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Virologic Outcomes of Changing Enfuvirtide to Raltegravir in HIV-1 Patients Well Controlled on an Enfuvirtide Based Regimen: 24-Week Results of the CHEER Study
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JAIDS Journal of Acquired Immune Deficiency Syndromes:
August 2009 - Volume 51 - Issue 4 - pp 367-373
Towner, William MD, FACP; Klein, Daniel MD; Kerrigan, Hai Linh PharmD; Follansbee, Stephen MD; Yu, Kalvin MD; Horberg, Michael MD, MAS, FACP
From the Department of Internal Medicine, Kaiser Permanente, Los Angeles, CA; Division of Infectious Diseases, Kaiser Permanente, Hayward, CA; Division of Infectious Diseases, Kaiser Permanente, San Francisco, CA; Division of Infectious Diseases, Kaiser Permanente, West Los Angeles, CA; and Division of Research, Kaiser Permanente, Oakland, CA.
Abstract
Objectives: To determine the safety and efficacy of changing enfuvirtide to raltegravir in HIV-1-infected patients with HIV-1 RNA below the level of quantification for at least 6 months on an enfuvirtide-containing antiretroviral regimen.
Design: Prospective, nonrandomized, historical control study.
Methods: Patients were recruited from 11 Kaiser Permanente HIV clinics in California. Those patients eligible for inclusion (≥18 years old, well controlled on antiretroviral medications) had enfuvirtide changed to raltegravir 400 mg, given twice daily orally; all other background antiretrovirals remained unchanged. The primary end point was percentage of patients with HIV-1 RNA below the limit of quantification after 24 weeks of raltegravir therapy. Analyses were by intention to treat.
Results: Fifty-two patients were enrolled in the trial. After 24 weeks of therapy with raltegravir, 49 (94.2%, confidence interval: 1.2% to 15.9%) patients had HIV-1 RNA levels below the limit of quantification. Patients had a median CD4 cell increase of 32 cells per cubic millimeter after 24 weeks of raltegravir therapy. Treatment satisfaction as measured by patient questionnaires improved with the raltegravir-containing regimen. Adverse events were infrequent and generally mild in nature.
Conclusions: In treatment-experienced patients on a stable virologically suppressive enfuvirtide-containing regimen, raltegravir can safely be substituted for enfuvirtide.
INTRODUCTION
Tolerability and potential for long-term treatment adherence are critical components of any HIV medication regimen.1 Enfuvirtide is an effective antiretroviral agent against HIV, but it must be administered subcutaneously and is associated with side effects such as injection site reactions.2-4 After many years of setbacks, a novel class of HIV antiretroviral agents, the integrase inhibitor class, has recently advanced in clinical development. The first successful compound in this class has been raltegravir, an orally bioavailable agent which was approved in the United States in October 2007. The efficacy of raltegravir has been established in treatment-experienced patients and has thus far demonstrated an excellent safety profile with good patient tolerability.5-6 As a new class of drug, it is unlikely that any significant resistance against raltegravir exists, even in highly treatment-experienced patients.7 Raltegravir is thus an attractive option to substitute in advanced patients experiencing toxicity or drug side effects with their current regimen.
We report here the 24-week results of the CHEER (changing enfuvirtide to raltegravir) study, the aim of which was to assess the virologic effect of switching enfuvirtide to raltegravir in HIV-1-infected patients with plasma HIV-1 RNA below the level of quantification for at least 6 months on their current enfuvirtide-containing regimen.
DISCUSSION
This study demonstrates the safety and efficacy of substituting enfuvirtide with raltegravir among clinically stable HIV-infected patients. Twenty-four weeks after switching from an enfuvirtide-containing regimen to a raltegravir-containing regimen, a high proportion of patients (94%) maintained their HIV-1 RNA levels below the level of quantification. The large confidence interval (1.2% to 15.9%) was in part a result of the rigorous intention to treat analysis utilized, with noncompleters for any reason being counted as failures. The raltegravir-containing regimens were well tolerated by patients and resulted in higher patient treatment satisfaction than the prior enfuvirtide based regimens.
