The influence of antiretroviral-resistance tests on treatment effectiveness in patients with HIV and virological failure

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1 /2007/31/1/23 FARMACIA HOSPITALARIA Copyright 2007 ARÁN EDICIONES, S. L. FARM HOSP Vol. 31. N. 7, pp , 2007 ORIGINAL The influence of antiretroviral-resistance tests on treatment effectiveness A. Gamero Martín-Granizo, C. Martínez Roca, L. Margusino Framiñán, I. Martín Herranz Pharmacy Department. CHU Juan Canalejo. Sergas. La Coruña, Spain Resumen Objetivo: El objetivo trabajo es conocer la influencia de los test de resistencias a antirretrovirales sobre la negativización del VIH (< 400 copias/ml) en pacientes con fracaso virológico que requieren un cambio de tratamiento antirretroviral. Método: Estudio observacional retrospectivo de cohortes en pacientes adultos. Se definieron 2 grupos: casos (grupo A) en el que la prescripción de antirretrovirales se basó en test de resistencia y controles (grupo B) en los que no se realizó dicho test. Cada grupo se dividió en dos subgrupos según fuese el primer cambio de tratamiento (A1 y B1) o sucesivos (A2 y B2). La variable principal se definió como la proporción de pacientes con carga viral negativa (< 400 copias/ml) al tercer mes de tratamiento; variables secundarias fueron la proporción de pacientes con carga viral negativa (< 400 copias/ml) al sexto mes y la variación media del nivel de CD4 al tercer y sexto mes de dicho cambio. Resultados: Se incluyó un total de 152 pacientes en el estudio, 59 del grupo de casos y 93 del de controles. No se encontraron diferencias en el estadio de la enfermedad en el momento del cambio del tratamiento. Un 59,3% de los pacientes del grupo A y un 47,3% de los pacientes del grupo B negativizaron la carga viral VIH al tercer mes, sin que esta diferencia fuese estadísticamente significativa (p = 0,149). No se encontraron diferencias estadísticamente significativas en las variables secundarias. Conclusiones: La utilización de las pruebas de resistencia a antirretrovirales permitió una mayor efectividad en la respuesta al tratamiento antirretroviral seleccionado en el grupo a estudio, si bien no se obtuvieron diferencias significativas en comparación con el grupo de pacientes en los que no se realizaron dichas pruebas. Gamero Martín-Granizo A, Martínez Roca C, Margusino Framiñán L, Martín Herranz I. The influence of antiretroviral-resistance tests on treatment effectiveness. Farm Hosp 2006; 31: Received: Accepted: Correspondence: L. Margusino Framiñán. Servicio de Farmacia. CHU Juan Canalejo. As Xubias, La Coruña. Fax: luis_margusino@canalejo.org. Palabras clave: Resistencia a fármacos. Viral. Tests de resistencias a antirretrovirales. Síndrome de inmunodeficiencia adquirida. Agentes anti-vih. VIH. Summary Objective: The objective of this study is to determine the influence of antiretroviral-resistance tests on the suppression of HIV (< 400 copies/ml) in patients with virological failure who require an alternative antiretroviral treatment. Method: A retrospective observational study on cohorts of adult patients. Two groups were defined: cases in which the prescription of antiretrovirals was based on resistance tests (group A), and controls in which no such test was performed (group B). Each group was divided into two sub-groups according to the number of changes in treatment: first treatment change (A1 and B1); a subsequent change (A2 and B2). The main variable was defined as the proportion of patients with negative viral load (< 400 copies/ml) at the third month of treatment; secondary variables were the proportion of patients with negative viral load at the sixth month and an average variation in the CD4 level at the third and sixth months after this change. Results: A total of 152 patients were included in this study, 59 in group A and 93 in group B (control). No differences were found in the stage of the disease at the time of administering an alternative treatment. 59.3% of the patients in group A and 47.3% of the patients in group B had suppressed the HIV viral load at the third month, although this difference was not statistically significant (p = 0.149). No statistically significant differences were found in the secondary variables. Conclusions: The use of antiretroviral-resistance tests increased effectiveness in the response to the selected antiretroviral treatment in the study group, although we did not obtain significant differences for the group of patients in which these tests were not performed. Key words: Drug resistance. Viral. Microbial sensitivity tests. Acquired immunodeficiency syndrome. Anti-HIV agents. HIV.

