Evaluation of Indinavir/Ritonavir Versus Saquinavir/Ritonavir in HIV Patients: The MaxCmin-1 Trial

Although HIV and Hepatitis.com has reported on these study data several times, presented most recently at the 5th Lipodystrophy Workshop in Paris (July 9-11, 2003), complete results of this randomized, multi-center, phase IV trial appear in the current issue (September 1, 2003) of The Journal of infectious Diseases. Following is a summary review of that article.

The MaxCmin-1 trial was designed to assess whether equivalence exists in efficacy and safety between Crixivan (indinavir/IDV) plus Norvir (ritonavir/RTV) 800/100 mg b.i.d. and Fortovase (saquinavir/SQV) plus RTV 1000/100 mg b.i.d., in combination with at least 2 non-PI drugs, with the primary outcome being the incidence of protocol-defined virological failure.

When this comparative trial started in 2000, the combination of IDV/RTV 800/100 mg b.i.d. was a commonly used RTV-boosted protease inhibitor (PI) regimen. A switch to the RTV-boosted regimen was motivated by poor adherence to IDV 800 mg three times daily (the FDA-approved IDV dose) as well as by data suggesting the IDV dosing frequency could be reduced to twice daily. Furthermore, the pharmacokinetic data also suggested that the RTV-boosted twice-daily regimen might allow for dropping the fasting requirement for IDV.

There have been a number of studies evaluating use of the double PI combination of SQV/RTV, primarily in a twice-daily dosing schedule. In most patients, this regimen is associated with gastrointestinal adverse events. In addition, there was a concern that in a SQV/RTV regimen at a dose of 1000/100 b.i.d, only SQV would show virologic activity, compared to the SQV/RTV 400/400 mg b.i.d. regimen, in which both drugs had virological activity.

The MaxCmin-1 trial is the first direct comparison of two RTV-boosted PI regimens.



Patients and Methods

Patients were primarily white (84%) men (78%) who engaged in homosexual- or bisexual-risk behavior (49%) with a median age of 39 years. The median CD4 cell count nadir was 110 cells/microliter, the median CD4 cell count was 277 cells/microliter, and the median VL was 3.9 log₁₀ copies/mL; 39% of patients had a baseline VL of <400 copies/mL, and 30% had had a prior clinical AIDS-defining disease.

At enrollment, 25% of patients were ART-naive, 14% were ART-experienced but PI-naive, and 61% were PI- experienced. However, only patients with an equal chance of benefit from and/or risk of development of treatment-related AEs to the two study PIs at the time of screening could be randomized.

Randomized patients, irrespective of whether they started receiving or switched from the assigned treatment, were followed up at baseline (first day of intake of assigned treatment) and at weeks 4, 12, 24, 36, and 48.

During follow-up visits, the following procedures were performed: clinical evaluation, safety analyses (hemoglobin; white blood cell, lymphocyte, and platelet counts; and creatinine, aspartate aminotransferase and/or alanine aminotransferase, bilirubin, and amylase levels), and viral load (VL) and CD4 cell count measurements.

In addition, fasting total cholesterol, low-density lipoprotein (LDL) cholesterol, and total triglyceride levels were measured at baseline and at weeks 4 and 48.     

Patients randomized to receive SQV/RTV were allowed to change from the SQV soft-gel formulation (Fortovase) to the hard-gel formulation (Invirase) without this being considered a switch from the assigned treatment.

During the trial, modification of the randomized treatment was allowed in the case of virological failure or treatment-limiting toxicities. If available, dose reduction was performed on the basis of therapeutic-drug monitoring. Of note, patients experiencing virological failure, according to the protocol's definition, were allowed to continue receiving the assigned treatment at the discretion of the treating physician.

Definition of Virological, Immunological and Clinical Failure    

For patients entering the study with a VL of <200 copies/mL, virological failure was defined as a VL of  > or = 200 HIV-1 RNA copies/mL. For patients entering the study with a VL of  > or = 200 copies/mL, virological failure was defined as any increase in HIV-1 RNA load of  > or = 0.5 logs and/or a VL of > or = 50,000 HIV-1 RNA copies/mL at week 4, > or = 5000 copies/mL at week 12, or > or = 200 copies/mL at week 24 or thereafter.

