Let's face it. No drug—or combination of drugs—is going to work for everyone, or work forever. Studies have pretty much confirmed that for every two people who are 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 cells up, or tolerate the side effects while on their first HIV drug combination of choice.

The good news is that treatment options have greatly expanded in recent years. 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.

What does treatment failure mean?
Simply put, treatment failure means that the antiretroviral (ARV) drugs you are taking are no longer doing what they should. In the past, the only way to determine whether or not an HIV drug—or combination of drugs—was working was to measure CD4 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 ARV 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 HIV combination therapy—or stay down while taking the drugs—you are at risk of seeing your CD4 cell count decrease once again and, quite possibly, experience symptoms of disease progression. Your viral load and CD4 cell count can help you determine how healthy your immune system is and when you should switch therapy.

How do I know if my treatment is not working?

You and your provider will need to keep an eye on your viral load and CD4 cell counts using routine blood tests. If any of the following occur, it might be possible that your drugs aren't working correctly:

  • 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 effective is to look for a 90 percent 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.
  • 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". There are tests in existence that can detect HIV when there are less than 50 copies present, but they are commonly used for research purposes only.
  • 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. If the blip is less than 400 copies, and only occurs once, this is not usually something to worry about. If virus is over 400 copies, however, or detectable on two tests in a row, this might be a sign that treatment is no longer working.
  • If your CD4 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 CD4 cell count high. A CD4 cell count should improve, on average, by 150 during the first year of treatment. If you started therapy with a low CD4 cell count, it could take more than a year to see your CD4 cell count improve by this much. You and your provider might want to consider altering your drug combination if your CD4 cell count does not improve by at least 25 to 50 during the first year of treatment. And if your CD4 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?
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 your provider about the HIV drugs you are taking to make sure you are on a potent (strong) combination of drugs.
Poor absorption. Absorption refers to the amount of drug that is absorbed into the bloodstream after being swallowed. If someone vomits frequently as a result of taking an 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 ARV treatment with respect to food and liquids. And be sure to tell your provider about any nausea, vomiting, or diarrhea you are experiencing.
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 HIV drugs in the blood. Make sure you tell your provider about any and all medications you are taking—either by prescription or over-the-counter—before starting ARV therapy, and from then on.
Poor adherence. Adherence refers to how well you follow your provider's instructions regarding the medications you take. If you do not take your 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 ARVs or do not understand how you are supposed to take them, be sure to tell your provider immediately.
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 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.

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 HIV combination therapy and are experiencing a severe side effect—a few examples include rash and uncontrollable and persistent diarrhea—you can talk with your provider 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. One example is lipodystrophy, a possible side-effect of ARV therapy that can lead to disfiguring body-shape changes, along with increased levels of fats (triglycerides and cholesterol) and sugar (glucose) in the blood. Other examples include progressive liver damage, kidney damage and bone loss.

Because adherence is so important, finding a regimen that is easy to take is also important. This can mean reducing not only the number of medications that are being taken, but also the number of pills or the number of times per day that pills must be swallowed. Switching treatments to simplify a regimen is a reasonable strategy, but should be approached with care, especially in a person whose virus is resistant to many of the available drugs.

What if my virus becomes resistant to the medication?
We've come a long way in terms of managing virus that has become resistant to ARV therapy. 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, providers are better equipped to deal with drug-resistant HIV.

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.

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. Most insurance companies, Medicaid programs, and state-run AIDS Drug Assistance Programs (ADAP) cover the costs of these tests.

What should I switch to?
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 provider should consider when figuring out which therapies to switch to:

  • Prior treatment with low levels of virus (50 to 1,000 copies): When very low levels of virus occur, it is always important to determine what role adherence might be playing. If a person is having a difficult time with adherence, additional support should be offered. Some HIV viral load tests are more commonly associated with temporary minor elevations in virus, commonly called "blips." If virus remains above 50 copies, but less than 1,000, some providers would suggest staying on the same treatment, while others would suggest switching.
  • Prior treatment with detectable virus and drug resistance: The goal is to resuppress virus to less than 50 copies. When resistance is detected, changing to another regimen should occur as soon as possible so as to avoid developing further drug-resistant HIV mutations. This is particularly true if someone has developed resistance to an NNRTI, as the newer NNRTIs work less if a person has several NNRTI mutations. Similarly, failing regimens containing either Fuzeon (enfuvirtide) or Isentress (raltegravir) should also be changed soon after failure is detected to avoid developing further resistance mutations. A new regimen should contain at least two—and preferably three—drugs in the regimen that a resistance test shows are still fully active.
  • Extensive prior treatment with drug resistance: Given the number of new drugs approved in the last several years, it is often possible for people who are heavily treatment experienced to construct an effective new regimen. As always, the goal is suppression of virus to less than 50 copies. Partial suppression, however, when less than 50 copies isn't possible, can still protect a person from developing opportunistic infections and other illnesses. However, the benefits of partial suppression should be weighed against the potential danger of developing new resistance mutations.
  • When a person doesn't have the option of at least two active drugs available: It is reasonable to for a person to remain on a failing regimen if they have few other treatment options. In fact, it may be preferable to save the single other drug to which they may be sensitive, until newer experimental therapies become available. Studies show that even on a failing regimen, a person may still preserve their CD4 count and guard against illness. This may be particularly true for people whose virus stays under 10,000 to 20,000 copies. Another consideration is whether the person has or has had serious opportunistic infections. For such individuals, the best course might be to add a single new drug to which their virus is still sensitive. Though this substantially increases the risk that their virus will develop resistance to the new drug, even transient decreases in viral load and increases in CD4 counts have been associated with better survival. When no other approved treatments are available, the guidelines recommend exploring the possibility of accessing an experimental therapy through single-patient access of investigational new drugs (IND).

I’ve already tried most of the HIV medications, what now?
The best approach is to look for new HIV drugs that have proven to be effective for HIV-positive people who have tried and failed other ARVs in the past. Fortunately, a number of drugs have been approved in recent years specifically for people with multiple-drug-resistant HIV.

Prezista and Aptivus (tipranavir) often work for people who have taken and become resistant to other protease inhibitors.

Entry inhibitors, including the injectable drug Fuzeon (enfuvirtide) and the oral medication Selzentry, may also have a great deal to offer HIV-positive people with limited treatment options. Isentress, an integrase inhibitor, is another potent option. 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.

Another option is a regimen made up of more than two or three classes, and sometimes five or more drugs. Though such an approach is often less necessary today,compared with several years ago, it is still sometimes necessary. The main problem with taking so many drugs, aside from inconvenience, is the potential for multiple side effects and drug interactions.

Should I continue on a regimen that isn’t working?
Some people who are taking an ARV combination therapy may be seeing their viral loads increase while on therapy. At the same time, they may also be seeing their CD4 cell counts continue to increase or remain at a relatively high level. In turn, some providers 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 CD4 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 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?
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 HIV drugs on each of our drug class pages: 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. It might also be possible for people in certain circumstances to obtain access to an experimental drug outside of a clinical trial through a single-patient IND (arranged on a case-by-case basis with the help of a health care provider, the pharmaceutical company and the U.S. Food and Drug Administration).

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 the U.S. National Institutes of Health (AIDSinfo.nih.gov). They also have "health information specialists" you can talk to at their toll-free number at 1-800-HIV-0440 (1-800-448-0440).

Last Revised: February 14, 2016