2 24 The influence of antiretroviral-resistance tests on treatment effectiveness FARM HOSP INTRODUCTION The aim of administering antiretroviral treatment in patients infected with the human immunodeficiency virus (HIV) is to achieve the maximum and prolonged suppression of the viral load, restore the immune system, reduce morbidity and mortality associated with acquired immunodeficiency syndrome (AIDS) and, finally, to improve quality of life. In achieving these objectives, a therapeutic strategy including the following should be used as a basis 1 : The appropriate selection of the initial therapeutic treatment, with the aim of completely suppressing the virus with the minimum adverse side-effects. Maintaining future therapeutic options, since numerous changes in antiretroviral treatment in cases of virological failures due to viral resistance or poor adherence to the selected therapeutic treatment can rapidly exhaust future treatment options. Performing antiretroviral-resistance tests before starting treatment (some studies have shown an increase of the prevalence of antiretroviral resistance of up to 6-16% in antiretroviral-naïve patients). The regular use of antiretroviral drugs as initial and rescue therapy with the aim of having at least two classes of drugs available for subsequent use, thereby potentially reducing or delaying specific adverse side-effects of each one. An improvement in treatment adherence; viral suppression, a reduction in resistance rates and an increase in the survival of AIDS patients are all correlated with high degrees of treatment adherence. However, various factors can reduce the rate of therapeutic compliance and limit the efficacy and safety of the selected antiretroviral treatment: The development of adverse side-effects to a treatment of indefinite duration, the complexity of the different therapeutic treatments, pharmacological interactions, the large number of doses that must be administered daily in some cases and certain psychosocial factors associated with the HIV patient, such as a history of addiction to parenteral drugs, depression or lack of social support. HIV resistance to antiretrovirals is an evolutionary adaptation mechanism (based on the high error level of the enzymes involved in viral replication, the plasticity of the viral proteins and the high kinetic values of viral replication in the infected organism), which leads to a drastic reduction in treatment efficacy. The use of antiretroviral drugs for the treatment of this infection generates a selective pressure that provokes a reduction in viral replication and the generation of a virus that is resistant to the medications used, characterised by changes in the target enzymes of these drugs, namely protease and reverse transcriptase. In this context, the genotypic or phenotypic antiretroviral resistance tests (ARTs) (laboratory tests that characterise HIV resistance) have been developed over recent years: Genotypic tests analyse specific sequences of the HIV genotype to detect mutations that are resistant to certain antiretroviral drugs. Advantages include the fact that they are quick and easy methods, available in many laboratories and they provide complete information regarding the sequence of the region being analysed. Disadvantages include the fact that complex genotypes are difficult to interpret, false negatives can occur when the viral sequence contains polymorphisms in adjacent codons, and the limited information they provide regarding interactions between mutations or cross-resistance. Phenotypic tests determine whether a HIV strain is sensitive or resistant to a certain antiretroviral medication by measuring its replication capability in varying concentrations of the medication in vitro. They have the advantage that they provide direct information about the sensitivity of the HIV to various antiretrovirals and about cross-resistance. Their drawbacks include their complexity due to the delay in obtaining results, the fact that they are only available in commercial and research laboratories, and their high cost. Different studies have evaluated the use of ARTs in the selection of antiretroviral treatment 2-8. The results of these studies have shown that ARTs are currently considered to be a basic procedure in the therapeutic monitoring of HIV patients and are included in the major reference guidelines for antiretroviral treatment as being of maximum usefulness in specific clinical situations (for primary infection, therapeutic failure or pregnant patients) 1,9-12. Nevertheless doubts have arisen over recent years regarding the actual usefulness of ARTs in clinical practice 13,14, due to an inappropriate selection of patients that were suitable to undergo this analytical