Immunological failure was defined as a decrease in the CD4 cell count of  >50% from the baseline level, provided that the baseline CD4 cell count was >150 cells/microliter. For patients with a baseline CD4 cell count of 100 150 cells/microliter, immunological failure was defined as a CD4 cell count of <50 cells/microliter and, for patients with baseline CD4 cell count of <100 cells/microliter, immunological failure was defined as a CD4 cell count of <25 cells/microliter.

All cases of suspected immunological failure were confirmed by a second CD4 cell count measurement performed at least 1 week later. Once reconfirmed, the time of immunological failure was defined as the time of the first measurement that met the failure criteria. Clinical failure was defined as the development of a new AIDS-defining disease or as the relapse of an AIDS-defining disease that had been successfully treated previously.

Power Calculation and Statistics

The trial was powered to show equivalence between the study arms, with an 80% chance that the 95% confidence interval (CI) for the difference in virological failure rates would exclude a difference of >15% in either direction. This was based on a sample size of 150 patients/arm and an underlying failure rate of 20% in both arms.

The primary population for analysis was the intention-to-treat/exposed (ITT/e) population, including all randomized patients who had taken at least one dose of the assigned treatment. This analysis is also termed the "ITT switch included" analysis. In the other protocol-stipulated analysis, switching from the assigned treatment constituted failure (ITT/e/switch = failure [ITT/e/s]). In both analyses, patients who withdrew consent, who were lost to follow-up, or who died, constituted failure, and the time of failure was the time of the event (whichever came first). Some patients withdrew their consent during follow-up but permitted reporting of laboratory data measured as part of their routine care. For these patients, withdrawn consent did not constitute (virological) failure.

Results

Complete week-48 follow-up data were available for 285 (93%) of the 306 patients who initiated the assigned treatment, 202 (66%) of whom continued to receive the assigned treatment. No difference was seen between the 2 study arms in the rate of patients lost to follow-up (7%).

The 104 patients who prematurely switched from the assigned treatment did so primarily because of nonfatal, clinical AEs (n = 67). Among the 104 patients, no significant differences were observed between the study arms in the proportion of patients who switched treatment regimens.

Nine patients switched from IDV/RTV to SQV/RTV, and 4 patients switched from SQV/RTV to IDV/RTV. There was a significantly higher percentage of patients in the IDV/RTV arm (41%) than in the SQV/RTV arm (27%) who prematurely switched from the assigned treatment. This difference was driven by patients who discontinued the randomized treatment because of a nonfatal, clinical AE (28% of patients assigned to IDV/RTV arm vs. 15% in the SQV/RTV arm).

Of the nonfatal, clinical AEs that led to patients' switching from the assigned treatment, 66% were of grade 1 or 2. More renal, skin and hair, and gastrointestinal AEs were observed in patients in the IDV/RTV arm. Twenty-two patients reduced the dose of the assigned treatment during follow-up (21 in the IDV/RTV arm and 1 in the SQV/RTV arm).

Virological, Immunological and Clinical Outcomes

The primary efficacy outcome, rate of virological failure, was seen in 77 (25%) of 306 patients, with no difference between the study arms. The median VL at the time of failure was 2279 copies/mL, slightly higher in the IDV/RTV arm (3857 copies/mL) than in the SQV/RTV arm (881 copies/mL) (P = .40). The difference between the 2 study arms in the proportion of patients experiencing virological failure was 2.2% (95% CI, -2.8% to 7.2%), with a higher proportion of protocol-defined virological failures in the IDV/RTV arm.

Using a Farrington-Manning equivalence test, the investigators found sufficient evidence at the 5% level of significance to claim that the difference in success rates between the 2 treatments is <15% (P < .0048).

The higher discontinuation rate in the IDV/RTV arm resulted in a significantly higher virological failure rate in this arm in the ITT/e/s analysis. No difference was seen between the study arms in the during-treatment analysis.

Only 6 patients experienced immunological failure (4 in the IDV/RTV arm and 2 in the SQV/RTV arm). An increase of > or = 100 CD4 cells/microliter at any time during follow-up was seen in 181 patients, at a median of 98 days. There was no significant difference between the study arms in the number of patients or time to an increase of > or = 100 CD4 cells/microliter.

Clinical failure was seen in 23 patients after a median of 80 days (13 patients classed as CDC category B, 7 patients classed as CDC category C, and 3 deaths); of these clinical failures, 14 (4 patients classed as CDC category C and 1 death) were observed in the IDV/RTV arm, and 9 (3 patients classed as CDC category C and 2 deaths) were observed in the SQV/RTV arm.

