Chapter 37: Drugs for Viral Infections

Viruses are non-living. Once they infect a HOST, they hijack its enzymes and cellular structures to replicate. – they can infect plants/ animals/ and bacteria. Antivirals are the least effective of all the anti-infectives. ** Have a capsid protective protein coat + some have an envelope around the capsid. Envelope has spikes that help host recognize it as foreign for destruction. VIRION- mature infective particle Viruses are considered INTRACELLULAR PARASITES. They have to be inside a host cell to be able to replicate. Many viruses- self limiting, resolve w in 7-10 days HIV→ fatal if untreated HEP B→ can cause permanent liver damage and increase r/o hepatocellular carcinoma. HERPES VIRUS→ significant pain and for ocular herpes → permanent disability. Antivirals sometimes don’t work bc drugs quickly become ineffective due to RAPID MUTATIONS of viruses. OR bc they are so deep within a host , that requires antivirals to damage adjacent HEALTHY CELLS. 3 strategies for antiviral pharmacotherapy : - Prevent viral infections → w vaccines Tx active infections w drugs → such as ACYCLOVIR (Zovirax) PPX drugs to boost immune response → immunostimulants so that virus remains LATENT/SLEEPING and patient remains S/S FREE. AIDS Acquired immune deficiency syndrome is characterized by PROFOUND IMMUNOSUPPRESION that leads to opportunistic infections and malignancies that are not commonly found in patients w healthy immune defenses. HIV → LEADS TO AIDS. REPLICATION OF HIV HIV virus has spikes coming out of the envelope that have GP120 on the end and it binds to T4 cells that have CD4 receptors. Once binded → CORECEPTORS (CCR5 &/OR CXCR4) also help to bind for entry Goes inside and spills contents Reverse transcriptase turns its single stranded RNA → double stranded VIRAL DNA Vial DNA then goes into Nucleus INTEGRASE ENZYME IS RELEASED IN NUCLEUS → binds viral DNA to HOST DNA to make more viral mRNA. Viral proteins are cut by PROTEASE ENZYME to help w maturation → bud off and infect other T4 lymphocytes. Cycle repeats. HIV produces as many as 10 BILLION new virions every day, and the patients shot immune system is unable to remove them at that point → THERES TOO MANY. REMEMBER the 3 enzymes that HIV brings in 1) Reverse transcriptase 2) Integrase 3) Protease Central dogma is usually : DNA→ RNA → proteins But with HIV its RNA→ DNA →RNA→proteins * STARTS with RNA so its known as RETROVIRUS Meds used to tx retroviruses-→ ANTIRETROVIRALS Worsening of HIV → AIDS is characterized by decline in CD4 T-lymphocytes Decline becomes evident when pt begins to experience opportunistic BACTERIAL, FUNGAL, VIRAL INFECTIONS and CERTAIN MALIGNINCIES. PTS immune system becomes so SHOT, cannot fight off anything → DEATH. HIV most transmitted through sexual contact. Can be managed chronically but if non adherence or pharmacotherapy is stopped = RAPID rebound in HIV replication ( Remember HIV mutates rapidly so new medication approaches must remain ONGOING) LATENT PHASE: once inside the nucleus it may remain dormant for months → yrs w no s/s , pts will not realize they are infected. Once dx is made→ START PHARMACOTHERAPY ASAP, sometimes this is impossible bc of how EXPENSIVE meds are. Newer meds → cost 40K- 60K/yr. MEDICATION GOALS: - Reduce HIV morbidity → prolong survival Improve Quality of life. Restore and preserve IMMUNE FUNCTION Suppress plasma HIV VIRAL LOAD Prevent transmission of HIV 2 lab tests let us determine progression and severity of virus: CD4 count and HIV RNA in the plasma CD4 T cell count → important indicator of immune function bc it shows actual degree of immune system damage cause by virus. GOOD predictor of likelihood of pt getting OPPORTUNISTIC INFECTIONS. Remember CD4 T-cells determine how strong your IMMUNE SYSTEM/RESPONSE is. CD4 T cell count: performed Q 3-6months NORMAL RANGES: 500-16000 NORMAL – people w no AIDS are here 250-500- IMMUNE SYSTEM COMPROMISED and one reason could be that you have HIV (but usually patient is asymptomatic at this point) <200 infection has likely progressed to AIDS. MD will DX. VIRAL LOAD- determined by measuring HIV RNA in the blood. VIRAL LOAD