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Keith. W. Crawford, RPH, PhD Assistant Chief of Public Health Research
Global Health Programs U.S. Military HIV Research Program
Sponsor Accreditation: Howard University College of Medicine is accredited by the Accreditation Council for Continuing Medical Education to provide continuing
medical education for physicians.
Credits for Physicians: Howard University College of Medicine, Office of Continuing Medical Education, designates this live activity for a maximum of 0.5 AMA PRA Category I Credit(s)TM . Physicians should claim
only the credit commensurate with the extent of their participation in the activity.
Funded by Health Resources Services Administration (HRSA) Grant #H4AHA24081 Goulda A. Downer, PhD, RD, LN, CNS – Principal Investigator/Project Director
AETC-Capitol Region Telehealth Project Planning Committee : The following committee members have nothing to disclose in relation to this activity: Keith W. Crawford, RPH, PhD I. Jean Davis, PhD, PA, AAHIVS Goulda A. Downer, PhD, RD, LN, CNS John I. McNeil , MD Denise Bailey, MEd Marjorie Doulas-Johnson, BA Speaker: The following speaker has nothing to disclose in relation to this activity: Keith W. Crawford, RPH, PhD
Intended Audience: Low volume clinicians (i.e. those with fewer than 25 patients in their case load who are HIV positive): Physicians, Physician Assistants, Nurse Practitioners, Pharmacists, Dentists, Nurses, Social Workers, Case Managers and other Clinical Personnel.
Webinar Requirements: A computer, phone, etc. with Internet accessibility and a
telephone line. Ø Your presence on the call must be acknowledged at the start of each session. Please log in for
the session announce your name loud and clear at the beginning of the session.
Ø You will not be able to receive CME credits if you leave the session early. Ø At the end of the Webinar, please send an email request to our Training Coordinator at
[email protected], to receive the CME Evaluation Survey. Ø To receive CME credits, you are required to complete and return the CME Evaluation Survey
at the end of each session. It may be scanned and emailed back to [email protected] , or faxed to: AETC-‐Capitol Region Telehealth Project (FAX#: 202.667.1382) ATTN: Training Coordinator.
At the end of this webinar the participating providers will have an enhanced ability to:
1. Know the classes of antiretrovirals, anti-‐mycobacterials and
anti-‐HCV drugs that have the greatest potential to interact with other drugs used to treat these infections.
2. Understand the common mechanisms by which these drugs produce pharmacokinetic interactions when combined.
3. Make rational therapeutic decisions in treating patients who are HIV Positive and co-‐infected with TB and HCV that minimize the potential for drug-‐ drug interactions.
Ø Occur when either the pharmacokinetics or the pharmacodynamics of one drug (or both drugs) is altered as a consequence of their co-‐administration.
Ø Are graded responses that are dependent upon the plasma/tissue concentration of the interacting species (related to dose and schedule).
Ø Are a source of variability in drug response.
Etoposide Daunomycin Paclitaxel Vinblastine Doxorubicin
Ø The interacting drugs are both substrates at the active sites of the enzyme.
Ø A competition for access to the active site ensues where one or both drugs may have increased plasma concentrations (one of the drugs may be a preferred substrate).
Ø This interaction occurs in real time.
Drug Enzyme Inhibition Enzyme Induction
Atazanavir ++ — Delavirdine ++ — Efavirenz + +++ Fosamprenavir + ++ Indinavir ++ — Lopinavir/ritonavir[1] ++++ ++
Tipranavir/ritonavir[1] ++++ +++
Nelfinavir ++ + Nevirapine — ++ Ritonavir ++++ ++ Saquinavir[2] — —
Ø HCV protease inhibitors are potent inhibitors of CYP3A4 and are also substrates.
Ø Telapravir is a substrate of p-‐glycoprotein.
Ø The inducing drug causes an upregulation (increased transcription and translation) of the enzymes and transporters that metabolize and transport the interacting drugs.
Ø This process requires days-‐weeks before an effect is observed on plasma concentration of the target drug.
Ø The pharmacologic effect persists even when the culprit is discontinued, as it takes time for enzyme levels to normalize.
Ø Efavirenz may lower levels of both telapravir and bocepravir, and these combinations should be avoided.
Ø Bocepravir may moderately increase Efavirenz AUC and Cmin, through inhibition of CYP’s.
Ø Bocepravir reduces the area-‐under the curve of LPV/r, ATZ/r and DRV/r.
Ø LPV/r and DRV/r, but not ATZ/r, reduce the AUC of bocepravir.
Ø Affects on raltegravir may be minimal.
