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marianna13
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litarch

+{"file": "sr0381_NBK362499/CLABB.nxml", "text": "antiretroviral therapy\nzidovudine\nCADTH Common Drug Review\nconfidence interval\ncobicistat\nUS Department of Health and Human Services\ncobicistat-boosted darunavir\nritonavir-boosted darunavir\nFood and Drug Administration\nfixed-dose combination\nemtricitabine\nhuman immunodeficiency virus\nnucleoside reverse transcriptase inhibitor\nprotease inhibitor\nresistance-associated mutation\nribonucleic acid\nritonavir\ntenofovir disoproxil fumarate\ntime to loss of virologic response", "pairs": [], "interleaved": []}
+{"file": "sr0381_NBK362499/PE3.nxml", "text": "In a region where genotypic resistance testing is not available or may be limited, patients who are treatment-experienced may not be able to be tested for DRV RAMs. In this case, the darunavir/cobicistat FDC should be given to only treatment-naive patients.\nWhile the availability of regimens for co-formulated FDCs offers benefits to patients in terms of convenience, and potentially adherence, it presents challenges to generic entrants as individual drug patents expire.", "pairs": [], "interleaved": []}
+{"file": "sr0381_NBK362499/PE2.nxml", "text": "Evidence Supporting Equivalent Clinical Efficacy\nThere are no head-to-head trials for the darunavir/cobicistat FDC, as clinical information focuses on bioequivalence. Consequently, the assessment of its effectiveness compared with other treatments and, as a result, its comparative cost-effectiveness, is uncertain. Moreover, the manufacturer assumed cobicistat-boosted and ritonavir-boosted darunavir to be clinically equivalent. This assumption was based on the results of their naive indirect comparison, which included only single-group trials. Given the lack of good-quality comparative clinical evidence, there is significant uncertainty in the manufacturer\u2019s economic analysis regarding the assumption of clinical equivalence; this assumption was the reason why the manufacturer chose to perform a cost-minimization analysis.\nExclusion of Relevant Comparator\nAtazanavir boosted with ritonavir was not considered in the manufacturer\u2019s base-case analysis. This comparator is a recommended initial ART regimen (with appropriate backbone drugs) in the HHS guidelines.7 Further, the CADTH Common Drug Review (CDR) clinical expert indicated that the availability of a darunavir/cobicistat FDC would significantly displace the use of atazanavir boosted with ritonavir, in addition to the use of darunavir boosted with ritonavir. Inclusion of this comparator would allow for a more complete cost comparison.\nCost Comparison of Darunavir/Cobicistat FDC Versus Other Antiretrovirals\nThe cost comparison of the darunavir/cobicistat FDC versus other antiretrovirals was not adequate, as the manufacturer did not include backbone regimens and the associated costs for the darunavir/cobicistat FDC, while the drugs being compared included the complete regimen (full regimen costs). This overestimates the cost savings associated with the darunavir/cobicistat FDC when compared with other antiretrovirals, especially in the case of regimens that are listed as first-line treatment options in HIV-1 in infected adults.\nComparators Based on 2013 HHS Guidelines\nThe manufacturer\u2019s choice of comparators was based on the HHS guidelines from February 2013.6 The Guidelines were recently updated in May 2014,7 but may not have been available at the time the manufacturer conducted their analysis. The May 2014 update to includes several changes to the recommended and alternative regimens for treatment-naive and treatment-experienced patients, affecting the interpretation of the cost savings associated with the darunavir/cobicistat FDC versus other ART regimens.", "pairs": [], "interleaved": []}
+{"file": "sr0381_NBK362499/CL4.nxml", "text": "Summary of Available Evidence\nThe evidence for this review was drawn from one phase 3, 48-week, open-label, single-group study. GS-US-216-0130 (N = 314) evaluated the safety and efficacy of DRV/COBI 800 mg/150 mg as separate dosage forms administered in combination with two fully active NRTIs in treatment-naive (n = 296) and treatment-experienced (n = 18) HIV-1\u2013infected patients with no DRV RAMs. Patients who completed 48 weeks of treatment were given the option to continue receiving open-label DRV/COBI 800 mg/150 mg in combination with NRTIs in an open-label rollover phase (no data from this phase were available).