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Navigating Therapy

Summer, 1999

The following articles all address some of the most common dilemmas people face when considering drug therapies. STEP's TalkLine receives countless calls about these questions and we wanted to address them here to share with our readers up-to-date information on when to start, what to start with, when to switch, and when to intensify drug treatments.

When to Start Therapy (or When to Radically Change Your Life)

There is no right or wrong time to start therapy. However, people with very high loads of the virus (HIV RNA) and/or very low CD4 counts clearly benefit from antiretroviral therapy. The most important point is that you should not start therapy until you are mentally and physically ready and fully understand the requirements of the treatment program. It is important to fully understand how many pills you must take, how often you must take them, and what food restrictions must be followed, day after day, year after year. Starting therapy before you are ready may burn bridges and limit future therapy options.

For a person living with HIV, starting therapy is one of the biggest adjustments to make, second only to dealing with a positive HIV test result. It should be emphasized that the decision to begin therapy is not an emergency response, but is rather a process. Before you make the decision to start therapy, you can, and should, take your time to fully investigate all options and analyze the impact that beginning therapy will have on your life.

While the Public Health Service (PHS) guidelines are useful in deciding when to begin anti-HIV (antiretroviral) therapy, the decision must be made on an individual basis. Too often, healthcare providers focus only on the numbers -- the CD4 counts and the viral load -- in recommending therapy. The PHS guidelines clearly state the treatment decisions should be individualized. (The guidelines are available from the Internet at

There are many factors to consider before beginning anti-HIV therapy:

  • Do you have a stable medical and social environment?

  • Do you have adequate control of any mental health and substance abuse problems?

  • Do you have a general long-term commitment to a potentially complex and physically and mentally demanding process?

  • What is your prior history of disease state?

  • Do you have co-existent medical conditions?

  • What is the length of your HIV infection?

  • What is the rate of disease progression?

All these variables must be considered in addition to the numbers (CD4 cell counts and viral load).

The scientific basis for the PHS guidelines comes primarily from the data generated by the Men's AIDS Cohort Study (MACS), which studied the rate of progression to AIDS (prior to modern triple drug combinations) based on initial CD4 counts and HIV RNA. The MACS studies showed that the risk of progression to AIDS in 1 to 3 years was significantly higher if the CD4 count was less than 500, or if the HIV RNA was greater than 10,000 copies of HIV/ml of blood. Thus, these are the numbers used by most healthcare providers in deciding when to recommend initiation of anti-HIV treatment. Also, early studies of combination antiretroviral therapy that included a protease inhibitor showed clinical benefits to people treated when their CD4 counts were very low.

The decision to begin therapy must be made with careful consideration of the consequences of initiating anti-HIV treatment. If medications are not taken as prescribed -- which can be a challenge, considering the number of pills and timing of doses, and food restrictions -- then resistance may rapidly develop and future options may be severely limited as a result of that resistance. Even missing as few as 1 in 10 doses may contribute to failure of a regimen, depending, in part, on the specific drugs.

There are some potential significant benefits to beginning anti-HIV treatment soon after infection (during the primary infection stage, usually defined as within the first 3 months). Dr. Bruce Walker and others have shown preservation of significant immune response to HIV when therapy is begun early. However, it is unclear whether these benefits will persist after therapy is discontinued. Many healthcare providers feel that people recently infected with HIV should be offered anti-HIV therapy. However, there is no data that shows that the long-term benefits outweigh the costs of an extra 5 to 10 years of treatment when anti-HIV treatment is started soon after infection, versus waiting until later in the course of HIV infection to start antiretroviral therapy. This is an area of intense ongoing research.

Combination Therapy -- What to Start With (Or Don't Burn Those Bridges)

There are many combinations possible in selecting your first drug combination. Make sure your healthcare provider is knowledgeable and discusses all the options with you in detail. There is no right combination for everyone. The best combination is the one that you will be able to take, day in and day out, year after year.

The PHS guidelines provide recommendations for drug combinations for people who have never taken anti-HIV drugs before (who are referred to as treatment naïve). The term "highly active antiretroviral therapy" (HAART) is widely used to describe the general usage of three- or four-drug combinations. Multiple trials over the last 3 years have shown that when you begin therapy, a three-drug regimen is preferable to a one- or two-drug combination. For example, one AIDS Clinical Trial Group (ACTG) study, ACTG 320, showed indinavir with AZT and 3TC was better than AZT with just 3TC.