IS THE MOST IMPORTANT INDICATION OF HOW THE VIRUS IS REPLICATING IN THE BLOOD Measured to determine effectiveness of meds of failure of them Goal of meds is to reduce HIV RNA to undetectable levels or < 50 copies/mL ( takes 12-24 wks to achieve this level.) MEDS don’t completely eliminate virus – TREATMENT IS LIFE LONG. Relapses are common GENOTYPIC drugs identify specific mutations in viral genes that are r/t drug resistance for the diff classes of HIV meds . helps determine which meds would be most effective. S/E of antiretroviral meds: N/D, rash, lipid abnormalities, hepatotoxicity, neuropathy, increase r/o cardiovascular events. Pts always take 2-3 meds at a time sometimes more. Usually start w 3 meds from 2 different classes. Success requires ADHERENCE Pts may not adhere d/t INCONVENIENT SCHEDULES 3-4x/day Others bc meds make them feel WORSE. Some patients develop AIDS within months while others do not- could be r/t GENETICS. But theres not enough testing on this yet. EARLY S/S of HIV infection present only as : FLU-LIKE S/S ; fever, chills, sore throat, malaise – that’s why ppl may not seek tx. They might think that they just have a cold or the flu. Antiretrovirals target replication stages of HIV ART- anti retroviral therapy is AGGRESSIVE treatment with multiple drugs concurrently . use of multiple drugs reduces probability of resistance GOAL OF ART→ to reduce plasma HIV RNA in the blood (reduction in blood does not = cure. Bc virus lives in other places, such as LYMPH NODES*) ART is enhanced by BOOSTER MEDS AKA PHARMACOKINETIC BOOSTING. 2 main booster meds are → 1) RITONAVIR & 2) COBICISTAT Addition of boosters drugs INCREASE the plasma concentration of the MED and allows for longer dosing interval. ( Meaning that you take it less frequently throughout the day ?) Treatment NAIVE- for patients that are receiving HIV drugs for the FIRST TIME Treatment EXPERIENCED- for patients that have been receiving HIV drugs for months-yrs. Fixed dose regimens have combined drugs and dosages into a single tablet or capsule, these drugs only need to be take 1-2 times a day and lower the pill burden= IMPROVES ADHERENCE. TRUVADA = reduces the r/o getting HIV. It’s a PPX . Recommended for ppl at high risk. For effectiveness- must be taken EVERYDAY. Does not guarantee effectiveness, should not replace established methods for HIV prevention → abstinence, condom use, safe sex. PREVENTION OF PEINATAL TRANSMISSION OF HIV Best approach→ PREVENTION If pregnant and HIV + tx focus on aggressively lowering the viral load in the mother by protecting the transmission of HIV to unborn child. REDUCING VIRAL LOAD IN MOM IS KEY !!* → Equals <1% r/o transmission o baby ART must begin as early in the pregnancy as possible and cont through labor and delivery. During labor→ mom has continuous infusion of ZIDOVUDINE ( this med rapidly crosses the placenta) ** remember most transmission happens near to or during labor and delivery ART recommended to all newborns perinatally exposed to HIV- SHOULD BEGIN IMMEDIATELY → 6-12 hrs after delivery. HIV infection establishes in 1-2 wks. ART tx started after 48hrs is < EFFECTIVE. If moms viral load was suppressed → baby tx w 4 weeks of ppx zidovudine If moms viral load not suppressed → baby tx w 6 weeks of ppx zidovudine + 3 doses of nevirapine and sometimes a 3rd med; lamivudine * CDC- recommends no breastfeeding WHO- says its OK as long as mom is taking antiviral drugs and has no detectable HIV RNA in blood 1-2 months old – babys can have definitive HIV dx of HIV through virologic testing If test is (-) before 6 week ppx tx is over- meds can be dc’d If (+) for HIV- baby switched to ART tx. Can HIV be prevented AFTER accidental occupationl exposure? YES. For successful preventions → PEP ( post exposure prophylaxis) must begin ASAP , w/in 72hrs after exposure w someone KNOWN to have HIV. Exposed worker needs baseline HIV RNA level test ASAP + f/u testing x4 months. If HIV status is UNKNOWN→ PEP is decided on case by case Sometimes PEP started for a few days until source can be tested PEP only IF exposure was sufficiently severe and the source fluid is known or STRONGLY suspected to have