Our findings confirm those reported by another study that evaluated switching enfuvirtide to raltegravir in patients with an HIV viral level below the level of quantification.10 In this descriptive and retrospective study, after an average of median time of 7 months of raltegravir therapy, 34 of 35 patients had maintained an HIV-1 RNA level below the level of quantification. Similar to our study, adverse events were uncommon and raltegravir was well tolerated by study participants. Several other small retrospective studies have also reported results which are similar to ours.11-12
The rate of adverse events was generally low throughout our study. The adverse events that did occur were for the most part mild and not treatment limiting. These findings are consistent with previously reported adverse events in raltegravir-containing antiretroviral regimens.5-6 Importantly, although we did observe significantly elevated levels of LFTs in patients on tipranavir-containing regimens, all of these were grade 1 in nature and none necessitated discontinuation of therapy. Nonetheless, until data from larger studies examining raltegravir and tipranavir concurrent utilization are available, we feel caution is warranted with tipranavir and raltegravir coadministration, particularly in the context of switching enfuvirtide to raltegravir.
The decline in CD4 cells seen with some patients (although there was a net mean increase in CD4 cells) in our study was unexpected. When examining CD4 percentage changes in these patients, no significant change was noted. Prior studies with raltegravir have not reported a decline in CD4 cells. In the pivotal registration studies for raltegravir, a statistically significant CD4 cell increase (when compared with that seen in the placebo arm) of 109 cells per cubic millimeter was seen in patients after 48 weeks of raltegravir therapy.6 When correlating changes in T cells with historical nadir T-cell data, no significant pattern was noted. It is also not possible to comment on potential CD4 changes among those patients starting with low CD4 cell counts; there were no patients in our study who changed to raltegravir with CD4 counts <200 cells per cubic millimeter. Given the stability of the CD4 percentages in the CHEER study, and the continuing high proportion of participants with HIV-1 RNA levels below the level of quantification, it may be possible that, in fact, the immune systems of study participants have not significantly changed over the 24 weeks of the study period.
Not unexpectedly, patient treatment satisfaction improved significantly when patients switched from enfuvirtide to raltegravir, given the necessity of subcutaneous administration with enfuvirtide and the associated injection site reactions. Although long-term use of enfuvirtide has been shown to be associated with overall patient satisfaction in prior studies,13-14 the patients on enfuvirtide in these studies were followed for a shorter duration (24 or 48 weeks) than the patients in our study (who had been on enfuvirtide for a median duration of 2.7 years at time of switch to raltegravir). It is possible that with longer duration of enfuvirtide use, patients become more fatigued with the ongoing process of drug reconstitution and injection site reactions.
The patients enrolled in our study were heavily treatment experienced. That raltegravir would be effective in this treatment population is not unexpected given the results of pivotal trials utilizing raltegravir.6 However, raltegravir substitution for a single agent in a suppressive regimen may not be appropriate in all clinical circumstances. A recently reported study randomized patients with virologic suppression who were receiving lopinavir/ritonavir plus at least 2 nucleoside reverse transcriptase inhibitors to either continue their lopinavir/ritonavir therapy or switch to raltegravir.15 Unlike the high virologic success rate that was seen in our study, in this study, raltegravir was shown to be inferior to lopinavir/ritonavir after 24 weeks of therapy. The success of the patients enrolled in our study may have been due to the high proportion of patients who remained on ritonavir-boosted PIs as a part of their background therapy (90%). The discordant findings seen in our study versus this one highlight the importance of careful consideration of the likely activity of background regimens when substituting raltegravir for a single agent in a virologically suppressive regimen.
A limitation of our study was the lack of a separate control arm. However, patients did serve as their own control by virtue of at least 6 months of HIV-1 RNA levels below the level of quantification before enrollment in the study. In fact, patients had been on stable enfuvirtide-containing regimens for a median of more than 21/2 years before the switch. At the time of switch, the only change made was to substitute raltegravir for enfuvirtide. Although 1 viral blip in the 6 months before raltegravir substitution was permitted, these blips did not correlate with virologic failure post switch. We therefore feel that our study design is valid to answer the question posed.
In conclusion, our findings support the safety and efficacy of replacing enfuvirtide with raltegravir in treatment-experienced HIV-infected patients with sustained viral suppression. Given the long-term nature of HIV infection, providing evidence for another effective and potentially better tolerated treatment option for patients with advanced disease may help long-term treatment success.