The general backbone of most regimens is two nucleoside reverse transcriptase inhibitors (NRTIs) combined with either a non-nucleoside reverse transcriptase inhibitor (NNRTI) or a protease inhibitor (PI). The two most common NRTI combinations prescribed are d4T with 3TC, or AZT with 3TC. Other options include d4T with ddI, or abacavir with 3TC.

Considerations in selecting an NNRTI versus a PI as the third drug include stage of disease and the personal preferences (or biases) of the healthcare provider and the person deciding to begin therapy. Prior to the availability of the NNRTI efavirenz (Sustiva), it was generally believed that the other two NNRTIs, nevaripine and delavradine, were not as strong as the PIs. Thus, many clinicians were reluctant to use the NNRTIs in people with low CD4 counts or high viral loads. However, the DuPont 006 trial, comparing efavirenz to indinavir in a three-drug combination with zidovudine and 3TC, showed that efavirenz did as well as or even better than indinavir in people with viral loads above 100,000. (This may be due in part to the longer half-life of efavirenz, which means it stays in the body much longer than indinavir.)

Other studies evaluating nevaripine also have shown it to be equivalent to PIs in people with high viral loads or low CD4 counts. Thus, more clinicians are prescribing an NNRTI-containing regimen to people with low CD4 counts or higher viral loads. But others still feel more comfortable with a regimen containing with one or even two PIs for this group of people. One consideration when including more drugs is the possibility of drug interactions or the need for dosage modifications.

Another major factor in selecting a drug combination is ease of administration and ability to incorporate the regimen into your daily routine. Nelfinavir may be taken twice a day without major food restrictions, while indinavir must be taken three times a day on an empty stomach. Efavirenz only needs to be taken once a day, but has some significant central nervous system side effects the first few weeks in 50 percent of people taking the drug, and may reactivate (worsen) current or prior mental illness such as depression or psychosis.

An unresolved issue remains the use of four-drug therapy. Many healthcare providers believe that use of four drugs is preferable when therapy is begun in someone with very high viral loads (above 100,000) or very low CD4 cells (below 200). This view is supported by some data that shows that a four-drug regimen may provide better HIV suppression in people with lower CD4 counts or higher loads of the virus (HIV RNA). The ACTG has a large ongoing study comparing the use of one PI, to two PIs, to a PI plus an NNRTI, all in combination with 2 RTIs, in such people (ACTG 388). By the end of 1999, some preliminary data may be available from this study.

A second unresolved issue is an alternative approach that uses only three RTIs as the initial regimen. This would preserve two classes of drugs, if needed, for secondary treatment regimens. There is a study ongoing comparing indinavir to abacavir (Ziagen), a new NRTI, with each drug used in combination with AZT and 3TC (CAN 3005).

The third major unanswered question is which sequence of regimens is best for you. Is it better to start with a PI, or an NNRTI, or maybe a triple-NRTI regimen? No one knows. The ACTG has a 900-person trial ongoing (ACTG 384) that compares beginning with a PI to beginning with an NNRTI-containing regimen. This study is also comparing beginning with AZT and 3TC versus beginning with d4Tand 3TC. Some results from this trial should be available in 2000.

When to Change Therapy (or When to Hold and When to Fold)

Prior to beginning antiretroviral therapy, you should have a detailed discussion with your healthcare provider about the goals of therapy, including when you should plan to change therapy if your goals are not met, and what drugs you will switch to. The aggressiveness with which you change a regimen must be balanced by the probability that new drugs will achieve better results. The best chance of achieving long-term suppression of viral replication is with your first treatment regimen.

There are two ways to evaluate the success of a treatment regimen. Blood tests can give you the numbers by measuring the CD4 cell count and the viral load. The other method is a clinical evaluation; how are you doing? The long-term effectiveness of a regimen is rated by how low and for how long is HIV replication suppressed. The goal is to get the viral load below the limit of detection. The current tests can reliably detect as few as 50 copies of HIV/ml of blood. Thus, if your level is "undetectable," that really means that you have fewer than 50 copies of HIV/ml of blood. So, in strictly controlled trials if a person had previously had undetectable levels, treatment failure would be defined as two HIV levels above 50. It is important to always get a second test to confirm the first, because there is quite a bit of variability in these results.

