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 it is determined that your antiretroviral drugs are unable to achieve the goals of therapy—namely the suppression of HIV viral activity or the restoration of immune function to prevent opportunistic infections. A treatment failure can be classified as virologic (pertaining to the virus), immunologic (pertaining to the immune system), or both.

When a treatment failure occurs, the first step is to identify the factor or factors that may have contributed to the failure, which might include:

  • Suboptimal drug adherence
  • Acquired drug resistance
  • Previous treatment failure(s)
  • Poor adherence to food restrictions 
  • A low pre-treatment CD4 count
  • Co-infections (such as hepatitis C or tuberculosis)
  • Drug-drug interactions
  • Problems with drug absorption or metabolism
  • Drug side effects, which can impact adherence
  • Untreated depression or substance use, which can also impact adherence

Virologic Failure

Virologic failure is defined as the inability to achieve or maintain an HIV viral load of less than 200 copies/mL. This doesn't mean that person should immediately change therapy should the viral load drop below 200. It simply serves as the measure by which a doctor can make an informed clinical judgment once patient adherence and dosing practices are assured.

Similarly, the definition shouldn't suggest that it is acceptable to maintain less than optimal viral suppression. Even "near undetectable" viral loads (i.e., 50 -199 copies/mL) should be of concern, with recent studies suggesting that persistent, low-level viral activity over a six-month period can increase the risk of virologic failure within a year by some 400%.

(By contrast, occasional viral "blips" are generally not predictive of a virological failure.)

Inadequate drug adherence and acquired drug resistance are today considered the two primary causes of virologic failure, particularly in first-line therapy. According to research, an average of one in four patients will experience failure as result of poor adherence, while between 4% and 6% of patients will fail due to an acquired drug resistance.

If poor adherence is at the heart of failure, it's important for both the treater and the patient to identify any underlying cause. In many cases, simplification of therapy (e.g., reducing pill burden, dosing frequency) can help minimize functional barriers to adherence. Emotional or substance abuse issues should also be addressed, with referrals made to treatment centers or support counselors, if needed.

Even if virologic failure is confirmed by way genetic resistance testing, it's important to correct any adherence issues before moving forward with a new therapy. Unless adherence is addressed as an on-going facet of HIV management, the likelihood of a repeat lapse will be high.

Changing Therapy After a Virologic Failure

A virologic failure means that a sub-population of virus within the patient's "viral pool" is resistant to one or several drug agents. If allowed to grow, the resistant virus will build resistance upon resistance until multi-drug failure occurs.

If drug resistance is suspected and the patient's viral load is above 500 copies/mL, genetic resistance testing is recommended.

Testing is performed either while the patient is still taking the failing regimen or within four weeks of discontinuation of therapy. This, along with a review of the patient’s treatment history, will help direct the choice of therapy moving forward.

Once drug resistance is confirmed, it's important to change therapy as soon as possible in order to prevent additional drug resistant mutations from developing.

Ideally, the new regimen will contain at least two, but preferably three, new active drugs. Adding a single active drug is not recommended as it may only increase the development of drug resistance.

Drug selection should based on specialist review in order to assess potential cross-class drug resistance, or to determine whether certain drugs may have continued utility despite partial resistance.   

Research has shown that patients tend to respond better to subsequent therapies.This may be due to the fact that patients generally have a higher CD4 count/lower viral load when starting new therapy, or that newer generation drugs are simply better in treating patients with deep resistance. Studies have also shown that patients who have failed therapy due to poor adherence tend to improve adherence rates on second-line therapy.

However, it's important to note that complete viral suppression may not be possible in all patients, particularly those who have been on multiple therapies over the course of years. In such cases, therapy should always be continued with the aim of ensuring minimal drug toxicities and preservation of the patient's CD4 count.

In experienced patients with CD4 counts less than 100 cells/mL and few treatment options, the addition of another agent may help reduce the risk of immediate disease progression.

Immunologic Failure

The definition of an immunologic failure is considerably more obtuse, with some describing it as

  • the inability to increase a patient's CD4 count above a specific threshold (e.g., over 350 or 500 cells/mL) despite viral suppression, or;
  • the inability to increase a patient's CD4 by a certain amount above pre-treatment levels despite viral suppression.

Although data remain highly variable, some studies have suggested that the proportion of patients with abnormally low CD4 counts despite viral suppression can be as high as 30%.

The difficulty in addressing an immunologic failure is that it most often associated with either a low pre-treatment CD4 count or a low "nadir" CD4 count (i.e., the lowest, historic CD4 count on record).  Simply put, the more a patient's immune system has been compromised before therapy, the more difficult it is to restore that immune function.

It is why current HIV guidelines recommend early initiation of therapy when immune function is still intact.

On the other hand, immunologic failure can occur even with higher pre-treatment CD4 counts. This may be a result of past or active co-infections, older age, or even the impact of the persistent inflammation caused by HIV itself. At other times, there is no clear reason why this happens.

Even more problematic is the fact that there is no real consensus on how to treat an immunologic failure. Some treaters suggest changing  therapy or adding an additional antiretroviral agent, although there is no evidence that this has any real impact.

However, if an immunologic failure is identified, patients should be fully assessed as to whether there are

  • any concomitant medications that could decrease white blood cell production (particularly CD4+ T cells), substituting or discontinuing the drugs whenever possible, or;
  • any untreated co-infections or serious medical conditions that may be contributing to the low immunologic response.

Several immune-based therapies are being investigated, although none are currently recommended outside of the context of a clinical trial.


U.S. Department of Health and Human Services (DHHS). “Management of the Treatment-Experienced Patient: Virologic and Immunologic Failure.” Rockville, Maryland; accessed February 21, 2014.

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