\nThe open-label, single-group design of study GS-US-216-0130 precluded definitive conclusions regarding comparative effectiveness and safety versus other anti-HIV regimens, including DRV/r. With respect to generalizability, the enrolled population reflected a more advanced disease stage than what would be seen in clinical practice, with a lower proportion of Caucasian patients than what would be seen in Canada. As well, almost all of the treatment-naive patients in study GS-US-216-0130 were on a backbone regimen of Truvada (\u25ac\u25ac\u25ac\u25ac), which is a higher proportion than what would be seen in Canadian clinical practice. The treatment-experienced cohort was small (n = 18), limiting the generalizability of these findings to this patient population. There were limited data beyond 48 weeks of treatment and there were no data on quality-of-life outcomes.\nThe manufacturer submitted two pharmacokinetic bridging studies (TMC114IFD1001 and TMC114IFD1003). These were provided to demonstrate the bioequivalence of DRV boosted with COBI 150 mg versus DRV boosted with RTV 100 mg, and the bioequivalence of DRV 800 mg as an FDC with COBI 150 mg versus DRV 800 mg and COBI 150 mg administered as single drugs (APPENDIX 5: SUMMARY OF DRV/COBI PHARMACOKINETIC STUDIES [TMC114IFD1001 AND TMC114IFD1003]). Health Canada considered that a trial comparing the clinical efficacy and safety of DRV/COBI with DRV/r was not required for approval given the results of the pharmacokinetic bridging studies confirming bioequivalence; the results from the phase 3 trial program for DRV/r; and the safety results for DRV/COBI from study GS-US-216-0130.14\nInterpretation of Results\nEfficacy\nTreatment-Naive HIV-1 Patients\nThe efficacy and safety of DRV/r was assessed in treatment-naive HIV-1 patients in the ARTEMIS18 study. ARTEMIS (N = 689) was a phase 3 randomized, open-label, 192-week study comparing DRV/r 800 mg/100 mg once daily with ritonavir-boosted lopinavir (LPV/r) 800 mg/200 mg once daily with a backbone regimen of FTC/TDF in treatment-naive HIV-1 patients.18 ARTEMIS found that DRV/r 800 mg/100 mg was statistically non-inferior and superior to LPV/r 800 mg/200 mg in the proportion of virologic responders (HIV-1 RNA < 50 copies/mL) at week 48 (84% versus 78%) and week 192 (69% versus 57%).\nIn study GS-US-216-0130, the proportion of treatment-naive patients achieving an HIV-1 RNA VL suppression of below 50 copies/mL with DRV/COBI 800 mg/100 mg was similar at week 24 (83.7%) and week 48 (82.7%). The proportion of treatment-naive HIV-1 patients with virologic failure was also similar at week 24 (\u25ac\u25ac\u25ac\u25ac) and week 48 (\u25ac\u25ac\u25ac\u25ac). As this was a single-group study, it is difficult to estimate the efficacy of DRV/COBI compared with placebo or other anti-HIV regimens with certainty. Naive comparisons with trials of DRV/r are fraught with limitations, as the degree of comparability of trial populations is uncertain. Nevertheless, the results of study GS-US-216-0130 are generally consistent with those seen at week 48 in the DRV/r group of the ARTEMIS study. In addition, changes from baseline in HIV-1 VL and CD4+ cell count over time in treatment-naive patients from study GS-US-216-0130 (DRV/COBI) and ARTEMIS (DRV/r) followed a similar trend (2,3). The clinical expert consulted for this review noted that HIV-1 VL is a more valid measure of clinical efficacy than CD4+ cell counts, which may be more variable.\nWithout a direct comparative trial, the manufacturer provided an adjusted comparative analysis to compare DRV/COBI 800 mg/150 mg once daily with DRV/r 800 mg/100 mg once daily (see APPENDIX 6). According to this analysis, DRV/COBI was found to be non-inferior to DRV/r based on patients\u2019 virologic response at 48 weeks. There was uncertainty with regard to the validity of the results of this analysis. This was due to concerns regarding comparability between treatment groups and the effectiveness of adjustments made for potential confounders; the lack of transparency in the analytical model; and the use of non-standard methods for performing the indirect comparison.\nTreatment-Experienced HIV-1 Patients\nThe efficacy and safety of DRV/r was assessed in treatment-experienced HIV-1 patients in the POWER,19 TITAN,20 and ODIN21 studies. POWER 1 and POWER 2 were phase 2, randomized, open-label, 96-week studies. The POWER studies compared DRV/r 600 mg/100 mg twice daily with a control group of investigator-selected PI regimens, plus an optimized background regimen, in highly treatment-experienced HIV-1 patients who had at least one primary PI resistance mutation at screening.19 Pooled analyses from POWER 1 and POWER 2 (N = 255) showed that the DRV/r 600 mg/100 mg twice-daily group had higher efficacy than the control PI group, based on the proportion of patients with a VL of less than 50 copies/mL at week 48 (45% versus 10%). The DRV/r dose from the POWER studies was used in TITAN (N = 595), a phase 3, randomized, open-label, 96-week study. TITAN compared DRV/r 600 mg/100 mg twice daily with LPV/r 400 mg/100 mg twice daily with an optimized background regimen in treatment-experienced HIV-1 patients.20 TITAN found that DRV/r 600 mg/100 mg twice daily was non-inferior to LPV/r 400 mg/100 mg twice daily. ODIN (N = 590) was a phase 3, randomized, open-label study. ODIN compared DRV/r 800 mg/100 mg once daily with DRV/r 600 mg/100 mg twice daily with a backbone regimen of two or more investigator-selected NRTIs in treatment-experienced HIV-1 patients who had no DRV RAMs.21 ODIN found that DRV/r 800 mg/100 mg once daily was non-inferior to DRV/r 600 mg/100 mg twice daily on virologic response at week 48 for HIV-1 patients with no DRV RAMs. Based on the results of the DRV/r clinical trials, the Health Canada\u2013recommended dosing regimen for DRV for treatment-experienced adult patients with at least one DRV RAM is DRV/r 600 mg/100 mg twice daily with food.5\nIn study GS-US-216-0130, the treatment-experienced cohort consisted of 18 patients, limiting the data on the efficacy of DRV/COBI 800 mg/100 mg once daily for this patient population. Consistent with the DRV/r studies, the proportion of virologic responders in treatment-experienced patients was lower than that seen in the treatment-naive cohort (week 24: 61.1%; week 48: 50.0%).\nBioequivalence Studies\nAs described previously, the efficacy of DRV/r in treatment-naive and treatment-experienced patients was established in phase 2 and phase 3 trials. The manufacturer conducted one pharmacokinetic study (TMC114IFD1001) to demonstrate that the bioavailability of DRV 800 mg when boosted with COBI 150 mg was similar to that when boosted with RTV 100 mg (see APPENDIX 5). Study TMC114IFD1001 found that the steady-state DRV Cmax and AUC24h parameters after repeat dosing confirmed bioequivalence between the COBI and RTV groups, but the DRV Cmin and C0h parameters were lower in the COBI group compared with the RTV group. The manufacturer noted that the Cmin and C0h values for DRV 800 mg when boosted with COBI 150 mg were higher than the half maximal effective concentration (EC50) for both wild-type HIV-1 and DRV-susceptible viruses. However, according to the Health Canada Reviewer\u2019s Report, the lower DRV Cmin and C0h values with COBI were identified as a concern, since treatment-experienced HIV-1 patients with DRV RAMs may have a higher EC50.14 Should the Cmin fall lower than the EC50 in these patients, there would be a risk of losing virologic suppression. Due to these concerns, the Health Canada\u2013approved indication for DRV/COBI is restricted to patients with no DRV RAMs and, if genetic testing is not feasible, use is recommended in PI-naive patients only. The clinical expert consulted for this review stated that in typical clinical practice, patients with DRV RAMs may be administered DRV/r 600 mg/100 mg twice daily with food to overcome the concern regarding suboptimal trough concentrations.\nIn study GS-US-216-0130, DRV and COBI were administered as separate drugs instead of an FDC. The manufacturer conducted a single-dose pharmacokinetic study (TMC114IFD1003) that demonstrated the bioequivalence of DRV/COBI 800 mg/150 mg FDC versus the two drugs administered separately (see APPENDIX 5).\nAdherence\nThe clinical expert consulted for this review noted that the FDC of DRV/COBI 800 mg/150 mg would be a preferred option to DRV/r 800 mg/100 mg administered as separate drugs due to the potential for better adherence with lower pill burden. Patient group input received by the CADTH Common Drug Review (CDR) on this submission also referenced the potential for improved adherence and convenience of DRV/COBI compared with DRV/r. Poor adherence to treatment regimens plays a significant role in the development of resistance mutations. In study GS-US-216-0130, adherence was generally high, with 95.5% of patients having \u2265 90% adherence by the end of the study. In addition, the development of resistance mutations was low, with only one treatment-experienced patient developing a DRV RAM (that was not associated with phenotypic resistance to DRV), and one treatment-naive patient and one treatment-experienced patient developing an NRTI RAM while receiving FTC. While adherence in clinical practice may be lower than in the controlled setting of a clinical trial, it is reasonable to assume that adherence with the DRV/COBI FDC would be at least as high, and likely higher, than DRV and RTV or COBI administered separately.