El perfil de resistencia a darunavir (DRV) se ha extrapolado inicialmente del análisis combinado de los 3 estudios POWER del subgrupo que llevaba desde el comienzo la dosis aprobada para DRV (n = 467) y, posteriormente, ampliado con la rama placebo sin etravirina de los 2 estudios DUET (n = 604), midiendo la eficacia a las 24 semanas. Se han configurado como los 2 mejores factores predictivos de la respuesta virológica: por una parte, el fenotipo basal expresado como el aumento del número de veces o fold change (FC) en la concentración eficaz del 50% (EC50), describiéndose 2 puntos de corte clínicos en 10 y 40 como disminución y pérdida de respuesta respectivamente; por otra, un primer listado (DRV score 2006) de 11 mutaciones en 10 posiciones: V11I, V32I, L33F, I47V, I50V, I54L, I54M, G73S, L76V, I84V y L89V, recientemente revisado (DRV score 2007) quitando del anterior la G73S y añadiendo la T74P, y la respuesta virológica está disminuida con la presencia de 3 o más mutaciones de ambos listados con una ligera mejora de la predicción de respuesta para el de 2007, siempre en el contexto de un alto número de mutaciones (mediana 10) de la International AIDS Society, además hay una muy buena correlación genofenotípica comprobando una disminución progresiva del FC con el acúmulo paulatino de mutaciones de ambos listados. En cuanto a las mutaciones seleccionadas al fallo a DRV, en los pacientes multirresistentes de los estudios POWER y DUET se describen también mayoritariamente las del DRV score sobre todo la pareja V32I e I54L; comparativamente los pacientes del estudio TITAN con un menor nivel de resistencia seleccionan mutaciones similares pero de manera muy escasa en los pocos fallos virológicos descritos, muchos menos fallos y menos mutaciones que la rama de lopinavir (LPV); por último, no aparece ninguna mutación en la proteasa de fracasos a DRV en pacientes naïve (estudio ARTEMIS), efecto ya conocido del grupo de inhibidores de la proteasa potenciados, pero también másacentuado para DRV frente a LPV

RECORD STATUS:

This is a bibliographic record of a published health technology assessment. No evaluation of the quality of this assessment has been made for the HTA database.

CITATION:

All Wales Medicines Strategy Group (AWMSG). Darunavir (Prezista®) Penarth: All Wales Therapeutics and Toxicology Centre (AWTTC), secretariat of the All Wales Medicines Strategy Group (AWMSG). AWMSG Secretariat Assessment Report Advice No. 0311. 2011

RECORD STATUS:

This is a bibliographic record of a published health technology assessment. No evaluation of the quality of this assessment has been made for the HTA database.

CITATION:

All Wales Medicines Strategy Group (AWMSG). Darunavir (Prezista®) Penarth: All Wales Therapeutics and Toxicology Centre (AWTTC), secretariat of the All Wales Medicines Strategy Group (AWMSG). AWMSG Secretariat Assessment Report Advice No. 2246. 2014

Objective: The objective of this study was to examine the potential. of once-daily dosing with, darunavir/ritonavir 800/100 mg in a HIVinfected, treatment-experienced patient population with no baseline darunavir resistance-associated mutations (RAMs). Methods: Patients in the randomized controlled POWER 1 and 2 trials were treatment experienced, with ≥l International AIDS Society-USA primary protease inhibitor (PI) mutation. The virological and immunological responses in patients with no baseline darunavir RAMs receiving darunavir/r 800/100 mg once daily (n = 23), darunavir/r 600/100 mg twice daily (n = 29), or currently available PI(s) (n = 28) plus an optimized background regimen were compared. Results: The proportion, of patients achieving HIV RNA <50 copies per milliliter at week 24 was 67% for the group receiving darunavir/r 800/100 mg once daily and 62% for the group receiving darunavir/r 600/100 mg twice daily (P = 0.774); both were superior to control PI(s) (11%; P < 0.0001). Mean HIV RNA change from baseline was 22.39 and 22.35 log10 copies per milliliter for the group receiving darunavir/r 800/100 mg once daily and for the group receiving 600/100 mg twice daily, respectively (P = 0.895); mean CD4 increases were 88 and 111 cells per milliliter, respectively (P = 0.526). Conclusions: Treatment-experienced, HIV-infected patients with no baseline darunavir RAMs achieved similar high responses with darunavir/r 800/100 mg once daily and 600/100 mg twice daily. This suggests that once-daily darunavir/r 800/100 mg therapy, which has been, shown effective in treatment-naive patients and is currently being studied in treatment-experienced patients, shows potential in patients with no darunavir RAMs. Copyright © 2008 by Lippincott Williams & Wilkins.

