| |
The Efficacy of Lopinavir in Individuals Experiencing Protease Inhibitor Failure
|
| |
| |
JAIDS Journal of Acquired Immune Deficiency Syndromes 2003; 32(2):238-240
To the Editor:
Lopinavir/ritonavir (LPV/r) is a boosted protease inhibitor (PI) combination product in which pharmacokinetic enhancement or "boosting" of a PI with ritonavir can provide more predictable PI plasma levels and improve dosing
regimens. A further benefit is that viral resistance may be overcome by the high plasma levels of PIs achieved. However, toxicity may also be increased and the benefits of such combinations must therefore be balanced against
potentially increased adverse events. Clinical studies with LPV/r have thus far suggested benefit among treatment-naive, first PI-failure, and multiple-PI-experienced patients, but they have been solely among nonnucleoside
reverse transcriptase inhibitor (NNRTI) -naive patients who have additionally received an NNRTI.
We therefore assessed the virologic and immunologic response to LPV/r as salvage therapy in heavily antiretroviral experienced individuals, both NNRTI-naive and experienced, who had previously failed a PI-based regimen, with
particular attention to tolerability and effects on lipids. LPV/r was largely prescribed, via the Lopinavir Named Patient Programme, for individuals who had received at least 2 PIs previously and were experiencing virologic failure on their current regimen. We prospectively extracted data on all HIV-1-positive individuals, between April 2000 and September 2000, receiving LPV/r at our central London clinic, which has over 3000 HIV-1-positive patients attending each year. Data was collected on sex, age, status, antiretroviral history, CD4 count, viral load, and lipid levels at baseline, 1, 3, 6, 9, and 12 months. For patients who underwent resistance testing, genotypic analysis was performed by ABI DNA sequencing of HIV-1 cDNA PCR fragments derived from viral plasma RNA (Vircogen II methodology) (6, 7) within 3 months of commencement of LPV/r. VirtualPhenotype interpretation of these data was performed by VIRCO (8).
Primary statistical analysis of this study was based on rates of virologic success at 12 months. Secondary analysis was based on data from 1 and 6 months. Data were analyzed as on treatment and intention-to-treat (noncompleter equals failure). We employed logistic regression models using Genmod procedure in SAS with binomial error distribution and logit link function to determine factors associated with virologic success at 12 months. Data are presented as numbers with percentage, together with estimated relative risks with 95% confidence intervals (CI).
During the study period 80 patients received LPV/r as salvage therapy: 72 (90%) were male and 8 (10%) were female. Mean age was 40.2 years (range 28 to 81 years). Median CD4 cell count was 75 cells/mm3 (range 28 to 165) and
median viral load (VL) was 5.0 log10 (range 4.6 to 5.5 log10). Forty-six patients (58%) had had a previous AIDS-defining illness. All 80 patients had previously failed multiple antiretroviral regimens over many years and all had experienced virologic failure while taking at least 1 PI. The mean number of PIs previously received by patients was 2.8 and the median total time on PIs was 1304 days (range 844 to 1869 days). Sixty-nine percent of patients had been previously treated with a ritonavir-boosted PI regimen. The median time on nucleoside reverse transcriptase inhibitors (NRTIs) was 2940 days (range 80 to 7171 days). Fifty-nine (73%) individuals were NNRTI-experienced. Forty-four (55%) individuals were currently receiving a PI before commencing LPV/r.
A resistance test was performed in 61 of 80 individuals within 3 months of commencement of new therapy. The number of active drugs in the new regimen was calculated using the virtual phenotype derived from the resistance tests. Seven patients had no active drugs in addition to LPV/r, 11 patients had 1 active drug, 21 had two, 22 had three, and 2 patients had 4 active drugs in addition to LPV/r. The number of PI mutations seen among our patients ranged from 0 to 8, and the median number of PI mutations was 4.
The median viral load fell from 5.0 log10 at baseline to below the level of detection using an ultrasensitive assay (<50 copies/mL, as represented by 1.7 log10) at month 6, and remained undetectable to month 12. The median CD4 count was 75 cells/mm3 at baseline and progressively increased to 262 cells/mm3 by month 12. By on treatment analysis, virologic suppression to below 500 copies/mL was achieved by 45% of patients at 1 month, peaking at 6 months with 76% of patients. 72% of individuals were undetectable by this assay at 12 months. Using the ultrasensitive assay, virologic suppression was at a maximum at 6 months (70%), falling to 54% at 12 months.
By intention-to-treat analysis, virologic suppression to below 500 copies/mL was achieved by 43% of patients at 1 month, with a maximum at 3 months (68%), falling to 48% at 12 months. Using the ultrasensitive assay, virologic
suppression peaked at 55% of patients at 6 months but persisted in only 39% of individuals by 12 months.