test (currently recommended for patients with a HIV viral load of higher than 1,000 copies/ml, with high therapeutic adherence if they are being treated with antiretrovirals and falling within the following four clinical situations: Initial infection, antiretroviral-naïve patients with chronic infection, therapeutic failure, pregnant women, paediatric patients and those receiving post-exposure prophylaxis), the time of taking the sample, the selection of the most suitable method in each case, the reliability of the virtual phenotype or the interpretation of the results by the doctors who are monitoring the HIV patients. The objective of this study is to determine whether the selection of antiretroviral treatment in patients with virological failure who need a change of treatment based on the results of an ART, suppresses the HIV viral load to a greater extent in patients in our hospital. METHOD Scope A multidisciplinary working group, consisting of the Medical Management Unit, the Immunodeficiency Unit of the Internal Medicine Department, the Virology Unit

3 Vol. 31. N. 1, 2007 The influence of antiretroviral-resistance tests on treatment effectiveness 25 of the Microbiology Department, and the Pharmacy Department, was formed at the CHU Juan Canalejo in 2002 in order to establish guidelines for the use of ART in the selection of antiretroviral treatments. The protocol establishes the situations for use of ART (virological failure in previously treated, pregnant and new-born patients) based on the ART Guidelines for Use of the Autonomous Community of Galicia 15, and the work flow and coordination between the different units, which established the following responsibilities of the pharmacy department: Inform of the previous pharmacotherapeutic history: The pharmacy department should send the pharmacotherapeutic history of antiretroviral drugs administered to the virologist from the microbiology laboratory that carried out the ART. Communicate treatment adherence: On a weekly basis, the pharmacy department should inform the doctors responsible for monitoring the HIV patients of the degree of therapeutic compliance of those patients receiving ART and for whom a resistance test has been requested. They should jointly analyse collection of the medication in the pharmacy department on the correct date, the dates on which the medication is dispensed, the quantity of medication dispensed and the dispensing period. Check the appropriate collection of samples according to the periods indicated; if the resistance test is being performed in order to change antiretroviral treatment due to virological failure, this sample is only valid if the patient is currently undergoing antiretroviral treatment. Evaluate the information from the ART based on the patient-selection criteria of the previously agreed protocol. Patient selection Male and female patients over the age of 18 with a documented HIV-1 infection and undergoing HAART (defined as the use of a combination of at least three antiretroviral drugs based on non-nucleoside analog protease inhibitors or third nucleoside analog if one of these is Abacavir) whose treatment has been changed at least once due to virological failure with a previous treatment of at least eight weeks duration. Following this change, patients must have been receiving treatment for at least six months with 100% treatment adherence (patients with medication dosage units dispensed which did not correspond to 100% of those to be administered during the period analysed were excluded). Response variables The response variables were correlated with HIV plasma viral load suppression and the recovery of the immune function. The main variable was defined as the proportion of patients with negative HIV viral load (< 400 copies/ml) at the third month after a change in treatment. The secondary variables included the proportion of patients with negative HIV viral load (< 400 copies/ml) at the sixth month following the change in treatment and the average variation of the CD4 level at the third and sixth months after this change with respect to the value at the time of the change in antiretroviral treatment. The selection of these variables in terms of value and time was based on the definition of treatment objectives and the definition of first and successive virological failure of the European AIDS Clinical Society 16. Study type An observational cohort study was performed by retrospectively reviewing all patients whose treatment had been changed due to their lack of response to HAART over a five-year period ( ). The source of the data was the outpatient register of the pharmaceutical care clinic of outpatients in the pharmacy department. Two study groups were defined: Case group (group A): Patients whose plasma viral load was determined and on whom an ART was performed by the virology laboratory of the microbiology department. Control group (group B): Patients in whom only the HIV plasma viral load was determined with no subsequent ART (selected during the period before ARTs became available in our hospital). Each of these groups was subdivided into two groups depending on the change in antiretroviral treatment: first change since the beginning HAART (sub-groups A1 and B1), or second or subsequent change since beginning HAART (sub-groups A2 and B2). Determination of the plasma viral load HIV-1 and -2 antibodies were detected using chemoluminescence (Ortho) and the confirmatory test by Immunoblot (Innogenetics). Plasma viral load was determined by real-time PCR (Roche Lab). Antiretroviral-resistance tests Resistance was detected by means of protease and the reverse transcriptase gene-sequencing with a Trugene HIV-1 Genotyping System (Bayer Lab). The same doctor who requested the ART, interpreted the ART results and selected the subsequent antiretroviral treatment; no committee of experts was consulted in the evaluation of the genotypic and/or phenotypic resistances identified. Statistical study A statistical analysis of the data was performed by comparing the proportions using the Chi squared method,

4 26 The influence of antiretroviral-resistance tests on treatment effectiveness FARM HOSP and comparing the averages for independent data using the t-student method for normal distributions and the Mann-Whitney method for abnormal distributions. RESULTS A total of 257 patients underwent a change of HAART during the study period due to virological failure of a previous treatment. Of these, 57 were excluded from the study due to lack of data needed to analyse the results and 48 patients did not comply with the required treatment adherence criterion (100%). Therefore, a total of 152 patients were included in the study. Distribution with respect to case or control groups and first or subsequent therapeutic failure was as follows: group A: 59 patients (sub-group A1: 10 patients; sub-group A2: 49 patients); group B: 93 patients (sub-group B1: 24 patients; sub-group B2: 69 patients). The characteristics of the patients included in this study with respect to demographic variables (age and sex), virological variables at the time of treatment change (plasma viral load PVL in copies/ml), immunological variables (CD4+), antiretroviral treatment (type of HAART and duration before change) and the time between determination of the PVL and the change of HAART are shown in table I. The results of the variables analysed in this study are shown in table II. With respect to the main variable, 59.3% of the patients in the study group (A) and 47.3% of the patients in the control group (B) had a viral load of under 400 copies/ml at the third month following treatment change, although this difference was not statistically significant. This tendency remains the same for sub-groups 1 and 2, although similarly it is not sta- Table I. Basic characteristics of the patients included in the study A1 B1 A2 B2 A B (n = 10) (n = 24) (n = 49) (n = 69) (n = 59) (n = 93) Age (years) Average ± SD 42.1 ± ± ± ± ± ± 8.53 Median (interquartile range) 39.5 ( ) 39.5 ( ) 39 (35-45) 36 (32-42) 39 (35-45) 36 (32-41) p = p = p = Sex (%) Male 90% 75% 61.2% 69.6% 66.1% 71% Female 10% 25% 38.8% 30.4% 33.9% 29% p = p = p = PVL Average ± SD 4.26 ± ± ± ± ± ± 0.85 Median (interquartile range) 4.25 ( ) 4.79 ( ) 4.4 ( ) 4.52 ( ) 4.4 ( ) 4.69 (4.1-5) p = p = p = CD4+ (cells/ml) Average ± SD ± ± ± ± ± ± Median (interquartile range) ( ) ( ) 301 ( ) 259 ( ) 301 ( ) 254 ( ) p = p = p = HAART type (%) Based on PI 50% 45.8% 40.8% 42.3% 42.4% 43% Based on NNRTI 40% 29.2% 45% 4.8% 44.1% 33.35% 3 NRTI 10% 0% 8.2% 7.2% 8.5% 5.4% Other 0% 25% 6% 16% 5% 18.3% T1 (days) Average ± SD 77.2 ± ± ± ± ± ± 85.7 Median (interquartile range) 47 ( ) 24 ( ) 51 (33-106) 28 (17-53) 49 (34-106) 28 (17-53) p = p < p = T2 (days) Median ± SD 775 ± ± ± ± ± ± Median (interquartile range) ( ,128.3) ( ) 531 ( ) 305 ( ) 533 ( ) 315 ( ) p = p < p < PVL: log copies/ml of the HIV plasma viral load at the time of the change in treatment; CD4+: absolute value (cells/ml) at the time of the change in treatment; HAART: highly active antiretroviral therapy; PI: protease inhibitors; NNRTI: non-nucleoside analog reverse transcriptase inhibitors; NRTI: nucleoside analog reverse transcriptase inhibitors; T1: time between the determination of the HIV viral load and ART and change in treatment (group A) or between the determination of HIV viral load and change in treatment (group B); T2: duration of the previous antiretroviral treatment before change in treatment.

