When to switch from a failing combination will depend on various individual factors such as previous treatment history and available treatment options, as well as the definition of 'treatment failure'.

The most common definition of 'treatment failure' is viral load rebound above 50 copies/ml. If you are in this situation, you may be considering a change of treatment. British treatment guidelines recommend you consider changing treatment or carefully monitoring your viral load if your viral load rebounds to detectable levels. While viral load remains low (e.g. below 10,000 copies/ml) there is little risk of health deteriorating. However, the problem of continuing on a combination with detectable viral load is the risk of drug resistance, which may ultimately undermine your response to this and other combinations.

United States treatment guidelines suggest the following definitions of treatment failure:

• Less than a 0.5 to 0.75 log₁₀ reduction in viral load by 4 weeks following initiation of therapy, or less than 1 log₁₀ reduction by 8 weeks (Cozzi-Lepri 2001). Both outcomes predict that the current regimen will not result in viral load suppression by week 24 of treatment.

• Failure to suppress viral load to below detectable levels (less than 50 copies/ml) within four to six months (16 to 24 weeks) of commencing therapy. However, it is important to bear in mind that, in people taking their first regimen, it may take longer to reach this level if viral load was higher than 100,000 copies/ml before starting treatment (Moyle). See Reasons to change in Anti-HIV therapy: Changing treatment for further discussion of the possibility of intensifying treatment at this point.

• Repeated detectable HIV in plasma following suppression to undetectable levels. Viral load blips are not uncommon in patients on HAART (Havlir; Greub). A progressive upward trend indicates treatment failure. See Viral load blips in Anti-HIV therapy: Changing treatment for more information on this subject.

• Declining CD4 cell count, measured on at least two separate occasions. A regimen defined as failing in virological terms may continue to provide benefits to the immune system for months or even years, particularly in people who experienced a strong reduction in viral load when the regimen was begun. A viral load reduction of greater than -1.68 log has been associated with a sustained CD4 cell response despite viral rebound, with benefits lasting for up to three years after rebound in some cases (Deeks). The degree of initial viral load suppression predicts the likelihood of subsequent CD4 cell decline whilst the failing regimen continues to be used.

• Clinical deterioration.

Of course, what drugs you are taking may influence your response to viral rebound. Several studies have suggested that it may be important to identify protease inhibitor (PI) failure promptly and to switch to a new regimen as soon as possible, to maximise your chances of benefit from a second PI. Resistance to PIs is usually associated with the gradual appearance of mutations in HIV protease, one after the other. The longer you remain on a PI to which resistance is developing, the greater the number of mutations you may accumulate. The more resistance mutations you have, the less chance you have of benefiting from subsequent regimens (Bodsworth; Boucher).

NNRTI regimens should also be changed promptly when viral load becomes detectable because resistance mutations quickly make this class of drug ineffective.

In practical terms, the need to avoid drug resistance may make frequent viral load tests imperative. Current UK treatment guidelines suggest a test every 12 weeks whilst on treatment, even if your viral load has been `undetectable' for many months. A resistance test may be conducted before switching to identify which drugs HIV has become resistant to.

A study of 984 people at various European clinics who switched from a first PI to a second PI found that people who switched when their viral load was still low were much more likely to achieve undetectable viral load on their new protease inhibitor (Mocroft 2001). This study also found that people who switched at higher CD4 cell counts did better on their second PI, and that people who could also add one or more new nucleoside analogues had better rates of undetectable viral load.

In addition, a sustained CD4 cell count rise is associated with reduced risk of disease progression. The study of CD4 cell count benefits in the presence of viral rebound found that a cut-off point was reached at around 30,000 copies; individuals who experienced viral rebound above this level were less likely to sustain any existing CD4 cell increases once viral load went above this point (Mocroft 2001).

See Options when treatment is failing in Anti-HIV therapy: Changing treatment for more details.

References

Bodsworth N et al. RTV and IDV therapy at 28 weeks after 32 weeks' SQV therapy - influence of HIV-1 protease mutations. Fifth Conference on Retroviruses and Opportunistic Infections, Chicago, abstract 396, 1998.

Boucher CAB et al. Increased fitness of drug resistant HIV-1 protease as a result of acquisition of compensatory mutations during suboptimal therapy. AIDS 13(17):2349-2359, 1999.

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. Duration and predictors of CD4 T-cell gain in patients who continue combination therapy despite detectable plasma viremia. AIDS 16: 201-207, 2002.

Mocroft A et al. The use of and response to second-line protease inhibitor regimens: results from the EuroSIDA study. AIDS 15: 201-209, 2001.

Moyle G et al. Time to treatment success: 24 weeks is not enough in patients starting with high viral load in DP-006. 40th Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, abstract 547, 2000.