B7 CRIBS – April 2012 Brendan McQuellon Jason Milton Morgan Newsome Vivak Patel Shirley Payne

Overview of Antivirals for HIV, HCV and VZVMechanisms of Action and Most Important Side Effects B7 CRIBS – April 2012 Brendan McQuellon Jason Milton Morgan Newsome Vivak Patel Shirley Payne Pete Ton

HIV MOA NNRTIs (NED) NRTIs Zidovudine (AZT, ZDV) Didanosine (ddI) Zalcitabine (ddC) Stavudine (d4T) Lamivudine (3TC) Abacavir (ABC) Emtricitabine (FTC) Emtriva • Nevirapine • Efavirenz • Delaviradine

PIs (-navir) Fusion Inhibitors (just remember it) Enfuvirtide (Fuzeon) • Ritonavir • Amprenavir • Lopinavir • Fosamprinavir • Saquinavir • Indinavir • Nelfinavir • Azatanavir

Integrase inhibitors (unlikely to be tested, but fair game) • Raltegravir

HIV MOA Maturation inhibitors (Low yield) CCR5 antagonists (Low yield)

High Yield facts you just need to know • On COMLEX/USMLE if you pick a drug regimen, it will always be a 3-drug regimen • 2NRTI + PI or NNRTI. All regimens on COMLEX/USMLE will look like this! • More complex regimens exist in practice, but Step I doesn’t test them • “Don’t go back to Abacavir”-hypersensitivity reaction • PIs = Lipids Glucose (very HY on boards and in practice!!)

Question 1 A 53 year old HIV patient comes into your clinic for routine management. Upon assessment of his lab values, you note increased glucose. In addition, you note glucose on urinalysis. Which of the following regimens is this patient most likely on? • Enfuviratide • Zidovudine, Stavudine, Efavirenz • Zidovudine, Stavudine, Abacavir • Didanosine, Zalcitabine, Ritonavir • Zalcitabine, Nevirapine, Declaviridine

HIV Antivirals Side Effects Source: http://emedicine.medscape.com/article/1533218-overview

Nucleoside Reverse Transcriptase Inhibitors

Non Nucleoside Reverse Transcriptase Inhibitors

Protease Inhibitors

Integrase inhibitor • Raltegravir • N/D, HA, CK elevation, myopathy, rhabdomyolysis (rare)

CCR5 Antagonist • Maraviroc • Constipation, dizziness, infection, rash.

Fusion Inhibitor • Enfuvirtide • Injection site reactions (pain, erythema, induration, nodules)

Question 2 A 35 year old male patient presents to your office with complain of unexplained weight loss, fever and rash for 1 month. He confesses to you that in his many travels around the world he has been quite promiscuous, and had many instances of unprotected sex. His symptoms began shortly after his return from Thailand and he’s convinced he got a tropical disease. From his past social history, you suspect something much more serious. You order an HIV titer and a CD4 count amongst other tests. His HIV titer came back positive, his CD4 count is 350 cells/uL. Because of his CD4 levels, you decide to begin prompt treatment. You consider a drug with a safe side effect profile compared to other drugs of the same class. However, in order for it to be the best choice, with very few side effects for this patient, he must test negative in an HLA screen before initiating treatment. Based on this description, which drug are you considering? • Tenofovir • Atazanivir • Efavirenz • Abacavir • Stavudine.

Hepatitis C Virus Source: Harrison’s 1932-1963

Hepatitis C • Linear, single strand + sense RNA virus. • Member of the Flavivirus family (Yellow fever, Dengue, St. Louis encephalitis, West Nile virus) • Enveloped and Icosahedral (Enveloped viruses are denatured by ether = World ?) Image taken from http://www.prn.org/index.php/provider_resources/prn_art/hepatitis_c_virus_hcv_3_d_model_with_cut_away/

HCV • Does not incorporate into host DNA. • 6 distinct genotypes • Immunoassays detect anti-HCV antibodies for acute infections. • PCR is the most sensitive test for HCV infection. • Transmitted by blood transfusion, IV drug use. • It accounts for 40% of chronic liver disease and is the most frequent indication for liver transplantation in the US.

HCV • Infection is contained by cell mediated immune responses and elaboration of antiviral cytokines by T cells. • Degree of HCV-associated liver damage is due to CD8 cytotoxic T cell activation by virus-activated CD4 helper T cells.