After initiating therapy, most people who achieve long-term suppression get to viral load levels of below 400 after 12 weeks, and below 50 copies after 6 months. Aggressive healthcare providers advocate that you add more drugs, or change drugs, until you get the viral load below 50. Unfortunately, for many people, this is not possible. Only about 50 percent of patients achieve long-term suppression below 50 (as reported by Steven Deeks, from the University of California San Francisco, and other large clinics). There are many reasons why not all patients are able to get their viral load below 50, including drug side-effects, resistance due to prior therapy, and the inability to take a regimen as prescribed, day in and day out.

Finally, the decision to change a regimen based on a viral load result must be balanced by the options available to a person. Many clinicians advocate saving drugs until you have significant weakness in your immune system, such as CD4 cells below 200.

The Public Health Service Guidelines give the following recommendations for changing therapy

The Discordant Response: Normally, the number of CD4 cells increases with a decrease of the viral load, and falls with a rising viral load. However, about 15 percent of people on antiretroviral therapy will get an increase in viral load with an increase in CD4 counts, or conversely, a drop in viral load with a drop in CD4 counts. These are known as "discordant responses" and their clinical impact on the course of HIV progression is not known.

When to Stay on a "Failing" Regimen: There is some clinical and laboratory data that suggest that HIV that is resistant to some drugs is actually a weaker virus. It may not reproduce as fast as the non-resistant virus (known as wild type) and it may not do as much damage to the body. So for people with few treatment options there may be some benefit to staying on a regimen that is not achieving total viral suppression. Once you stop drug treatment, the wild type tends to become the most dominant virus, so staying on drugs may suppress the more aggressive virus in your body.

Treatment Intensification (or Putting Another Log on the Fire)

One of the most interesting issues in treatment of HIV today is when and whether to intensify a regimen. Intensification means adding a drug or drugs to a regimen when the viral load is falling, but not completely suppressed. Adding drugs when there has not been a decrease in viral load to below 400 after 12 weeks of treatment is called early intensification, and adding drugs when a person has not gotten to below 50 copies of HIV after 6 months of treatment is called late intensification. This is to be distinguished from the situation where a person has never achieved a viral load of below 400 after 12 weeks, or below 50 after 6 months, but now has a rising viral load. There are several trials ongoing, or being planned, to test whether this is a valid approach and beneficial to the person in the long run.

If you initially had a substantial decrease in viral load but now have an increasing viral load, most health care providers would recommend changing as many drugs as possible in the regimen to avoid resistance to the new drugs.

Drug Failure (Or When Good Drugs Go Bad)

Why do some treatment regimens fail? The first thing to note is that regimens fail people, people do not fail regimens. The most common causes for a treatment regimen not to fully suppress viral replication to below the limits of detection (less than 50 copies/ml) are these:

  • Resistance due to prior therapy

  • Infection with a resistant virus

  • Resistance that develops due to irregular adherence to a prescribed treatment plan

  • Inability to tolerate a drug due to side effects

  • Interactions with other prescribed drugs

  • Poor absorption of a drug due to vomiting or diarrhea

  • Individual variations in drug metabolism or activation within cells

Drug resistance is a very common problem with HIV because the virus can vary its genetic code whenever it makes copies of itself inside of your body. Most of these "errors" lead to a defective virus. However, every so often, the virus gets lucky and one of these random mistakes allows the virus to grow in the presence of a particular drug. These genetic changes in the virus are what is measured when a genotype test for resistance is performed. Studies in the laboratory have identified which mutation points are known to correlate with resistance to a certain drug in the clinic.

Until recently, the belief has been that when a person fails to achieve or maintain complete viral suppression on a drug combination, they have become resistant to all the drugs. However, several recent studies have found that when a person has not completely suppressed HIV production on a regimen containing a protease inhibitor (PI) and two nucleoside reverse transcriptase inhibitors (NRTIs), they often show resistance to only the NRTIs, and not the PI. This has led some clinicians to question the need to change all of the drugs when a person has "failed" a regimen. However, STEP would note that even a PI should give very good viral suppression prior to development of resistance. So if the drug is not working, then maybe it should be changed, no matter what the resistance tests show. Much more investigation is needed into this important issue.

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This article was provided by Seattle Treatment Education Project. It is a part of the publication STEP Perspective.