\nHarms\nThe incidence of adverse events in study GS-US-216-0130 was similar through week 24 and week 48. The most common adverse events were diarrhea, headache, nausea, rash, and upper respiratory tract infections. A total of 16 treatment-naive patients (5.1%) withdrew from study treatment due to an adverse event, with 6 patients withdrawing due to rash. There were no deaths reported until week 48.\n\u25ac\u25ac\u25ac\u25ac treatment-experienced patients were on a backbone regimen of AZT plus FTC/TDF, which is not normally used in current Canadian clinical practice due to adverse effects, according to the clinical expert consulted for this review. This may have impacted the adverse event profile in the study, but the impact would be minimal as few patients were on this background regimen. Generally, the incidence of adverse events did not differ greatly between treatment-naive and treatment-experienced patients.\nSkin reactions were observed during the clinical development program for DRV.5 In study GS-US-216-0130, skin and subcutaneous tissue disorders were reported in \u25ac\u25ac\u25ac\u25ac patients. The clinical expert consulted for this review indicated that skin reactions with DRV are usually not a major concern and rarely lead to treatment discontinuation. The Health Canada product monograph for DRV/COBI contains a warning to discontinue treatment immediately if signs or symptoms of severe skin reactions develop.22\nCOBI has been known to inhibit creatinine tubular secretion and thereby increase serum creatinine levels.6 In study GS-US-216-0130, there was a decrease from baseline in estimated glomerular filtration rate at week 24 and week 48, with a concomitant increase from baseline in serum creatinine levels at week 24 and week 48. \u25ac\u25ac\u25ac\u25ac patients experienced a renal or urinary disorder. The clinical expert consulted for this review did not expect these changes to cause concern, although patients would be monitored for renal function regularly. A phase 3 study is currently being conducted (projected completion February 2015) that assesses the safety and tolerability of COBI-containing regimens in HIV-1 patients with mild to moderate renal impairment (clinicaltrials.gov NCT01363011).23\nWhile informal indirect comparisons are prone to bias, overall, the adverse event profile of DRV/COBI appears to be similar to DRV/r.5 Unfortunately, the manufacturer\u2019s adjusted analysis of DRV/COBI compared with DRV/r did not assess safety outcomes. In the patient group input received by CDR on this submission, concerns were expressed regarding fatigue, high cholesterol, and gastrointestinal adverse effects. While DRV was generally considered to be well tolerated, ritonavir was perceived to be associated with considerable gastrointestinal effects. Diarrhea and nausea occurred in a considerable proportion (more than 20%) of patients in the GS-US-216-0130 study. Reported rates of diarrhea with DRV/r were 8% to 14% for diarrhea and 4% to 7% for nausea.24 While direct comparison of these figures with the DRV/COBI data is difficult, they do not suggest that DRV/COBI has better gastrointestinal tolerability than DRV/r.\nAs COBI is a selective inhibitor of CYP3A, it is expected to result in fewer and more predictable off-target drug interactions.6 RTV does not selectively inhibit CYP3A and may induce the activity of CYP1A2, CYP2C0 and CYP2C19, resulting in more off-target drug interactions.6\nOther Considerations\nDRV/r is indicated for treatment-experienced pediatric patients from 3 to 18 years of age using a weight-based dosing (in tablet form or with an oral suspension) that does not exceed 600 mg/100 mg twice daily.5 DRV/COBI has not been studied in a pediatric population, but a phase 2/3 trial is currently under way to study the pharmacokinetics, safety, and efficacy of DRV/COBI and atazanavir/COBI in treatment-experienced HIV-1 patients between 3 and 18 years of age (clinicaltrials.gov NCT02016924).25", "pairs": [], "interleaved": []}
+{"file": "sr0381_NBK362499/PEABB.nxml", "text": "antiretroviral therapy\nCADTH Common Drug Review\n(US Department of) Health and Human Services\ndarunavir\nfixed-dose combination\nresistance-associated mutation\nprotease inhibitor", "pairs": [], "interleaved": []}