METHODS
Patients and Procedures
The CHEER trial was a multicenter, open-label, historical control study that enrolled patients from 11 Kaiser Permanente HIV clinics in Northern and Southern California. HIV-infected individuals ≥18 years of age on a stable antiretroviral regimen consisting of enfuvirtide plus at least 2 other antiretrovirals with documented plasma HIV-1 RNA level(s) of <75 copies per milliliter by bDNA assay or <50 copies per millilier by ultrasensitive polymerase chain reaction (PCR) for at least 6 months before the study screening visit were eligible to enroll. Patients were required to have at least 1 documented HIV-1 RNA performed in the 6 months before the screening visit. Exclusion criteria included any prior therapy with raltegravir or any other HIV-1 integrase inhibitor, plasma HIV-1 RNA >75 copies per milliliter by bDNA assay, or >50 copies per milliliter by Ultrasensitive PCR assay in the 6 months before screening visit (a single blip of plasma HIV-1 RNA greater than the level of detection but less than 400 copies/mL in the 6 months before the screening visit with at least 2 subsequent plasma HIV-1 RNAs below the level of detection was allowed). Any female patient who was pregnant or breast-feeding or expecting to conceive or donate eggs during the study was also excluded from enrolling.
The study treatment period consisted of a maximum 4-week screening period, a 24-week treatment period, and a 4-week follow-up study period. A prospective, nonrandomized, historical control trial design was utilized, with patients serving as their own controls by virtue of at least 6 months of virus levels below the level of quantification on an enfuvirtide-based regimen. All patients had at least 1 HIV-1 RNA performed in the 6 months before baseline, and 50 of 52 (96%) had 2 or more HIV-1 RNA levels performed in this 6 month period (excluding study screening and baseline visits). Six patients had 1 viral blip in the 6 months before switch to raltegravir.
Patients who met all inclusion criteria and no exclusion criteria replaced enfuvirtide 90 mg, given subcutaneously twice daily, with raltegravir 400 mg orally twice daily, whereas all other background antiretroviral agents in their regimen remained unchanged. Changes to background therapy were permitted for protocol-defined virologic failure or for single antiretroviral drug toxicity management.
Efficacy and Safety Assessments
Laboratory assessments (serum electrolytes, blood urea nitrogen, creatinine, alanine aminotransferase/aspartate aminotransferase, complete blood cell count with differential CD4/CD8 cell panel and HIV-1 RNA) were assessed at screening, baseline, and at weeks 4, 12, and 24 after regimen change to raltegravir. Baseline demographics of age, gender, years of known HIV infection, antiretroviral history, and prior resistance testing results from Monogram Biosciences and Stanford University were also recorded. The primary efficacy outcome was the proportion of patients who maintained a level of HIV-1 RNA below the limit of quantification of the assay used after 24 weeks of raltegravir therapy. Predefined secondary efficacy outcomes included changes in the median concentration of CD4 cell counts and impact of regimen change on quality of life as assessed by changes in scores in patient treatment satisfaction surveys administered at baseline, week 12 and week 24.
All laboratory tests were performed by the Kaiser Permanente laboratories at North Hollywood and Berkeley, California. Plasma HIV-1 RNA was measured by either Roche Amplicor HIV-1 Monitor test (version 1.5; Roche Molecular Systems, Branchburg, NJ; lower limit of quantification: <50 copies/mL) or with Versant HIV-1 RNA bDNA Assay (version 3.0; Siemens Medical Solutions Diagnostics, Tarrytown, NY; lower limit of quantification: <75 copies/mL).
A loss of response (ie, virologic failure) was defined as 2 consecutive measures of HIV-1 RNA >75 copies per milliliter by bDNA or >50 copies per milliliter by ultrasensitive PCR at any study evaluation after baseline. Confirmation had to be performed within 2 weeks of the first detectable HIV-1 RNA test result. Upon investigator discretion, subjects had the option to stay on the study medication or change to a new antiretroviral regimen based on each individual subject's drug susceptibility profile.
Patient treatment satisfaction surveys were administered at baseline, week 12 and week 24 study visits (Fig. 1). The patients completed the surveys without any reference to previously completed study surveys.
Safety assessments were performed on the basis of clinically observed adverse events, clinical laboratory tests, and physical examinations. All abnormal laboratory tests were graded using the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events. The Kaiser Permanente Northern and Southern California institutional review boards reviewed all adverse events per standard operating procedure.
Statistical Analysis
The trial was designed utilizing an open-label, nonrandomized, historical control design. All analyses used the intention to treat population, defined as all patients who received at least 1 dose of raltegravir, and all treated patients were included in the efficacy and safety analyses. The primary end point was calculated as the percentage of patients at week 24 who maintained a viral load below the level of quantification. The secondary end point was change in CD4 T-cell count after 24 weeks of raltegravir therapy.
