Caring for HIV infected patients in Spain during the current economical crisis

Transcription

1 Caring for HIV infected patients in Spain during the current economical crisis Bonaventura Clotet. HIV Unit Univ Hosp Germans Trias i Pujol Badalona, Barcelona, Catalonia Spain

2 CRISIS? WHAT CRISIS?

3 Rationale. The country big numbers. Xavier Sala Martin, personal communication.

4 Rationale. The country big numbers. Xavier Sala Martin, personal communication.

5 Cost-cutting measures to reduce the antiretroviral prescription bill under an urgent government requirement due to the economic crisis. A Spanish view. Josep M Llibre, Glòria Cardona, Xavier Bonafont, Bonaventura Clotet. HIV Unit, Pharmacy Univ Hosp Germans Trias i Pujol Badalona, Barcelona Spain

6 Rationale. Spain is under a huge economic crisis that also (and particularly) involves the Public Health System. The value of prescriptions in the hospital sector increased 55% from 2008 to 2011, and hospital-based expensive prescriptions have been identified as a special target for cost-cutting measures: Chemotherapy agents. Antiretrovirals (in Spain ARVs are supplied through Hospital pharmacies) Biologic agents. Others: PegIFN, anti-hep C antivirals, EPO, etc. HIV Units are forced to immediately reduce their antiretroviral budgets by 10%.

7 Rationale. Hospital-based drug costs. The current (end 2011) payment to pharma industries by gov. is delayed by an average of 525 days (>800 days in 4 Autonomous Communities). Spain's 17 regions owed pharmaceutical companies million in hospital-based drugs (a 36% increase vs 2010). Autonomous Community Debts (milion ) to pharma industry. Autonomous Community Median delay in payment to pahrma ind. * Only hospitals belonging to ICS * Only hospitals belonging to ICS Spanish Association for the Pharmaceutical Industry in Spain (FARMAINDUSTRIA). Available at: Accessed Feb 1, 2012.

8 Rationale. The case of an HIV Unit. In a 600 bed University-affiliated Hospital in Barcelona (Spain) a reference HIV Unit gives antiretroviral treatment to 2401 HIV-1-infected subjects. Antiretrovirals accounted for 47.8% of the overall hospital pharmacy budget (excluding Oncology): 17, (out of 37, , including treatments of hospitalized subjects) in Three main areas were identified in order to reduce the ARV budget: Inclusion of subjects into Clinical Trials (treatment payed by the trial). Reduction in the prize of ARV by pharma drugmakers. Cust-cutting measures undertaken in patients receiving ART.

9 Methods. Analysis of cost-cutting measures (CCM) undertaken in HIV-1 patients receiving ART during a period of 6 months (May-Nov 2011). CCM defined as any change in ART leading to a cost-reduction in subjects successfully treated without toxicity, virological failure or any other reason to change the treatment. The HIV Unit has 14 treating physicians.

10 Results. Treatment changes undertaken. 673 total treatment changes undertaken during the period (187% increase vs the same period May-Nov in 2010). 28% of all the patients treated had a treatment change. 378 (16% of overall cohort) subjects treated had a cost-cutting measure. Treatment change goal Month Cost ( ) N Percentage Cost-cutting measures ,80 378,00 56,17% Inclusion in Clinical Trials ,00 27,00 4,01% Ends a Clinical Trial 3.826,80 9,00 1,34% Toxicity ,50 76,00 11,29% Toxicity plus adherence or PK issues 1.406,70 2,00 0,30% Virological failure ,85 44,00 6,54% Others 8.100,00 31,00 4,61% Naives, news in the center or ART reinitiation ,60 64,00 9,51% PEP ,00 22,00 3,27% Total general ,85 673,00 100,00%

11 Results. CCM, total saved. TPV substitution Inactive NRTI withdr. 2% Switch to NVP 5% ATV/r ATV 1% DRV dose reduct. 4% MVC dose reduct. 2% 3TCgen (break FDC) MVC withdr. ETR substitution ETR withdr. 1% 0% 4% 3% Switch to Atripla 2% 1% 1% FPV dose reduct 2% Other 13% TVD to KVX Percentage of total savings ( ) achieved with every category of ARV change. Total savings per month: DRV/r mono 23% 9% RAL substitution 15% 15% RAL withdr LPV/r mono

12 Results. CCM effect in the overall framework. Total savings ( ) achieved per month with every cost saving category. * saved per month * Median ARV pharma Industry discount during the period: 14.5%.

