PH 7 Drugs for Viral and Retroviral Infections.pdf

6 Antivirals and Antiretrovirals LEARNING OUTCOMES 1. Describe the pathophysiology of viruses and retroviruses, and how they cause infections. 2. List the names, actions, possible side effects, and adverse effects of common antiviral drugs for herpes simplex viral infections and influenza infection...

6 Antivirals and Antiretrovirals LEARNING OUTCOMES 1. Describe the pathophysiology of viruses and retroviruses, and how they cause infections. 2. List the names, actions, possible side effects, and adverse effects of common antiviral drugs for herpes simplex viral infections and influenza infections. 3. Explain what to teach patients and families about the common antiviral drugs for herpes simplex viral infections and influenza. 4. List the names, actions, possible side effects, and adverse effects of antiviral drugs for cytomegalovirus and respiratory syncytial virus. 5. Explain what to teach patients and families about antiviral drugs for cytomegalovirus and respiratory syncytial virus. 6. List the names, actions, possible side effects, and adverse effects of antiviral drugs for hepatitis B and C. 7. Explain what to teach patients and families about antiviral drugs for hepatitis B and C. 8. List the names, actions, possible side effects, and adverse effects of the common reverse transcriptase inhibitors and protease inhibitors. 9. Explain what to teach patients and families about reverse transcriptase inhibitors and protease inhibitors. 10. List the names, actions, possible side effects, and adverse effects of the common entry inhibitors, fusion inhibitors, and integrase inhibitors. 11. Explain what to teach patients and families about entry inhibitors, fusion inhibitors, and integrase inhibitors. KEY TERMS AIDS (p. 98) The later stage of HIV disease that causes a breakdown in the immune system, leaving the patient unable to fight infection. antiretroviral (ăn-tī-RĔT-rō-vī-rălz, p. 99) Drugs that are a subset of antiviral drugs and specifically suppress the reproduction of retroviruses. antiviral (ăn-tē-VĪ-răl, p. 94) Drugs capable of interfering with the ability of the virus to carry out its reproductive functions. cART (p. 99) A combination of antiretroviral drugs that must be taken every day to combat the progression of HIV disease from becoming AIDS or to prevent 191 HIV infection after exposure. entry inhibitor (ĔN-trē ĭn-HĬ-bă-tĕr, p. 102) Antiretroviral drugs that prevent cellular infection with HIV by blocking the CCR5 receptor on CD4+ T cells. fusion inhibitor (FYŪ-zhŏn ĭn-HĬ-bă-tĕr, p. 102) Antiretroviral drugs that prevent cellular infection with HIV by blocking the ability of HIV's surface protein gp41 to fuse with the host cell's CD4 receptor. HIV (p. 98) The specific retrovirus responsible for the immune system problems associated with desruction of helper T cells (CD4 cells) when the infection results in HIV disease and progresses to AIDS. integrase inhibitor (ĭn-TĔ-grās ĭn-HĬ-bă-tĕr, p. 102) Antiretroviral drugs that inhibit the HIV enzyme integrase, which the virus uses to insert the viral DNA into the host cell's human DNA. non-nucleoside reverse transcriptase inhibitor (NNRTI) (nŏn-NŪ-klē-ă-sīd rĭVĔRS trăn-SKRĬP-ˌtās ĭn-HĬ-bă-tĕr, p. 99) Antiretroviral drugs that work by binding directly to the HIV-1 enzyme reverse transcriptase, preventing viral cell DNA replication, RNA replication, and protein synthesis. nucleoside reverse transcriptase inhibitor (NRTI) (NŪ-klē-ă-tīd rĭ-VĔRS trănSKRĬP-ˌtās ĭn-HĬ-bă-tĕr, p. 96) Antiretroviral drugs that have a similar structure to the four nucleoside bases of DNA, making them “counterfeit” bases. When these counterfeit bases are used by the HIV enzyme reverse transcriptase, viral DNA synthesis and reproduction are suppressed. opportunistic infection (p. 98) A virus, bacteria, protozoa, or fungi that takes the “opportunity” to cause an infection in an immunocompromised host. protease inhibitor (PI) (PRŌ-tē-āz ĭn-HĬ-bă-tĕr, p. 99) Antiretroviral drugs that suppress the formation of infectious virions by inhibiting the retroviral protease enzyme. retrovirus (RĔT-rō-vī-rŭs, p. 98) Viral organisms that carry special enzymes (reverse transcriptase, integrase, and protease) with them and use RNA (ribonucleic acid) instead of DNA as their genes to reproduce. virion (VĪ-rē-ŭnz, p. 94) New viral particles reproduced in cells infected with retroviruses that can leave the cell and infect more human body cells. virus (VĪ-rŭs, p. 94) A small infectious agent that can reproduce only inside other living cells, including human cells. Virus A virus is a small infectious agent that can reproduce only inside other living cells of a host organism, including human cells. Viruses consist of RNA or DNA genetic material and are surrounded by a protein or fatty (or combination) coating, known as a capsid. The virus inserts its own genetic information into the host cell's nucleus and hijacks the cell's function. This causes the host cell to produce and release more virus particles (virions), so the infection spreads. Damage, breakdown, and eventual death of the infected cell itself also occur with a viral infection. Viruses cannot survive or reproduce without the host. Viral infections are not killed or suppressed 192 by antibiotics. Drugs that are capable of interfering with the ability of the virus to carry out its reproductive functions are called antivirals. Antivirals Antiviral drugs are used to treat a variety of common conditions caused by different viruses. These include viruses that cause herpes zoster, herpes simplex, genital herpes, varicella, some influenza infections, and hepatitis B and C. Antiviral drugs must enter the infected cell and act at the site of infection to be effective. Antivirals do not kill the virus but rather stop viral reproduction. This action means that all antivirals are only virustatic, not virucidal. The antiviral drugs work in a variety of ways: by blocking the virus from entering the host cell, by targeting the enzymes and proteins inside the host cell that allow the viruses to replicate and leave the infected cell to then find new cells to infect, or by helping the host's immune system fight the viral infection. Antiviral Drugs for Herpes Simplex Virus Infections Herpes simplex virus type 1 (HSV-1) is the virus responsible for common “cold sores” of the mouth. This infection can become widespread in newborns and in anyone whose immune system is not functioning well. Herpes simplex virus type 2 (HSV-2) is the virus responsible for genital herpes infections and lesions. Just like all other viruses, once a person is infected, the viruses are always present in some tissues. However, actual symptoms