INTERVENTION:

Trade Name: Celsentri Product Name: maraviroc Product Code: UK‐427,857 Pharmaceutical Form: Film‐coated tablet INN or Proposed

INN:

Maraviroc CAS Number: 376348‐65‐1 Current Sponsor code: UK‐427,857 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 150‐ Pharmaceutical form of the placebo: Film‐coated tablet Route of administration of the placebo: Oral use Trade Name: Truvada Product Name: emtricitabine & tenofovir Pharmaceutical Form: Film‐coated tablet INN or Proposed

INN:

EMTRICITABINE CAS Number: 143491‐57‐0 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 200‐ INN or Proposed

INN:

TENOFOVIR DISOPROXYL FUMARATE CAS Number: 147127‐20‐6 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 245‐ Pharmaceutical form of the placebo: Capsule Route of administration of the placebo: Oral use Trade Name: Prezista Product Name: Darunavir Pharmaceutical Form: Film‐coated tablet INN or Proposed

INN:

DARUNAVIR CAS Number: 206361‐99‐1 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 800‐ Trade Name: Norvir Product Name: Ritonavir Pharmaceutical Form: Film‐coated tablet INN or Proposed

INN:

RITONAVIR CAS Number: 155213‐67‐5 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 100‐

CONDITION:

HIV infection ; MedDRA version: 14.0 Level: LLT Classification code 10068341 Term: HIV‐1 infection System Organ Class: 10021881 ‐ Infections and infestations Therapeutic area: Diseases [C] ‐ Virus Diseases [C02]

PRIMARY OUTCOME:

Main Objective: To assess whether maraviroc (SelzentryTM, Celsentri®) administered once daily (QD) is non inferior to a reference regimen of emtricitabine/tenofovir administered QD each in combination with darunavir/ritonavir in the treatment of antiretroviral naïve HIV 1 infected subjects as measured by the proportion of subjects with HIV 1 RNA below the limits of assay detection (<50 copies of HIV 1 RNA per milliliter of plasma) at Week 48. Primary end point(s): The proportion of subjects with plasma HIV 1 RNA <50 copies/mL at Week 48. Secondary Objective: 1. To assess the safety and tolerability of maraviroc when administered in combination with darunavir/ritonavir.; 2. To assess the utility of genotype testing or the enhanced Trofile assay (ESTA) for tropism testing in predicting virologic outcomes of a maraviroc containing regimen.; 3. To compare the proportion of subjects with HIV 1 RNA below the limits of assay detection at Week 96 for maraviroc versus emtricitabine/tenofovir.; 4. To compare the differences in the magnitude of changes in CD4+ and CD8+ cell counts and CD4+/CD8+ ratio from baseline through Weeks 48 and 96 for maraviroc versus emtricitabine/tenofovir.; 5. To examine tropism change and the evolution of viral resistance in virologic failure subjects. ; 6. To compare the effects on peripheral fat distribution and trunk to limb fat ratio of maraviroc versus emtricitabine/tenofovir.; 7. To compare the effects on bone mineral density of maraviroc versus emtricitabine/tenofovir; Timepoint(s) of evaluation of this end point: Week 48 ; 3. Virologic Response: ; Proportion of subjects with plasma HIV RNA <50 copies/mL at Week 96. ; 4. Immunological Response at Week 48 and Week 96: ; a. Changes in CD4+ T lymphocyte (CD4) cell counts and percent change from Baseline; ; b. Changes in CD8+ T lymphocyte (CD8) cell counts and percent change from Baseline; ; c. Changes in CD4+/CD8+ ratio and changes from Baseline. ; 5. Evolution of viral resistance and tropism change between Screening or Baseline and the time of confirmation of virologic failure or the last on treatment time point: ; a. HIV 1 tropism (Genotype test)

SECONDARY OUTCOME:

Secondary end point(s): 1. Safety: Frequency, severity and relationship of adverse events to test drug; serious adverse events; discontinuations due to adverse events; and frequency and severity of abnormal laboratory values. ; 2. The relationship between the proportion of subjects with plasma HIV 1 RNA <50 copies/mL at the Week 48 and Week 96 visits and the screening tropism test (Genotype test or ESTA) in the maraviroc‐containing regimen.. ; b. For virologic failure with R5 virus, viral resistance to maraviroc (maraviroc treated subjects only). ; c. Viral resistance (Genotype and Phenotype) to nucleoside/nucleotide reverse transcriptase inhibitors (NRTI) and non nucleoside reverse transcriptase inhibitors (NNRTI) [reverse transcriptase inhibitors, RTI] and protease inhibitors (PI). ; 6. Changes in peripheral fat distribution and trunk to limb fat ratio (using DEXA scan) from Baseline and at Weeks 48 and 96 (approximately 109 subjects per treatment arm). ; 7. Changes in bone mineral density (using DEXA scan and serum markers) from Baseline and at Weeks 48 and 96 (approximately 109 subjects per treatment arm). ; Timepoint(s) of evaluation of this end point: Weeks 48 and 96

INCLUSION CRITERIA:

1. Evidence of a personally signed and dated informed consent document indicating that the subject (or a legally acceptable representative) has been informed of all pertinent aspects of the study 2. At least 18 years of age at the Screening Visit. 3. Plasma HIV 1 RNA equal to or more than 1,000 copies/mL measured at the Screening Visit. 4. CD4 count equal to or more than 100 cells/mm3 at Screening. 5. Have only R5 HIV 1 at Screening as verified by a randomized tropism assay. 6. A negative urine pregnancy test at Screening and at the Baseline Visit, prior to receiving the first dose of study medication, for Women of Child Bearing Potential (WOCBP).

