What to Do If an HIV Treatment Fails

Identifying the Causes and Selecting a New Drug Regimen

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HIV treatment failure occurs when your antiretroviral drugs are no longer able to suppress the virus or prevent the deterioration of your immune system, leaving you vulnerable to opportunistic infections.

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Treatment failure can be classified as being either virologic (pertaining to the virus), immunologic (pertaining to the immune system), or both. In the United States, treatment failure is based almost entirely on virologic values—namely the viral load.

There are guidelines in place directing the appropriate treatment of virologic failure. If it occurs, your healthcare provider will perform tests to determine which antiretroviral drugs you are most sensitive to so that a new set of drugs can get your viral load back to undetectable.


If treatment failure occurs, the first step is to identify the factors that may have contributed directly or indirectly. In most cases, the failure will be the result of poor drug adherence, wherein medication doses were frequently missed or treatment was interrupted.

There may be other causes, some of which may be unrelated to adherence and others that may predispose you to poor adherence. According to the Office of AIDS Research at the National Institutes of Health, these include:

  • Acquired drug resistance, in which you "pick up" a drug-resistant variant through sex, shared needles, or other modes of transmission
  • Previous treatment failure, during which you will likely have developed levels of resistance to antiretrovirals of the same class
  • High baseline viral load, as some drug regimens are less effective when you have a very high pretreatment viral load
  • Intolerable side effects, which can lead some people to skip doses or altogether quit the offending pill
  • Drug interactions, in which another drug may inadvertently reduce the concentration of an antiretroviral in your blood, reducing its effectiveness
  • Poor drug absorption, which can happen to people with chronic HIV-associated diarrhea or other malabsorption issues
  • Not following food requirements, which can also affect drug absorption and metabolism
  • Cost and affordability, including the lack of adequate health insurance
  • Substance abuse and mental health problems, which can lead to inconsistent dosing and risk-taking behaviors
  • Other psychosocial issues, like poverty, unstable housing, stigma, and the fear of disclosure, each of which can make adherence more difficult

Unless these factors are reasonably resolved, there will remain an increased risk of treatment failure with future drug regimens.

Virologic Failure

Virologic failure is defined as the inability to maintain a viral load of fewer than 200 copies per milliliter (mL) despite adherence to antiretroviral therapy.

When antiretroviral therapy is working, the viral load should be fully undetectable, meaning that it is below the level of detection (under 20 to 75 copies/mL, depending on the test). If failure is allowed to continue, the viral load will continue to rise, in some cases into the millions.

This doesn't mean that you should immediately change treatment the moment the viral load hits 200. In order for virologic failure to be declared, there must be repeated evidence of viral elevation over the course of six months.

The healthcare provider will also need to determine the possible causes of the increase (including poor adherence) and rectify them if there is a reasonable chance of preserving the current drug regimen.

With that said, "near-undetectable" viral loads should not be allowed to persist. Research has shown that persistent low-level viral activity (between 50 and 199) can increase the risk of virologic failure within a year by some 400%.

The longer that low-level viremia (viral activity) is allowed to persist, the greater the opportunity there is for additional mutations to develop, leading to ever-deepening drug resistance.

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Immunologic Failure

Immunologic failure occurs when defensive immune cells, called CD4 T-cells, fail to recover despite fully suppressive antiretroviral therapy. These are the cells that HIV preferentially attacks, and their depletion is a reliable marker for your immune status.

The immune status of people with HIV is measured by a blood test called the CD4 count. "Normal" values are typically defined as being 500 cells/mL or above, while those below 200 are classified as AIDS.

In the past, the CD4 count (and other values such as the CD4/CD8 ratio) factored greatly into how HIV was treated. While these values are still important, their impact on treatment decisions has changed considerably in recent years for several reasons:

  • Inconsistency of definitions: There remains no clear definition of immunologic failure. Some describe it as the inability to increase the CD4 count above a specific threshold (say, 350 or 500) despite an undetectable viral load. Others simply define it as the inability to do so above pretreatment values.
  • Inconsistency of recovery: Not all people will respond to antiretroviral therapy in the same way. People with extremely low pretreatment CD4 counts may never achieve normal CD4 counts. Similarly, those with mild to moderate immune suppression will sometimes see an improvement of several hundred T-cells, while others will see their numbers shoot well above 1,000 or 1,500.
  • Inconsistency of effect: While a low CD4 count places you at an increased risk of an opportunistic infection, it does necessarily mean you will get one. On the other hand, having a normal CD4 count doesn't mean you won't get one. Some people have been known to get a severe opportunistic infection during even the early acute stage of infection.

