The latest British HIV Association (BHIVA) guidelines (BHIVA Writing Committee 2005) recommend that when viral load that has previously been suppressed - i.e. it has been 'undetectable' on a test that measures viral load to 50 copies/ml - rises above 400 copies/ml on two consecutive tests, that should be a trigger to think about changing treatment. This is known as virological failure, and is not a reflection on you, nor the sole determinant of how quickly you will become sick, since it is CD4 cell levels that actually determine how well the immune system is functioning. See Factors affecting disease progression in The immune system and HIV: How HIV damages the immune system.

However, the decision about when and whether to change will also depend upon what drug options are left open to you. If your CD4 count is stable and above 200 cells/mm³ there is an increasingly strong argument to remain on the same 'failing' regimen if there are not enough active new drugs available to make up a regimen. See Options when treatment is failing in Anti-HIV therapy: Changing treatment.

If your CD4 count is unstable and falling close to or below 200 cells/mm³, there is a strong argument to change regimens even if that means recycling or taking mega-HAART. See Choosing a salvage regimen in Anti-HIV therapy: Changing treatment.

You may also want to change from a regimen which is successfully suppressing HIV due to your being unable to tolerate it due to side-effects, or your inability to take the medication as prescribed, or both. See Changing due to toxicity or poor adherence in Anti-HIV therapy: Changing treatment.

You may be on a regimen that is no longer recommended by the latest BHIVA Guidelines, for example, if you are on your first combination and it contains stavudine (d4T) or you are on less than three drugs. See The British HIV Association and the National Association of Providers of AIDS Care and Treatment in Anti-HIV therapy: Guidelines.

Additionally, if you have recently become co-infected with hepatitis B or hepatitis C viruses, you may need to change your therapy due to liver toxicity or due to the incompatibility of your current regimen with the treatments for these viruses. See Hepatitis B or Hepatitis C - overview in Symptoms and illnesses: A to Z of illnesses for further information.

Virological failure

The most common definition of 'virological failure' is viral load rebound above 50 copies/ml. If you are in this situation, you may be considering a change of treatment.

BHIVA guidelines recommend you consider changing treatment or carefully monitoring your viral load if your viral load rebounds to greater than 400 copies/ml on two successive occasions. However, drug resistance testing - which is also recommended before making a switch - is only considered reliable when viral load is 1000 copies/ml or more.

Studies have found that the majority of people can achieve a level of 1000 copies/ml of virus within four weeks of starting therapy, and failure to achieve this is a strong predictor of failure to reach undetectable levels within 24 weeks (Cozzi-Lepri 2001).

Although the risk of disease progression and/or falls in CD4 counts are not likely with a low-level of detectable virus, the likelihood of this happening rises as viral load rises toward pre-treatment levels (Deeks 2000).

The main concern, however, of continuing on a combination with even a low detectable viral load is the risk of drug resistance, which may ultimately undermine your response to this and other combinations.

The United States Department of Health and Human Services also provides treatment guidelines (US Panel on Clinical Practices for Treatment of HIV Infection 2003), and their definition of 'virological failure' is one of the following:

• A confirmed HIV RNA level above 400 copies/ml after 24 weeks.

• Viral load above 50 copies/ml after 48 weeks.

• A confirmed viral load above 400 copies/ml after prior suppression of HIV.

See also Factors affecting the effectiveness of treatment in Anti-HIV therapy: Effectiveness of HIV therapy

Viral load blips

It is possible that your viral load will temporarily rise to detectable levels in one test before returning to undetectable in the next. This is known as a viral load blip. One blip is nothing to worry about, but frequent blips may be a sign that your combination will stop working. (Greub 2002)

See Viral load blips in Anti-HIV therapy: Changing treatment for further discussion of this issue.

Reasons for virological failure

The reasons for virological failure (either rebound or failure to achieve an undetectable result) must be considered and investigated before switching therapy. If you dont investigate the reasons first-line treatment failed, it is quite possible that the reasons for treatment failure will persist and subsequent combinations will also achieve poor results.