NOTE:

WOCBP include any female who has experienced menarche and who has not undergone hysterectomy, bilateral oophorectomy or tubal ligation or any other successful surgical sterilization or is not post menopausal (age >45 years, amenorrheic for >2 years, and serum FSH

OBJECTIVE:

To evaluate 24-week virologic effectiveness of novel antiretroviral regimens for treatment of three-class experienced adult patients in a clinical practice setting following the US Food and Drug Administration approval of darunavir (DRV) for this population.

DESIGN:

A prospective cohort study.

SETTING:

A single-center, academic HIV clinic.

PARTICIPANTS:

Three-class antiretroviral-experienced patients changing regimens between July 2006 and May 2008. Sociodemographic, psychosocial, and clinical characteristics were collected at baseline and during prospective follow-up.

OUTCOME MEASURES:

Plasma HIV viral load below 50 copies/ml and change in CD4 cell count at 24 weeks following regimen change. The Stanford Genotype Database was used to analyze HIV genotype resistance results and determine the number of active drugs in each regimen. Multivariate models and propensity score methods were employed to assess outcome measures.

RESULTS:

Among 109 three-class experienced patients, who previously received an average of 10.5 prior antiretrovirals, 55% achieved viral load below 50 copies/ml at 24 weeks. Treatment strategy was classified as nonprotease inhibitor (n = 25), DRV/ritonavir (DRV/r) (n = 51), or other protease inhibitor (n = 33). The number of active drugs was not significantly different across strategies (P = 0.24). In multivariate analysis, patients treated with DRV/r (65%, odds ratio = 4.24 vs. nonprotease inhibitor strategy, 95% confidence interval = 1.28-14.06), raltegravir (65%, odds ratio = 3.10, 95% confidence interval = 1.12-8.62), or both were more likely to achieve viral load below 50 copies/ml.

CONCLUSION:

Among antiretroviral-experienced patients changing regimens, those treated with DRV/r, raltegravir, or both were more likely to achieve a viral load below 50 copies/ml at 24 weeks. The effectiveness of these agents in routine clinical care mirrors their efficacy in clinical trials and has ushered in a new era in the therapy of three-class experienced patients.

RECORD STATUS:

This is a bibliographic record of a published health technology assessment. No evaluation of the quality of this assessment has been made for the HTA database.

CITATION:

All Wales Medicines Strategy Group (AWMSG). Darunavir (Prezista®) for the treatment of HIV-1 infected, treatment-naïve adults in combination with other antiretroviral medicinal products Penarth: All Wales Therapeutics and Toxicology Centre (AWTTC), secretariat of the All Wales Medicines Strategy Group (AWMSG). AWMSG Secretariat Assessment Report Advice No. 2009. 2009

OBJECTIVE:

To compare the relative antiviral efficacy of TMC114 with low-dose ritonavir (TMC114/r) and tipranavir with low-dose ritonavir (TPV/r) vs. control protease inhibitor (CPI) in treatment-experienced patients, using data from the POWER 1/2 and RESIST 1/2 trials. These trials recruited antiretroviral-experienced patients with HIV RNA > 1000 HIV-1 RNA copies/mL and at least one primary PI mutation, and used optimized nucleoside reverse transcriptase inhibitors with or without enfuvirtide, plus investigator-selected CPI in the control arms.

METHODS:

For the POWER trials, data from the 600/100 mg twice a day (bid) dose and CPI arms (n=201) were included, while all data from the RESIST trials (TPV/r 500/200 mg bid and CPI; n=1159) were included. The difference in week 24 efficacy (intent to treat) for the new PI vs. CPI was compared between the trials.

RESULTS:

Overall baseline characteristics were well matched across the trials. At week 24, 72% of TMC114/r patients achieved a > or =1 log(10) copies/mL reduction in HIV RNA compared with 40% of TPV/r patients (for CPI patients, this percentage was 21 and 18%, respectively, in the POWER and RESIST trials). The treatment benefit of TMC114/r over CPI in the POWER trials was greater (outside the 95% confidence intervals) than the benefit of TPV/r over CPI in the RESIST trials, for the 24-week HIV RNA endpoints of 1 log(10) copies/mL reduction, <400 copies/mL and <50 copies/mL, and also for the mean rise in CD4 count. In sensitivity analysis, this difference in efficacy was strongest for those who did not also use enfuvirtide.