By contrast, the one goal of treatment that remains consistent is an undetectable viral load. This is true irrespective of age, CD4 count, the presence or absence of symptoms, or the number of years you've had HIV.

It is for this reason that virologic failure, rather than immunologic failure, is the determining factor for when an antiretroviral treatment needs to be changed.

Changing Therapy

If virologic failure is declared, your healthcare provider will order one or more tests to evaluate your "viral pool." When you have HIV, you do not have just one virus but rather a multitude of variants, some of which are drug-resistant. Under the pressure of antiretroviral therapy, the viral pool can change with drug-resistant variants becoming more and more predominant.

In some cases, the resistance will be deep and affect not only the current regimen of drugs but also drugs of the same class. In other instances, some of the drugs in the regimen will be affected and others not.

Testing Recommendations

To identify the best treatment plan, your healthcare provider will order a genetic resistance test to look for specific mutations that confer resistance. Based on the number and types of mutations you have, the lab can predict with a high degree of accuracy which drugs you are susceptible to and which you are not.

Genetic resistance testing (also known as genotyping) needs to be performed while you are still taking the failing drug regimen. This allows the lab to evaluate your viral pool while the drug-resistant variants still predominate. If treatment is stopped, the original "wild-type" virus will once again become the predominant variant and skew the results.

Genetic resistance testing should be performed when the viral load is over 500 while still on therapy or no less than four weeks after stopping therapy.

You may also be given a phenotypic test in which the virus is directly exposed to individual antiretroviral drugs to see which ones are best able to neutralize them. While extremely useful, a phenotypic test cannot foresee developing resistance in the same way that a genotypic test can and is rarely, if ever, used on its own.

Drug Selection

Based on the findings, your healthcare provider can select the combination of drugs best suited to overcome your resistant mutations.

At least two (and ideally three) drugs in the regimen should be changed. Changing one drug is not recommended as it is likely to allow low-level resistant variants to further mutate and become even more resistant.

If the level of drug resistance is deep, certain once-daily drugs may need to be taken twice a day, or additional agents may be added to the regimen. Generally speaking, the healthcare provider will consider drugs from a class that you have not yet been exposed to.

There are currently 26 individual antiretroviral drugs and 22 fixed-dose combination drugs comprised of two or more antiretrovirals approved by the Food and Drug Administration.

A Word From Verywell

Treatment failure can also occur in people who are fully adherent, typically after many years of treatment. This is particularly true for those who take some of the older antiretroviral drugs, some of which are more durable (longer-lasting) than others.

However, if treatment failure occurs within a relatively short period of time, poor adherence almost invariably plays a part. If this is the case, be honest with your healthcare provider and say so. There may be ways to improve adherence so that the next set of drugs you are given is more durable and better able to protect your health.

6 Sources
Verywell Health uses only high-quality sources, including peer-reviewed studies, to support the facts within our articles. Read our editorial process to learn more about how we fact-check and keep our content accurate, reliable, and trustworthy.
  1. DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents. Management of the treatment-experienced patient.

  2. Laprise C, de Polomandy A, Baril JG, Dufresne S, Trottier H. Virologic failure following persistent low-level viremia in a cohort of HIV-positive patients: results from 12 years of observation. Clin Infect Dis. 2013 Nov;57(10):1489-96. doi:10.1093/cid/cit529

  3. Boulasel MR, Chomont N, Pant Pai N, Gilmore N, Sekaly RP, Routy JP. CD4 T cell nadir independently predicts the magnitude of the HIV reservoir after prolonged suppressive antiretroviral therapy. J Clin Virol. 2012 Jan;53(1):29-32. doi:10.1016/j.jcv.2011.09.018

  4. Tobin SC. Atypical symptoms of acute retroviral syndrome seen in one-third of patients with primary HIV infectionAIDS. 2015;29(15):N15. doi:10.1097/QAD.0000000000000831

  5. DHHS Panel on Antiretroviral Guidelines for Adult and Adolescents. Drug-resistance testing.

  6. U.S. Department of Health and Human Services. FDA-approved HIV medications.

By James Myhre & Dennis Sifris, MD
Dennis Sifris, MD, is an HIV specialist and Medical Director of LifeSense Disease Management. James Myhre is an American journalist and HIV educator.