With growing awareness of the importance of good adherence in successful treatment responses, many doctors suggest that a rebound in viral load should prompt a thorough review of pill-taking habits. Offering support and information to improve patient adherence may correct the rebound without the need to change drugs.

Other possible reasons for drug failure which may be investigated include low drug levels, drug resistance and lack of drug potency.

See Anti-HIV therapy: Testing drug levels, Testing for resistance and Resistance testing to select treatment in Anti-HIV therapy: Resistance for further discussion of these issues.

Unacceptable side-effects

The reasons for virological failure (either rebound or failure to achieve an undetectable result) must be considered and investigated before switching therapy. If you do not investigate the reasons first-line treatment failed, it is quite possible that the reasons for treatment failure will persist and subsequent combinations will also achieve poor results.

With growing awareness of the importance of good adherence in successful treatment responses, many doctors suggest that a rebound in viral load should prompt a thorough review of pill-taking habits. Offering support and information to improve patient adherence may correct the rebound without the need to change drugs. See What level of adherence is necessary? in Anti-HIV therapy: Adherence for further discussion of this issue.

Other possible reasons for drug failure which may be investigated include low drug levels, drug resistance and lack of drug potency. See Anti-HIV therapy: Testing drug levels, Testing for resistance and Resistance testing to select treatment in Anti-HIV therapy: Resistance for further discussion of these issues.

Pill burden

If you are having difficulty with the number of pills, or the number of doses, you must take each day, see Options for simplifying therapy in Anti-HIV therapy: Choosing a Combination for further information on ways of reducing pill burden.

Different triggers for different people

It is clear that there will be different triggers for changing treatment depending on the number of options you have left.

For example, if you have already been on two previous PI-based regimens, it may not be worth switching quickly from the second because there is a high likelihood that you will have cross-resistance to all the currently available drugs. Instead, some doctors would advise sticking with the second drug until another class of drugs becomes available or your immune system begins to deteriorate. Several studies have shown that some people with detectable and rising viral load on protease inhibitors continue to enjoy rising or stable CD4 counts for many months after viral rebound begins (see Immune recovery in Anti-HIV therapy: Choosing your treatment strategy).

On the other hand, if your first PI-regimen is showing evidence of failing you may be advised to switch as quickly as possible, since there is some evidence that changing treatment when viral load is still low (below 5,000-10,000 copies) is associated with a more successful response to the second protease inhibitor. Boosting with a small additional dose of ritonavir is another option.

As anti-HIV treatment becomes more and more individualised, with the use of resistance testing (see Resistance testing to select treatment in Anti-HIV therapy: Resistance) and therapeutic drug monitoring (TDM) (see Anti-HIV therapy: Testing drug levels), there cannot be any across-the-board prescriptions for when to change therapy. It will depend on your personal circumstances, the drugs that are available to you, and what you feel comfortable with.

References

BHIVA Writing Committee. British HIV Association guidelines for the treatment of HIV-infected adults with antiretroviral therapy, 2003. http://www.bhiva.org/guidelines/2003/hiv/index.html

Cozzi-Lepri A et al. The virological response to highly active antiretroviral therapy over the first 24 weeks of therapy according to the pre-therapy viral load and the weeks 4-8 viral load. AIDS 15(1): 47-54, 2001.

Deeks SG et al. Delayed immunological deterioration among patients who virologically fail protease inhibitor-based therapy. Seventh Conference on Retroviruses and Opportunistic Infections, San Francisco, abstract 236, 2000.

Greub G et al. Intermittent and sustained low-level HIV viral rebound in patients receiving potent antiretroviral therapy. AIDS 16(14): 1967-1969, , 2002.

US Panel on Clinical Practices for Treatment of HIV Infection. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents, 2003. http://aidsinfo.nih.gov/guidelines/default_db2.asp?id=50