Ø Telapravir plasma concentrations are decreased by HIV protease inhibitors ranging from 20% (ATZ) to 50% (LPV/r). Telapravir decreases APV and DRV AUC, do not combine. Minimal effects on LPV. ATV+Telapravir can be safely co-‐administered.
Ø Affects on Efavirenz may be minimal. Increasing telapravir dose to 1125 mg may counteract the affect of EFV co-‐administration.
Ø Telapravir can lead to increases in tenofovir AUC and Cmin.
Ø Effects on raltegravir are minimal, safe to co-‐administer.
Ø Nucleoside analogue antivirals (e.g. zidovudine, acyclovir, ribavirin) require metabolic activation to triphosphates.
Ø AZT and D4T are both thymidine analogues, so the compete with each other for activation. Co-‐administration results in markedly reduced levels of AZT-‐triphosphate and D4T-‐triphosphate.
Ø Abacavir and Ribavirin are both guanosine analogues and require the same host enzymes for activation. Does co-‐administration of abacavir and ribavirin in HIV/HCV co-‐infected patients decrease the levels of the active drugs.
Ø There appears to be no interaction between abacavir and ribavirin. Solas et al., AIDS. 2012 Nov 13;26(17):2193-‐9
Ø Use an agent from a different class. o raltegravir instead of a Protease Inhibitor combined with bocepravir/telapravir.
Ø Use an agent from the same class with lower risk of interaction. o rifabutin (reduced dose) vs. rifampin with HIV protease/integrase inhibitors.
o atanzanavir instead of darunavir with Telapravir. Ø Adjust the dosage to counteract the affect of the interaction.
Ø Closely monitor and counsel patients about side effects that could indicate a drug interaction.
Case Study Discussion:
¡ F.W. is a 40 year-‐old male seropositive for HIV-‐1 with a CD4+ cell count of 271 cells (CD4+%=12%), viral load is 26,244 copies/ml. Patient is naïve and baseline genotype indicates no transmitted resistance.
¡ Also infected with HCV (genotype 1A) through IVDU 9 years earlier. HCV viral load is 18 x 106 IU/ml. Liver biopsy shows fibrosis stage 2 of 4 (moderate fibrosis).
¡ ALT= 51 U/L ¡ AST= 68U/L ¡ Total bilirubin = 0.5 mg/dL
¡ Alk Phos 152 U/L ¡ Albumin 4.2 g/dl ¡ WBC = 7.3 x 103/ul
¡ INR = 1.1 ¡ Hgb = 13.9 gm/dL ¡ Platelet 194 X 103 /ul ¡ HBVsAg -‐neg ¡ HBVsAb -‐ neg ¡ HBVcAb -‐neg
So what should be the first step in managing this patient?
¡ Patient started on atazanavir/r + emtricitibine/tenofovir.
¡ In 6 months, CD4+ cell count is 457/ul and VL is undetectable.
¡ Patient is ready to start HCV treatment.
¡ What would be the best option?
Patient is started on: ¡ Peginterferon alpha 180 ug/week
¡ Ribavirin 1200 mg QD (Pt weighs 80 kg)
¡ Telapravir 750 mg TID
Just prior to treatment: ¡ Hgb=13.7 ¡ Total bilirubin = 1.7 mg/dl
¡ At week three, patient comes in complaining of fatigue.
¡ What are the possible culprits?
¡ The Hgb is found to be 9.5 g/dL.
Now, what is the most likely culprit and the best plan of action?
¡ Ribavirin dose reduced to 800 mg QD.
¡ Patient HCV is undetectable at weeks 4 and 12 (extended rapid virologic response).
Case provided through IAS-‐USA archives
1. What other options could have been used to initiate HIV treatment?
2. Would treatment with peginterferon and ribavirin have been a good choice in this patient?
3. Any concerns over the use of tenofovir in the HIV regimen?
4. Are there other safe options for treating the HCV?
Ø Pharmacists
Ø Hospital and University-‐based drug-‐information services
Ø DHHS Guidelines (http://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf)
Ø Johns Hopkins HIVguide http://www.hopkinsguides.com/hopkins/ub
Ø NY/NJ AIDS Education and Training Center, HIV/HCV drug-‐drug interaction cards (John Faragon et al., 2012)
Howard University HURB 1
1840 7th Street NW, 2nd Floor Washington, DC 20001 202-865-8146 (Office) 202-667-1382 (Fax)
At the end of the Webinar, please email Ms. Marjorie Douglas-‐Johnson
at [email protected] and she will send you the CME Evaluation Survey to fill in.
www.capitolregiontelehealth.org
www.aetcnmc.org