New evidence favours routine measurement of plasma concentrations in salvage therapy to maintain sustained drug levels
Graham McKerrow, HIV i-Base
New evidence from researchers in Italy and the UK supports the practice of routine measurements of plasma concentrations in salvage therapy to help maintain sustained drug concentrations in plasma.
Researchers at the University of Turin and the University of Liverpool studied the pharmacokinetics and pharmacodynamics in the clinical use of lopinavir/ritonavir (LPV, Kaletra) in salvage therapy.
In a letter published in the 18 October issue of the journal AIDS, Dr Marta Boffito and colleagues report a study where LPV was administered to 35 HIV-infected patients after therapeutic failure with other protease inhibitors. The pharmacokinetics (trough concentrations) and baseline viral genotype were determined, together with the immunovirological outcome.
The 22 responders had significantly higher mean lopinavir concentrations and lower baseline numbers of mutations. On multivariate analysis, a lopinavir concentration of 5.7 µg/ml or greater was an independent predictor of viral suppression over a nine month follow-up period.
Although the therapeutic efficacy of LPV has been repeatedly confirmed in patients with previous PI exposure and failure, it is not clear to what extent such a regimen is able to overcome pre-existing resistance to other PIs, and whether this can be predicted by the determination of measurable parameters such as baseline viral genotype or pharmacokinetics.
In PI-experienced patients who had a therapeutic failure under lopinavir-containing regimens, mutations at codons 82, 54 and 10 were seen in combination with four additional mutations in the protease genome. According to the latest available information, the assessment of viral susceptibility to lopinavir based on genotyping seems to be quite a quantitative rather than a qualitative matter, with a greater number of protease mutations being associated with increasing EC50 values. In the clinical use of lopinavir in PI-experienced patients, however, it is not yet known whether variations in individual drug levels may have any substantial influence on the therapeutic outcome.
In order to provide additional information on this, the researchers investigated both the pharmacokinetic and genotyping profile of PI-experienced patients who started LPV after therapeutic failure with PI-containing antiretroviral regimens.
Lopinavir plasma trough concentrations and viral genotypes were determined at baseline, and lopinavir trough concentrations were measured by high-performance liquid chromatography–mass spectrometry/mass spectrometry monthly during follow-up, with at least three lopinavir measurements for each patient. Two groups of patients were defined according to the kinetics of their plasma viral load after the initiation of the LPV-containing regimen.
The researchers defined responders (n = 22) as those who achieved and maintained plasma viral loads below the current detectable limit of 50 copies/ml, whereas those whose viral load did not fall to less than 50 copies/ml or showed an increase in viral load during follow-up (median 10 months, range 9–12) or had a detectable viral load at the last evaluation were considered to be non-responders (n = 13).
Patients had a heavy previous intake of nucleoside reverse transcriptase inhibitors (100%; median 78 months, range 8–180) and non-nucleoside reverse transcriptase inhibitors (89%; median 12 months, range 1–58). The time of the previous intake of PI-based combination therapy was 30 months (range 8–58), including saquinavir hard-gel (91.4%), indinavir (74.3%), nelfinavir (68.6%), saquinavir soft-gel (14.3%), ritonavir (11.4%) and amprenavir (11.4%).
No significant difference was recorded by the researchers between responders and non-responders in terms of the previous intake of antiretroviral agents. The intake of LPV led to significant immunological recovery and the inhibition of HIV replication: the mean viral load and CD4 cell count at baseline were 4.9 ± 0.8 log and 235 ± 155 cells/mm3, with no difference between responders and non-responders (4.8 ± 0.9 versus 5.2 ± 0.5 log, P = 0.142; 241 ± 175 versus 225 ± 118 cells/mm3, P = 0.771). At last follow-up, the viral load had declined to 2.3 ± 1.4 log and the CD4 cell count increased to 359 ± 212 cells/mm3, both changes over the follow-up being significant with respect to the baseline values (P = 0.000). 90M, 10I and 71I were the mutations more frequently detected (49, 51 and 40%, respectively).
The mean lopinavir trough concentration was 5.9 ± 1.8 µg/ml (25th and 75th percentiles 4.9 and 6.2 µg/ml). Not surprisingly, report Boffito and colleagues, the 22 full responders had both higher trough lopinavir concentrations (6.5 ± 1.9 versus 4.9 ± 1.1 µg/ml, P = 0.014) and a baseline lower, but not significantly lower, mean number of mutations in the HIV protease genome compared with the rest of the series (4.2 ± 2.4 versus 5.4 ± 2.9, P = 0.194). However, on multivariate analysis, only a lopinavir trough concentration in plasma of 5.7 µg/ml or greater was confirmed as being an independent predictor of viral suppression at the end of follow-up (odds ratio 17.7, 95% confidence intervals 1.1–39.6, P = 0.015).
The researchers write: “Interestingly, all the seven women investigated here had a full response to LPV compared with 15 out of 28 men. Their lopinavir trough concentration was higher than that of the men (7.5 ± 1.5 versus 5.5 ± 1.7 µg/ml, P = 0.012). Moreover, their body weight was significantly lower compared with that of non-responders (61.9 ± 13.8 versus 70.7 ± 6.8 kg, P = 0.040) as well as compared with that of the men (44.7 ± 2.2 versus 70.2 ± 7.1, P = 0.000).
“It would seem that when the number of protease mutations is below five, HIV suppression below 50 copies/ml is achieved and maintained, even at relatively low lopinavir concentrations, but higher drug levels are required to achieve the same result when protease mutations are more than five.
“The cut-off of lopinavir concentration determined here (5.70 µg/ml, relative operating characteristic curve analysis) was just below the mean drug level measured in the whole group, thus suggesting that such an effective concentration was achieved by the majority of patients with ordinary drug dosing. “These data also suggest that in patients whose response to LPV is suboptimal, an increase in dosage could be a useful option. The combination of LPV, as with most other antiretroviral drugs, is administered at the same standard dosage, independently of body weight. According to the lopinavir trough concentrations measured in our patients, and especially considering that no concentration-related side-effects were seen even with drug levels as high as 12.0 µg/ml, it would seem that the opportunity to administer higher dosages in selected cases deserves attention. As there are so far no data on the maximum lopinavir concentration that is tolerated in clinical practice, further investigations are warranted to explore the therapeutic potential of LPV fully.”
They conclude: “We believe that these data lend support to the current practice of measuring plasma concentrations routinely in a salvage therapy setting, as they stress the importance of maintaining sustained drug concentrations in plasma, a solution that allows us to overcome any pre-existing resistance to PIs.”
In general higher trough levels in salvage regimens are desirable, however, to balance efficacy and adverse effects a resistance guided trough level, the “virtual IQ”, may represent the best approach currently available for a rational, individualized salvage strategy.
Boffito, Marta; Arnaudo, Isabellaa; Raiteri, Riccardoa et al. Clinical use of lopinavir/ritonavir in a salvage therapy setting: pharmacokinetics and pharmacodynamics (Research Letters) AIDS 16(15): 2081-2083 Oct 2002