13 Conclusions Direct pharma industry discounts are the main source of savings in the antiretroviral budget in Spain. In an environment of deep economic crisis involving the public health system, CCM in ART can, to a lesser extent, reduce the antiretroviral budget as well. Changes to boosted PI monotherapy, ABC/Kivexa, NVP, and withdrawing or substituting expensive drugs whenever possible (RAL, ETR) account for 87% of the overall savings achieved with CCM. The durability of these CCM should be confirmed, and a 48-week costeffective analysis be done before its widespread implementation (ongoing). Clinical trials with paid ART are also a significant source of saving.

14 T mg c/12h MVC 1 comp c/12h RAL 400 mg c/12h TPV/r 500/200 c/12h DRV/r 600/100 mg c/12h DRV/r 800/100 mg c/24h ATV/r 300/100 mg c/24h ATV 400 mg c/24h LPV/r 2 comp c/12h FPV/r 700/100 mg c/12h SQV/r 1000/100 mg c/12h SQV/r 1500/100 mg c/24h RTV 100 mg c/12h ETR 200 mg c/12h EFV 600 mg c/24h NVP 200 mg c/12h Atripla 1 comp c/24h Trizivir 1 comp c/12h Truvada 1 comp c/24h Kivexa 1 comp c/24h Combivir 1 comp c/12h TDF 245 mg c/24h ABC 300 mg c/12h ddi 400 mg c/24h FTC 200 mg c/24h 3TC 300 mg c/24h d4t 40 mg c/12h d4t 30 mg c/12h AZT 300 mg c/12h ddi 250 mg c/24h COST PER MONTH OF ARVs 2010 ARV euros / patient / year

15 T mg c/12h MVC 1 comp c/12h RAL 400 mg c/12h TPV/r 500/200 c/12h DRV/r 600/100 mg c/12h DRV/r 800/100 mg c/24h ATV/r 300/100 mg c/24h ATV 400 mg c/24h LPV/r 2 comp c/12h FPV/r 700/100 mg c/12h SQV/r 1000/100 mg c/12h SQV/r 1500/100 mg c/24h RTV 100 mg c/12h ETR 200 mg c/12h EFV 600 mg c/24h NVP 200 mg c/12h Atripla 1 comp c/24h Trizivir 1 comp c/12h Truvada 1 comp c/24h Kivexa 1 comp c/24h Combivir 1 comp c/12h TDF 245 mg c/24h ABC 300 mg c/12h ddi 400 mg c/24h FTC 200 mg c/24h 3TC 300 mg c/24h d4t 40 mg c/12h d4t 30 mg c/12h AZT 300 mg c/12h ddi 250 mg c/24h COST PER MONTH OF ARVs 2010 ARV euros / patient / year

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17 Journal of Antimicrobial Chemotherapy (2007) 60,

18 2012 (under revision)

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23 Three-year cost efficacy analysis of the MONET trial of darunavir/ritonavir monotherapy using UK antiretroviral drug prices Brian Gazzard Chelsea and Westminster Hospital, London, UK Steve Curtis Janssen, High Wycombe, UK Anne Anceau Janssen-Cilag, Issy-les-Moulineaux, France Andrew Hill Pharmacology Research Laboratories, University of Liverpool, UK

24 Cost of treating 20,000 people with triple combination treatment versus DRV/r monotherapy over three years millions UK: DRV/r monotherapy budget impact 412 million Before switching to DRV/r monotherapy Cost saving 163 million 248 million After switching to DRV/r monotherapy 25 Gazzard et al., EACS 2011 Belgrade PE10 4.4

