JAC Advance Access originally published online on September 6, 2006
Journal of Antimicrobial Chemotherapy 2006 58(5):1024-1030; doi:10.1093/jac/dkl375
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The LOPSAQ study: 48 week analysis of a boosted double protease inhibitor regimen containing lopinavir/ritonavir plus saquinavir without additional antiretroviral therapy
1 Medical HIV Treatment & Research Unit, Hospital of the Johann Wolfgang Goethe University Frankfurt, Germany 2 Private HIV Practice Gute/Locher/Lutz Frankfurt, Germany 3 Internistisches Facharztzentrum Stresemannallee Frankfurt, Germany 4 Department of Virology, Hospital of the Johann Wolfgang Goethe University Frankfurt, Germany
*Corresponding author. Tel: +49-69-6301-83381; Fax: +49-69-6301-5712; E-mail: brenda.dauer{at}hivcenter.de
Received 27 June 2006; returned 10 August 2006; revised 17 August 2006; accepted 20 August 2006
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Abstract |
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Objectives: To evaluate the virological, immunological and clinical responses to the boosted double protease inhibitor (PI) regimen combination of lopinavir/ritonavir and saquinavir (‘LOPSAQ’) without reverse transcriptase inhibitors (RTI) in HIV-positive patients who have few viable RTI treatment options.
Methods: Cohort study of 128 heavily pre-treated patients who were experiencing therapy failure on their current regimen due to RTI resistance and/or systemic toxicities. Patients with PI-resistance mutations or RTI toxicity underwent a structured treatment interruption (STI) (n = 76) until virus reverted to wild-type or until resolution of toxicity symptoms. Baseline was defined as the time point when lopinavir/ritonavir plus saquinavir therapy was initiated. Virological response was defined as viral load <400 copies/mL at week 48.
Results: A total of 78 (61%) patients experienced a virological response to therapy (ITT). Median viral load at baseline was 5.06 log10 copies/mL; at week 48 median was 2.16 log10 copies. Median CD4 at week 48 was 280 cells/mm3 compared with 172 cells at baseline. At week 48, 78/128 patients were still on therapy. In univariable analyses, significant predictors of virological response included higher CD4 count (P < 0.001), lower viral load (P = 0.002), less PI-experience (P = 0.006) at baseline and fewer PI-resistance mutations (P = 0.043) at end of prior failing regimen; in the multivariable analysis only higher CD4 count at baseline (P = 0.009) and fewer number of drugs previously taken (P = 0.003) could be specified as independent predictors for response.
Conclusions: The combination of lopinavir/ritonavir and saquinavir without RTIs is a potential option as salvage therapy for patients experiencing therapy failure due to RTI resistance or toxicity. This regimen may not be suitable for patients with very low baseline CD4 cell counts, very broad antiretroviral therapy experience or extensive PI-resistance mutations.