+{"file": "sr0381_NBK362499/PE1.nxml", "text": "Darunavir (DRV)/cobicistat 800 mg/150 mg (Prezcobix) is a fixed-dose combination (FDC) protease inhibitor (PI). In combination with other antiretroviral therapies, darunavir/cobicistat is indicated for the treatment of HIV infection in treatment-naive and treatment-experienced patients without DRV resistance-associated mutations (RAMs).1 Darunavir/cobicistat is available in an 800 mg/150 mg film-coated tablet at a recommended dose of one tablet daily. The manufacturer submitted a price of $23.17 per 800 mg/150 mg tablet.\nSummary of the Economic Analysis Submitted by the Manufacturer\nThe manufacturer submitted a cost-minimization analysis. The analysis considered the daily drug costs of the darunavir/cobicistat (800 mg/150 mg) FDC compared with the cost of the individual drugs (darunavir [800 mg] boosted with ritonavir [100 mg]). The manufacturer\u2019s assumption of similar efficacy for the darunavir/cobicistat FDC versus darunavir boosted with ritonavir was based on a manufacturer-submitted naive indirect comparison (i.e., comparison of the results from single groups from different trials)2 based on data from a phase 3 single-group open-label study (GS-US-216-0130)3 and two registration studies (ODIN and ARTEMIS).2 From this analysis, the manufacturer concluded non-inferiority in overall response, defined as patients achieving an HIV-1 ribonucleic acid (RNA) of less than 50 copies/mL for both the darunavir/cobicistat FDC and darunavir boosted with ritonavir. The unit drug prices for all comparators were obtained from the Ontario Drug Benefit,4 except for the prices for maraviroc and zidovudine which were obtained from the R\u00e9gie de l\u2019assurance maladie du Qu\u00e9bec Liste de m\u00e9dicaments.5 All prices excluded markup and dispensing fees. The manufacturer considered drug costs only, omitting any costs associated with adverse events or drug administration or monitoring, as the drugs were assumed to be equivalent.\nIn the base-case analysis, the manufacturer indicated that the cost of the darunavir/cobicistat FDC ($23.17 daily) was equivalent to darunavir boosted with ritonavir.\nIn addition, the manufacturer compared the cost of the darunavir/cobicistat FDC with other antiretroviral therapy (ART) regimens. These regimens were based on the \u201cpreferred,\u201d \u201calternative,\u201d and \u201cother regimens\u201d (regimens that may be selected for some patients but are less satisfactory than preferred and alternative regimens) outlined in the US Department of Health and Human Services (HHS) guidelines on the use of antiretroviral drugs in HIV-1\u2013infected adults and adolescents (February 2013).6 In the 2013 guidelines, the following were listed under \u201cpreferred\u201d regimens: efavirenz/emtricitabine/tenofovir FDC (600 mg/200 mg/300 mg); atazanavir/ritonavir (150 mg/100 mg) plus emtricitabine/tenofovir (200 mg/300 mg); darunavir/ritonavir (400 mg/100 mg) plus emtricitabine/tenofovir (200 mg/300 mg); and raltegravir (400 mg) plus emtricitabine/tenofovir (200 mg/300 mg). The manufacturer reported the cost of the darunavir/cobicistat FDC is lower than all preferred (and alternative) regimens.", "pairs": [], "interleaved": []}
+{"file": "sr0381_NBK362499/APP1.nxml", "text": "\nThis section was summarized by CADTH staff based on the input provided by patient groups.\n\nBrief Description of Patient Group(s) Supplying Input\nThe Canadian Treatment Action Council (CTAC) is a national non-governmental organization addressing access to treatment, care, and support for people living with HIV and hepatitis C. CTAC\u2019s organizational goals are to meaningfully engage community members, service providers, policy-makers, and other relevant stakeholders to identify, develop, and implement policy and program solutions.\nCTAC received unrestricted organizational and educational grants from the following organizations in the 2013\u20132014 fiscal year: Abbott/Abbvie, Boehringer Ingelheim, Gilead Sciences, Janssen, and ViiV Healthcare. CTAC declared no conflict of interest in the preparation of its submission.\nCondition and Current Therapy-Related Information\nInformation for this submission was collected from a survey (five HIV-positive individuals responded) in follow-up to a national webinar on the CADTH Common Drug Review (CDR) patient input process and key findings from the Prezcobix clinical trials, and survey data used in submissions for Stribild, Tivicay, and Triumeq.\nHIV is a serious, life-threatening illness that threatens the immune system. Over time, if left untreated, HIV can compromise a person\u2019s immune system to the point that the body may no longer be able to fight off opportunistic infections. At that point, an AIDS diagnosis as well as death may occur. In most cases, people taking highly active antiretroviral treatment achieve an undetectable viral load (or viral suppression) and can live long lives, managing their HIV as a chronic illness.