CONCLUSIONS:

Given the caveats of this type of analysis (for example, possible differences in trial conduct, and undetected differences in baseline resistance profiles), the efficacy benefits of TMC114/r vs. CPI in the POWER trials appear to be greater than the benefits of TPV/r vs. CPI in the RESIST trials, for patients who did not also use enfuvirtide.

BACKGROUND:

The development of tipranavir and darunavir, second generation non-peptidic HIV protease inhibitors, with marked improved resistance profiles, has opened a new perspective on the treatment of antiretroviral therapy (ART) experienced HIV patients with poor viral load control. The aim of this study was to determine the virologic response in ART experienced patients to tipranavir-ritonavir and darunavir-ritonavir based regimens.

METHODS AND FINDINGS:

A computer based literature search was conducted in the databases of HINARI (Health InterNetwork Access to Research Initiative), Medline and Cochrane library. Meta-analysis was performed by including randomized controlled studies that were conducted in ART experienced patients with plasma viral load above 1,000 copies HIV RNA/ml. The odds ratios and 95% confidence intervals (CI) for viral loads of <50 copies and <400 copies HIV RNA/ml at the end of the intervention were determined by the random effects model. Meta-regression, sensitivity analysis and funnel plots were done. The number of HIV-1 patients who were on either a tipranavir-ritonavir or darunavir-ritonavir based regimen and achieved viral load less than 50 copies HIV RNA/ml was significantly higher (overall OR = 3.4; 95% CI, 2.61-4.52) than the number of HIV-1 patients who were on investigator selected boosted comparator HIV-1 protease inhibitors (CPIs-ritonavir). Similarly, the number of patients with viral load less than 400 copies HIV RNA/ml was significantly higher in either the tipranavir-ritonavir or darunavir-ritonavir based regimen treated group (overall OR = 3.0; 95% CI, 2.15-4.11). Meta-regression showed that the viral load reduction was independent of baseline viral load, baseline CD4 count and duration of tipranavir-ritonavir or darunavir-ritonavir based regimen.

CONCLUSIONS:

Tipranavir and darunavir based regimens were more effective in patients who were ART experienced and had poor viral load control. Further studies are required to determine their consistent viral load suppression effect as the duration of treatment is more prolonged.

Background: The present primary analysis of AntiRetroviral Therapy with TMC114 ExaMined In naive Subjects (ARTEMIS) compares the efficacy and safety of once-daily darunavir/ritonavir (DRV/r) with that of lopinavir/ritonavir (LPV/r) in treatment-naive patients. Methods: Patients with HIV-1 RNA at least 5000 copies/ml were stratified by HIV-1 RNA and CD4 cell count in a phase III, open-label trial, and randomized to receive DRV/r 800/100 mg qd or LPV/r 800/200 mg total daily dose (bid or qd) plus fixed-dose tenofovir and emtricitabine for 192 weeks. The primary objective was to demonstrate non-inferiority of DRV/r as compared with LPV/r in HIV-1 RNA less than 50 copies/ml per-protocol time-to-loss of virologic response at 48 weeks. Results: Six hundred and eighty-nine patients were randomized and treated; mean baseline HIV-1

RNA:

4.85 log10 copies/ml and median CD4 count: 225 cells/μl. At 48 weeks, 84% of DRV/r and 78% of LPV/r patients achieved HIV-1 RNA less than 50 copies/ml (estimated difference = 5.6 [95% confidence interval -0.1-11]%), demonstrating non-inferiority of DRV/r as compared with LPV/r (P < 0.001; per-protocol time-to-loss of virologic response). Patients with HIV-1 RNA at least 100 000 copies/ml had a significantly higher response rate with DRV/r (79%) versus LPV/r (67%; P < 0.05). Median CD4 cell count increases (non-completer = failure; cells/μl) were 137 for DRV/r and 141 for LPV/r. DRV/r had a lower incidence of possibly treatment-related grade 2-4 gastrointestinal-related adverse events (7 versus 14%) and treatment-related moderate-to-severe diarrhea (4 versus 10%) than LPV/r. Adverse events leading to discontinuation were DRV/r: 3% and LPV/r: 7%. Conclusion: DRV/r 800/100 mg qd was non-inferior to LPV/r 800/200 mg at 48 weeks, with a more favorable safety profile. Significantly higher response rates were observed with DRV/r in patients with HIV-1 RNA at least 100 000 copies/ml. DRV/r 800/100 mg offers a new effective and well tolerated once-daily, first-line treatment option for treatment-naive patients. © 2008 Wolters Kluwer Health / Lippincott Williams & Wilkins.