Keywords: HIV drug resistance , toxicity , boosted double PI , reverse transcriptase inhibitors
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Introduction |
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Nucleoside analogues were the first antiretroviral agents to demonstrate clinical efficacy against HIV infection and are today regarded as an important backbone of highly active antiretroviral therapy (HAART). However, resistance and cross-resistance can limit their use in some patients. Furthermore, current nucleoside reverse transcriptase inhibitors (NRTIs) are associated with a diverse spectrum of adverse effects that are believed to be linked to a central pathophysiological mechanism—mitochondrial toxicity—which arises as a result of the high affinity for uptake of NRTIs by host cell mitochondrial DNA polymerase gamma. These class effects appear to be treatment-duration dependent and include lactic acidosis, myopathy, pancreatitis, peripheral neuropathy and lipodystrophy.1,2 Although newer NRTIs, such as tenofovir, do not seem to show these patterns of toxicity, their use may be limited by resistance, therefore effective NRTI-sparing antiretroviral regimens are needed in the clinic.3
A current NRTI-sparing treatment strategy is to combine a non-nucleoside reverse transcriptase inhibitor (NNRTI) with either a protease inhibitor (PI) or a boosted PI.4,5 This approach has several potential limitations: (i) recent studies have shown a trend towards virological failure with this strategy;6,7 (ii) given the low genetic barrier to resistance for NNRTIs and the high level of NNRTI cross-resistance at NNRTI failure,8 this approach is only likely to work in NNRTI-naive patients; (iii) failure of an NNRTI/PI combination can result in a total loss of treatment options from both classes, due to broad cross-resistance within the two classes;9 (iv) involvement of cytochrome P450 (CYP450) in the metabolism of NNRTIs and PIs can result in unpredictable pharmacokinetic (PK) interactions requiring complicated dose adjustments;10–14 and (v) the combination of a PI and an NNRTI carries an increased risk of additive detrimental effects on lipid profiles.15–17
The clinical efficacy of dual boosted PI regimens incorporating lopinavir/ritonavir and saquinavir with an RTI backbone has been investigated in several trials of salvage therapy in heavily pre-treated patients and results have generally been encouraging.18–21 A growing number of patients, however, have no viable RTI treatment options available to them as a result of resistance or toxicity. In the LOPSAQ study we therefore evaluated the approach of treating these heavily RTI antiretroviral therapy (ART)-experienced patients with a salvage therapy of the boosted double PI regimen of lopinavir/ritonavir plus saquinavir without the addition of RTIs. The purpose of this study was to assess the virological, immunological and clinical efficacy of this RTI-sparing regimen and identify any disadvantageous PK interactions between the PIs.
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Methods |
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Participants in this open, cohort study included 128 treatment-experienced patients in the Frankfurt HIV Cohort who were encountering treatment failure on their current regimen due to RTI resistance and/or toxicity.
Study candidates were identified by reviewing patients' charts for prior ART, current and past toxicities, HIV resistance profile, co-morbidities, clinical events and concomitant medications. The study recruited patients who had limited RTI treatment options available to them. For individuals with detectable viral load (>400 copies/mL), resistance to lopinavir/ritonavir and saquinavir was determined by genotypic testing while patients were still taking their failing regimen using the ViroSeqTM HIV-1 Genotyping System Version 2 (Abbott, Wiesbaden, Germany) as described elsewhere.22
Patients with PI-resistance mutations or who entered the study with RTI toxicity (n = 76/128) underwent a structured treatment interruption (STI) until virus showed no resistance-associated mutations to saquinavir and lopinavir/ritonavir or until resolution of RTI toxicity symptoms. Changes in viral drug resistance-associated mutations from the end of the last failing regimen, during the STI and before starting saquinavir/lopinavir/ritonavir, were assessed by genotyping. In our analyses only those mutations in the protease gene which were associated with resistance to lopinavir/ritonavir and saquinavir were included (L10FIRV, K20MR, L24I, V32I, L33F, M46IL, I47VA, G48V, I50V, F53L, I54VLAMTS, L63P, A71VT, G73S, V77I, V82TAFS, I84V, L90M) from the definition of the IAS-USA Drug Resistance Mutations Group dated 04/2005 (www.iasusa.org).
Baseline was defined as the time point when saquinavir/lopinavir/ritonavir therapy was initiated. Baseline data, including age, sex, prior ART, reasons for treatment switch and past PI-resistance profiles, were obtained from all patients; the last available CD4 cell count and viral load evaluation prior to starting the study regimen were used as baseline CD4 and HIV RNA measurements.
All patients were also asked to participate in a 12 h PK evaluation to investigate any potential disadvantageous drug interactions among the three PIs. A standardized PK assessment was performed before and 1, 2, 4, 6, 9 and 12 h after drug intake, under steady-state conditions after a minimum of 14 days on the study regimen. Plasma levels of saquinavir, ritonavir and lopinavir were determined by liquid chromatography-tandem mass spectrophotometry. Minimum and maximum plasma concentrations (Cmin and Cmax), the clearance and the area under the concentration–time curve (AUC) were calculated.