\nHIV can present a number of complications, and these can vary day to day and from patient to patient. Many people living with HIV experience negative mental health outcomes, either as side effects from treatment, or from facing stigma and discrimination and related stress. Most of these individuals also experience fatigue, both before and after they initiate treatment, making it difficult to maintain diet and exercise routines, and even to work. A few respondents stated that their quality of life related to these areas has improved as a result of treatment. A few respondents as well as caregivers noted the substantial impact that the social determinants of health, particularly living conditions, have had on managing their HIV. One patient noted: \u201c\u2026 Taking the medication, side effects and having poverty, no food and no housing. Navigating through social services, addictions and child protection safely. How does a parent take medications consistently when they are worried about their children being apprehended.[sic]\u201d\nAll five survey respondents are currently on HIV therapy. Four have been on a treatment regimen ranging from one to 30 years and on their current treatment regimen from one to six years (median = 4). The four respondents noted that their current HIV therapy includes darunavir/ritonavir plus tenofovir plus lamivudine; Complera; Isentress; and Intelence plus Kivexa. They expressed concern about adverse events including fatigue, high cholesterol, loose stools, and \u201cbig stomach.\u201d\nPatients who responded to the Stribild, Tivicay, and Triumeq surveys also indicated several advantages and challenges with current therapy. While these respondents indicated that the adverse events with darunavir have been minor, one of the respondents reported several gastrointestinal adverse events due to ritonavir, specifically \u201c\u2026 GI distress, diarrhea, gas, weight gain.\u201d This adverse event is particularly important to include in this submission as ritonavir has typically been used as a booster with darunavir, and Prezcobix now offers cobicistat as an alternative pharmacoenhancer in a fixed-dose combination regimen.\nRespondents identified lack of funding and transportation costs as barriers to accessing treatment. Respondents from previous patient input surveys highlighted that the challenges \u2014 including staff time, funding, transportation, and other associated costs \u2014 were barriers to providing support and had an impact on treatment adherence, mental health, and other determinants of health. Patients also noted difficulties when being obliged to seek services from specialists.\nRelated Information About the Drug Being Reviewed\nNone of the five survey respondents had experience with the treatment under consideration. Out of five respondents, one person stated he was not certain if he would consider taking Prezcobix instead of current therapy or therapy taken in the past. He was not certain if the side effects associated with Prezcobix seemed more severe, less severe, or similar to current or past therapy. Another respondent suggested that the adverse events would be similar to currently existing treatment and noted that adverse events would more likely be associated with the product if a Kivexa backbone regimen were administered. During the webinar discussions, a participant expressed the need for more information about the safety profile of cobicistat compared with ritonavir. While noting the benefit of Prezcobix is its simplified dosing, which may increase adherence and convenience, the participant stated that cobicistat does not appear to be an improvement over ritonavir in terms of gastrointestinal adverse events.", "pairs": [], "interleaved": []}
+{"file": "sr0381_NBK362499/recommendation.nxml", "text": "Recommendation\nThe Canadian Drug Expert Committee (CDEC) recommends that darunavir/cobicistat (DRV/COBI) be listed for the treatment of HIV infection in treatment-naive and treatment-experienced patients without darunavir (DRV) resistance-associated mutations (RAMS), if the following condition is met:\nCondition\nList in a manner similar to darunavir (DRV)\nReasons for the Recommendation\nA 48-week, open-label, single-group study (GS-US-216-0130 [study 130]; N = 314) demonstrated that treatment with DRV/COBI in combination with nucleoside reverse transcriptase inhibitors (NRTIs) resulted in a significant proportion of patients achieving virologic success (i.e., HIV-1 ribonucleic acid (RNA) < 50 copies/mL) at 24 weeks (82.4%; 95% CI, 77.8% to 86.5%) and 48 weeks (80.8%; 95% CI, 76.0% to 85.0%).\nAt the submitted price ($23.17 per tablet), the daily cost of treatment with DRV/COBI is similar to darunavir boosted with ritonavir (DRV/r) ($23.18) and less than atazanavir boosted with ritonavir (ATV/r) ($23.90).\nOf Note\nStudy 130 did not include pediatric patients with HIV-1 infection, and DRV/COBI is not currently indicated for use in this population.