Associations • Hepatocellular Carcinoma • Porphyria CutaneaTarda • Lichen Planus • Immune Complex Glomerulonephritis

Question 3 A 54 year old male presents to your office with jaundice and right upper quadrant pain. The patients history is significant for a liver transplant 2 years ago. The patient tells you the pain and jaundice started a month ago when his wife passed and he started drinking. The patients liver transplant was most likely related to which of the following: • Alcoholic liver cirrhosis • Hepatocellular Carcinoma • Chronic hepatitis B • Chronic hepatitis C • Polycystic liver disease • Budd-Chiarisyndrome

HCV Drugs Side Effects Suppiah V (2009) . “IL28B is associated with response to chronic hepatitis C interferon-alpha and ribavirin therapy.” Nat. Genet. 41(10):1100-4. Ge D (2009) . “Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance.” Nature 461(7262):399-401. Tanaka Y (2009) . “Genome-wide association of IL28B with response to pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C.” Nat. Genet. 41(10):1105-9. Wikiuniversity Buxton, Bonnie, PhD.

Common SE of HCV Tx • Adverse effects with HCV treatment are common • With regular combination therapy, approximately 50% of people get flu-like symptoms and ~33% experiencing emotional problems. • With Peginterferon by itself, over 10% of patients get fatigue, anemia, nausea, rash, other

Interferon Depression and other psychiatric disorders Difficulty concentrating Exacerbation of autoimmune disorders Bone marrow suppression (neutropenia) Ribavirin Teratogenicity Anemia GI upset Sore throat, cough, dyspnea Rash Other Common Side-Effects Chronic HCV Treatment Courtesy of Dr. Buxton, 2012

Caution with Ribavirin • The primary observed SERIOUSadverse side effect of ribavirin is hemolytic anemia, which may worsen preexisting cardiac disease. • The mechanism for this effect is due to ribavarin's buildup inside erythrocytes. • Increase ribivirin-> decreased ATP -> leads to inhibition of glutathione -> permitting oxidative erythrocyte cell lysis-> anemia • The anemia is dose-dependent and may sometimes be compensated by decreasing dose. • Ribavirin is also a teratogen in some animals species and thus poses a theoretical reproductive risk in humans, remaining a hazard as long as the drug is present, which can be as long as 6 months after a course of the drug has ended.

What is Riba Rage? • Riba rage is the popular, though misleading, name for side effects from combination treatment • Reminder: pegylatedinterferon (either Peginterferon Alfa-2a or Peginterferon Alfa-2b) and ribavirin. • While patients generally get good results from this combination treatment, interferon has some nasty side effects. Two of these are intense depression and general irritability. • These side effects are unofficially known as Riba Rage, even though they're really caused by the interferon.

Question 4 • A 25 y.o. former heroin addictis undergoing hepatitis C treatment with a combination therapy of peginterferonand ribavirin. Lately, however, his friends and family has notice that he has become very irritable. They assume that he is just stressed out from work or from not using. • However, as a good friend, and most importantly a good DO, you prescribe him sertraline. This is because you know that his irritability is really a common side effect of: • Him missing his girlfriend • Interferons • His secret steroid use • His constant worrying that he might also have the “clap” (aka the “drip” aka gonorrhea) • Ribavirin

Varicella Zoster Virus

Varicella Zoster Antiviral MOA Antiviral therapy includes: Acyclovir Famciclovir Other related compunds MOA: Drug is monophosphorylated by thymidine kinase. This makes it a guanosine analog. Inhibits viral DNA polymerase by chain termination.

Varicella Zoster Antiviral Side Effects The most frequently reported side effects in HIV infected patients famciclovir and acyclovir. famciclovir(500 mg twice daily; n=150) vs. acyclovir (400 mg, 5x/day; n=143) • headache (16.7% vs. 15.4%) • nausea (10.7% vs. 12.6%) • diarrhea (6.7% vs. 10.5%) • vomiting (4.7% vs. 3.5%) • fatigue (4.0% vs. 2.1%) • abdominal pain (3.3% vs. 5.6%)

Question 5 A 72-year old man comes to your office complaining of a rash on his chest. He also complains of pain in the area of the rash. Upon further examination, you determine it is a maculopapular rash that is located in the pattern of the T-4 dermatome. What would be the mechanism of action for the treatment given to this patient? Blocks viral penetration/uncoating Inhibits synthesis of guanine nucleotides Guanosine analog Fusion inhibitor Protease inhibitor

B7 CRIBS – April 2012 Brendan McQuellon Jason Milton Morgan Newsome Vivak Patel Shirley Payne