All patients received a boosted double PI regimen of saquinavir 1000 mg twice daily plus lopinavir/ritonavir 400 mg/100 mg twice daily without any additional ART.
We evaluated changes in CD4 cell count, viral load and plasma levels of study medications. Changes in lab parameters such as cholesterol, triglycerides, amylase, lipase and lactate were also investigated.
Viral load was measured using the COBAS AMPLICORTM HIV-1 MONITOR Test, v1.5 (Roche Diagnostics, Mannheim, Germany).
Virological response was defined as <400 copies/mL at week 48. In a subanalysis, we also investigated proportion of patients with less than 50 copies/mL.
Patients gave verbal informed consent to be evaluated in this study. All ethical standards have been observed and adhered to, in accordance with local criteria.
Statistical analysis
Factors associated with virological response in univariable analyses were identified using Fisher's exact tests (for categorical variables) or Mann–Whitney U-tests, as appropriate. Factors that were associated with response in univariable analyses were included in a multivariable logistic regression analysis to identify factors independently associated with response. The analysis was performed using a backwards selection process with the Logistic Regression procedure in the SPSS program, Version 12.0. All P values quoted are two-sided and a value of P < 0.05 was considered statistically significant.
Data were analysed both on an intent-to-treat [with lastobservation carried forward (ITT, LOCF)] basis and on an as-treated (AT) basis, and values quoted are median changes. In the AT analysis, only data from patients continuing treatment were considered for the analysis. If a week 48 value was missing, the nearest value within ±8 weeks was used if available; otherwise, missing values were excluded.
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Baseline characteristics are shown in Table 1. Study participants were extensively pre-treated, with a mean of 6.3 years of ART experience and previous exposure to a median of nine antiretroviral drugs. The patients were taking a median of three antiretroviral drugs at the time of last therapy failure. One hundred and six patients (83%) were PI-experienced, 82 patients (64%) were triple-class-experienced and 42 patients (33%) had a PI in the last regimen.
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At baseline (commencement of saquinavir/lopinavir/ritonavir therapy) the median CD4 count was 172 cells/mm3 (range 2–998) and median viral load was 116 000 copies/mL (range <50–
1 000 000). The differences in values reflect the changes that occurred in those patients who stopped all ART for at least 4 weeks before initiating saquinavir/lopinavir/ritonavir treatment. At week 48, 78 (61%) patients were still on saquinavir/lopinavir/ritonavir therapy. Fifty patients (39%) discontinued therapy due to virological failure (n = 11), non-virological reasons (n = 27) or both (n = 5). Five patients were lost to follow-up and for two patients the reasons of discontinuation were not documented and could not be reconstructed. One patient died due to an unrelated cause.
The most common non-virological reason for discontinuation was a dose change for one of the drugs subsequent to the saquinavir/lopinavir/ritonavir plasma drug level assessment (n = 10), followed by diarrhoea (n = 5), patient choice (n = 4) and lipodystrophy (n = 3).
The most common adverse events reported during the study period included lipodystrophy (n = 12), gastrointestinal disturbances (n = 10), diarrhoea (n = 9) and hyperlipidaemia (n = 9).
One patient experienced a new CDC class C AIDS-defining event during saquinavir/lopinavir/ritonavir therapy.
Virological and immunological responses
Intent to treat analysis.
At week 48, 78 (61%) patients demonstrated a virological response to LOPSAQ (less than 400 copies/mL). In the ITT analysis, the median viral load for all study participants at week 48 was 144 copies/mL (range <50–1 000 000); viral load had decreased by a median of 2.9 log10 copies/mL from baseline (Figure 1). In the subanalysis, 59 (76%) of the 78 responders achieved a viral load of <50 copies/mL. The median CD4 count at week 48 was 280 cells/mm3 (range 1–934). This represents an increase of 90 cells/mm3 from baseline (Figure 2).
