Introduction
Let's face it. No drug – or combination of drugs – is going to work for everyone. Studies have pretty much confirmed that for every one person who is able to stay on a selected treatment regimen for a long period of time, there is another person who is unable to keep their viral load down, CD4 (T4) cells up, or tolerate the side effects while on their first HIV drug combination of choice.
The good news is that treatment options to choose from have greatly expanded in recent years. During the early years of combination HIV treatment, the take-home message was that the first regimen used was the "best bet" in terms of keeping viral load undetectable and CD4 cells high. If the first regimen stopped working properly, due to the emergence of drug resistance, there simply wasn't any guarantee that subsequent drug combinations would provide long-last effects. Today this is no longer the case. With greater understanding of drug resistance and drug-resistance testing, along with the approval of drugs specifically designed to treat drug-resistant virus, maintaining control of HIV for long periods of time is entirely possible.
Like figuring out when to start therapy and what drugs to start with, deciding when to switch therapies and what drugs to switch to is a complex process. The following questions and answers (Q&A) are intended to help you figure out why treatment switches are necessary, when they are likely needed, and what can be done if and when the time comes.
What does treatment failure mean?
Simply put, treatment failure means that the anti-HIV drugs you are taking are no longer doing what they should. In the past, the only way to determine whether or not an anti-HIV drug – or combination of drugs – was working was to measure T-cell counts and to look for signs and symptoms of disease progression. But these are all indirect consequences of HIV infection. The best way to see if anti-HIV drugs are working is to directly measure the amount of virus in the blood using viral load tests.
If your viral load does not decrease significantly while on anti-HIV combination therapy – or stay down while taking the drugs – you are at risk of seeing your T-cell count decrease once again and, quite possibly, experience symptoms of disease progression.
You and your doctor can monitor your viral load and T-cell count using routine blood tests. Used together, these tests can help you determine how healthy your immune system is and when you should start therapy. For more information about understanding these test results, click on the following lesson links:
Understanding Your T-Cell Test
Understanding Your Viral Load Test
How would I know if my drugs have stopped working?
You and your doctor will need to keep an eye on your viral load and T-cell counts upon starting a treatment regimen and over the months and years you continue to take it. If any of the following occur, it might be possible that your drugs aren't working correctly:
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If your viral load is not lower than 400 after 24 weeks (six months) of starting therapy. An early way to tell if a drug regimen is being effective is to look for a 90% drop in viral load between 2 to 8 weeks after starting therapy. For example, if your viral load starts off at 50,000 and drops to 5,000 after 8 weeks, chances are good that your viral load will be less than 400 after six months of treatment.
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If your viral load is not lower than 50 ("undetectable") after 48 weeks (almost a year) of starting therapy. Undetectable does not mean zero -- it means that your viral load is less than the minimum amount of virus the test can detect. Today's more sensitive tests can measure 50 copies/mL or above, so undetectable means "less than 50".
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If an undetectable viral load is detectable again. Some experts believe that a viral load that goes from being undetectable to detectable is a possible sign of treatment failure. But the results of one viral load test showing this jump is nothing to panic about. You should repeat the test – it may simply be an error or nothing more than a temporary "blip." If a second test confirms the results of the first test, it might be time to alter your regimen.
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If your T-cells do not improve while on combination therapy, regardless of viral load. No, it certainly is not only about viral load. The goal is to keep viral load low and the T-cell count high. A T-cell count should improve, on average, by 150 during the first year of treatment. If you started therapy with a low T-cell count, it could take more than a year to see your T-cell count improve by this much. You and your doctor might want to consider altering your drug combination if your T-cell count does not improve by at least 25 to 50 during the first year of treatment. And if your T-cell count continues to fall while you are on treatment, changing your medications will likely be necessary. |
What causes HIV to stop responding to therapy?
There are a number of possible reasons why anti-HIV therapy can stop working. These include:
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Weak drug combinations (low potency). Some people living with HIV who have high viral loads before starting therapy—for example, over a million copies—might not see their viral load decrease to undetectable levels using just three drugs. Some researchers suggest that four or more drugs should be used to control very high viral loads. Be sure to talk with our doctor about the anti-HIV drugs you are taking to make sure you are on a potent (strong) combination of drugs.
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Poor absorption. Absorption refers to the amount of drug that is absorbed into the bloodstream after being swallowed. If someone vomits a lot as a result of taking an anti-HIV drug or combination of drugs, this might affect the amount of drug that remains in the stomach and absorbed by the body. Not following dietary requirements carefully can also affect the amount of drug that is absorbed by the body. Some drugs must either be taken on an empty stomach or a full stomach. Make sure you understand how you are supposed to take your anti-HIV drugs with respect to food and liquids. And be sure to tell your doctor about any nausea, vomiting, or diarrhea you are experiencing.
