Clinical Cut-offs
HIV-1 drug resistance is not an all-or-nothing phenomenon, but usually develops gradually as the virus accumulates resistance-associated mutations. Contrary to Biological Cut-Offs (BCO), Clinical Cut-Offs (CCO) give a better appreciation of the resistance continuum and provide an indication of the 'relative resistance' of the virus to each drug.
Clinical Cut-Offs (CCO) are based on virologic response observations (change in viral load) in treated patients, and give an indication of how the response is affected by viral resistance. Compared to Biological Cut-Offs (BCO), CCO represent a different approach to interpreting resistance information, providing a higher degree of correlation with virologic outcomes.
Latest Clinical Cut-Off Values: Virco's Clinical Database has grown considerably between 2006 and 2008, as is evidenced by the increase in the number of Development and Validation data-set Treatment Change Episodes (TCEs) in Figure 1 below, allowing us to capture the most up-to-date relationship between baseline resistance and virological outcome for each drug.
The latest CCOs are based on the Development data-set of 6550 Treatment Chabge Episondes (TCEs), and the Validation data-set of 2299 TCEs. A TCE is defined as a Patient Record Including:
- Baseline viral load (VL) and genotype before switch (Genotype used to conduct virco®TYPE HIV-1 resistance analysis)
- Post switch regimen
- Post switch VL at 8 weeks
For two of the most recently introduced antiretrovirals, Tipranavir and most recently, Etravirine, CCOs were developed on smaller data-sets of highly experienced patients. The virco®TYPE HIV-1 report contains a cautionary note that the relevance of these CCOs for patients different from these study participants has not been evaluated.
Data for the development of virco®TYPE HIV-1 Clinical Cut-Offs for tipranavir/r were obtained from the patients who participated in the RESIST studies, and for Etravirine from the patients who participated in the Phase IIb and DUET (Phase III) studies.
The table below lists all currently available vircoTYPE HIV-1 CCO values ( status Jan 2008). The CCO were validated by a number of different methodologies, including the use of unseen data and a bootstrap analysis (random re-sampling with replacement), which resulted in the listed 90% confidence intervals around the cut-offs.
VircoTYPE HIV-1 Clinical Cut-Offs are derived from an extensive dataset of clinical observations in treated patients from both clinical cohorts and clinical trials. Through multiple linear regression modeling, drug-specific mathematical models were developed that correlate baseline Fold Change in IC50 with virologic response. Unboosted and Ritonavir boosted Protease Inhibitors were treated as separate drugs.
To isolate the effect of a single drug X in an entire combination regimen, the activity of all other drugs in the regimen was included as a covariate in the model of that particular drug. The effect of a single drug X is defined as the difference in viral load response to the entire treatment regimen predicted for a wild type virus (greatest effect) and that predicted for a virus that is highly resistant to drug X (least effect).
Figure 1 shows a typical correlation between baseline Fold Change and Percent Loss of Virologic Response. For a wild type virus the virologic response is maximal, hence the loss in response is 0%. As the Fold Change increases the virus becomes more resistant (resistance continuum), which results in a greater loss of virologic response. For highly resistant viruses virtually all virologic response is lost (minimal response).
Figure 1
Unboosted and boosted Protease Inhibitors were treated as separate drugs, resulting in separate models describing the relationship between resistance and virologic response. Figure 2 shows typical virologic response curves for an unboosted and a boosted Protease Inhibitor. The boosting effect of ritonavir (pharmacokinetic enhancement) is reflected in these models: the loss of virologic response occurs more gradually(at higher FC values) for the boosted than for the unboosted drug.
Figure 2
VircoTYPE HIV-1 Clinical Cut-Offs are landmarks on the resistance continuum, associated with increasing loss of virologic response (Figure 3)
- CCO1 is the baseline Fold Change associated with a 20% loss of the wild type virologic response due to viral resistance.
- CCO2 is the baseline Fold Change associated with a 80% loss of the wild type virologic response due to viral resistance.
Figure 3
Overall Regimen Response as a Function of Baseline Resistance Observed with Virco CCO. The slides included in this section are intended to assist users of the vircoTYPE HIV-1 report better appreciate the ranges of response (measured as a 1 log or greater reduction in viral load at weeks 8 and 24) that were observed when Virco's Clinical Cut-Offs are used to define subgroups of patients according to their baseline susceptibility to one of the drugs included in their treatment regimen. Response rates were calculated for the entire CCO study population (combined development and validation datasets), and reflect response to the entire regimen. These illustrations demonstrate how response varied in this specific population as a function of resistance to one component of the regimen, and are not adjusted for other influential variables such as baseline viral load or the activity of the other drugs used in the combination regimen. Response rates in populations with different baseline characteristics than those presented here are not expected to be the same.