Currently, the strategy for HIV treatment is based on combination therapy to achieve durable viral suppression. Long-term use of HIV treatment can be jeopardized by the development of resistance and drug toxicity. Multidrug resistance and cross-resistance to agents within the same drug class lead to restricted treatment options.
The introduction of the integrase inhibitor raltegravir (RAL) has broadened the treatment possibilities for highly treatment experienced patients considerably. 1-3 4-7
In Switzerland, RAL has been registered since February 2008 for use only in highly antiretroviral treatment (ART) experienced patients with detectable HIV-1 RNA. Phase 2 and phase 3 clinical trials showed that RAL, together with an optimized background regimen, provided good HIV-1 suppression, in particular, in patients with triple-class drug failure and extensive drug resistance.
Success rates were comparable with what has been achieved in earlier salvage studies. 5,6,8 There are no major pharmacokinetic interactions known with other antiretroviral drugs, although atazanavir increases and tipranavir decreases the plasma concentration of RAL moderately. 9-13 RAL is the last option to achieve complete viral suppression for many highly treatment-experienced patients. Due to its good tolerance and high efficacy, RAL may also be an option for treatment simplification, for example, to circumvent a regimen including enfuvirtide (T20), which is difficult to administer and causes allergic injection site reactions, 14-18 or potentially to reduce drug toxicity caused by other drugs, such as dyslipidemia or liver toxicity. 19,20
Using data from the Swiss HIV Cohort Study (SHCS), we aimed to identify the main factors associated with a change of the ART to a regimen containing RAL. We further analyzed the outcome of this switch in terms of sustained undetectable viral loads and CD4 cell count recovery after 24 weeks of treatment. For patients with incomplete viral suppression after 24 weeks of RAL treatment, we attempted to identify factors associated with suboptimal treatment response by assessing adherence, results from therapeutic drug monitoring, and HIV drug resistance.
Patient Selection and Study Design
The SHCS is a nationwide, multicenter, clinic-based, highly representative cohort with continuous enrolment and at least semiannual study visits.
The study has been approved by ethical committees of all participating institutions, and written informed consent has been obtained from all participants (ClinicalTrials.gov, #NCT00904644). For the present analysis, we included patients with at least one SHCS study visit after February 1, 2008, and patients who participated in the expanded access program before the registration of RAL in Switzerland. Two analyses with different study populations were performed; one analysis aimed to assess factors associated with the switch to RAL, and the second analysis was an efficacy study. 21 Patient Selection for Identification of Factors Associated With Switching to RAL
We identified factors for switching the previous ART to a regimen containing RAL. Because in Switzerland RAL is only approved for use in highly treatment experienced patients, we included only individuals who had experienced triple-class failure on nucleoside reverse transcriptase inhibitor (NRTI), nonnucleoside reverse transcriptase inhibitor (NNRTI), and protease inhibitor (PI). Virologic failure was defined as viral rebound after previous suppression with 2 consecutive viral loads greater than 500 copies/mL or a single value greater than 500 copies/mL followed by a stop or a modification of the current therapy. In addition, we considered patients with evidence for triple-class failure based on cumulative information from genotypic drug resistance testing, defined as the presence of at least 1 class-specific IAS-USA mutation against each of all 3 classes.
22 Patient Selection for Efficacy Analysis
Additionally, we aimed to study the efficacy of RAL, defined as an HIV-1 RNA < 50 copies/mL after 24 weeks (window 20-28 weeks) of continuous treatment with RAL. Contrary to the first analysis, in the efficacy analysis we included all patients who had started a treatment with RAL, irrespective of their treatment history or resistance pattern to obtain most representative estimates for RAL efficacy in a routine clinical care setting.
Routinely performed measurements of RAL plasma levels were included in the study and compared with previous published levels, where logarithmic RAL plasma concentrations were approximately linear between the peak (1.7 hours) and 12 hours after administration. We considered plasma levels below the lower 90% confidence interval (CI) as too low.
Drug levels were measured with liquid chromatography-tandem mass spectrometry. 23 24 Statistical Method
Baseline was defined as the start of the first ART including RAL. Multivariable logistic regression was used to identify predictors for switching to a treatment containing RAL. The following baseline characteristics were considered in the model: sex, ethnicity, age, risk group, CD4 cell count, number of drugs in the last treatment, the presence of T20 in the last regimen, self-reported adherence, genotypic sensitivity score (GSS) of the optimized background regimen, lipid profile [triglycerides, high-density lipoprotein (HDL) cholesterol, total cholesterol], and the Framingham risk score.