5 Vol. 31. N. 1, 2007 The influence of antiretroviral-resistance tests on treatment effectiveness 27 tistically significant. As can be seen in table II, the difference in the effect of the use of ARTs is higher for changes due to a first therapeutic failure (A1 vs. B1) than for subsequent changes (A2 vs. B2). Considering the secondary variables, better results were obtained for the efficacy variables analysed when an ART is used in order to select the treatment, as can be seen in table II, although, once again, the differences observed are not statistically significant. DISCUSSION The generation of genetic polymorphisms in HIV (and subsequent development of resistance) and the poor adherence to the prescribed antiretroviral treatment are associated with lack of response to HAART, the development of AIDS and death. Numerous studies have evaluated the use of ARTs to establish guided treatments and improve the short-term results of antiretroviral treatment by determining the PVL 2-10,17. These studies have obtained varying results, and some have concluded that the use of ARTs does not improve the efficacy of HAART (Table III). It is important to emphasise that in our study, higher levels of PVL suppression were obtained for the group of patients in which ATRs were carried out than for the group of patients in which these tests for the selection of rescue treatment were not carried out (Table II) in both the third month (59.3 vs. 47.3%) and sixth month (57.6 vs. 44.0%) after the change in treatment. Although the differences observed are not statistically significant, a relevant difference in effect is observed between these two groups. At an immunological level, patients who underwent a change in treatment as a result of an ART experienced increases in their CD4 levels greater than those patients whose treatment change was not due to an ART (Table II) both in the third month (27.2 vs. 25.6%) and in the sixth month (43.6 vs. 32.9%) after the change in antiretroviral treatment. However, the differences observed were not statistically significant. Another possible analysis is based on the number of treatments prior to the change in treatment being considered 18. For patients who changed treatment for the first time (first therapeutic failure), it is more feasible to prescribe a strong antiretroviral treatment based on drugs without cross-resistance suggested by the ART. On the Table II. Results of the response variables by sub-group A1 B1 A2 B2 A B (n = 10) (n = 24) (n = 49) (n = 69) (n = 59) (n = 93) PVL (log copies/ml) 3 months 2.69 ± ± ± ± ± ± months 2.83 ± ± ± ± ± ± 1.14 % of patients with PVL < 400 copies/ml 3 months p = p = p = months p = p = p = CD4 + (median; range) 3 months 463 ( ) (77-534) 388 (12-940) 316 (16-1,529) 390 (12-940) 312 (16-1,529) 6 months 418 ( ) 327 ( ) 406 (57-1,859) 349 (11-1,346) 407 (57-1,859) 345 (10-1,346) % Increase CD4+ (median) 3 months p = p = p = months p = p = p = HAART type (%) Based on PI Based on NNRTI NRTI Other PVL: HIV plasma viral load; HAART: highly active antiretroviral therapy; PI: protease inhibitors; NNRTI: non-nucleoside analog reverse transcriptase inhibitors; NRTI: nucleoside analog reverse transcriptase inhibitors.