Cronbach alpha sets, both raw and standardized, were run on the patient treatment satisfaction surveys, overall and by time. The sum of scores on the questionnaires between baseline and 12 weeks and between 12 weeks and 24 weeks were compared using the Wilcoxon signed rank test. The scores between baseline and 12 weeks and between 12 weeks and 24 weeks for each of the individual questions were also compared using a Wilcoxon signed rank test. All statistical analyses were performed using SAS version 9.1.3 (SAS Institute, Cary, NC).
The protocol was reviewed and approved by the Kaiser Permanente Institutional Review Boards in Northern and Southern California, and the trial was done in accordance with the principles of Good Clinical Practice and the Declaration of Helsinki. Written informed consent was obtained from all patients before any trial-related procedures.
The trial was supported in part by a research grant from the Investigator-Initiated Studies Program of Merck & Co, Inc. The opinions expressed in this article are those of the authors and do not necessarily represent those of Merck & Co, Inc. The principal investigator had primary responsibility for trial design, conduct, and data analysis. All authors had full access to the 24-week data. The corresponding author had final responsibility to submit the article for publication.
This trial is registered with ClincalTrials.gov, number NCT00529243.
RESULTS
A total of 54 patients were screened; 52 patients were enrolled and began treatment with raltegravir. Two patients were deemed to be screen failures by the virtue of detectable HIV-1 RNA levels at the screening visit. All enrolled patients were highly treatment experienced, with a median of 15 prior antiretroviral agents previously or currently taken (Table 1). These patients had heavily resistant HIV infection; with a median of 5 nucleoside reverse transcriptase inhibitor mutations, 1 nonnucleoside reverse transcriptase inhibitor mutation, and 3 protease inhibitor (PI) primary mutations before beginning therapy on their enfuvirtide-based regimen, based upon the most recent International AIDS Society-USA drug mutation listings.8 They had been on enfuvirtide-containing regimens for a median of 2.7 years (997 days) before switching to raltegravir. The background regimen of the patients contained a ritonavir-boosted PI in 47 of 52 patients (90%).
For the primary end point of HIV-1 RNA below the level of quantification after switching raltegravir for enfuvirtide, 49 of 52 (94.2%, confidence interval: 1.2% to 15.9%) met the protocol-defined definition of success after 24 weeks of raltegravir therapy (Table 2). Of the 3 patients who did not meet the primary end point criteria, 1 patient did not complete the study treatment period due to geographic relocation and 1 patient died before completing the study. Both these patients are counted as failures per the intention to treat analysis. The patient who died had completed 12 weeks of raltegravir therapy, with his last HIV-1 RNA (via bDNA) resulting in <75 copies per milliliter at the visit before his hospital admission, which occurred 48 days after his week 12 study visit. This patient had a history of long-standing gastroparesis and delayed emptying unrelated to his HIV disease, which required feeding via a jejunostomy tube for over 1 year before enrollment in this study. For every study visit and for the 6 months before enrollment in the study, his HIV-1 RNA levels were consistently below the level of quantification. For the 12 weeks he was in the study, his HIV-1 RNA levels remained consistently below the level of quantification at every study visit. Due to the fact that no viral breakthrough occurred when switching from enfuvirtide to raltegravir, it was believed that switching from a subcutaneously administered medication (enfuvirtide) to raltegravir was unlikely to result in any worsening of his HIV disease, particularly considering his HIV-1 RNA level remained consistently low. He died shortly after hospital admission, and his death was thus deemed by the investigators to be related to a worsening of his overall level of malnourishment and dehydration and not his antiretrovirals.
The final patient who did not meet the primary end point criteria had detectable viremia 4 weeks after switching to raltegravir, despite excellent medication adherence. Per the protocol, a confirmatory HIV-1 RNA was performed 1 week later, with an elevated HIV virus level of 14,921 copies per milliliter. This virologic breakthrough was temporally related to the clinical recurrence of a left knee Mycobacterium avium complex infection (athroscopically documented and verified by culture). The patient was started on Mycobacterium avium complex therapy (clarithromycin, ethambutol, moxifloxacin, rifabutin, and amikacin) at the time of the initial week 4 HIV-1 RNA level. One week after the confirmatory HIV-1 RNA, the investigator repeated the HIV-1 RNA, and without any antiretroviral medication changes, the viral load had resuppressed to <75 copies per milliliter. However, per the intention to treat analysis, the patient was considered a treatment failure.