Predictors were included in the multivariable analysis if the univariable 25 P value was <0.2 and sex, ethnicity, risk group, and age, irrespective of its P value. As an a priori hypothesis we postulated that for patients with detectable HIV-1 RNA at start of RAL the main factor for RAL initiation may be to achieve viral suppression, whereas switches to RAL in patients with prior undetectable HIV-1 RNA may be driven by the wish for treatment simplification and toxicity concerns. We therefore developed 2 separate logistic regression models for patients with undetectable baseline HIV-1 RNA (switch patients) and patients with detectable baseline viral load (salvage patients).
An intent-to-treat analysis was performed to determine RAL efficacy. Two strategies were used to account for missing information on endpoints: missing values were considered failures (m = f), or we carried forward the last HIV-1 RNA measurement obtained before week 20 to impute the week 24 HIV-1 RNA [last observation carried forward (LOCF)]. Factors for a virologic nonresponse to RAL after 24 weeks were assessed with logistic regression models using the same covariables for adjustment as in the prediction model for switching to RAL. In addition, we also included baseline HIV-1 RNA, CD4 nadir, coadministration of boosted PIs, GSS of the background regimen, and central nervous system (CNS) penetration effectiveness (CPE) rank of the background regimen as covariables. The GSS was calculated based on the Stanford algorithm (version 6.0.1; HIV Drug Resistance Database, Stanford, CA) for all approved NRTI, NNRTI, and PI drugs. Viral susceptibility to T20 and maraviroc (MVC) was considered to be intact if these drugs had not been included in a previous failing regimen. Genotypic data were obtained from the SHCS resistance database which contains all genotypic HIV resistance tests performed by the 4 authorized laboratories in Switzerland, stored in SmartGene's (Zug, Switzerland) Integrated Database Network System (IDNS version 3.5.4).
A CPE of 0, 0.5, or 1 indicated low, intermediate, or high CNS penetration, respectively. The CPE of MVC was estimated as 1 and the CPE of etravirine (ETV) as 0.5.
Mixed-effects linear regression was performed to estimate the increase in CD4 cell count after week 24.
Statistical analysis was performed with Stata 10 SE (StataCorp, College Station, TX). The level of significance was set at
P < 0.05. RESULTS
Factors Associated With a Switch to RAL
We identified 423 patients who had experienced triple-class failures and were actively participating in the SHCS in February 2008 of whom 238/423 (56.3%) had undetectable viral loads at the last HIV-1 RNA measurement and 185/423 (43.7%) had detectable viral loads, respectively. In total, 123 (29.1%) patients changed the ART to a regimen containing RAL, 48/238 (20.2%) of whom had undetectable and 75/185 (40.5%) had detectable viral loads (HIV-1 RNA ≥ 50 copies/mL) at the time of treatment change. Mentionable, 48/123 (39.0%) of patients who started RAL had an undetectable viral load.
As shown in
Table 1, in patients with undetectable viral load at baseline (n = 238) the multivariable model indicated that low CD4 cell counts (<200 cells/μL), exposure to T20 and increased triglycerides (>2.3 mmol/L) were important factors to change the current ART to a RAL-containing regimen. Heterosexual patients received RAL less likely compared with homosexual men. Additionally, age, more than 5 drugs in the last regimen, decreased HDL cholesterol (<0.9 mmol/L), increased Framingham score, and low GSS of the background regimen were significantly associated with RAL administration in the univariable model. TABLE 1:
Univariable and Multivariable Logistic Regression to Identify Factors Associated With a Switch to RAL (n = 48) in Patients With Triple-Class Failure (n = 238) and Undetectable HIV-1 RNA (<50 copies/mL)
In patients with detectable viral load, the multivariable model showed that exposure to T20 in the previous regimen, low CD4 cell counts, self-reported adherence, and low GSS of the optimized background regimen were associated with the decision to include RAL in the salvage ART (
Table 2). Intravenous drug users received RAL less likely compared with homosexual men. Additionally, in the univariable model also heterosexual patients received RAL less likely. In contrast to patients with suppressed viremia, lipid abnormalities were not correlated with the change in patients with detectable viral load. TABLE 2:
Univariable and Multivariable Logistic Regression to Identify Factors Associated With a Switch to RAL (n = 75) in Patients With Triple-Class Failure (n = 185) and Detectable HIV-1 RNA (≥50 Copies/mL)
We performed an intent-to-treat analysis to investigate whether the change to RAL was successful in patients with detectable (salvage patients) or suppressed (switch patients) viral load at baseline, respectively. In total, 243 patients had started a regimen containing RAL since February 2008. Three (1.2%) patients were excluded because of missing baseline data and 52 patients were excluded, because RAL was started within less than 20 weeks before the cut-off date for this analysis (February 28, 2009). Thus, for the efficacy analysis, we included 188 patients, of whom 184 still were on RAL after 24-week follow-up. A total of 117 patients were salvage patients and 71 switch patients. During follow-up, 4 patients interrupted ART for a median time of 25 days (range: 1-136) and 4 patients interrupted the intake of RAL for a median time of 57 days (range: 10-61), but all except 1 continued with a regimen including RAL later on. Additionally, 25 patients changed their background regimen during the follow-up. Further, 1 patient (0.5%) died because of AIDS, 1 committed suicide (0.5%), and 1 patient died of unknown reasons (0.5%) within the first 20 weeks of follow-up, and 36/188 (19.2%) patients had no available HIV-1 RNA measurement within weeks 20 and 28 after RAL start.