25 Monotherapy with PIs should not be used because it does not appropriately protect the CNS??

26 Abstract: E-117 Long-Term Monotherapy With Lopinavir/ritonavir (>2 years) is not Associated with Greater HIV-Associated Neurocognitive JR Santos Impairment 1, JA Muñoz-Moreno 1, J Moltó 1, I Bravo 1, A Prats 1, DR McClernon 2, A Curran 3, P Domingo 4, JM Llibre 1, B Clotet 1,5 1 Lluita contra la Sida Foundation, HIV Clinic, Hospital Universitari Germans Trias i Pujol, Badalona, Spain, 2 biomontr, Research Triangle Park, North Carolina, USA, 3 Infectious Diseases Department, Hospital Vall d'hebron, Barcelona, Spain, 4 Infectious Diseases Unit, Hospital de la Santa Creu I Sant Pau, Barcelona, Spain, 5 IrsiCaixa Foundation, HIV Clinic, Hospital Universitari Germans Trias i Pujol, Badalona, Spain Contact Information: Jose R. Santos, MD Lluita contra la SIDA Foundation Germans Trias i Pujol Hospital Barcelona, Catalonia, Spain jrsantos@flsida.org ABSTRACT Background: Monotherapy with boosted protease inhibitors might be insufficiently potent to fully suppress HIV replication in the central nervous system (CNS), which has been connected to HIV-associated neurocognitive decline. However, evidence to support such hypothesis is limited. The objective of this study was to compare the presence of HIV replication in cerebrospinal fluid (CSF) and neurocognitive performance in HIV-infected patients on lopinavir/ritonavir (LPV/r) antiretroviral treatment with standard triple therapy (HAART) or monotherapy (MT) for at least 96 weeks. Methods: Exploratory, cross-sectional study in HIV-infected patients on LPV/r-HAART or LPV/r- MT during at least 2 years, while maintaining plasmatic viral load <50 c/ml. Groups were matched according nadir of CD4, age, gender and time on current LPV/r-HAART or MT. Demographic and clinical variables were recorded, and HIV-1 RNA load in plasma and CD4+ count were analyzed. A CSF sample was obtained from each participant, and HIV-1 RNA load in CSF was determined by a SuperLow assay (LLD 1 c/ml). Patients underwent a neuropsychological battery covering 7 cognitive and motor areas. The proportions of patients with viral load in CSF 1 c/ml and neurocognitive impairment were compared between groups. A neuropsychological global deficit score (GDS) was also used for comparisons. Results: A total of 37 patients were eligible for the study. Three patients did not fulfill the inclusion criteria and were excluded. Thus, 17 patients were included in each study group. Patients characteristics: 85% male, with a mean (SD) age of 45 (±7) years, CD4+ count 664 (±239) cells/mm3, nadir CD4+ INTRODUCTION count 199 (±144) cells/mm3, time on current LPV/r therapy 3.7 (±1.2) years, time with undetectable plasmatic viral load 5.7 (±2.9) years, Interest in NRTIs-sparing strategies aimed to prevent NRTIs-related toxicity has grown during recent with no significant differences between groups regarding those variables. Viral load years. Monotherapy (MT) with protease inhibitors (PIs) as a NRTIs-sparing strategy, in cases where NRTIsrelated toxicity has appeared, is still recognized in some guidelines. 1 In addition, this strategy could increase the adherence, reduce costs, and preserve future treatment options. According to data obtained from both clinical trials and routine clinical practice, lopinavir/ritonavir monotherapy (LPV/r-MT) as treatment simplification or NRTIs-sparing strategies, seems to be equally effective compared to the present triple based standard of care therapy (HAART) for maintaining virological suppression (HIV-1 RNA <50 copies/ml) in HIV-infected patients. 2,3 LPV/r shows intermediate penetration in cerebrospinal fluid (CSF), 4 but both the virological efficacy of LPV/r-MT in this compartment, and its possible consequences, have been questioned. 