come and go in patterns called outbreaks. An infected person is more likely to spread the virus to other people just before symptoms are present and during actual outbreaks. Outbreaks are uncomfortable and have other consequences; therefore the goal of HSV antiviral therapy is to prevent outbreaks (or at least reduce the frequency and intensity of symptoms), which also helps reduce spread of the disease. Actions The common antiviral drugs for HSV are acyclovir (Zovirax), famciclovir (Famvir), and valacyclovir (Valtrex) (Table 6.1). They are viral DNA polymerase inhibitors that work to reduce viral reproduction by forming “counterfeit” molecules that block the virus and its enzymes from making more genetic material and virions in an infected host cell. Without the genetic material, the virus cannot reproduce. Table 6.1 Antiviral Drugs for Influenza and Herpes Simplex Virus Neuraminidase inhibitors: prevent influenza spread and reduce the symptoms of influenza by suppressing the viral neuraminidase enzyme. As a result, the influenza virus cannot enter uninfected cells and the virions in infected cells are not released for further spread. DRUG/ADULT DOSAGE RANGE NURSING IMPLICATIONS oseltamivir (Tamiflu) 75 mg orally twice daily for 5 days • Before giving zanamivir, ask patients whether they have asthma zanamivir (Relenza): 2 oral inhalations of a 5 mg blister Diskhaler (total of 10 mg) because this orally inhaled drug can cause bronchospasms. twice daily for 5 days with an active influenza infection or for 10 days for • Before giving zanamivir, ask patients whether they have a true uninfected adults in the same household with an infected person milk allergy because this is a contraindication to zanamivir therapy because there is cross-reactivity of the antibodies. • Observe patients for confusion, hallucinations, nightmares, and depression because these drugs cross the blood–brain barrier and can cause central nervous system (CNS) side effects. Uncoating inhibitors: prevent initial influenza infection and spread of influenza infection by interfering with viral uncoating, which is needed for viral fusion with host cells, the first step of cellular infection. 193 DRUG/ADULT DOSAGE RANGE NURSING IMPLICATIONS amantadine (Symmetrel) 200 mg orally once daily or 100 mg orally twice daily • Before giving either of these drugs, ask the patient about all other within 24–48 hours of the onset of symptoms until symptoms are gone drugs he or she takes and check with a pharmacist because of the rimantadine (Flumadine) 100 mg orally once daily within 24–48 hours of symptom numerous possible drug interactions. onset for 5–7 days • Observe patients for confusion, hallucinations, nightmares, and depression because these drugs cross the blood–brain barrier and can cause CNS side effects. • Warn patients to change positions slowly because these drugs can cause orthostatic hypotension. Viral DNA polymerase inhibitors: work to reduce viral reproduction by forming “counterfeit” molecules that block the virus and its enzymes from making more genetic material and virions in an infected host cell. DRUG/ADULT DOSAGE RANGE NURSING IMPLICATIONS acyclovir (Zovirax) 5 mg/kg intravenously for 7 days initially; 400 mg orally twice • Before giving any of these drugs, ask the patient about all other daily to decrease frequency of outbreaks drugs he or she takes and check with a pharmacist because of the famciclovir (Famvir) 1 g orally twice daily for the first day of an outbreak, numerous possible drug interactions. followed by 500 mg orally twice daily for 7 days (HSV-2) • Assess urine output and teach patients to stay hydrated because penciclovir (Denavir): apply 1% cream every 2 hours while awake for 4 days when these drugs can damage the kidneys. lesions appear • Assess patients for fatigue and excessive bruising because these valacyclovir (Valtrex) 1 g orally twice daily for 10 days at first sign of outbreak; drugs decrease bone marrow production of red blood cells and 500 mg orally once daily continually to prevent a person with herpes from platelets. spreading it to an uninfected sexual partner • For patients taking acyclovir or famciclovir, assess for yellowing of the skin and sclera, and elevated liver enzymes because these drugs are liver toxic. • Tell families to watch for confusion or behavior changes because the systemic drugs can affect the CNS. • Warn patients that the skin may become red where the topical cream is applied to reduce their anxiety when the symptom appears. • Warn patients that excessive use of the topical cream can cause systemic side effects and adverse effects because of skin absorption of the drug. • Before giving acyclovir, ask patients whether they have a true milk allergy because this is a contraindication to acyclovir therapy because there is cross-reactivity of the antibodies. Uses Drugs in this class are most often used to prevent and control HSV infections. However, although chicken pox and shingles are caused by a different virus (the varicella zoster virus [VZV]), these drugs can help to control the symptoms of VZV infections. This is because VZV and HSV are very similar and have similar enzymes. Antiviral Drugs for Influenza Actions For influenza viruses to infect cells, they must first open their outer coats to be able to fuse with the host's cell membranes. In addition most viruses that cause common influenza (flu) use a special viral enzyme on their surfaces known as neuraminidase to help cause the infection. This enzyme helps the virus burrow its way into cells that line the respiratory tract. The enzyme also helps new viral particles (virions) made in the infected cells leave the infected cell to spread throughout the respiratory system and infect more cells. So the two types of drugs to treat for influenza are the neuraminidase inhibitors oseltamivir (Tamiflu) and zanamivir (Relenza), and drugs that prevent the virus from opening the outer coat are amantadine (Symmetrel) and rimantadine (Flumadine) (see Table 6.1). Uses All of the antiviral drugs for influenza are used either to prevent an infection in a patient who has been exposed to the virus or to reduce the symptoms of an existing influenza infection. They work best when given after exposure and before symptoms start or within 48 hours of the onset of symptoms. Those that prevent viral uncoating are most effective against influenza A, and the neuraminidase inhibitors are most effective against influenza B. They are used for short-term therapy, usually 2 to 4 194 days. Unfortunately many strains of influenza are becoming resistant to these drugs. Antiviral Drugs for Cytomegalovirus and Respiratory Syncytial Virus Cytomegalovirus (CMV) is a virus