Transcript file (Dolutegravir Presentation)

The Use of Dolutegravir (Tivicay®)
in Treatment-Experienced HIV-1
Patients
Stefanie L. Drahuschak
University of Pittsburgh
School of Pharmacy
PharmD Candidate 2014
Objectives
 Review a patient case and determine the
appropriateness of dolutegravir for the patient
 Understand the MOA, pharmacodynamics, dose, and
other important dolutegravir facts
 List the key counseling points of dolutegravir
 Determine the place of dolutegravir in HIV therapy
Patient Case: DM
 44 yo male
 CC: myopathy
 PMH: HIV-1, asthma, pain, constipation, multiple drug resistance
Current Medications
Dose and frequency
Darunavir
600 mg PO BID
Ritonavir
100 mg PO BID
Etravirine
200 mg PO BID
Maraviroc
150 mg PO BID
Azithromycin
1200 mg PO once weekly
Proventil HFA
2 puffs q4h PRN
Tramadol
50 mg PO q6h PRN pain
Docusate
100 mg PO BID PRN
Patient Case: DM
 Pertinent laboratory values:
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Viral Load: 543 copies/mL (9/17/13)
CD4 T cell count: 149 cells/mm3 (8/6/13)
CPK 731 U/L (10/8/13)
Hep C negative
Urinalysis negative
HIV virus is CCR5 co-receptor
Patient DM
 Previous ART regimen used (until June 2013):
 Truvada + raltegravir + boosted atazanavir
 CD4 T-cell count (3/5/13)
 46 cells/mm3
 Viral load (3/5/13)
 102,449 copies/mL
 Patient exhibited noncompliance
DM: Genotype (3/11/2011)
DM: Genotype (3/5/13)
To Summarize…
 Patient DM is currently on salvage regimen of
boosted darunavir, etravirine, and maraviroc
 Patient continues to experience detectable viral load
and low CD4 count
 Patient shows non adherence and multiple drug
resistances
Dolutegravir (Tivicay®)
A Novel Antiretroviral Agent
Indications and Usage
 Dolutegravir is an integrase inhibitor used in Human
Immunodeficiency Virus type 1 (HIV-1)
 Indicated in combination with other antiretroviral
agents for the treatment of HIV-1 infection in adults
and children aged 12 years of age and older and
weighing at least at least 40 kg
Tivicay [package insert]. Triangle Park, NJ: ViiV Healthcare; 2013.
Mechanism of Action
 Integrase Inhibitor
 Prevents viral replication by inhibiting viral DNA
insertion into the host’s cellular genome
 Works similarly to raltegravir and elvitegravir
Dolutegravir. In: MicroMedex® System [Internet Database].
Greenwood Village, Colo: Thomson Healthcase. Updated periodically
Availability
 Tivicay®-available as brand name only
 50 mg tablets
 Yellow, circular tablet with “SV 572” imprint
http://www.empr.com/fda-approves-new-hiv-1-drug/article/307094/
Dosage and Administration
 May be taken without regards to meals
Adult Population
Recommended Dose
Treatment naïve or treatmentexperienced INSTI-naïve
50 mg PO once daily
Treatment-naïve or treatmentexperienced INSTI-naïve when
co-administered with potent
CYP3A4 inducers: efavirenz,
rifampin, tipranavir/r,
fosamprenavir/r
50 mg PO twice daily
INSTI-experienced with certain
INSTI-associated resistance
substitutions or clinically
suspected INSTI resistance
50 mg PO twice daily
Tivicay [package insert]. Triangle Park, NJ: ViiV Healthcare; 2013.
Contraindications
 Coadminstration with dofetilide (Tikosyn®) is
contraindicated
 Concurrent use could increase dofetilide concentrations
and increase the risk of serious or life-threatening
events
Dolutegravir. In: MicroMedex® System [Internet Database].
Greenwood Village, Colo: Thomson Healthcase. Updated periodically
Resistance Issues
 Poor response was seen in subjects with INSTIresistance Q148 substitution plus 2 or more additional
INSTI-resistance substitutions:
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L741/M
E138A/D/K/T
G140A/S
Y143H/R
E157Q
Tivicay [package insert]. Triangle Park, NJ: ViiV Healthcare; 2013.
G163E/K/Q/R/S
G193E/R
Warnings and Precautions
 Should be promptly discontinued if s/sx of
hypersensitivity reaction occur (rash, hepatic injury)
 Patients with underlying hepatitis B/C may be at risk
for worsening of disease and increases in AST/ALT
 Initial and periodic monitoring for liver disease patients
 Immune Reconstitution Syndrome has been reported
in patients treated with combination ART.
Tivicay [package insert]. Triangle Park, NJ: ViiV Healthcare; 2013.
Adverse Events
 Increases in AST/ALT in hepatitis B or C patients
 Fat redistribution
 Central obesity, dorsocervical fat enlargement (buffalo
hump), peripheral wasting, facial wasting, breast
enlargement, and “cushingoid appearance”
 Hyperglycemia, headache, insomnia
 Relatively well tolerated
 Humans lack the integrase enzyme, so inhibiting it does
not infer much toxicity to the patient
Tivicay [package insert]. Triangle Park, NJ: ViiV Healthcare; 2013.