\nBackground\nDRV/COBI is a fixed-dose combination product with a Health Canada indication for the treatment of HIV-1 infection in treatment-naive and treatment-experienced patients with no DRV RAMs, when administered in combination with other antiretroviral drugs. DRV/COBI is available as a fixed-dose combination tablet containing 800 mg DRV and 150 mg COBI, and the recommended dose is one tablet taken once daily with food.\nSummary of CDEC Considerations\nCDEC considered the following information prepared by the CADTH Common Drug Review (CDR): a systematic review of randomized controlled trials (RCTs) and pivotal studies of DRV/COBI, a critique of the manufacturer\u2019s pharmacoeconomic evaluation, and patient group\u2013submitted information about outcomes and issues that are important to individuals living with HIV.\nPatient Input Information\nThe following is a summary of key information provided by one patient group that responded to the CDR call for patient input:\nHIV affects patients in a variety of ways, which may include negative mental health outcomes, fatigue, difficulty maintaining diet and exercise routines, and work.\nPatients and caregivers noted the impact of social determinants of health, particularly living conditions, on the management of HIV with regard to medication adherence. The simplified dosing of DRV/COBI may increase adherence and convenience.\nClinical Trials\nThe CDR systematic review included one phase 3, 48-week, open-label, single-group study. Study 130 (N = 314) evaluated the safety and efficacy of DRV/COBI as separate dosage forms administered in combination with two fully active NRTIs in treatment-naive (n = 295) and treatment-experienced (n = 18) HIV-1 infected patients with no DRV RAMs. The majority of patients (97%) were on a backbone regimen of emtricitabine/tenofovir.\nOutcomes\nOutcomes were defined a priori in the CDR systematic review protocol. Of these, CDEC discussed the following:\nVirologic success \u2014 percentage of patients with a viral load < 50 copies/mL using the FDA-defined snapshot analysis at 24 weeks (primary outcome) and 48 weeks (secondary end point) and using the FDA-defined time to loss of virologic response (TLOVR) algorithm (secondary end point).\nReduction of log10 viral load from baseline to week 48.\nChange in CD4+ cell count from baseline to week 48.\nTotal adverse events, serious adverse events, withdrawals due to adverse events, and renal adverse events.\nEfficacy\nThe proportion of treatment-naive patients achieving HIV-1 RNA viral load suppression below 50 copies/mL using the snapshot analysis with DRV/COBI was similar at week 24 (83.7%) and week 48 (82.7%). Similar results were demonstrated using the TLOVR analysis (week 24: 83.7%; week 48: 83.1%). The treatment-experienced cohort consisted of 18 patients, limiting the data on the efficacy of once-daily DRV/COBI for this patient population.\n\u25ac\u25ac\u25ac\u25ac.\nThe mean (SD) increase from baseline in CD4+ cell count was 145 (131.6) cells/\u00b5L at week 24 and 194 (152.1) cells/\u00b5L at week 48 in treatment-naive patients. In treatment-experienced patients, the mean (SD) increase was 99 (161.9) cells/\u00b5L at week 24 and 121 (157.0) cells/\u00b5L at week 48.\nHarms (Safety and Tolerability)\nA total of 4.8% and 8.3% of patients experienced a serious adverse event through week 24 and week 48, respectively.\nA total of 91.4% of patients experienced an adverse event of any severity through week 48. The most commonly reported adverse events included diarrhea (27.8%), headache (12.1%), nausea (23.0%), rash (15.7%), and upper respiratory tract infection (14.1%).\nA total of 16 (5.1%) treatment-naive patients discontinued study treatment due to an adverse event through week 48.\n\u25ac\u25ac\u25ac\u25ac.\nCost and Cost-Effectiveness\nThe manufacturer submitted a cost-minimization analysis comparing DRV/COBI with darunavir alone (800 mg) boosted with ritonavir (100 mg) (DRV/r), considering daily drug costs only. The assumption of similar efficacy for DRV/COBI and DRV/r was based on an adjusted comparison of study 130 with trials of DRV/r using non-standard methods that was submitted by the manufacturer. The manufacturer also considered the costs of other antiretroviral treatment (ART) regimens. These were based on the \u201cPreferred,\u201d \u201cAlternate,\u201d and \u201cOther \u2014 Regimens that may be chosen but are less satisfactory than preferred and alternate regimens\u201d as outlined in the US Department of Health and Human Services (HHS) guidelines for the use of antiretroviral drugs in HIV-1\u2013infected adults and adolescents (February 2013).