from the herpes family that can infect human cells. In people who have a fully functioning immune system, CMV infection causes few problems and may even go unnoticed. However, in the person whose immune system is not functioning well, such as people with AIDS, newborns, and people who are immunosuppressed from chemotherapy, CMV infection can cause serious problems such as brain infection (encephalitis), which can lead to brain damage and death, and serious eye infections (retinitis) that can lead to blindness. Respiratory syncytial virus (RSV) is a common respiratory virus that infects the lungs and the bronchial tubes. It is a very common cause of chest colds, croup, and even pneumonia in children. For healthy people who have good immune function, the diseases it causes are mild, and most people recover in 5 to 7 days without treatment. However, in premature infants, newborns, small children who have chronic illnesses, and older adults with weakened immune systems, the respiratory infection can be severe and lead to death. Actions and Uses Drugs to treat CMV come from the viral DNA polymerase inhibitor class. These drugs inhibit the viral enzyme's need to make more DNA for viral reproduction. As a result, fewer virions are made and the infection symptoms subside. The drugs used for this purpose are cidofovir (Vistide) and foscarnet (Foscavir) (Table 6.2). They are both extremely toxic, are given intravenously, and are used on a short-term basis to reduce infection symptoms. Table 6.2 Antiviral Drugs for Cytomegalovirus and Respiratory Syncytial Virus Anticytomegalovirus drugs/DNA polymerase inhibitors: These drugs inhibit the viral form of the enzyme needed to make DNA for viral replication. As a result, fewer virions are made and the symptoms of the acute infection are stopped. DRUG/ADULT DOSAGE RANGE NURSING IMPLICATIONS cidofovir (Vistide) 5 mg/kg intravenously once weekly for 2 weeks • Do not mix these drugs with other drugs because they are incompatible with foscarnet (Foscavir) 40 mg/kg intravenously every 8–12 hours for 14– most other drugs. 21 days • Be sure the patient receives adequate hydration during therapy because these drugs are very toxic to the kidneys. • Should not be used in women who are pregnant unless the infection is lifethreatening because the risk for birth defects is high. • Ask patients whether they have a seizure disorder because these drugs increase the likelihood for seizures. • Assess patients frequently for signs of infection because bone marrow production of white blood cells is suppressed, increasing the risk for infections. • Give drugs by slow infusion to reduce the risk for immediate adverse reactions. • Frequently assess the patient's red blood cell counts because these drugs suppress the bone marrow and can cause severe anemia. • Assess the patient's heart rate, rhythm, and respiratory system frequently because these drugs can cause heart and respiratory adverse events. • Use gloves and masks when giving these drugs because they are both classified as “hazardous drugs” and precautions are needed to avoid exposure of these drugs to anyone except the patient. • For patients receiving foscarnet, check their serum electrolytes whenever they are drawn because this drug causes many electrolyte imbalances. • Before giving cidofovir, ask about allergies to sulfonamides or probenecid because cross-reactivity can result in a similar cidofovir allergic reaction. Drugs for RSV: The only drug in this class is ribavirin, which directly damages genetic material, both RNA and DNA, and causes cell mutations. The mutated virions are unable to reproduce. DRUG/ADULT DOSAGE RANGE NURSING IMPLICATIONS ribavirin (Virazole) aerosol or nasal inhalant of 190 mcg/L air or • Avoid all contact with this drug because it is very hazardous. Use these 195 oxygen (for children and adults) 600 mg orally twice daily for adults receiving therapy for hepatitis C precautions when giving the aerosol form: • Wear gloves, a mask, and a gown during administration. • Close the door to the patient's room to prevent the drug from entering the hallway and endangering others. • If you are pregnant, do not give this drug because it can cause severe birth defects or fetal death. • Assess the patient's red blood cell counts frequently because these drugs suppress the bone marrow and can cause severe anemia. • Assess patients frequently for signs of infection because bone marrow production of white blood cells is suppressed, increasing the risk for infections. The only drug approved for RSV treatment is ribavirin (Virazole). It is also very toxic, even when given in aerosol form, and requires careful handling (see Table 6.2). It also has some efficacy for treating hepatitis C virus (HCV). For treating RSV, it is used only short-term as an aerosol. For hepatitis C, it is taken orally along with other drugs for years. Antiviral Drugs for Hepatitis B and Hepatitis C Viruses Hepatitis B virus (HBV) and HCV are both hardy viruses that can live in a variety of environments. In the United States and Canada the most common ways these viruses cause infection are by the blood-borne route and by sexual transmission. Both have a long incubation period (2–26 weeks) after infection followed by first an acute illness and then often a chronic illness. The acute phase of HBV may result in a noticeable illness in about 30% of infected people. For others the acute phase is so mild that there may be no obvious symptoms. For HCV, few infected individuals have any symptoms during the acute phase. With both HBV and HCV, active virus remains in the blood forever. Some people with HBV have chronic recurrence of symptoms from time to time. With HCV, the disease remains dormant for years (although it can be transmitted) and then causes profound liver damage with cirrhosis. The major drugs used to treat HBV fall into three classes: the nucleoside reverse transcriptase inhibitors (NRTIs), the DNA polymerase inhibitors, and interferon. The NRTI drug is lamivudine. This is the same class of drugs used as part of treatment for HIV infection and AIDS (see the Antiretrovirals section later in this chapter for the actions and nursing implications of this drug). This oral drug works in the same way against HBV (although it is not a true retrovirus), at a lower dosage than what is needed for HIV infection. The DNA polymerase inhibitors are adefovir (Hepsera), entecavir (Baraclude), lamivudine (Epivir), and telbivudine (Tyzeka). This is the same class of drugs used to treat CMV infection, but these are oral drugs given once daily long term (Table 6.3). Interferon, specifically interferon alfa-2b (Intron A), is a synthetic injected drug similar to the interferon the human body makes to fight viral infections. Chapter 14 describes the mechanism of action, drug dosages, and nursing implications for interferon therapy. Table 6.3 Drugs for Hepatitis B and Hepatitis C DNA polymerase inhibitors: These drugs inhibit the viral form of the enzyme needed to make DNA for viral replication. As a result, fewer virions are made and blood levels of the virus decline. DRUG/ADULT DOSAGE RANGE NURSING IMPLICATIONS adefovir (Hepsera) 10 mg orally once daily • Assess patients for yellowing of the skin and sclera, and elevated liver enzymes because these entecavir (Baraclude) 1 mg orally once daily drugs are toxic to the liver. telbivudine (Tyzeka) 600 mg orally once daily • Assess patients for nausea, vomiting, and severe epigastric pain because these drugs increase the risk for pancreatitis. • Ask patients taking adefovir about bone pain because it can cause bone thinning and increased risk for fractures. 