BHIVA draft adult antiretroviral treatment guidelines: Initial failure

5.1 Initial failure

The viral load nadir achieved within the first few months on treatment is predictive of the subsequent risk of virological failure. In one cohort study the risk of virological failure was four times greater in those achieving a viral load 50 copies/ml than in those achieving viral loads

Although resistance to all drugs in a treatment regimen may not be detected in patients experiencing virological failure, it is likely that higher the copy number the more probable the development of resistance (ref). For some drugs (eg. 3TC, NNRTIs) mutations at one position in the reverse transcriptase gene can cause high level phenotypic resistance (ref) and usually emerge at low levels of viral load rebound. Reduced susceptibility to other drugs require the accumulation of two or more mutations in the viral genome and occur with ongoing viral replication in the presence of drugs (ref). Thus if viral replication is shown to be persisting and other options are available which can completely suppress it then changing therapy should be considered.

Once a patient shows a rise in viral load to just above detectable, the viral load should be rechecked within 2-4 weeks. Transient rises in viral load to levels to just above detectable (viral blip) are reported to occur in a significant proportion of patients on treatment, overtime (ref). Patients who are developing virological failure would show further increases in viral load whereas those whose viral load is transiently detectable because of assay related problems or other factors will show no further rise or revert to undetectable. This latter pattern maybe seen in patients who experience transient virological/bacterial infections or receive vaccination. It is controversial whether viral blips are associated with an increased future risk of virological failure in those who have already achieved viral suppression. One study showed no such association (ref) but another (ref) suggested that although a low level viral blip was not a predictor of failure those with repeated episodes or sustained low level viral rebound were more likely to experience virological failure in the future. Patients with frequent blips should perhaps be monitored more regularly and maybe candidates for intensification or change of therapy.

5.2 Changing therapy (BII)

The following groups of patients should be considered for changing therapy:

(i) Patients who are receiving incompletely suppressive antiretroviral therapy (for historical reasons, usually single or double NA therapy). Some physicians and patients may not want to change such therapy if the viral load is stable and the CD4 count is at a clinically safe level, but further rises in viral load or falls in CD4 count should result in therapy change to a more effective regimen. The risk is that these individuals with ongoing viral replication will develop increasing number of mutations in the viral genome making subsequent therapy more difficult.

(ii) Patients who have been on a HAART regimen and whose viraemia was initially suppressed to undetectability but has now become consistently detectable.

(iii) Patients started on HAART whose viraemia was never suppressed to below detectable limits. Although initially it was felt that individuals should be below 50 copies/ml by 24 weeks it may take considerably longer especially in individuals with high baseline viral load (ref)

5.2.1 Recommendations for changing therapy (BII)

In general, good virological responses are mostly likely to be obtained when adherence is optimised and as many of the drugs as possible in the regimen are changed. The more components of the regimen that can be changed, the more likely it is that clinical events will be delayed because of complete viral suppression by the second regimen. A resistance test with expert interpretation is highly recommended.

Table 7 - Changing therapy on first virological failure: summary of recommendations

• Some physicians may prefer for viral load to rebound to >1,000 copies/ml to allow resistance testing to be performed. Although resistance testing with expert interpretation has been shown to have a benefit on short term virological response of the subsequent regimen, there maybe a risk of developing further mutations by allowing a patient to remain on a failing regimen for this time, limiting further options for treatment.
• Although one study (ref) has shown the benefit of intensification with a single agent in individuals with low level failure, most of whom were receiving dual nucleoside therapy, this is not a recommended approach.

5.3 Failure of two nucleoside analogues plus a protease inhibitor

As stated above, the causes of failure are complex. There is no clear evidence to guide the choice of drugs and it is likely that the best regimen, and choice of subsequent therapy, will depend on whether failure is due to lack of potency, lack of adherence or poor pharmacokinetics of an individual drug. Resistance testing is of particular importance at this stage to identify which NA(s) will be of most benefit in the new regimen and help guidance of new PIs if to be included.

Many physicians would change both NAs and switch the PI to an NNRTI. Others would argue that there is a high risk of virological failure with this strategy and would give 2 PIs or a ritonavir boosted PI guided by resistance testing and an NNRTI, switching the NAs. If resistance testing is available and no or little resistance is found, alternative approaches might be to change from a single to a dual PI or ritonavir boosted PI combination to improve pharmacokinetics with or without switching NAs.

5.4 Failure of two nucleoside analogues plus a non-nucleoside reverse transcriptase inhibitor

No clinical endpoint study has addressed this issue. A PI-based regimen improves the clinical outlook after NA therapy [58] and is likely to do so after 2NAs and an NNRTI. Most physicians would treat virological failure of this type of regimen by discontinuing the NNRTI, changing the two NAs if possible and adding a PI component (single, dual or ritonavir boosted PI).

5.5 Failure of triple nucleoside analogue therapy

There are too few data as to the cause(s) of failure on a triple NA regimen to comment on what would be the optimal regimen to use in this situation. Most physicians would probably switch to a regimen comprising two new NAs plus a PI or an NNRTI. Alternatively, both a PI and an NNRTI might be used with new NAs [109].

Footnotes: (1) Both NAs should be changed, but potential exists for cross-resistance to other NAs and, if present, could lead to rapid development of resistance to NNRTIs. (2) Should be strongly considered if primary reason for failure is poor adherence or pharmacokinetics. (Resistance to PIs will often not be found on testing.) May be more successful if nelfinavir is the initial PI. (3) Initial studies with lopinavir/r+ritonavir+nevirapine have shown good results. No obvious salvage regimen following use of all three classes. (4) This regimen is still being evaluated.