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Drug-drug interactions. Many drugs used to treat HIV—including all the protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs)—are broken down in the body (metabolized) by an important liver enzyme known as P450. This enzyme is also responsible for metabolizing other common medications, including painkillers, antifungal drugs, birth-control pills, and antibiotics. Because of this, P450 can either increase or decrease the amount of anti-HIV drugs in the blood. Make sure you tell your doctor about any and all medications you are taking—either by prescription or over-the-counter—before starting anti-HIV therapy, and from then on.
We have a cool feature on this site that allows you to take the preventive step of determining whether the drugs you are taking interact with each other, or interact with a certain food, and cause a bad reaction in your body. Just click on Check My Meds for your personalized drug/drug & drug/food interactions report.
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Poor adherence. Adherence refers to how well you follow your doctor's instructions regarding the medications you take. If you do not take your anti-HIV drugs exactly as prescribed—such as the correct number of times each day, every day—this can affect the amount of drug in your blood and, in turn, allow the virus to flourish. If you are missing doses of your anti-HIV drugs or do not understand how you are supposed to take them, be sure to tell your doctor immediately.
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Drug resistance. Drug resistance—loosely defined as a series of changes, or mutations, in HIV's genetic structure that can render the virus less sensitive to anti-HIV drugs—is one of the most common and serious reasons for treatment failure. Some of the factors that can contribute to the development of drug resistance include the factors listed above, so it's important to understand what resistance is, how it can be avoided, and what to do if it occurs. |
For a more complete understanding of adherence and resistance, click on the following lesson links:
Can I switch when side effects are a problem?
Whether you've just started therapy or have been on therapy for several months or years, side effects are a major reason for switching therapies.
If you recently started anti-HIV combination therapy and are experiencing a severe side effect – uncontrollable and persistent diarrhea, for example – you can talk with your doctor about switching the offending drug for another drug that is similar in potency (strength) and associated with fewer or different side effects.
The same holds true if you've been receiving therapy for a while, have an undetectable viral load, but are experiencing a debilitating long-term side effect. A perfect example is lipodystrophy, a possible side-effect of anti-HIV therapy that can lead to disfiguring body-shape changes, along with increased levels of fats (triglycerides and cholesterol) and sugar (glucose) in the blood.
While the jury is still out regarding the exact cause of this problem, many researchers believe that it is a common side effect of most of the Protease Inhibitors (PIs), with the possible exception of Reyataz® (atazanavir). Some research has shown that switching the protease inhibitor for a Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI) (e.g., Viramune® [nevirapine] or Sustiva® [efavirenz]) might help reduce the severity of lipodystrophy. It is also believed that some of the Nucleoside Reverse Transcriptase Inhibitors (NRTIs) – particularly Zerit® (stavudine) – are responsible for the loss of fat in the arms, legs, and face of some people with HIV, a condition known as lipoatrophy. Some reports suggest that switching Zerit for another NRTI, most notably Epivir® (3TC), Ziagen® (abacavir), or Viread® (tenofovir DF), may help prevent further loss of fat, but may not necessarily help restore the fat that was lost.
For more information on lipodystrophy, click on the following lesson link:
Changes to Your Body (Lipodystrophy & Wasting)
What if my virus has become resistant to the drugs I'm taking?
We've come a long way in terms of managing virus that has become resistant to anti-HIV drugs. In the past, if your viral load became detectable while taking a combination of three drugs, the general advice was to stop the three drugs and switch to a batch of three different drugs. Research studies have demonstrated that, when a combination of drugs is unable to keep viral load undetectable, it is usually because the virus has become partially or fully resistant to one or two drugs – not the entire regimen.
Now that drug-resistance testing is widely available, doctors are better equipped to deal with drug-resistant HIV. For example, let's say you are taking a drug combination consisting of Sustiva® (efavirenz) and Combivir® (zidovudine/lamivudine). Your viral load goes undetectable. Approximately a year later, you see your viral load increase to 5,000 – a sign that your drug combination is no longer working correctly. After a drug-resistance test is performed, it is determined that your virus is still sensitive to the Combivir, but has become resistant to Sustiva. With this information, you and your doctor may simply want to stop the Sustiva – perhaps switching it for a protease inhibitor – and keep the Combivir. In other words, drug-resistance testing can help you save the drugs that are working for you while helping you find new options for those drugs that aren't working for you.
Sometimes, it's not necessary to switch any medications. An option that is becoming increasingly popular is to add new medications to an existing regimen. For example, let's say you are taking a regimen consisting of Lexiva® (fosamprenavir) and Truvada® (tenofovir/emtricitabine). After several months of your virus being undetectable while taking this regimen, your viral load rises to 5,000 and a drug-resistance test determines that your virus has become partly resistant to the Lexiva. One option might be to switch the Lexiva for another protease inhibitor. But this might not be effective, because if your virus becomes resistant to one protease inhibitor, it may be less sensitive to other protease inhibitors as well (this is called "cross resistance"). Another option is to add the protease inhibitor Norvir® (ritonavir) to your regimen. This is because Norvir can increase the amount of Lexiva in the bloodstream, thereby making the drug much more effective against the virus, even if it has started to become resistant to the drug. When Norvir is added, a low dose of the drug is used and the dose of Lexiva is reduced.