HIV. Using PEP if u don’t need it is expensive + can be dangerous. FOR HIV patients- teach adequate infection control measures, hand washing, avoiding crowded indoor places, adequate nutrition and diet- especially if currently immunocompromised. Advise HIV pt to not share needles and to not donate blood. A complete blood count (CBC) is a test routinely performed for people living with HIV to monitor for signs of other infections, assess the response to treatment, and identify drug side effects like anemia. In order for HIV to be considered infections and be able to be transmitted it has to be in a certain fluids, blood, semen, vaginal fluid or breastmilk. **SEROCONVERSION PERIOD: Seroconversion is the period during which the body starts producing detectable levels of HIV antibodies. This usually occurs several weeks after initially contracting the virus. During seroconversion, a person may experience flu-like symptoms, such as fever and body aches. HIV WILL NOT BE DETECTABLE ON A TEST AT THIS TIME. Nucleic acid tests are the earliest detector tests of HIV Precautions for people with HIV to prevent OPPORTUNISTIC INFECTIONS: THINK → “WEAKEN” W- Water from tx sources- don’t drink water from rivers, etc E-eat foods that are not raw – FULLY COOKED ONLY A-Avoid risky sexual and drug activity K- keep vaccines up to date E- exposure to animal feces limited- cats/dogs where there is constant exposure to feces N- need to to take ART meds – helps keep immune system strong HERPESVIRUSES HSV’s are family of DNA viruses that cause repeated blister like lesions on the skin, genitals, and other mucosal surfaces. Antiviral drugs can lower freq of acute episodes and lower intensity of episodes when they do occur Herpes- usually acquired through DIRECT contact. BUT can also go from mom → baby= CNS disease ** Different types of Herpes viruses: HSV1: lips HSV2: genitals CYTOMEGALOVIRUS: affects multiple body systems + IMMUNOSUPPRPESSED VARICELLA ZOSTER-VZV: Shingles EPSTEIN BARR VIRUS-EBV: causes infection mononucleosis and form of CA called ‘Burkitt’s Lymphoma’ HERPESVIRUS-TYPE6: causes roseola in kids & HEP/Encephalitis in immunosuppressed patients. Remember virus can remain latent but is triggered by things like : Immunosuppression Physical challenges Stress GOAL of herpes tx : to RELIEVE acute s/s To PREVENT recurrences Its not a cure. Its only TREATMENT. TREATMENT IS LIFELONG- virus remains in the body FOREVER. Recurrent lesions- usually mild and often require NO TX. If therapy starts w/in 24h, acute episode is short Pts w severe recurrent episode or freq (6+/yr) – may benefit from ppx meds PPX also may be needed for – immunosuppressed pts. Ex: pts with antineoplastic drugs or AIDS. HERPES SIMPLEX KERATITIS: herpes of eye is the MOST COMMON infectious cause of CORNEAL BLINDNESS in the US→ causes painful inflamed lesion on eyelid or eye surface Ocular eye herpes tx: Trifluridine and gancivclovirl ophthalmic preps → PO acyclovir given when eyedrops/ointments contraindicated. ACYCLOVIR (Zovirax) Antiviral for herpes / nucleoside analog Most effective for HSV1 & HSV2 Prevents viral DNA synthesis which decreases duration and severity of acute herpes episodes As a PPX- may decrease freq of herpes appearances 5% ointment- for acute lesions PO – for PPX tx IV- for severe episodes Has SHORT HALF LIFE- sometimes given 5x/day IV admin can cause painful inflammation to vessels at site of infusion ADMINISTER ATC- even if interrupts sleep. GIVE W FOOD Preg. Cat: C S/e: PO – FEW IV- nephrotoxic/neurotoxic. Increase fluid intake to prevent accumulation in the kidneys, 2-3L/day Neurotoxic s/s (particularly in pts w IV Acyclovir): drowsiness, dizziness, tremors, HA, confusion, changes in LOC, seizures. Resistance developed- especially in AIDS/HIV pts Prebenecid ( med for gout) causes decreased elimination of Acyclovir Zidovudine ( med for HIV) causes > drowsiness & lethargy Pt teaching: teach patient to practice abstinence even if genital lesions are not present * GENITAL HSV infections can be transmitted even in asymptomatic periods. For ointments and creams→ wash hands before and after application ( if CG applying it- wear gloves) *