The low number of clinical failures precluded formal statistical analysis. In none of the fatal cases was the death directly related to the assigned treatment: the death in the IDV/RTV arm was due to Castleman disease, and the 2 deaths in the SQV/RTV arm were due to Pneumocystis carinii pneumonia and hepatitis C end-stage liver failure.

Adverse Events

Of the patients exposed to the study medication, 100 (33%) of 306 experienced at least 1 AE of grade 3 or 4 (65 [41%] in the IDV/RTV arm vs. 35 [24%] in the SQV/RTV arm. Of these, the treating physician assessed the relationship to the assigned treatment as being at least possible in 46 (29%) in the IDV/RTV arm versus 19 (13%) in the SQV/RTV arm. There was a significant difference between the 2 study groups in the distribution by organ system of AEs grade 3 and 4, with a higher number of renal, dermatological, and gastrointestinal side effects in the IDV/RTV arm.

Lab Results

The median percentage change from baseline in fasting total cholesterol, LDL cholesterol, and total triglyceride is shown in Figure 1 below. Significantly higher lipid elevations were seen in the IDV/RTV arm, compared with the SQV/RTV arm, at weeks 4 and 48 (ITT/e analysis).

Figure 1

Median percentage change from baseline in fasting total cholesterol, low-density lipoprotein (LDL) cholesterol, and total triglyceride levels in the intention-to-treat/exposed analysis. Nos. within the bars are the no. of measurements (i.e., patients) at each time point. IDV, indinavir; RTV, ritonavir; SQV, saquinavir.

No difference between the study groups was seen in hematological, renal, or hepatic laboratory parameters, except for bilirubin levels, which were 10 and 11 micromole/L at baseline in the IDV/RTV and SQV/RTV arms, respectively (normal range, 4 22 micromole/L). In the SQV/RTV arm, the bilirubin level did not change over time, whereas, in the IDV/RTV arm, it increased to 20 micromole/L at week 4, followed by a decline to 15 micromole/L at week 48.

Commentary

Equivalence was observed for efficacy, whereas IDV/RTV led to an increased risk of treatment-limiting AEs and AEs of grade 3 and/or 4. As a consequence of the safety profile of IDV/RTV, fewer patients continued to receive this treatment throughout the 48 weeks, leading to differences in the efficacy analyses, in which continuation with study medication influences the outcome. In addition, IDV/RTV was found to cause a higher risk of elevating blood levels of lipids and bilirubin.

In the analysis in which switching from the assigned treatment is equal to virological failure or lack of virological suppression, SQV/RTV tended to have superior virological activity than did IDV/RTV. This result was to be expected, because a higher proportion of patients in the IDV/RTV arm switched from the randomized treatment.

The trial was not designed and did not have the statistical power to test whether there were differences in risk of protocol-defined immunological and clinical failures between the 2 study arms.

In the present trial, 21 (13%) of 158 patients in the IDV/RTV arm reduced the IDV dose. The trial was not designed to evaluate whether this strategy lowered the risk of AEs or affected the efficacy of the treatment, nor was the sample sufficiently large for formal testing of these important questions.

Compared with patients in the SQV/RTV arm, patients in the IDV/RTV arm had significant increases from baseline in total cholesterol, LDL cholesterol, and triglyceride levels at weeks 4 and 48. Other drugs (NNRTIs and stavudine) that could potentially influence these parameters were well balanced between the 2 groups at baseline.

Therefore, these findings suggest that, relative to SQV/RTV, IDV/RTV affects the lipid metabolism adversely. Because the same RTV dosing was used in both arms, it is likely that it is the IDV component that causes lipid levels to increase. However, another possibility is that the RTV metabolism is affected differently by IDV, compared with SQV.

In conclusion, the authors state, “We have found that, in this open-label study of a heterogeneous patient population, reflecting the real-life situation, SQV/RTV has antiretroviral effects comparable to those of IDV/RTV in the doses studied. We observed more treatment-limiting AEs in the IDV/RTV arm, relative to the SQV/RTV arm, and found that more patients in the SQV/RTV arm remained virologically suppressed at week 48, probably because of a better toxicity profile.”

09/10/03

Reference
UB Dragsted and others (for the MaxCmin1 Trial Group). Randomized Trial to Evaluate Indinavir/Ritonavir versus Saquinavir/Ritonavir in Human Immunodeficiency Virus Type 1 Infected Patients: The MaxCmin1 Trial. The Journal of Infectious Diseases 188:635-642. September 1, 2003.