In this large collaborative analysis we found that the rate with which patients experienced virologic failure of the original three drug classes rose over the first 3-4 years from start of ART to around 1% per year, and then stayed around this level thereafter. By 9 years from the start of ART, an estimated 8.6% of patients had developed TCVF. While this confirms the low rate with which the virological benefits of these classes are lost 3-5, 10
, from the perspective of life-long maintenance of viral suppression it suggests that many patients are likely to eventually require newer drugs within the coming decades. It is worth noting that development of TCVF may not necessarily mean that all three classes have been exhausted, particularly given the availability of newer PIs and NNRTIs such as darunavir and etravirine, which have been shown to be effective in treatment experienced patients 21
. Drugs from new classes are now available in high-income countries 22-24
, and encouraging results have been obtained in clinical trials. However, they all have limitations in routine clinical practice: integrase inhibitors are somewhat prone to lose efficacy due to resistance development 25
, enfuvirtide requires injection, and CCR5 antagonists are only active against R5 strains of virus. Thus, in patients who have experienced virologic failure of the three original classes it is uncertain whether these new classes will then be able to ensure lifelong viral suppression. Some will eventually require further options and given the length of the drug development process it is important that new compounds continue to be developed.
The rate of development of TCVF was very similar according to whether ART was started with NNRTI-containing regimens or PI/r-containing regimens, consistent with previous observations from cohort studies 4, 10
. This supports current guidelines which recommend specific drugs within either class be used in first-line regimens 13-16
. Factors in our analysis associated with slower development of TCVF included being in the homosexual male risk group and older age. While the latter observation, which has been identified in previous studies 4
, is likely to be explained by a tendency for better adherence in older people 26, 27
, the reasons for the former are less clear, although factors such as adherence, socio-economic status, migration status and health-seeking behaviour could also play a role. We also found that those with lower pre-ART viral load and those with higher pre-ART CD4 count tended to develop TCVF more slowly, in common with previous observations 4, 5
. This could partly be explained by differences in health seeking behaviour, and hence adherence, between those who present early for therapy and therefore start ART at higher CD4 count.
We also investigated the rate of development of TCVF in people who had virologically failed an NNRTI regimen and who then started a PI/r containing regimen, as their first PI. Due to their failure history this group will tend to be generally more susceptible to poorer adherence than those who have not previously experienced virological failure. There are relatively few robust data on virological responses in patients using PI/r-containing second-line regimens and our estimate of 46% with TCVF by 5 years (55% in the heterosexual risk groups) provides a benchmark against which comparisons can be made, including studies of second-line regimens in resource-limited settings. Those comparisons will have to consider the factors associated with a slower time to TCVF in our analysis. Again, homosexual men experienced a slower rate of TCVF, as did those with lower viral load and those with higher CD4 count, possibly partially due to these markers reflecting the patients’ adherence. The observed increased risk of TCVF in patients starting the PI/r in later calendar years is difficult to interpret, but a possible explanation is that as avoidance of initial virologic failure improves in later calendar years, in this analysis patients with more serious adherence issues are over-represented in later years of starting a PI/r after NNRTI failure.
For those patients who virologically failed an NNRTI-based first-line regimen, and subsequently started a PI/r as second-line ART, the time to the start of the PI/r was long at a median of 0.8 years, but in line with previous data 28
. Lower CD4 count and higher viral load at the time of first virologic failure were associated with shorter time to starting the third antiretroviral class (data not shown). In the present study we observed that TCVF developed more slowly in patients who, between failing an NNRTI and starting the PI/r, had spent less than 3 months on ART with a viral load above 500 copies/ml. This is consistent with the view that earlier detection of failure of NNRTI-containing drug regimens and switch to a PI/r without delay could potentially significantly reduce the rate of TCVF.
We considered the effect of modifications in our definition of triple class failure, but none of these resulted in sizeable changes to our estimates.
There are several limitations to our analysis. First, we only studied virologic failure of drugs and did not directly factor in data on resistance mutations detected. In some cases, virologic failure will occur in the absence of resistance mutations, perhaps largely due to poor adherence. If adherence issues can be overcome then the drugs should remain active and options have not been lost. Second, in our comparison of NNRTI and PI/r-containing regimens patients were not randomized to receive one regimen or the other so there were differences at ART initiation between these two patient groups. While we adjusted for factors measured at the start of ART that were associated with the rate of TCVF, bias in the comparison due to unmeasured confounding may well remain. Thirdly, although the maximum follow-up after starting ART was in excess of ten years, the available follow-up for many patients was substantially less. It may be that, with longer follow-up, the incidence of TCVF would eventually begin to decrease with time from starting ART, both as patients most susceptible to periods of poor adherence are selected out and as the long-term impact on adherence of the more recent easy-to-take combination pills is realised 29, 30
. A further limitation is that patients included in COHERE tend to be treated in large clinics with strong research links, and so may not be representative of the population of patients on ART in Europe.
The rates of TCVF that we observed may at first sight seem inconsistent with results from randomized trials in which relatively high proportions of people are observed to fulfil the definition of failure within 1-2 years of the start of therapy. However, most trials tend to use composite definitions of failure so that stopping of some drugs, or the fact that a viral load value is missing, are criteria for defining failure, in the same way as raised viral load itself 31
so it is not possible to directly compare with our findings. Further, most trials consider failure only of one regimen, typically containing two drug classes, while we are considering failure of three classes over at least two separate regimen failure episodes.
In conclusion, the rate of virologic failure of the three original drug classes is low, but not negligible, and does not appear to diminish with time from start of ART. If this trend continues many patients are likely to eventually need newer drugs, possibly other than those currently available, in order to maintain viral suppression for their lifetime. It is important to continue to monitor the development of TCVF over longer periods of follow-up, and to study the incidence of multiple class failure following exposure to the newer antiretroviral classes. The rate of triple class failure from start of a PI/r after previous NNRTI failure is relatively high at around 46% by 5 years and provides a relevant comparator for future studies in resource-limited settings.