovir), ddI (Videx), ddC (HIVID), d4T (Zerit) and 3TC (Epivir) - with one strong protease inhibitor or PI - indinavir (Crixivan), nelfinavir (Viracept), or ritonavir (Norvir). The current version of the protease inhibitor saquinavir (Invirase) is not recommended as a first choice anti-HIV drug because it isn't well absorbed by the body and has less anti-HIV effect than other protease inhibitors.

Some of the experts who worked on the guidelines point out that three drug combinations using two NRTIs with one of the class of drugs called non-nucleoside reverse transcriptase inhibitors or NNRTIs - nevirapine (Viramune) and delavirdine (Rescriptor) - may be just as good as combinations using a protease inhibitor. The problem is that not enough studies have been done to know this for sure.

No one combination of anti-HIV treatments works best for everyone. It's important to try and work out which combination is best for you, depending on your situation. See page 8 for guidelines about specific drug combinations.

How Do You Know if Anti-HIV Drugs are Working?

An anti-HIV drug combination that's working should be able to reduce your viral load by about 99% after 4-8 weeks of treatment. So if your viral load is 100,000 to start with, it should be reduced to around 10,000 after 4-8 weeks of treatment. A drug combination may take up to 6 months or even a year to reduce your viral load to undetectable levels. If your viral load then stays undetectable after repeated tests, HIV activity has been very effectively reduced or even stopped. When treatments work this well, it's much harder for the virus to become resistant to the drugs and cause illness and disease progression.

Studies also show that if anti-HIV treatments keep the viral load undetectable, T4 cell counts can go up. There is often a fast rise in T4 cells in the first few weeks of treatment, followed by a slow but continuing rise in the following months. In studies of combination therapies, these increases in T4 cells have been shown to improve health and lead to fewer opportunistic infections.

What if You Need to Change Drugs?

Side effects from an anti-HIV drug may mean you need to change to another similar drug that doesn't have the same side effects. For example, if you're on a combination of AZT, 3TC and a protease inhibitor and you get severe nausea and vomiting from the AZT, your doctor may change the AZT for d4T (Zerit) which is a similar drug but with different side effects. As long as the combination is having a good anti-HIV effect, there is no reason to change the other drugs in the combination.

Another very different reason for changing drugs is if the combination you're taking is not having a strong enough anti-HIV effect. If you don't get a 99% drop in viral load 4-8 weeks after starting treatment, the combination may not be strong enough. If the viral load is still detectable after 6 months of treatment, this may also mean the combination is not having a strong enough anti-HIV effect.

There are currently 11 anti-HIV drugs available. Some doctors worry about changing treatments too quickly. The guidelines note that if a combination of treatments seems to be keeping the viral load below 10,000 it may not be necessary to change treatments right away. However, a three-fold increase in viral load, which should be double-checked by doing two viral load tests, is reason to consider changing treatments. For example: if the viral load goes below 10,000 for a while but then increases to over 30,000 on two separate viral load tests, HIV is probably becoming resistant to the anti-HIV drugs and a new combination should be tried.

Before changing combinations, you and your doctor should check that you've been taking the drugs correctly. Your doctor should also check to make sure there are not other reasons your treatment isn't working. Other drugs you're taking may be interacting with your combination treatment. Diarrhea or liver disease can also affect how well the drugs work.

What Should You Change to if Your First Combination Stops Working?

HIV can get resistant to the effects of anti-HIV drugs. HIV makes many copies of itself in the body. There is a chance that some of the new HIV that gets made will be less affected by an anti-HIV drug. This HIV is said to be drug resistant. But if the amount of HIV is reduced enough, there's less chance of a resistant virus being made.

If HIV becomes resistant to the drug combination you're using, the guidelines recommend changing to a completely new anti-HIV drug combination, if possible. If you've already tried a lot of the available anti-HIV drugs you may need to include drugs that you haven't taken recently.

Although the guidelines recommend three-drug combinations including protease inhibitors as first treatment, there have been few studies done in people whose HIV has become resistant to these combinations. Based on a few, small studies, the guidelines recommend some possible second combinations. A second combination might include two new NRTI drugs, an new NNRTI drug and a new protease inhibitor. Another option may be a combination that includes two protease inhibitors such as saquinavir (Invirase) and nelfinavir (Viracept) or saquinavir and ritonavir (Norvir). For more information on possible first and second anti-HIV drug combinations see pages 8 and 9.

Considerations for Pregnant Women

For pregnant women with HIV, decisions about the best anti-HIV treatment to use should be based on the health of the mother. These decisions should be based on the guidelines described above. Because the chances of anti-HIV drugs harming the fetus are greatest during the first trimester of pregnancy, it may be a good idea to wait until after the first trimester before starting anti-HIV treatment, if this is possible.