In switch patients, the median number of drugs in the background regimen was 3 (range: 1-7). 40.9% had an NNRTI, 84.5% at least 1 NRTI, and 60.1% a boosted PI. Unboosted PIs were coadministered in 5 (7.4%) cases. At baseline, 46.5% had T20, which was replaced in almost all patients (n = 30, 90.9%). 22.5% were treated with ETV, the latest approved NNRTI, and 5.6% with MVC.
Salvage patients had a median number of 3 (range: 1-7) coadministered drugs. The background regimen included an NNRTI in 45.3% of the patients, an NRTI in 76.1%, a boosted PI in 70.9%. Unboosted PIs were rarely coadministered (6.8%). At baseline 16 (13.6%), patients were treated with T20, which was replaced in most cases (75%). The newer drugs, ETV and MVC were administered in 37.6% and 13.7%, respectively.
Many salvage and switch patients had a documented 3 class failure before starting RAL, 57.3% and 59.2%, respectively.
Salvage patients had median plasma HIV-1 RNA of 3.8 log
10 copies/mL [interquartile range (IQR): 2.9-4.7] at baseline. Results from the intent-to-treat analysis are shown in Figure 1 according to the 2 imputation methods, which were missing equal failure (m = f) and LOCF. The overall week 24 response rates were 69.2% (m = f) and 80.9% (LOCF), respectively. Response rates for switch patients were 76.1% (m = f) and 95.8% (LOCF), respectively. For salvage patients, the estimates were 65.0% (m = f) and 71.8% (LOCF), respectively. Median baseline CD4 cell counts at baseline were 226 cells/μL (IQR: 134-328) and 351 cells/μL (IQR: 252-483) for salvage and switch patients, respectively. The CD4 cell count increased within 24 weeks by 51 cells/μL (95% CI: 39-64, P < 0.001) and by 22 cells/μL (95% CI: 7-37, P = 0.003), respectively. The overall increase was 42 cells/μL (95% CI: 32-52, P = <0.001). FIGURE 1:
Percentage of patients with plasma HIV-1 RNA levels less than 50 copies/mL after 24 weeks of RAL combined with a background regimen. Percentages are shown for patients with undetectable (HIV-1 RNA < 50 copies/mL), detectable HIV-1 RNA at baseline, and the overall response rate. Intent-to-treat analysis was performed for 2 imputation methods, missing equal failure [closed circle] and LOCF (n = 188) [open square]. Error bars represent 95% CIs.