Twenty-one individuals were NNRTI-naive, and 59 individuals had been previously treated with NNRTIs. Of those who were NNRTI-naive, on treatment, 81% had a viral load <500 copies/mL at month 12, compared with 60% of those
who were NNRTI-experienced; however this result did not achieve significance (p = .107). There was no difference in outcome between individuals who had previously failed single, dual or boosted PI regimens.
Twenty-two individuals ceased therapy during the study period for the following reasons: lymphoma (2), disease progression (1), death secondary to cardiomyopathy (1), patient request (2), virologic failure (7), perioral paraesthesia (1) and lost to follow-up (8).
Elevated triglyceride levels >10 mmol/L are associated with an increased risk of pancreatitis, and this level was thus chosen for analysis as the cut-off for nonfasting samples among our patients. Triglycerides above this threshold were
observed in 3.6% of patients at baseline, peaking at 6 months (16%), and persisting in 12% of patients at 12 months. Elevated cholesterol above 6.5 mmol/L (ULN) was observed in 4.9% of patients at baseline, reaching a maximum at 6 months (22%) and continuing in 19.7% of patients at 12 months. Hyperlipidemia was initially treated with diet and exercise, with statins and fibrates being employed if it persisted beyond 6 months. Despite treatment, hyperlipidemia continued in a substantial minority. The long-term complications of these changes in lipids remain unclear, but it is likely
that they will be associated with an increased incidence of cardiovascular events.
Univariate logistic regression analysis was used to identify determinants of achieving virologic suppression below 500 and 50 copies/mL. Variables analyzed were age, gender, previous ADI, baseline CD4 cell count, baseline VL, number of active drugs in addition to LPV/r and number of PI resistance mutations. Patients with a baseline VL <5.0 log10 were significantly more likely to achieve virologic suppression below 500 and 50 copies/mL than those with a starting VL >5.0 log10, RR = 4.79 (1.48-15.5) and RR = 3.67 (1.33-10.11), respectively. Patients were significantly less likely to achieve virologic suppression below 500 copies/mL at 3 and 12 months if their starting CD4 cell count was <75cells/mm3, RR = 0.17 (0.05-0.58), and RR = 0.22 (0.07-0.72) respectively, or if they received no other active drugs in addition to LPV/r at 3 months, RR = 0.04 (0.0-0.48). At 3 months, virologic suppression below 50 copies/mL was significantly less likely if the baseline CD4 cell count was <75 cells/mm3, RR = 0.29 (0.11-0.79). Surprisingly, in contrast to other reports, the number of genotypic resistance mutations to PIs was not significantly associated with virologic outcome (5, 11). Because 45% of patients were not currently receiving a PI, this may have been due to archiving of resistance mutations.
A reduction of VL by 1 log10 has been associated with a 95% survival benefit at 1 year (ACTG 175), and was observed in 95% of patients at 1 month and maintained in 85% of individuals on therapy at 12 months. Factors associated with an increased likelihood in achieving a VL drop of 1 log10 at 12 months by univariate analysis were baseline CD4 count >75 cells/mm3 (p = .038) and a baseline VL <5.0 log10 (p = .038). NNRTI-naive patients (100%) were more likely to achieve a 1 log10 drop in VL than their NNRTI-experienced counterparts (79%); however, this result did not achieve significance. Similarly patients receiving 2 or more active drugs (94%) in addition to LPV/r were more likely to achieve a VL drop than those who received no additional active drugs (20%), but again this result did not reach significance.
We believe our study is the first to show virologic suppression by LPV/r in both NNRTI-experienced and NNRTI-na•ve patients. For such highly antiretroviral experienced patients, the results seen in our study are excellent and are
comparable to other studies involving LPV/r in which patients were notably NNRTI-naive. Due to small patient numbers, although there was a trend towards NNRTI-naive patients achieving better virologic suppression than their
NNRTI-experienced peers, univariate analysis failed to show a significant difference between the two groups.
Notably, virologic failure was an infrequent event among our group of patients and was explained by nonadherence in only 50%. The other failures may be attributable to resistance to LPV/r and/or the other drugs in the regimen or to wide inter-patient variability in plasma drug concentrations. Despite multiple studies (13-15), the exact pattern of LPV/r resistance is not yet known and the optimal role for LPV/r in sequenced antiretroviral therapy remains under
debate.
In summary, our study has clearly shown that in patients with previous multiple PI failure, the majority of whom were also NNRTI-experienced, LPV/r achieved and maintained excellent levels of virological suppression which was
associated with a good CD4 count rise. Although well tolerated, elevation of triglycerides and cholesterol was frequent and required, often unsuccessful, therapy with lipid-lowering agents. Comparative studies with other boosted PIs are necessary to evaluate whether this degree of potency and tolerability is singular to LPV/r or is common to all boosted PI combinations.
Yvonne C. Gilleece; Nad A. Qazi; John F. Morlese; Sundhiya Mandalia; Brian G. Gazzard; Anton L. Pozniak; Mark R. Nelson
St. Stephen's Centre Chelsea & Westminster Hospital London, UK
|
|
| |
| |
|
|
|