For a woman who's already on combination anti-HIV treatment but who has a low risk of disease progression, consideration could be given to stopping anti-HIV treatment for the first trimester of pregnancy. If treatment is stopped, all anti-HIV drugs should be stopped at once to lower the chance of drug resistance (see "Interrupting Treatment," sidebar left). There is little information about the safety of any anti-HIV drugs in pregnancy apart from AZT. AZT has been shown to reduce the chances of transmitting HIV from mother to baby by about two-thirds.

Acute HIV Infection

Sometimes, a person will get symptoms when they're first infected with HIV. This is called acute infection. Several clinical trials are studying people just recently infected who are treated with anti-HIV drug combinations. The idea is to control the reproduction of the virus in the body early on so the immune system doesn't get damaged by HIV. We still don't know if it's possible to get rid of all the HIV in your body (sometimes called "eradication") using this approach.

The guidelines recommend that people who are diagnosed with very recent HIV infection consider joining a clinical trial of early treatment. Alternatively, one of the three drug combinations recommended as first-line treatment in the guidelines could be considered, although how long to stay on the drugs is not yet known.

Ultra Sensitive Viral Load Test

A new version of the Amplicor PCR viral load test should soon be available that can measure down to around 20 - 50 copies of HIV. This is sometimes called the Ultra Sensitive Test. When this test is available, the ideal goal of therapy will be to reduce the amount of HIV to levels too low for this test to detect. Currently this test is experimental but it can be ordered from some laboratories. In New York City, LabCorp is offering the Ultra Sensitive Test and can be reached at (800) 533-0567. Specialty Laboratories in California says that they can accept New York State Medicaid to cover the Ultra Sensitive Test. Specialty Labs can be reached at (800) 421-4449.

Interrupting Treatment

If you're taking an effective combination treatment and need to stop (because of side effects or other reasons), the guidelines recommend stopping all the anti-HIV drugs at once. Although the levels of HIV in the blood will probably go up when you stop treatment, the virus won't have had a chance to become resistant to any of the drugs, so they may work again if you restart treatment. However, repeated interruptions in treatment could lead to drug resistance and should be avoided, if possible.

Although not covered in the guidelines, one recent study showed that when anti-HIV treatment is stopped, the viral load often goes higher than before treatment was begun. However, after a few weeks the viral load usually returned to the roughly the same level as it was before treatment was started. It may not be a good idea to make treatment decisions based on viral load tests taken very soon after stopping an anti-HIV drug combination. A second viral load test done a few weeks later might be more accurate.

Recommendations for Starting Anti-HIV Treatment

AIDS diagnosis or symptomatic HIV disease: Anti-HIV treatment should be started regardless of T4 cell count and viral load. Symptoms of HIV disease can include unexplained fever, night sweats, shingles, weight loss and a fungal infection called thrush.

No symptoms, T4 cell count under 500 or viral load over 20,000: Anti-HIV treatment should be considered, but risk of disease progression and readiness to start a complicated drug combination with potential side effects needs to be taken into account. Some experts would delay treatment if the T4 cell count is between 350 and 500 and the viral load is less than 20,000 because the risk of disease progression in the near future is low. No symptoms, T4 cell count over 500 and viral load less than 20,000: Some experts would delay treatment and watch for changes. Some experts would recommend treatment for theoretical reasons.

Use of Viral Load Testing

Baseline: When a person is first diagnosed with HIV, two viral load tests should be done to help decide whether to start or delay treatment, depending on the risk of disease progression.

If treatment is delayed: Viral load testing should be repeated every 3-4 months to watch for any changes in viral load that might show treatment is needed.

If treatment is started: A viral load test should be done after 4-8 weeks of treatment to see if the drugs are working. The viral load test should then be done again 3-4 months later to make sure the treatments have reduced the viral load as much as possible. Currently this means getting the viral load below 400 copies which is called undetectable.

If treatments are working: Viral load tests should be done every 3-4 months to make sure the treatments are continuing to work.

Worsening health or dropping T4 cell count: If new symptoms develop or there is an unexpected drop in T4 cell count a viral load test should be done to look for changes in HIV levels.

Use of T4 Cell Counts

The guidelines recommend T4 cell counts every 3-6 months after testing HIV positive. Many doctors feel that monitoring any changes in T4 cell counts during the first six months after diagnosis can provide additional helpful information about risk of disease progression.

Which Viral Load Test?

Only one viral load test is currently approved. This is called the Amplicor HIV-1 PCR test, and often just gets called the PCR test. The viral load test numbers used throughout this issue of Treatment Review are based on the results you would get using this test. Another viral load test that will probably be approved soon is called the bDNA test. Some laboratories are using this test already. To make life even more complicated, the results of the bDNA test are usually about 50% lower than those from the PCR viral load test. So a viral load test result of 20,000 using the PCR test would be about the same as a viral load test result of 10,000 using the bDNA test.

Whichever type of viral load test you and your doctor choose, the guidelines recommend sticking with the same test once you've started in order to avoid confusion. It is a good idea to keep using the same laboratory, too. If you are already using the bDNA test, you should halve (divide in two) the PCR viral load numbers given in this issue of Treatment Review to make them the same as the results you would get using bDNA viral load testing.

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