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Of note, the patients who responded to saquinavir/lopinavir/ritonavir therapy (n = 78) had a median baseline CD4 count that was more than 2x higher than that of the 50 non-responders [203 versus 90 cells/mm3, respectively (P < 0.001)].
In univariable analysis, significant differences in the mean values for the group of responders in comparison with the non-responder group were seen; especially a higher CD4 count (P 
0.001), a lower viral load (P = 0.002), less PI-experience (P = 0.006) at baseline and fewer PI-resistance mutations (P = 0.043) at the end of failing regimen. The univariable analyses are shown in Table 2. For the multivariable analyses, CD4 cell counts and viral load at baseline were dichotomized, <200 versus 200 cells/mm3 and <100 000 versus 100 000 copies/mL, respectively. The only factors independently associated with virological response were higher CD4 count at baseline (P = 0.003, OR = 0.21, 95% CI = 0.076–0.594) and lower number of drugs taken previously (P = 0.003, OR = 1.275, 95% CI = 1.085–1.498).
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In a subgroup analysis comparing PI-naive with PI-experienced patients viral load at week 48 was 95 versus 185 copies/mL, respectively. No statistical significance in terms of virological response was noted (P = 0.35). CD4 count for the PI-naive group was 245 cells/mm3 compared with 279 cells/mm3 for the experienced group.
As-treated analysis
Although 78 patients remained on study at week 48, for the AT analysis 70 patients had viral load and CD4 count values available at week 48 (±8 weeks). Median viral load nadir by week 48 was <400 copies/mL (range <20–1 000 000), representing a median decrease of 3.5 log10 copies/mL from baseline. Median time to viral load nadir for these patients was 14 weeks. A total of 40 out of 70 patients (57%) had HIV RNA levels <50 copies/mL. Median CD4 count at week 48 was 353 cells/mm3 (range 35–934), representing an increase of 168 cells/mm3 from start of saquinavir/lopinavir/ritonavir therapy.
STI versus non-STI group
In the ITT analysis, both STI and non-STI patients reached <400 copies/mL by week 48.
The 76 patients with a treatment interruption before starting LOPSAQ had a median viral load of 260 000 copies/mL (range <50–1 000 000) at baseline and 243 copies/mL (range <50–1 000 000) at week 48, whereas the patients without a treatment interruption (n = 52) had a median viral load of 9320 copies/mL at baseline and <50 copies/mL at week 48 (range <50–750 000) (Figure 1). STI patients needed 12.7 weeks to reach <400 copies/mL while the patients without an STI needed 4.5 weeks.
CD4 counts at baseline were 154 cells/mm3 (range 2–588) for the STI group and 206 cells/mm3 (range 6–998) for the non-STI group. CD4 counts at week 48 were similar in both groups: 273 (range 1–934) versus 288 cells/mm3 (range 35–904) for the STI and non-STI groups, respectively (Figure 2).
Statistically, it appears that the STI in this group of patients was neither beneficial nor detrimental in terms of response. Both the STI patients and the non-STI patients reached <400 copies/mL by week 48 albeit the median was lower in the non-STI group, and both groups had similar absolute CD4 cell counts. A total of 43/76 (57%) of the STI patients and 35/52 (67%) of the non-STI patients reached <400 copies by week 48, whereas 30/76 (39%) STI patients and 20/52 (38%) non-STI patients discontinued before week 48.
Association of PI mutations during last failing regimen and subsequent response to therapy
At the start of therapy HIV genotypes for 112/128 patients were performed and a mean of 1.6 (range 0–5) PI mutations was identified. For those patients who had HIV genotypes performed while still taking their last failing regimen (n = 91), a mean of 2.5 PI mutations was identified (range 0–11). A total of 71/91 patients (78%) had 1 PI mutation and 15/91 patients had 6 PI mutations. In univariable analysis a relationship was seen between the number of PI mutations identified in these patients and subsequent virological response to saquinavir/lopinavir/ritonavir [non-responders had a mean of 3.5 (0–11) mutations while responders had a mean of 1.8 (0–8) mutations; P = 0.043].