5 Residual viral load in CSF has been associated with higher risk of developing neurocognitive function impairment. 6 The objective of this study was to compare the presence of HIV replication in CSF and the neurocognitive performance in HIV-infected patients who had been receiving LPV/r-based standard HAART (LPV/r- HAART) or LPV/r-MT for at least 96 weeks. METHODS Study design and patients This was a single centre cross-sectional, exploratory, case-control study in HIV-1 infected patients who had been receiving LPV/r-HAART or LPV/r-MT for at least 96 weeks and whose plasmatic HIV-1 RNA was <50 copies/ml. Patients with self-reported treatment adherence <90%, voluntary interruptions of their treatments during the current regimen, and who had medical contraindications for lumbar puncture, neurological or psychiatric disorders or were taking psychotropic drugs were not eligible. Patients on LPV/r-HAART or LPV/r-MT were matched according to the age, gender, nadir of CD4+ and time on LPV/r treatment before enrolment. Endpoints Primary: The proportion of patients with complete virological suppression (HIV-1 RNA <1 copy/ml) in CSF. Secondary: The proportion of patients with neurocognitive impairment (NCI), defined by performing at least 1 standard deviation below the standardized mean in at least 2 neurocognitive areas. 7 Differences on neurocognitive status in terms of global deficit score (GDS), which is a validated method to study compositely impairment on neurocognitive functioning. 8 Data and sample collection Demographic and clinical variables were recorded. A plasma samples for HIV-1 RNA load, CD4+ T cell count, and routine haematology and chemistry tests were collected from each participant. A 5 ml CSF sample was obtained within the 30 minutes before the plasma sample by standard lumbar puncture, and HIV-1 RNA in CSF was measured by SuperLow assay (LLD: 1 copy/ml). The neurocognitive functioning was assessed using a comprehensive neuropsychological tests battery that covers 7 areas recommended to be evaluated in HIV infection. 9 Standardized T scores were used for comparison of neurocognitive outcomes and were calculated by a converting process based on adjusting the raw scores according to available normative data. This Figure 1. Flowchart of the study. RESULTS Out of 162 potential candidates, 37 patients agreed to participate in the study. Of these, 3 subjects were excluded because they did not fulfill inclusion criteria (Figure 1) Table 1. Demographic and clinical characteristics of patients. LPV/r-MT LPV/r-HAART P value Age 45.2 ( ) 47.3 ( ) Male 15 (88.2) 14 (82.4) MSM 10 (58.8) 7 (41.2) Median years of education a LPV/r-MT n=17 37 eligible patients 34 patients included 3 patients excluded: -1 patient with <48 weeks on treatment. -1 patient was non-spanish speaker. -1 patient with plasmatic VL >50 copies/ml. LPV/r-HAART n=17 12 (9-17) 9 (8-12) 0.06 Presented at the 13 th Int. Workshop CDC stage C on Clin. Pharmacology 2 (11.8) 3 of (17.6) HIV Pharmacology , Barcelona Spain 16(3): Median CD4+ nadir 186 ( ) 169 (61-293) ACKNOWNLEDGMENTS All (cells/mm values are 3 ) expressed a as No. (%) except when specified. a Median (interquartile range) Abbreviations: MSM, men-sex-men; CDC, Centers for Disease Control and Prevention; ARV, antiretroviral; PIs, protease Median prior inhibitors; ARV NRTIs, nucleoside 6 (2-10) reverse transcriptase inhibitors; 2 (1-4) NNRTIs, nonnucleoside reverse transcriptase regimens a inhibitors; LPV/r, lopinavir/ritonavir; LPV/r-MT, lopinavir/ritonavir monotherapy; LPV/r-HAART, lopinavir/ritonavir triple-therapy; Median prior NNRTIs a