Another example: Let's say your virus has become resistant to the emtricitabine in Truvada. Instead of dropping the Truvada, your doctor may want to add Retrovir® (zidovudine), another nucleoside analogue. The reason for this is that the mutation (change) in HIV's structure that causes resistant to emtricitabine actually makes the virus more sensitive to Retrovir. In turn, adding Retrovir may improve the potency of the regimen and help bring viral load back down to undetectable levels.
Of course, dropping drugs – and, sometimes, an entire regimen – in order to switch to new drugs is still necessary for a lot of HIV-positive people in order to keep viral load low and CD4 cells high. To help maximize the effectiveness of switching drugs, drug-resistance testing has proved to be extremely useful.
Can drug-resistance tests help?
Drug-resistance tests are proving to be useful and are now being used by most, if not all, doctors in terms of helping their patients switch to effective regimens.
The use of drug-resistance testing is supported by two major medical organizations in the United States that oversee HIV healthcare policy: the United States Department of Health and Human Services (DHHS) and the International AIDS Society-USA (IAS-USA). According to official guidelines published by both organizations, drug-resistance testing should be used in the following circumstances:
- If HIV is diagnosed during the first few days/weeks of infection (this can help determine if the person was infected with a drug-resistant form of HIV);
- When viral load rebounds while on anti-HIV combination therapy; or
- When viral load fails to go below 400 within six months of starting a new anti-HIV drug combination.
To learn more about HIV drug resistance and drug-resistance testing, check out this lesson:
Understanding Drug Resistance and Drug-Resistance Testing
Most insurance companies, Medicaid programs, and state-run AIDS Drug Assistance Programs (ADAP) cover the costs of these tests.
If you're seeing your viral load increase while on therapy, talk with your doctor about having an HIV drug-resistance test.
When considering a switch, are there any rules to live by?
It's all based on your treatment history and the results of drug-resistance testing. Here are a few general rules, as established by the United States Department of Health and Human Services (DHHS), which you and your doctor should consider when figuring out which therapies to switch to:
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A detectable but low (up to 5,000) viral load and limited treatment use (e.g., failing your first, or second, treatment regimen): The goal here is to bring your viral load back down to undetectable without completely changing your regimen. One option to consider is "boosting" your current regimen by adding another drug. For example, if you are taking a protease inhibitor (PI), adding a low dose of Norvir® (ritonavir) will increase the amount of the PI in your bloodstream, thereby making it more effective against the virus (this works for all PIs with the exception of Viracept® [nelfinavir]). Another possible option is "intensification" of your regimen, perhaps adding another nucleoside reverse transcriptase inhibitor (NRTI) to increase the number of active HIV drugs being used. There is also the possibility of using drug-resistance testing to determine which drugs are no longer working so that you can switch them for more active options. If you decide to do nothing, watching viral load closely should be a priority; the higher the viral load gets, the more resistant HIV can become to the medications being used.
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Evidence of HIV resistance to one drug and limited treatment experience: Consider changing the one ineffective drug, adding another drug to "intensify" treatment, adding a low-dose Norvir booster (if applicable), or change two or more drugs in the regimen.
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Evidence of HIV resistance to more than one drug and limited treatment experience: The goal here is to bring your viral load back down to undetectable to prevent additional drug-resistance mutations from occurring. This may require changing classes of drugs, such as a switch from a non-nucleoside reverse transcriptase inhibitor to a protease inhibitor, and/or adding new drugs that drug-resistance testing suggests your virus is sensitive to.
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No resistance identified using drug-resistance testing: First it's important to consider when blood for the drug-resistance test was drawn. For the most accurate results, drug-resistance testing should be performed while the person is still taking treatment (and has a detectable viral load) or within four weeks after the treatment regimen was stopped. If the test was performed long after treatment was stopped, it may be necessary to restart treatment and repeat the test after two to four weeks. A detectable viral load while on therapy, without evidence of drug-resistance mutations, can also mean poor adherence.
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An undetectable viral load but poor CD4 cell count improvements: Some people see their viral loads decrease to undetectable levels while on treatment, but experience a further decrease or limited increase in their CD4 cell count. If this occurs, the first step should be to rule out other problems that can cause immune suppression, such as other infections or drug toxicity. Some HIV drugs, such as Viread (tenofovir) and Videx/Videx EC (didanosine) taken together, have been shown to cause CD4 cell count problems. Another possible solution might be to intensify treatment with another HIV drug or, perhaps, consider the use of an immune-based therapy such as Proleukin® (interleukin-2).