196 • Give entecavir on an empty stomach because stomach contents interfere with its absorption. Protease inhibitors: These drugs competitively block the viral protease enzyme, preventing viral replication and release of viral particles. DRUG/ADULT DOSAGE RANGE NURSING IMPLICATIONS simeprevir (Olysio) 150 mg orally daily along with • Assess patients for yellowing of the skin and sclera, and elevated liver enzymes because this drug other antiviral drugs is toxic to the liver. • Teach patients to protect themselves from the sun with clothing, hats, and sunscreen because this drug increases sun sensitivity and can result in severe sunburn. • Teach patients to take this drug with food to prevent GI side effects. Combination agent: This drug, now reported to “cure” hepatitis C, is a combination antiviral agent containing the viral protein inhibitor ledipasvir and the viral DNA polymerase inhibitor sofosbuvir. DRUG/ADULT DOSAGE RANGE NURSING IMPLICATIONS ledipasvir 90 mg/sofosbuvir 400 mg (HARVONI): 1 • Assess patients for yellowing of the skin and sclera, and elevated liver enzymes because this drug tablet orally daily for 8–12 weeks is toxic to the liver. • Ask the patient and family about any changes in mood or increase in depression because a higher incidence of suicide ideation has been seen with this drug. General antiviral drugs used to treat HCV include ribavirin (Virazole) (discussed earlier in this chapter) and interferon alfa-2b (discussed in Chapter 14). Additional drugs are listed in Table 6.3. Of note is a new drug, Harvoni, which suppressed HCV replication and presence in the blood to such an extent that it is thought to result in a “cure.” However, the extreme cost of this drug for 12 weeks of treatment (about $96,000 in 2016 prohibits many patients from using it and thus they continue with more standard therapy. General Antiviral Expected Side Effects, Adverse Reactions, and Drug Interactions Expected side effects to antivirals include vomiting, nausea, diarrhea, and headache. Adverse reactions are reported for some antivirals, and you should read current information before giving these drugs. Tables 6.1 through 6.3 provide specific adverse reactions and nursing implications for antiviral drugs. All drugs can cause hypersensitivity and/or anaphylactic shock. Always be aware of rashes, hives, difficulty breathing, and facial swelling. If hypersensitivity reactions occur, then the drug should be discontinued and the prescriber made aware. If an anaphylactic event occurs as indicated by difficulty breathing, swelling of the mouth and tongue, and unstable vital signs, emergency measures must be taken immediately. Many antivirals also have drug interactions. As antivirals become more widely used these interactions may increase. Again, to be prudent, always look up current information. Some antivirals can be applied topically and as such do not have systemic interactions as they would if they were taken orally or by injection. Nursing Implications and Patient Teaching Table 6.1 gives an overview of antivirals currently used to treat herpes infections and influenza infection or influenza prophylaxis. You may also notice that the antivirals have a common suffix of either -vir or -dine. Table 6.2 gives an overview of some very toxic intravenous antivirals used for the more serious problems of CMV retinitis and RSV. You may not be giving these drugs, but you may be responsible for caring for these patients. All of these drugs carry serious warnings for patients and black box warnings for healthcare providers, so caution should be taken. Top Tip For Safety Only two antivirals are used in treating or preventing influenza in children: 197 oseltamivir phosphate (Tamiflu) and zanamivir (Relenza). Patient and family teaching. Tell the patient and family the following: • When using topical drugs for treatment of HSV-1 (cold sores) or HSV-2 (genital herpes), use gloves and wash your hands thoroughly so the infection does not spread. • There is no cure for herpes. Antivirals can only treat herpes prophylactically or symptomatically. • To be effective, oral drugs should be started at the first sign of infection or reinfection. • The drugs must be used daily for suppression of the herpes virus. • When using antivirals for flu, it is best to begin usage within 2 days of being sick; however, starting them later may still be helpful in preventing serious flu symptoms. • Antivirals will not cure the flu, so there is still a need to reduce symptoms such as fever, cough, and pain. • Check yourself daily for worsening symptoms that may indicate pneumonia or bacterial infection. If these are present, notify your healthcare provider immediately so that antibiotics can be started instead of antivirals. • Antivirals can also be used for prevention or prophylaxis of the flu in unvaccinated persons who have been exposed to the disease. Prevention works best if these drugs are taken before flu symptoms are present or within the first 24 to 48 hours after they appear. • Follow the specific storage instructions listed on the package for the drug. Retrovirus Retroviruses are organisms that differ from viruses in that instead of merely hijacking a cell's DNA or RNA to reproduce, they transmit their own information into the cell's DNA. Normally, cellular DNA is unzipped by an enzyme called transcriptionase and then transmitted by RNA to the ribosome, where protein 198 synthesis takes place. Protein is the building block of all tissue and needs the DNA information to form. Retroviruses carry special enzymes (reverse transcriptase, integrase, and protease) with them and use RNA instead of DNA as their genes. The retrovirus inserts its own genetic material into the host cell DNA from its RNA. In this way the retrovirus