TDF, tenofovir; FTC, emtricitabine; ABC, abacavir, 3TC, lamivudine; AZT, zidovudine; ddi, didanosine; VL, viral load. 1 (0-2) 0 (0-1) Virological outcomes Figure 2. Patients with complete CSF-virological suppression (RNA HIV <1 copy/ml). Abbreviations: LPV/r-MT, Lopinavir/ritonavir monotherapy; LPV/r-HAART, LPV/r tripletherapy; CSF, Cerebrospinal fluid. The proportion of patients with HIV-1 RNA <1 copy/ml in CSF in the LPV/r-MT group was similar to LPV/r-HAART group. Three patients on LPV/r-MT had determinations of CSF HIV-1 RNA of 1, 75 and 120 copies/ml. One patient on LPV/r + ABC + 3TC ( LPV/r-HAART group) had a CSF HIV RNA of 2 copies/ml. Neurocognitive outcomes Figure 3. Percentages of subjects with neurocognitive impairment. % of impaired patients 100 p=0.48 p=0.43 LPV/r-MT 80 LPV/r-HAART 10 (59%) 8 (61%) 60 6 (46%) 7 (41%) % of patients 100 p= (82.4%) LPV/r-MT group 16 (94.1%) LPV/r-HAART group 0 All sample Non-comorbidities sample Confounding comorbidities included: depression or anxiety disorders, drug use, presence of a psychiatric diagnosis, psychopharmacologic treatment, or current or past opportunistic infection involving CNS. In the LPV/r-MT group 7 (41%) patients showed NCI while in LPV/r-HAART group this occurred in 10 (59%); p=0.48. When patients with possible confounding comorbidities were excluded, the results were similar: 6/13 (46%) patients showed NCI in LPV/r-MT group (46%) and 8/13 (61%) in LPV/r-HAART group (p=0.43). Considering neurocognitive functioning, values were mildly better in MT group. In total sample, GDS was 0.23 in MT group and 0.46 in HAART group (p=0.025), and in non-comorbities sample CONCLUSIONS 0.25 and 0.5 (p=0.04), respectively. The proportion of patients with complete virological suppression in CSF (ultrasensitive HIV-1 RNA <1 copy/ml) was similar between LPV/r-MT and LPV/r-HAART groups. Although the difference was not statistically significant, less patients on LPV/r-MT showed neurocognitive impairment compared to those on LPV/r-HAART. In addition, neurocognitive functioning showed to be mildly better (close to statistical significance) in patients on LPV/r-MT than patients on LPV/r-HAART. This study suggests that in patients receiving prolonged LPV/r-MT, the CSF-HIV replication is fully suppressed in most of them. Additionally, this strategy appears not to be associated with worse neurocognitive functioning. REFERENCES 1 Guidelines of European AIDS clinical Society (EACS 2011) version October 6th 2011; 2 Pulido F, et al. AIDS 2008; 22: F1 F9; 3 Moltó J, et al. J Antimicrob Chemother 2007; 60(2): 436-9; 4 Letendre S, et al. CID 2007; 45:1511-7; 5 Gutmann C, et al. AIDS 2010, 24: ; 6 Muñoz-Moreno JA, et al. ISNV Meeting, Miami, FL; Abstract P-130; 7 Antinori A, et al. Neurology 2007; 69(18): ; 8 Carey et al. J Clin Exp Neuropsychol. 2004; 26(3):307-19; 9 Muñoz-Moreno JA, et al. J Neurovirol 2010; We thank the staff at the clinical site where data were gathered for this study and the patients who participated. We also wish to acknowledge the contribution of Nuria Pérez-Álvarez who gave her support advice on the statistical analysis and Dr. Jaume Canet for his assistance in lumbar puncture procedure. This study received funding from Lluita contra la SIDA Foundation and from Abbott

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32 Monotherapy with PIs should not be used because requires almost perfect adherence

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38 Due to its low cost PI monotherapy definitely merits more research in the real world

39 ACKNOWLEDGEMENTS To all those from whom I borrowed or stollen slides for this presentation: From my team: JM Llibre Roger Paredes JR Santos Nuria Perez From other teams: JM Gatell JR Arribas