However, in the multivariable analysis of response, the number of PI mutations at the end of the last failing regimen could not be identified as an independent predictor for response, probably because of the small number of patients (n = 17/128) with extensive PI mutations (4 mutations) at the end of the failing regimen. For these 17 patients with PI resistance, the structured therapy interruption led to reversion of the virus to wild-type or to at least loss of resistance mutations to saquinavir and lopinavir/ritonavir, according to genotype testing. A mean loss of 5 PI mutations was observed by a median of 15 weeks between therapy interruption and genotype (range 12–43 weeks). A significant benefit with regard to virological response could be observed for 8 of these 17 patients—the median viral load decreased by 3.23 log from baseline to week 48 (from 238 500 at baseline to 224 copies/mL at week 48). The median viral load of the other 9 patients decreased from 455 000 copies/mL at baseline continuously until week 12 (43 000 copies/mL) before rebounding to 305 000 copies/mL at week 48, which was even higher than the median viral load at the end of last regimen (79 000 copies/mL). As expected, genotype showed a full return of PI mutations in these patients. The importance of a rapid reduction in viral load was evident, from 238 500 at baseline to 1650 copies/mL at week 4 for the responders in comparison with 455 000 at baseline to only 131 700 copies/mL in 4 weeks for non-responders.
Of note, the non-responders had a median of eight PI mutations at end of the last failing regimen whereas the responders had six. Nevertheless, statistically significant values for differences in mutational profiles could not be achieved, due to the small number (n = 17) of patients, as already stated. At the end of the failing regimen (prior to saquinavir/lopinavir/ritonavir therapy), the genotype profiles of responders and non-responders were similar, so an association between response and mutational profile could not be determined.
Pharmacokinetic results
No disadvantageous interactions among the PIs were noted. Effective plasma levels of both saquinavir and lopinavir were achieved by the co-administration of saquinavir and lopinavir/ritonavir. We also saw a wide inter-patient variability in the plasma levels of both lopinavir and saquinavir.23
Laboratory parameters
Cholesterol, triglycerides, lipase, amylase, SGPT, SGOT, GGT, bilirubin and lactate were regularly tested. Only cholesterol (median of 212 mg/dL by week 48, which showed a median increase of 52 mg/dL from baseline) and triglycerides (median of 275 mg/dL by week 48, which signed a median increase of 68 mg/dL from baseline) showed any notable changes. The increase for cholesterol was not significant, whereas the increase of triglycerides showed a high significance (P < 0.001) despite lipid-lowering agents. Triglyceride levels peaked at week 24 at 366 mg/dL, decreased again to 275 mg/dL at week 48, which was nevertheless a significant change from 224 mg/dL at baseline.
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Discussion |
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This clinical cohort study shows that the boosted double PI combination of lopinavir/ritonavir and saquinavir without the addition of RTIs may be an effective and generally well-tolerated nucleoside-sparing treatment strategy for patients with limited RTI options. Our findings therefore have important implications for the clinical management of patients who have resistance and/or toxicity to RTIs.
Patients in this study were heavily pre-treated, with prior exposure to a median of nine antiretroviral drugs, a median of two PIs and a mean of 6.3 years of ART experience. A total of 82 (64%) patients were triple-class-experienced and nearly 40% of the patient population had previously been exposed to saquinavir and more than one in six patients had had prior exposure to lopinavir/ritonavir. Previous exposure to the study PIs and the number of PIs previously taken showed significance in the univariable analysis, but could not be identified as independent predictors in the multivariable analysis.
Despite this, the majority of the patients who received saquinavir/lopinavir/ritonavir therapy experienced a reduction in viral load, an increase in CD4 count and no clinical progression. Our observations suggest that this dual PI combination may have sufficient antiviral activity to provide important benefit to treatment-experienced patients with limited NRTI options.