can expand and multiply all the while using the host cell's metabolic systems to make virions (new viral particles) that can leave the cell and infect more cells. HIV is the retrovirus responsible for the immune system problems when infection with this organism results in HIV disease and progresses to AIDS. Once a person has become infected with HIV, he or she will have the virus for life. HIV attacks the body's CD4 or helper T cells that are responsible for helping the immune system fight infections. If HIV is left untreated, the decreased number of CD4 cells in the body makes the person highly susceptible to infections such as tuberculosis, viruses such as CMV, and cancers such as non-Hodgkin lymphoma. These opportunistic infections signal that AIDS has developed in the person. AIDS is the later stage of HIV disease that causes a breakdown in the immune system, leaving the patient unable to fight any infection. In the United States the groups at highest risk for development of AIDS include homosexual and bisexual men, although the fastest growing group to develop AIDS is minority heterosexual women. When compared with other racial and ethnic groups, HIV mostly affects African American and Hispanic individuals. Transgender women who have sex with men are among the groups at highest risk for HIV infection. Intravenous drug users remain at significant risk for acquiring HIV. Other groups at high risk are children born to HIV-positive women and individuals whose sexual partners have HIV/AIDS. According to the Centers for Disease Control and Prevention, in 2013 people 55 years and older accounted for 26% of all Americans living with diagnosed or undiagnosed HIV infection. Appropriate treatment with combined antiretroviral drugs has prolonged the lives of patients with HIV/AIDS for as much as 35 years. The HIV life cycle occurs in seven steps, and the HIV drugs are designed to attack the virus at different steps. The steps in the HIV life cycle and where each category of HIV drug works are presented in the following list and shown in Fig. 6.1. 199 FIG. 6.1 Infection and cellular outcomes of HIV. HIV infection begins when a virion (1), or virus particle, binds to the outside of a susceptible cell and fuses with it (2), injecting the core proteins and two strands of viral RNA (3). Uncoating occurs, during which the core proteins are removed and the viral RNA is released into the infected cell's cytoplasm. The double-stranded DNA (4), or provirus, migrates to the nucleus, uncoats itself (5), and is integrated into the cell's own DNA (6). The provirus then can do a couple of things: remain latent (7A) or activate cellular mechanisms to copy its genes into RNA (7B), some of which is translated into virus proteins or ribosomes. The proteins and additional RNA are then assembled into new virions that bud from the cell. The process can take place slowly, sparing the host cell (7B), or so rapidly that the cell is lysed or ruptured (7C). (From Workman ML, LaCharity LA: Understanding pharmacology, ed 2, St. Louis, 2016, Elsevier.) 1. Attachment: The HIV binds or attaches to the outside of the CD4 (T helper) cell. Entry inhibitors work here to prevent the attachment. 2. Fusion: The HIV and the CD4 cell become locked or fused together and the HIV enters the cell. Fusion inhibitors work here to prevent the fusion. 3. Reverse transcriptionase: Inside the cell the reverse transcriptionase enzyme made by the HIV converts the HIV RNA into the DNA of the cell nucleus. This is where NRTIs and NNRTs work to prevent the transfer from occurring. 4. Integration: Inside the nucleus of the CD4 cell the HIV releases another enzyme integrase that places the viral DNA into the CD4 cell DNA. This is where integrase inhibitors work to prevent the release of the enzyme integrase. 5. Replication: The HIV has completely changed the CD4 cell DNA and the RNA messenger. Now the CD4 cell starts to make long HIV protein chains that will later break up into smaller chains and begin to infect other cells. 6. Assembly: All of the new long HIV chains move under the surface of the CD4 cell and assemble. They are not infective yet. 7. Budding: The HIV chains burst out of the cell and release an enzyme protease, which breaks up the long chain into small buds of protein particles that are now free to infect more CD4 cells. This is where the protease inhibitors (PIs) work to prevent the release of protease. 200 Antiretrovirals Antiretrovirals are an important group of drugs that slow the growth or prevent the duplication of retroviruses. They are used to limit or slow the advance of HIV and its progression to AIDS. Antiretroviral drugs are used in treating the patient infected with HIV or for adults and children at risk for acquiring HIV and AIDS. They do not cure HIV or AIDS, but they do help patients live healthier, longer lives by acting to interfere with the ability of the retrovirus to replicate (reproduce) and slowing the production of new retroviruses. All antiretroviral drugs are virustatic rather than virucidal. None of these drugs kill the virus. Drug therapy for HIV infection and AIDS works best when several different types of antiretroviral drugs are used together daily. This therapy is known as combination antiretroviral therapy (cART). The six categories of antiretroviral therapy drugs are NRTIs, non-nucleoside reverse transcriptase inhibitors (NNRTIs), PIs, integrase inhibitors, fusion inhibitors, and entry inhibitors. They are all called inhibitors because, rather than killing the virus, they suppress retroviral reproduction either by preventing HIV from infecting host cells or by inhibiting different steps in the HIV life cycle. None of these drugs are useful or effective against HIV when used alone. Table 6.4 lists the common drugs in each category and their nursing implications. Fig. 6.1 shows where in the HIV infection process and life cycle different categories of antiretroviral drugs inhibit retroviral reproduction. These drugs are used only for the management of HIV disease. Table 6.4 Examples of Antiretroviral Drug Therapy for HIV Infection Nucleoside reverse transcriptase inhibitors (NRTIs): These drugs have a similar structure to the four nucleoside bases of DNA, making them “counterfeit” bases. They fool the HIV enzyme reverse transcriptase into using these counterfeit bases so that viral DNA synthesis and replication are suppressed. All NRTIs are oral drugs. DRUG/ADULT DOSAGES RANGE NURSING IMPLICATIONS abacavir (Ziagen) 300 mg orally twice • Remind patients to avoid fatty and fried foods with these drugs because they cause digestive upsets and may daily or 600 mg orally once daily lead to pancreatitis when combined with NRTIs. didanosine (Videx EC) 125–200 mg • Teach patients to use precautions to prevent injury because these drugs induce peripheral neuropathy. orally twice daily • Teach patients taking abacavir to report flu-like symptoms to the provider immediately because these emtricitabine (Emtriva) 200 mg orally symptoms may indicate a hypersensitivity reaction that requires discontinuing the drug. once daily • Instruct patients to avoid or severely limit alcoholic beverages to reduce the risk for liver damage while on lamivudine (Epivir) 300 mg orally once these drugs. daily • Do not give abacavir to patients who test positive for the HLA-B 5701 tissue type because fatal allergic stavudine (Zerit) 40 mg orally twice responses are likely. daily • Tell patients that the solution form and capsule form of emtricitabine (Emtriva) are not interchangeable on a tenofovir (Viread) 300 mg orally once mg per mg basis daily zidovudine (Retrovir) 300 mg orally twice daily Non-nucleoside reverse transcriptase inhibitors (NNRTIs): These drugs work by binding directly to the HIV-1 enzyme reverse transcriptase, preventing viral cell DNA replication, RNA replication, and protein synthesis. This action suppresses viral replication of the HIV-1 virus but does not affect HIV-2 viral replication. All NNRTIs are oral drugs. DRUG/ADULT DOSAGE RANGE NURSING IMPLICATIONS delavirdine (Rescriptor) 400 mg orally • Check laboratory values for increases in liver enzymes and decreased red blood cells because the most three times daily common side effects are anemia and liver toxicity. efavirenz (Sustiva) 600 mg orally once • Teach patients to take these drugs at least 1 hour before or 2 hours after taking an antacid to avoid inhibiting daily at bedtime GI absorption. etravirine (Intelence) 200 mg orally • Instruct patients to notify the prescriber if a sore throat, fever, different types of rashes, blisters, or multiple twice daily bruises develop because these are indications of a serious adverse drug effect. rilpivirine (EDURANT) 25 mg once • Do not give delavirdine or efavirenz to pregnant women because these two drugs have the potential to cause daily with a meal birth defects and developmental problems. Protease inhibitors (PIs): These drugs competitively block the HIV protease enzyme, preventing viral replication and release of viral particles. The HIV initially produces all of its proteins in one long strand, which must be broken down into separate smaller proteins by HIV protease to be active. Thus, when inhibited, viral proteins are not functional and viral particles cannot leave the cell to infect other cells. All PIs are oral drugs. DRUG/ADULT DOSAGE RANGE NURSING IMPLICATIONS atazanavir (Reyataz) 300 mg orally • Instruct patients not to chew or crush these drugs because this action may cause the drug to be absorbed too daily rapidly and increase the risk for side effects. darunavir (Prezista) 800 mg orally • Teach patients to report jaundice, nausea and vomiting, or severe abdominal pain because these drugs can twice daily induce liver toxicity. fosamprenavir (Lexiva) 700 mg orally • Instruct patients to keep all appointments for laboratory work because these drugs increase blood lipid levels twice daily and increase the risk for atherosclerosis and pancreatitis. 201 indinavir (Chemet, Crixivan) 800 mg • Remind patients to avoid St. John's wort while taking these drugs because the supplement reduces the orally every 8 hours effectiveness of all PIs. lopinavir/ritonavir (Kaletra) 400 • Teach patients taking atazanavir and ritonavir to check their pulse daily and report low heart rate to the mg/100 mg orally twice daily prescriber because these two drugs can impair electrical conduction and lead to heart block. nelfinavir (Viracept) 1250 mg orally • Do not give darunavir or fosamprenavir to patients who have a known sulfa allergy because these two drugs twice daily with a meal contain sulfa. saquinavir (Fortovase, Invirase) 500 mg orally twice daily tipranavir (Aptivus) 500 mg orally twice daily Entry inhibitors/CCR5 antagonists: These drugs prevent cellular infection with HIV by blocking the CCR5 receptor on CD4+ T cells. (The virus's gp120 must bind to the CD4 receptor and its gp41 must bind to the CCR5 receptor or to the CXCR4 receptor for entry into host cells). These are all oral drugs. DRUG/ADULT DOSAGE RANGE NURSING IMPLICATIONS maraviroc (Selzentry) 150–600 mg • Instruct patients not to chew or crush this drug because this action may cause the drug to be absorbed too orally twice daily rapidly and increase the risk for side effects. • Teach patients to change positions slowly because hypotension is a common side effect, especially orthostatic hypotension. • Teach patients to report jaundice, nausea and vomiting, or severe abdominal pain because these drugs can induce liver toxicity. • Instruct patients to report pain or numbness in the hands or feet because this drug can induce peripheral neuropathy. Fusion inhibitors: These drugs block the fusion of HIV with a host cell by blocking the ability of gp41 to fuse with the host cell's CD4 receptor. Without fusion, infection of new cells does not occur. DRUG/ADULT DOSAGE RANGE NURSING IMPLICATIONS enfuvirtide (Fuzeon) 90 mg • Teach patients how to prepare and inject the drug subcutaneously to ensure correct dosage and effectiveness. subcutaneously twice daily • Assess injection sites for warmth, swelling, redness, skin hardening, or bump formation because these are indications of injection-site reactions. • Instruct patients to report pain or numbness in the hands or feet because this drug can induce peripheral neuropathy. • Teach patients to report jaundice, nausea and vomiting, or severe abdominal pain because this drug can induce liver toxicity. • Teach patients to observe for and report cough, shortness of breath, fever, and purulent mucus because this drug increases the risk for severe respiratory infections, including pneumonia. Integrase inhibitors: These drugs inhibit the HIV enzyme integrase, which the virus uses to insert the viral DNA into the host cell's human DNA. Without this action, viral proteins are not made and viral replication is inhibited. DRUG/ADULT DOSAGE RANGE NURSING IMPLICATIONS dolutegravir (Tivicay) 50 mg orally • Warn patients that diarrhea, nausea, rash, insomnia, and abdominal pain are common side effects of these once or twice daily drugs, because knowing the expected side effects decreases anxiety when they appear. elvitegravir (Vitekta) 85–150 mg orally • Suggest that patients take the drug with food to reduce the GI side effects. once daily • Instruct patients not to chew or crush these drugs because this action may cause the drug to be absorbed too raltegravir (Isentress) 400 mg orally rapidly and increase the risk for side effects. twice daily • Instruct patients to report new-onset muscle pain or weakness because these drugs can cause muscle breakdown (rhabdomyolysis), especially in adults taking a “statin” type of lipid-lowering drug. • Teach patients with diabetes to closely monitor blood glucose levels because these drugs increase hyperglycemia. • Do not give raltegravir to pregnant women because it is associated with an increased risk for birth defects. Combination products: Each ingredient has the same mechanism of action and nursing implications as the parent drug class. Atripla (emtricitabine, tenofovir, and efavirenz) Combivir (lamivudine and zidovudine) Complera (emtricitabine, rilpivirine, and tenofovir) Epzicom (lamivudine and abacavir) Genvoya (elvitegravir, cobicistat,a emtricitabine, and tenofovir) Stribild (elvitegravir, cobicistat,a emtricitabine, and tenofovir) Triumeq (dolutegravir, abacavir, and lamivudine) Truvada (emtricitabine and tenofovir) a Cobicistat is a metabolizing enzyme inhibitor that allows other drugs in the combination to remain active longer, boosting their antiretroviral action. Although cART is usually started and managed by healthcare providers in special settings and clinics for immune disorders, this drug therapy must continue for the rest of the patient's life. Therapy is effective only if the patient takes the prescribed drugs correctly and on time at least 90% of the time. So people who are HIV-positive and taking cART may be a patient or resident in any healthcare setting. Regardless of the setting, they must continue the prescribed therapy. Memory Jogger The six categories of antiretroviral therapy drugs are: 1. NRTIs 2. NNRTIs 3. PIs 202 4. entry inhibitors 5. fusion inhibitors 6. integrase inhibitors Lifespan Considerations Pregnancy and Pediatric With the exception of delavirdine or efavirenz, the NRTI, NNRTI, and PI classes of antiretroviral drugs are commonly given throughout pregnancy for HIV-infected women and for children who are HIV-positive. Taking this combination of drugs during pregnancy greatly reduces the risk for transmitting HIV to the unborn child. The other classes of antiretroviral drugs are not approved for use in children or pregnant women. Actions of Drugs Used for Antiretroviral Therapy Nucleoside Reverse Transcriptase Inhibitors NRTIs are antiretroviral drugs that have a similar structure to the molecules that comprise DNA, making them “counterfeit” molecules. The NRTIs work by blocking the function of reverse transcriptionase and preventing the complete synthesis of the viral DNA. Without reverse transcriptase, HIV cannot make new virus copies of itself. These drugs work early in the life cycle of the HIV (see Fig. 6.1). Non-nucleoside Reverse Transcriptase Inhibitors NNRTIs bind directly to the HIV-1 enzyme reverse transcriptase, preventing viral cell DNA replication, RNA replication, and protein synthesis. With these actions interrupted, HIV reproduction is slowed or stopped. These drugs work fairly early in the HIV life cycle (see Fig. 6.1). Memory Jogger Remember the class of NNRTIs by the letters vir in the middle of the generic names of drugs in this class. Protease Inhibitors PIs are antiretroviral drugs that suppress the formation of infectious virions by inhibiting the viral protease enzyme. They act later in the life cycle of the virus (see Fig. 6.1). One of the final stages of the HIV life cycle is the production of HIV proteins, which are first produced as one large protein strand. This single, large protein must be separated by the HIV enzyme protease (which acts like “chemical scissors”) into smaller activated proteins needed for the production of more infectious virions. PIs block the HIV enzyme protease and prevent these important proteins from being activated. As a result, infectious HIV virions are not produced 203 and released. Memory Jogger Remember the PI class of drugs by the suffix -navir at the end of the generic names. Entry Inhibitors Entry inhibitors, also known as CCR5 antagonists, are antiretroviral drugs that prevent cellular infection with HIV by blocking the HIV from attaching to special receptors on CD4+ T cells. Each HIV must bind to both of two specific receptors on the CD4 T cell for entry into this host cells. Thus this class of drugs protects uninfected cells from HIV infection. (see Fig. 6.1). Fusion Inhibitors Fusion inhibitors are antiretroviral drugs that prevent cellular infection with HIV by blocking the ability of HIV's surface protein to fuse or lock with the host cell's CD4 receptor. Without fusion, infection of new cells does not occur. Just like the entry inhibitors, fusion inhibitors protect uninfected host cells from becoming HIVinfected. (see Fig. 6.1). Integrase Inhibitors Integrase inhibitors are antiretroviral drugs that inhibit the HIV enzyme integrase, which the virus uses to insert the viral DNA into the host cell's human DNA. Without this action, viral proteins are not made and viral replication is inhibited. Integrase inhibitors work early in the life cycle of HIV infection (see Fig. 6.1). Expected Side Effects of Antiretroviral Drugs Most antiretroviral drugs are taken in combination; therefore determining which drug is causing side effects can be difficult. In addition some of the same problems are caused by the HIV disease as by the drugs used to treat it. Common expected side effects for all antiretroviral drugs include mouth ulcers, nausea, and diarrhea. Skin rashes and headaches are also common. Many patients report vivid dreams or nightmares while taking these drugs. Table 6.4 lists many of the common side effects of the drugs. Adverse Reactions of Antiretroviral Drugs Antiretrovirals often cause severe toxic reactions. Most of these drugs can also cause damage to the liver (hepatotoxic) or kidneys (nephrotoxic). Many also cause inflammation of the pancreas known as pancreatitis. Other possible adverse effects include lactic acidosis, peripheral neuropathy (loss of nerve function, especially in the hands and feet), and diseases that affect the blood. Pre-Exposure Prophylaxis 204 There is a new drug therapy to prevent HIV transmission to the uninfected sex partners of people who are HIV-positive and are using cART. The drug approved for this purpose is tenofovir 300 mg/emtricitabine 300 mg (Truvada), which is an oral tablet taken once daily for as long as the person remains at risk for infection. It can only be taken by people who are HIV-negative but are at high risk for becoming infected. After starting Truvada, the person must have his or her HIV status checked every 3 months. The person must take the drug as prescribed for at least 