Drug Interactions
 Drugs that are metabolic inducers of CYP3A4 or
UGT1A
 Should be taken 2 hours before or 6 hours after
taking cation-containing antacids or laxatives,
sucralfate, oral iron supplements, oral calcium
supplements, or buffered medications.
Tivicay [package insert]. Triangle Park, NJ: ViiV Healthcare; 2013.
Use in Special Populations
 Pregnancy
 Pregnancy Category B
 No adequate and well-controlled studies in humans
 Nursing Mothers
 Mothers should NOT breastfeed if they are receiving
dolutegravir
Tivicay [package insert]. Triangle Park, NJ: ViiV Healthcare; 2013.
Use in Special Population
 Geriatric-minimal data, use with caution
 Hepatic impairment
 Mild-moderate disease-no adjustment necessary
 Severe disease-use not recommended
 Renal impairment
 Mild-to-moderate impairment-no adjustment necessary
 Severe impairment-caution advised
Dolutegravir. In: MicroMedex® System [Internet Database].
Greenwood Village, Colo: Thomson Healthcase. Updated periodically
Monitoring
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Viral load at baseline, every 2-8 weeks
CD4 count at baseline, every 3-6 months
AST, ALT, T.bili at baseline, at 2-8 weeks
BMP at baseline, at 2-8 weeks
CBC with diff at baseline, every 3-6 months
FBG and HbA1c at baseline, every 3-6 months
Fasting lipid panel at baseline, at 4-6 weeks
Urinalysis at baseline, every 6-12 months
Dolutegravir. In: MicroMedex® System [Internet Database].
Greenwood Village, Colo: Thomson Healthcase. Updated periodically
Clinical Teaching
 Advice sex safe practices to minimize transmission
 Patient should report any s/sx of infection
 Patient should report rash and seek immediate
medical attention-could be hypersensitivity reaction
 Advise patients of common adverse events
 Instruct patient to space dose out from certain
supplements
 Many drug-drug interactions, patient should report
new medication use to HIV specialist
Dolutegravir. In: MicroMedex® System [Internet Database]. Greenwood
Village, Colo: Thomson Healthcase. Updated periodically
FLAMINGO Study
 Dolutegravir superior to boosted darunavir in ARTnaïve patients
 Primary endpoint was proportion of patients at week 48
with undetectable viral loads (<50 copies/mL)
 90% randomized to dolutegravir and 83% randomized to
boosted darunavir had an undetectable viral load
 Dolutegravir arm exhibited less withdrawal rates from
study due to adverse effects compared to darunavir
Dolutegravir vs Darunavir: Positive Data From
FLAMINGO. Medscape. Sep 26, 2013.
SPRING-2 Study
 Once-daily dolutegravir versus twice-daily raltegravir
 At week 96, 81% of patients in dolutegravir arm and 76%
patients in raltegravir arm showed VL < 50 copies/mL
 Virological non-response occurred less in dolutegravir
arm
 Dolutergravir showed non-inferiority efficacy to
raltegravir and similar tolerability as raltegravir
Lancet Infect Dis. doi: 10.1016/S1473-3099(13)70257-3
Back to Patient DM
 Protease Inhibitors
 Minimal resistance, currently on boosted darunavir
 NRTIs
 Emtricitabine, abacavir, and lamivudine – resistances
 NNRTIs
 Resistant to nevirapine/efavirenz; currently on etravirine, but
may be causing myopathy
 Integrase inhibitrors
 Could have developed resistance to raltegravir during non
compliant periods
 Dolutegravir??
The Plan for DM
 D/C etravirine
 Continue boosted darunavir and maraviroc
 Add dolutegravir 50 mg PO twice daily
 The problem…
 Patient’s health plan unable to process PA due to how new dolutegravir is on the
market
 Patient will remain on current regimen until dolutegravir can be processed
 Update
 Patient’s insurance did approve dolutegravir use
 Will most likely start new medication based on MD judgment
Conclusion
 Dolutegravir is a novel antiretroviral agent for the use
in HIV-1 positive patients
 May be beneficial for patients with regards to low
side effect profile and lower resistance rates
 Has been shown to be both superior and non-inferior
to raltegravir in clinical trials
 Cost and lack of clinical knowledge can limit use until
more information available
References
 Tivicay [package insert]. Triangle Park, NJ: ViiV Healthcare; 2013.
 Dolutegravir. In: MicroMedex® System [Internet Database].
Greenwood Village, Colo: Thomson Healthcase. Updated
periodically
 http://www.empr.com/fda-approves-new-hiv-1-drug/article/307094/
 http://www.multivu.com/mnr/62149-viiv-vhc-fda-approval
 Dolutegravir vs Darunavir: Positive Data From
FLAMINGO. Medscape. Sep 26, 2013.
 Raffi F, Jaeger H, Quiros-Roldan E, et al. Once-daily dolutegravir
versus twice-daily raltegravir in antri-retroviral naive adults with HIV1 infection (SPRING-2 study): 96 week results from a randomized,
double-blind, non-inferiority trial. Lancet Infect Dis. doi:
10.1016/S1473-3099. Ahead of Print.