Of the 6 participants who entered the study with a viral blip in the 6 months before study enrollment, none of these patients progressed to virologic failure. When comparing the number of viral blips in the 6 months before switch to raltegravir with the virologic failures seen post switch using the McNemar test, no statistically significant difference was noted (P = 0.06), although the small sample size does limit the power of the statistical analysis.
For the secondary end point of changes in the CD4 cell count, a mean increase of 32 cells per cubic millimeter (range -165 to +323 cells/mm3) was seen after 24 weeks of raltegravir therapy (Table 2). A mean increase of 0.27% was seen in CD4 percentage amongst all subjects. From baseline to week 24, 21 of 52 patients (40%) had a decline in CD4 absolute cell counts (mean decline in these patients was 68 cells/mm3). However, when examining CD4 cell count percentage among these 21 patients with an absolute CD4 cell count decline, the mean CD4 cell count percentage decrease was only -0.02%. Moreover, there were no clinical AIDS-defining events in those patients whose absolute CD4 cells decreased, and the median CD4 cell count in the group whose CD4 cells declined (335 cells/mm3) remained well above 200 cells per cubic millimeter. No correlation between nadir CD4 cell count and absolute CD4 cell changes during the study was noted.
Patient satisfaction was measured via a brief patient treatment satisfaction survey administered at baseline, week 12, and week 24 (Fig. 1). The raw Cronbach alpha across all 3 periods measured was 0.92, and the standardized value was 0.95. Questions 1 and 7 correlated the least with the total, at 0.62 and 0.79, respectively. In a factor analysis of the questions, the questions reasonably loaded on 1 factor, with the weakest (first) question loading at 0.70. The first eigenvalue, at 5.49, explained 78% of the variance, whereas the second eigenvalue at 0.58 explained only an additional 8% of the variance. It was therefore felt reasonable to compare total scores between periods.
The sum of the scores of the questions show a highly statistically significant change (P < 0.0001) between baseline and 12 weeks, but no statistically significant change between 12 weeks and 24 weeks (P > 0.64). In fact, every question showed a highly statistically significant change (P < 0.0001) between the baseline and 12 weeks, whereas there was no significant difference between the 12th and 24th weeks questionnaire results (P > 0.40). Comparing values between baseline and week 24, patient treatment satisfaction thereby significantly improved on raltegravir-containing regimens, on all questions measured.
No grade 3 or 4 laboratory abnormalities were seen in more than 1 patient throughout the study period. The majority of clinical adverse events (80%) were grade 1 or 2; a summary of the most frequent adverse events are shown in Table 3. Three patients (6%) did experience grade 2 elevations in serum creatinine at least once during the 24 weeks of the trial. However, all 3 of these patients did have preexisting stage 2 or 3 chronic kidney disease, with frequent fluctuations in serum creatinine noted in the 6 months before commencement of raltegravir therapy. There were no treatment discontinuations due to any laboratory adverse event.
A recent report has observed an increased rate of hepatic cytolysis in those patients switched from enfuvirtide to raltegravir when tipranavir/ritonavir was included as part of background therapy.9 Looking specifically at those patients in the CHEER study on a tipranavir/ritonavir-containing regimen at time of change to raltegravir therapy (n = 13), no liver function test (LFT) abnormalities were seen before therapy change, but 5 of these patients developed LFT elevations by week 24 (38.5%). In comparison, 2 of 38 patients (5.3%) not on tipranavir/ritonavir therapy developed LFT elevations by week 24 (odds ratio = 11.25, P = 0.003). However, no LFT elevation beyond grade 1 was observed in any patient on tipranavir, and no LFT elevation resulted in discontinuation of the study drug or any component of the background regimen. There were no patients on tipranavir-containing regimens with LFT elevations at the time of study entry. Although 3 patients were infected with chronic hepatitis B at the time of study entry, none of these patients has a rise in LFTs throughout the study. No hepatitis C-infected patients were enrolled in the study.
With the exception of the 1 patient who died, no adverse event led to discontinuation of raltegravir. Two other serious adverse events were noted during the study. A 49-year-old male without a prior history of diabetes mellitus developed diabetic ketoacidosis after 12 weeks of raltegravir therapy. The second patient who experienced a serious adverse event was a 51-year-old male who was admitted with Escherichia coli bacteremia just before completing the 24-week study period. Neither of these clinical events could be conclusively related to therapy with raltegravir by the investigators.
TABLE 3. Summary of Adverse Events Through Week 24
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