Characteristics of Failures
Univariable and multivariable logistic regressions (not shown) including risk group, ethnicity, sex, self-reported adherence, CPE, baseline HIV-1 RNA, and the GSS of the background regimen did not show any significant factor for treatment success. The number of patients with failure to achieve undetectable viral loads at week 24 was low, (n = 36, 33 salvage patients, 3 switch patient). As shown in
Table 3, characteristics for failure were identified descriptively. Patients classified as failures because of insufficient follow-up time (n = 15) were excluded. Six of the 21 patients listed in the table (#5, #6, #14, #17, #18, #20) had a low GSS ≤ 1 of the background regimen, 6 had very low plasma concentrations of RAL (#1, #2, #7, #11, #12, #20), and 5 patients had a poor self-reported adherence (#3, #9, #11, #15, #18). Five patients had a very high HIV-1 RNA (>100,000 copies/mL) at baseline (#6, #8, #10, #15, #16) and for 4 patients there was no clear explanation for the failure (#4, #13, #19, #21). Four patients had a genotypic resistance test performed while failing on RAL, 1 patient had the Q148R mutation, and 1 the Y143C mutation; the other 2 patients had no known RAL resistance-associated mutation ( Table 3). TABLE 3:
Patients (n = 21) With a Documented Failure (HIV-1 RNA > 50 Copies/mL) at Week 24 After RAL Start
Drug levels were measured for 54 patients, and 46.3% had a lower RAL plasma concentration than expected. Six of 25 (24.0%) patients with low and 4/29 (13.8%) with normal RAL plasma concentration were not suppressed after 24 weeks of follow-up. However, drug levels showed very large interpatient variation (
Fig. 2). FIGURE 2:
Plasma concentration of RAL after at least 10 days with twice daily doses of 400 mg. Patients with detectable [closed circle] (HIV-1 RNA ≥ 50 copies/mL) and undetectable HIV-1 RNA [open square] after 24 weeks follow-up were distinguished. Expected drug levels, mean [-] and upper and lower 90% CI [--] were indicated, based on previous pharmacokinetic studies.
In our study population, the main reasons to include RAL in an antiretroviral regimen were low CD4 cell counts and replacement of T20. Treatment success, defined as an HIV-1 RNA < 50 copies/mL after 24 weeks of follow-up, was analyzed with an intent-to-treat approach using LOCF imputation and yielded estimates of 95.8% for switch patients and 71.8% for salvage patients.
Our study reflects the introduction of the newly available drug RAL into a routine clinical care setting within the SHCS, a highly representative study for the Swiss HIV-infected population. 74% of all NRTI compounds sold within Switzerland are prescribed within the SHCS (B. Ledergerber, personal communication). Despite the knowledge that RAL has almost no interaction potential with other drugs and has a very favorable lipid profile, RAL received a very restricted approval by the Swiss health authorities, most likely because RAL prices are high compared with most licensed drugs. Interestingly, however, our study clearly demonstrates that 39% of RAL use was not within the approved indication (replicating virus), and among those the main reason for switching to RAL was the replacement of T20 (60.3%). Thus, health insurers in Switzerland were quite supportive with regards to approving the formal requests that had to be individually written for each patient by the treating physician if a drug is used outside the approved indication. As an a priori hypothesis, we postulated that for patients with detectable HIV-1 RNA at start of RAL the main factor for RAL initiation may be a low GSS of the background regimen, whereas switches to RAL in patients with prior undetectable HIV-1 RNA may be driven by the wish for treatment simplification and toxicity concerns. This hypothesis was partially confirmed by our results. Low GSS of the optimized background regimen and good self-reported adherence were positively associated with switching to RAL, being an intravenous drug user was negatively associated in patients with detectable viral load. In patients with undetectable viral load increased triglycerides were significantly associated and being heterosexual was negatively associated. In both models, exposure to T20 and low CD4 cell counts were positively associated with the treatment change.
This is a comprehensive observational study presenting efficacy data of RAL in routine clinical practice for salvage and switch patients. We implemented an intent-to-treat analysis with 2 strategies to handle missing data, which were to consider patients with missing endpoints as failures and to carry the LOCF and yielded an overall efficacy of 69.2% and 80.9%, respectively. In this observational data set, results from the LOCF imputation method are more meaningful, because the rate of missing values was quite high (19.5%). The efficacy when performing the LOCF imputation was slightly lower compared with the efficacy estimates including only patients with a HIV-1 RNA measurement between weeks 20 and 28 (86.1%), which were 98.2% and 79.2% (data not shown) for switch and salvage patients, respectively.
Based on the data from LOCF imputation, a switch from a previous treatment to a regimen containing RAL in patients with suppressed viral loads seemed highly effective because 95.8% of these study subjects had an HIV-1 RNA < 50 copies/mL at week 24. Only 3 highly treatment experienced patients had detectable viral loads at week 24. This is comparable with results from a study by Harris et al, which showed that 34/35 patients who switched from T20 to RAL were virologically suppressed after 7-month follow-up time.