The correlation between viral load levels, CD4 cell counts and disease progression has been well described.24–30 As this was a clinical cohort study, we looked at virological and immunological responses as well as clinical progression. Since treatment-induced changes in viral load and CD4 cell count, taken together, are valid predictors of the clinical progression of HIV-related disease,27 the 48 week virological and immunological responses reported here suggest the potential value of this convergent combination therapy in improving clinical outcomes for HIV-infected patients. While the outcomes of several studies have indicated the value of this combination as part of a salvage regimen that includes an RTI backbone, as far as we know this is the first study to evaluate saquinavir/lopinavir/ritonavir without the addition of other antiretroviral agents to the regimen in heavily pre-treated patients. One small study in treatment-naive patients was recently reported.31 Indeed, there are few data available regarding the use of any boosted double PIs as salvage therapy in regimens that do not have an RTI backbone.
As to the question of whether or not the therapy interruption produced any benefit, it appears that the STI was neither beneficial nor detrimental statistically in terms of response. Both STI and non-STI patients reached <400 copies/mL by week 48.
CD4 counts at week 48 were similar in both groups, 273 (STI) versus 288 (non-STI) cells/mm3. STI patients needed 12.7 weeks to reach <400 copies/mL while the patients without an STI needed 4.5 weeks. Much of the delay in achieving an optimal response may have been influenced by exposure to treatment interruption.
The analysis suggests that for patients with extensive PI mutations (4) at the end of the prior failing regimen, a short-term decrease in viral load can be achieved. In general it seems that if it was not possible to achieve a rapid reduction in viral load by week 4 (over 2 log reduction in our study), the chance of virological response was unlikely for patients with extensive PI mutations at the end of the failing regimen.
Our analyses suggest that saquinavir/lopinavir/ritonavir (without additional ART) may not be suitable for all treatment-experienced patients. In univariable analyses, significant predictors of virological non-response included CD4 cell count and viral load at baseline, ART experience and PI resistance in the patient's last failing regimen. These factors are in line with risks identified in other studies of salvage therapy.32–36
The only significant factors identified in multivariable analyses were the CD4 count at baseline and the number of drugs taken previously.
Although 76/128 patients underwent an STI due to resistance or toxicity, and at the start of LOPSAQ treatment genotyping showed no resistance-associated mutations to lopinavir/ritonavir and saquinavir, some of the patients may have been harbouring persistent low levels of drug-resistant HIV.
The LOPSAQ study had a number of limitations including the non-randomized nature of this cohort study. While we recognize that a controlled randomized study would be optimal, we hope to show however that real-life settings may also help clinicians in choosing alternative options for patients with limited RTI options. The presence of a comparator regimen group consisting of one boosted PI and two NRTIs with low mitochondrial toxicity would have lent strength to the conclusions of the study.
A second limitation was the heterogeneity of the population. Baseline CD4 and viral load varied widely within the study population, and whether or not a patient had a treatment interruption before starting LOPSAQ also varied according to physician and/or patient.
With regard to the homogeneity of the study population all patients with doses other than saquinavir 1000 mg twice daily plus lopinavir/ritonavir 400 mg/100 mg twice daily were not included in the evaluation. Thus a dose change was considered therapy discontinuation, though the patients concerned (n = 10) continued the boosted double PI regimen containing lopinavir/ritonavir/ plus saquinavir. Of these 10 patients who switched to another dose 8 were still on therapy at week 48.
In summary, double boosted PI therapy offers an RTI-sparing salvage treatment strategy with good immunological and virological activity for heavily ART-experienced patients with RTI toxicity and/or resistance, but may not be suitable for patients with very advanced disease. Consideration should be given to randomized, controlled studies to further evaluate this strategy.
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We have no conflicts of interest.
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No funding was received for the study.
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