\nCDR identified the following key limitation with the manufacturer\u2019s economic submission: clinical data for DRV/COBI focus on bioequivalence studies, complicating the assessment of comparative clinical effectiveness compared with other treatments. As a result, the clinical equivalence of DRV/COBI with other treatments has not been established, which is the basis for a cost-minimization analysis.\nAt the submitted price of $23.17 per 800 mg/150 mg tablet, the daily cost of DRV/COBI when used in combination with the backbone emtricitabine/tenofovir ($50) is similar to that of both the HHS recommended initial ART protease inhibitor (PI)\u2013based regimens (DRV/r and ATV/r, when used in combination with emtricitabine/tenofovir). Alternatively, when compared with single tablet integrase strand transfer inhibitor or non-nucleoside reverse-transcriptase inhibitors regimens, DRV/COBI plus emtricitabine/tenofovir is more expensive than rilpivirine/tenofovir/emtricitabine ($9 more costly), efavirenz/tenofovir/emtricitabine ($8 more costly), and elvitegravir/cobicistat/tenofovir/emtricitabine ($6 more costly).\nWhen backbone emtricitabine/tenofovir cannot be used, DRV/COBI may be used in combination with abacavir/lamivudine. The cost of this regimen ($47) is equivalent to the other ART PI-based regimens with the same backbone drugs.\nOther Discussion Points\nCDEC noted the following:\nStudy 130 is limited by the single-group design, which precluded an evaluation of the comparative effectiveness and safety of DRV/COBI versus other anti-HIV regimens.\nThe treatment-experienced cohort of study 130 was small (n = 18, 5.7%), limiting the generalizability of the study findings to this patient population.\nThere were no pediatric patients included in study 130; however, a phase 2/3 trial is currently under way to study the pharmacokinetics, safety, and efficacy of DRV/COBI and ATV/COBI in treatment-experienced HIV-1 patients between 3 and 18 years of age (NCT02016924).\nThe results of study 130 are generally consistent with those seen in the trials of DRV/r in treatment-naive and treatment-experienced patients.", "pairs": [], "interleaved": []}
+{"file": "sr0381_NBK362499/PE4.nxml", "text": "The daily cost of the darunavir/cobicistat FDC when used in combination with the backbone emtricitabine/ tenofovir ($50) is similar to that of both the initial ART PI-based regimens recommended in the HHS guidelines (darunavir boosted with ritonavir and atazanavir boosted with ritonavir, when used in combination with emtricitabine/tenofovir). Alternatively, when compared with first-line single-tablet integrase strand transfer inhibitors or non-nucleoside reverse transcriptase inhibitor regimens, darunavir/cobicistat plus emtricitabine/tenofovir is more expensive than rilpivirine/tenofovir/ emtricitabine ($9 more costly), efavirenz/tenofovir/emtricitabine ($8 more costly), and elvitegravir/ cobicistat/tenofovir/emtricitabine ($6 more costly).\nAs identified by the clinical expert, when the backbone regimen emtricitabine/tenofovir cannot be used (due to renal dysfunction or otherwise), the darunavir/cobicistat FDC may be used in combination with abacavir/lamivudine. The cost of this regimen ($47) is equivalent to the other ART PI-based regimens with the same backbone drugs that are either recommended for patients with a pre-ART plasma HIV RNA of less than 100,000 copies/mL, or alternative initial ART regimens.", "pairs": [], "interleaved": []}
+{"file": "sr0381_NBK362499/CL5.nxml", "text": "In one phase 3, open-label, single-group study, DRV/COBI 800 mg/150 mg administered as single drugs was shown to achieve relatively high rates of VL suppression (HIV-1 RNA < 50 copies/mL) in treatment-naive and treatment-experienced adult patients with HIV-1 infection, although data for the treatment-experienced population were limited, as only 18 such patients were enrolled in the trial. Efficacy results for both populations were broadly similar to those for DRV/r in previous studies, although definitive conclusions regarding comparative efficacy and safety could not be drawn without a direct comparative trial. There were no data available on quality-of-life outcomes. The most commonly reported adverse events included diarrhea, headache, nausea, and rash. Rash was the most common adverse event that led to treatment discontinuation in treatment-naive patients. Although serum creatinine levels increased from baseline, there were few renal-related adverse events.\nPharmacokinetic data demonstrated bioequivalence of DRV/COBI 800 mg/150 mg versus DRV/r 800 mg/100 mg with respect to DRV maximum plasma concentrations and AUC24h values, but DRV Cmin and C0h parameters were lower with COBI than with RTV. Bioequivalence was also demonstrated for DRV/COBI 800 mg/150 mg FDC versus administration as single drugs.", "pairs": [], "interleaved": []}