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More extensive prior treatment experience: For people who have tried and failed several HIV drugs in the past, making switch decisions can be a tricky process. Drug-resistance testing is a key tool to use in this situation. If drug-resistance testing determines that a person's virus is still sensitive to at least two available HIV drugs, using those drugs should be a priority, with the goal of pushing viral load to undetectable. The DHHS guidelines do not recommend adding on a single drug that a person's virus is sensitive to, as HIV will probably develop rapid resistance to that drug as well. With new drugs becoming available and entering clinical trials on a regular basis, it may be best to wait until it can be combined with a newer drug that the virus may also be sensitive to. Additional recommendations for people with few remaining HIV treatment options are provided in the next section.
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If I've already tried most of the anti-HIV drugs, what do I do next?
The best approach is to look for new anti-HIV drugs that have proven to be effective for HIV-positive people who have tried and failed other anti-HIV drugs in the past. Fortunately, a number of drugs have been approved in recent years specifically for people with multiple-drug-resistant HIV.
For patients who have used other protease inhibitors in the past, Prezista (darunavir) and Aptivus (tipranavir) have shown promising results in clinical trials.
Entry inhibitors, including the injectable drug Fuzeon (enfuvirtide) and the oral medication Selzentry (maraviroc), may also have a great deal to offer HIV-positive people with limited treatment options. Because these medications target HIV differently than other drug classes, such as protease inhibitors and non-nucleoside reverse transcriptase inhibitors used in initial drug combinations, many treatment-experienced people will likely benefit from their use.
For these drugs to be maximally effective, it is best to combine them with other drugs that your virus is most sensitive to, which may mean reusing antiretrovirals you've tried in the past. You should use the results of drug-resistance testing to determine which drugs you're most likely to benefit from. If you can pull together a handful of drugs that your virus is only "partly" or "moderately" resistant to—especially if you do have one or two new drugs to combine with them—you may be able to reduce your viral load to low levels and keep it there for a prolonged period of time.
Don't forget to keep your eyes open for experimental drugs that are proving to be effective for people who have become resistant to many or all of the currently available options (see the last section of this lesson).
Another option is multi-drug therapy, a strategy that calls for the combination of up to nine anti-HIV drugs. No matter how many drugs and drug combinations a patient has taken, the theory goes, it is unlikely that any one virus in the body will be resistant to all of the drugs in a complex, multi-drug regimen. This might involve a drug regimen containing up to three protease inhibitors and/or two non-nucleoside reverse transcriptase inhibitors. These types of regimens have been found to be useful in clinical trials, but definitely have their drawbacks—they usually mean multiple daily doses, may be associated with serious side effects, and possibly cause a number of drug-drug interactions.
What about continuing therapy with a regimen that isn't working?
Some people who are taking an anti-HIV drug combination may be seeing their viral loads increase while on therapy. At the same time, they may also be seeing their T-cell counts continue to increase or remain at a relatively high level. In turn, some doctors recommend – especially for patients who may not have a new combination of drugs to choose from – that a "failing" regimen should be continued. After all, the main goal of therapy is to keep the T-cell count high and the patient feeling healthy.
Other researchers argue that this is a poor choice. The longer a person stays on a failing therapy – as determined by an increasing viral load – the more likely it is that the virus will continue to mutate. This might cause the virus to become even more resistant to other anti-HIV drugs, including some that are still being researched as possible new treatments.
Again, deciding to remain on a "failing" regimen might be the best option for some HIV-positive people with limited options to choose from. But little is known whether this will do more harm than good.
What about new drugs being researched?
Yes, there are a number of new drugs being researched today, and most hold promise for people who have HIV resistant to currently marketed drugs. You can read more about these experimental anti-HIV drugs on each of our drug class pages (each one is listed in italics below the currently marketed drugs): protease inhibitors, non-nucleoside reverse transcriptase inhibitors (NNRTIs), nucleoside reverse transcriptase inhibitors (NRTIs), entry inhibitors, and integrase inhibitors.
These and other drugs being developed for HIV-positive people who have virus resistant to current options can often be accessed through clinical trials. If you would like to find out if you are eligible for any clinical trials that involve experimental treatments for drug-resistant HIV, there is an interactive web site run by ACRIA, the AIDS Community Research Initiative of America. Another useful service for finding clinical trials is AIDSinfo.nih.gov, a site run by the U.S. National Institutes of Health. They also have "health information specialists" you can talk to at their toll-free number at 1-800-HIV-0440 (1-800-448-0440).
To learn more about new drugs in development for HIV – both for people living with the virus who have not yet taken any therapy or for those who have tried and failed one or more of the current regimens – keep your eyes on AIDSmeds.com for the latest.
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