The SWITCHMRK trials studied the replacement of lopinavir/ritanovir-based regimens to a RAL-based regimen and obtained slightly lower efficacy estimates compared with the switch patients in our study, however, 60% of our patients were kept on a boosted PI containing regimen in contrast to the SWITCHMRK trials. 20,30 A replacement of T20 with RAL would have considerable advantages for patients concerning manageability and tolerance of the treatment. 30
After 24 weeks of follow-up, 71.8% of salvage patients had no detectable viral replication, which is comparable with previous published phase 3 randomized-control trials (BENCHMARK 1, 2) where approximately 78% of patients attained suppression of viral replication at week 16.
A careful in depth analysis of factors potentially associated with RAL failure did not reveal clear predictors for failure. In the first place, this may be surprising, however, due to the low overall number of documented failures (n = 21) in our study and due to multifactorial reasons for treatment failures in ART this finding makes sense. Of note is our observation of low RAL drug levels in more than 46% of patients, which clearly demonstrates that more knowledge is needed for useful interpretation of RAL drug levels in the context of virologic response. Although low RAL drug levels did not predict virologic failure in our and in other studies it has to be noted that 60% of our failures indeed showed very low RAL drug levels compared with 43% of patients with successful viral suppression.
To date it is not known how well RAL penetrates into the CNS. Thus, we speculated that if RAL would not penetrate well, failures would potentially be associated with a lower CPE score of the background regimen compared with nonfailures. However, our results do not support this hypothesis. 5,6
This study has some limitations. At this point we looked at 24-week efficacy, and in the future also long-term efficacy and safety of RAL in clinical practice will need to be further analyzed. This is an observational study, treatments were not randomized and patients had very different treatment histories, and as in all observational studies, residual confounding cannot be excluded. The particular indication to measure drug levels was unknown and the selection of the 54 drug levels measured might be biased. A strength of this study is the very comprehensive assessment of clinical and laboratory data, including adherence, genotypic resistance data, and data from therapeutic drug monitoring in a highly representative cohort.
In summary, this study demonstrated very good week 24 efficacy of RAL in patients with previous triple-class failure with detectable or undetectable viral load at baseline. The main reason for the selection of RAL in patients with undetectable viral load was to replace T20, although to date only little is known about the effectiveness of such changes. Moreover, RAL plasma concentration levels were lower than expected in a large proportion of patients but failed to predict clinical outcomes in our statistical analyses. Further studies are needed to analyze long-term efficacy of RAL.
We thank the patients who participate in the SHCS; the physicians and study nurses for excellent patient care; the resistance laboratories for high quality genotypic drug resistance testing; SmartGene, Zug, Switzerland for technical support; Brigitte Remy, Martin Rickenbach, MD, and Yannick Vallet from the SHCS Data Center in Lausanne for the data management and Marie-Christine Francioli for administrative assistance.
Funding: This study has been financed in the framework of the SHCS, supported by the Swiss National Science Foundation (SNF grant #3345-062041). Further support was provided by SNF grant # 3247B0-112594 (to H.F.G., S.Y., and B.L.) an unrestricted research grant of Merck Sharp and Dohme Chibret, Glattbrugg, Switzerland, and the SHCS projects # 470, 564, the SHCS Research Foundation, and by a further research grant of the Union Bank of Switzerland, in the name of a donor to HFG. The research leading to these results has received funding from the European Community's Seventh Framework Programme (pp7/2007-2013) under the project collaborative HIV and Anti-HIV Drug Resistance Network (CHAIN)-grant agreement n°223131. The funding agencies had no role in conducting the study and in preparing the manuscript.
The members of the SHCS are Battegay M, Bernasconi E, Böni J, Bucher HC, Bürgisser P, Calmy A, Cattacin S, Cavassini M, Dubs R, Egger M, Elzi L, Fischer M, Flepp M, Fontana A, Francioli P (President of the SHCS), Furrer H (Chairman of the Clinical and Laboratory Committee), Fux CA, Gorgievski M, Günthard HF (Chairman of the Scientific Board), Hirsch HH, Hirschel B, Hösli I, Kahlert C, Kaiser L, Karrer U, Kind C, Klimkait T, Ledergerber B, Martinetti G, Müller N, Nadal D, Paccaud F, Pantaleo G, Rauch A, Regenass S, Rickenbach M (Head of Data Center), Rudin C (Chairman of the Mother & Child Substudy), Schmid P, Schultze D, Schüpbach J, Speck R, de Tejada BM, Taffé P, Telenti A, Trkola A, Vernazza P, Weber R, Yerly S.
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