6 28 The influence of antiretroviral-resistance tests on treatment effectiveness FARM HOSP Table III. Summary of the studies concerning the influence of ARTs on the effectiveness of antiretroviral treatment Study Nº patients ART type Main variable ART group Control group P VIRADART, G % change in log PVL in week CPCRA, G % change in log PVL in weeks 4 and 8 week 4 = week 4 = week 8 = week 8 = NARVAL, G or P % of patients with undetectable PVL in month 3 G = 44% 36% P = 35% VIRA3001, P % of patients with undetectable PVL in month 4 46% 34% HAVANA, G % of patients with undetectable PVL in month % 36.2% < 0.05 ARGENTA, G % of patients with undetectable PVL in month 3 and 6 m 3: 27% 12% 0.01 m 6: 21% 17% 0.47 CERT, G or P Time until treatment failure G = 799 days 585 days 0.39 P = 736 days 0.29 CCTG 575, P % of patients with undetectable PVL in month 6 and 12 m 12 = 40% m 6 = 40% 0.9 m 12 = 38% m 12 = 39% 0.9 ART: type of antiretroviral-resistance test; G: genotypic ART; P: phenotypic ART; PVL: HIV plasma viral load; m: months. other hand, it is more difficult to select this new HAART for patients with various therapeutic failures, even with the help of an ART. In light of this, we analysed the subgroups in our study and found that the difference in effect with regard to the principle variable is much higher in patients who underwent their first therapeutic failure (90.0 vs. 54.2%) than in patients with numerous such failures and treatment changes (53.1 vs. 46.4%). Another aspect to be considered is the cost associated with the use of ARTs. In this sense we performed costeffectiveness studies to evaluate the decision to use these tests routinely in clinical practice both for first therapeutic failure and subsequent failures. We estimate that the cost increase of genotypic ARTs is approximately 22,500 per extra year of life ( 16,500-42,900) and they can therefore be considered cost-effective both for initial and subsequent therapeutic failure. This study has an important limitation as it considers retrospective observational groups that, as in all such cases, are difficult to interpret due to biases in the selection of patients to be analysed (those who will undergo ART and those who will not) due to the lack of randomness of its design, although, as can be seen in table I, there are no significant differences in the basic characteristics. Nevertheless, this study sheds some light on the real usefulness of ARTs in our hospital and shows that patients about to undergo their first change in treatment due to virological failure benefit most from their use. References 1. Panel on clinical practices for treatment of HIV infection convened by the Department of Health and Human Services (DHHS). Guidelines for the Use of Antiretroviral Agents in HIV-1- Infected Adults and Adolescents. May 4, (consultado ). Available at: 2. Cohen CJ, Hunt S, Sension M, Farthing C, Conant M, VIRA3001 Study Team, et al. A randomized trial assessing the impact of phenotypic resistance testing on antiretroviral therapy. AIDS 2002; 16: Haubrich RH, Kemper CA, Hellmann NS, Keiser PH, California Collaborative Treatment Group, et al. A randomized, prospective study of phenotype susceptibility testing versus standard of care to manage antiretroviral therapy: CCTG 575. AIDS 2005; 19: Baxter JD, Mayers DL, Wentworth DN, Neaton JD, Hoover ML, Winters MA, et al. A randomized study of antiretroviral management based on plasma genotypic antiretroviral resistance testing in patients failing therapy. Study Team for the Terry Beirn Community Programs for Clinical Research on AIDS. AIDS 2000; 14: F Meynard JL, Vray M, Morand-Joubert L, Race E, Descamps D, Peytarin G, et al; Narval Trial Group. Phenotypic or genotypic resistance testing for choosing antiretroviral therapy after treatment failure: A randomized trial. AIDS 2002; 16: Tural C, Ruiz L, Holtzer C, Schapiro J, Havana Study Group, et al. Clinical utility of HIV-1 genotyping and expert advice: The Havana trial. AIDS 2002; 16: Cingolani A, Antinori A, Rizzo MG, Murri R, Ammassari A, Baldini F, et al. Usefulness of monitoring HIV drug resistance and adherence in individuals failing highly active antiretroviral therapy: A randomized study (ARGENTA). AIDS 2002; 16: Durant J, Clevenbergh P, Halfon P, Delgiudice P, Porsin S, Simonet P, et al. Drug-resistance genotyping in HIV-1 therapy: The VIRADAPT randomised controlled trial. Lancet 1999; 353: Erratum in: Lancet 1999; 354: Yeni PG, Hammer SM, Hirsch MS, Saag MS, Schechter M, Carpenter CC, et al. Treatment for adult HIV infection: 2004 recommendations of the International AIDS Society-USA Panel. JAMA 2004; 292:

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