4 days before Truvada can begin to effectively protect against HIV infection. Nursing Implications and Patient Teaching Lifespan Considerations Older Adults • Immunocompromised older adult patients may have other chronic diseases. This may mean that they are taking 8 or 10 drugs at a time. These patients often need encouragement to continue taking all of their drugs. • Monitoring for adverse effects from some of the drugs used to treat patients with HIV is more difficult in older adult patients. It is sometimes difficult to know which drugs are causing the adverse reactions because older adults have other health problems and take other drugs. Safety Alert! Signs or Symptoms of Pancreatitis Upper abdominal pain and/or pain that radiates to the back, pain that worsens after eating, fever, rapid pulse, increased nausea, and vomiting may indicate pancreatitis, which is a medical emergency. Safety Alert! Symptoms of Lactic Acidosis Weakness, fatigue, unexplained muscle pain, nausea, vomiting, dizziness, cold arms and legs, irregular heart rate, and difficulty breathing are symptoms of lactic acidosis. Patient and family teaching. The patient taking cART has probably been doing so for some time and may know more about these drugs than you do. However, it is important to remind the patient 205 and his or her family about the following: • Take the drugs exactly as ordered every day to ensure the drugs work properly and your disease does not become resistant to the drugs. • Taking too little of the drugs or skipping doses leads to drug resistance and disease advancement. It is imperative not to skip doses or decrease the dosage. • Use pillboxes, pill reminders, and/or diaries to maintain strict compliance. • Take the drugs at the same time every day and use a cell phone reminder for time alerts. This way drug levels remain steady and viral suppression is ideal. • Alert your healthcare provider immediately to specific symptoms that may indicate adverse reactions. • Do not cut down or stop the drugs until told to do so by your healthcare provider. • Safer sexual practice and standard precautions must be taken to prevent disease transmission. • Impaired immunity makes it more likely to contract diseases. Avoid eating raw meats and fish, and fruits and vegetables that cannot be peeled or scrubbed. • If you are lactating, stop breast-feeding your baby because there is a high risk for HIV transmission in breast milk. • Report any new over-the-counter herbs, vitamins, illegal drugs, and nutritional supplements to your prescriber because they could cause increased adverse reactions. • Do not miss clinic or laboratory appointments. CD4 counts guide treatment. These drugs are highly liver toxic, so liver enzymes must be measured frequently. Complete blood counts monitor infections and adverse effects. Amylase and lipase levels monitor pancreatitis, and lactic acid levels monitor lactic acidosis because 206 symptoms of lactic acidosis are rather nonspecific. • Avoid alcohol and recreational drugs because of the increased risk for liver damage associated with these drugs. • Report signs of neuropathy: numbness; tingling in feet or hands, which spread to legs and arms; sharp, jabbing, throbbing, or burning pain in arms and legs; and decreased coordination and falling. • If you have symptoms of pancreatitis (upper abdominal pain that may radiate to your back, pain that worsens after eating, increased nausea and vomiting), notify your healthcare provider immediately so treatment can begin early. Get Ready for the NCLEX® Examination! Key Points • Viruses are organisms that cannot self-produce, so they “hijack” a cell to reproduce. • Retroviruses do not just hijack a cell, they actually become a part of the cell and therefore are highly efficient at spreading their infection. • All antiviral drugs are virustatic; they only suppress viral reproduction and do not kill the virus. • Antiretroviral drugs are most effective when combinations of drugs from several antiretroviral categories are given daily. This type of therapy is known as cART (combination antiretroviral therapy). • Teach patients to take antiviral drugs exactly as prescribed and not to stop unless ordered to do so by the prescriber. • To be most effective in preventing HIV infection and slowing HIV reproduction, cART drugs must be taken correctly and on time at least 90% of the time. • Except for the fusion inhibitor, enfuvirtide (Fuzeon), antiretroviral drugs are given orally. • Antivirals used for CMV retinitis and RSV (ribavirin and cidofovir) carry a black box warning and are never to be used or touched by anyone who is pregnant or breast-feeding. • Antivirals have many interactions with other drugs. Always check for interactions with a drug handbook before giving them. • Antiretroviral drugs are highly toxic to the liver, kidney, and pancreas. Teach 207 patients to be alert for signs and symptoms of toxicity. • Some antiretroviral drugs need to be taken together on an empty stomach or with food. Teach patients the importance of taking the drugs exactly as they were prescribed. Review Questions for the NCLEX® Examination 1. The patient has been started on an antiretroviral drug. He tells the nurse he has mouth ulcers. What does this finding suggest? 1. It is indicative of an anaphylactic reaction. 2. It is an expected side effect of the drug. 3. It is an unexpected toxic reaction of the drug. 4. It is indicative of liver or kidney damage. 2. Which classes of antiretroviral drugs are approved for use during pregnancy in HIV-positive women? (Select all that apply.) 1. Entry inhibitors 2. Fusion inhibitors 3. Integrase inhibitors 4. Non-nucleoside reverse transcriptase inhibitors 5. Nucleoside reverse transcriptase inhibitors 6. Protease inhibitors 3. Which antiretroviral drug belongs to the protease inhibitor class? 1. darunavir (Prezista) 2. dolutegravir (Tivicay) 3. etravirine (Viramune) 4. tenofovir (Viread) 4. For which antiretroviral drug does the nurse need to assess the patient's subcutaneous injection site for irritation, warmth, or bump formation? 1. abacavir (Ziagen) 2. indinavir (Crixivan) 3. enfuvirtide (Fuzeon) 4. raltegravir (Isentress) 5. Which antiviral is given by inhalation? 1. famciclovir 2. oseltamivir phosphate 3. zanamivir (Relenza) 4. acyclovir 6. Which drugs should not be used in persons with an allergy to milk products? (Select all that apply.) 1. acyclovir 208 2. famciclovir 3. amantadine hydrochloride 4. oseltamivir phosphate 5. zanamivir 6. penciclovir 7. Which antiviral can be given by mouth, by injection, or applied topically? 1. famciclovir 2. acyclovir 3. zanamivir 4. penciclovir 8. What is the action of a virustatic drug? 1. The drug kills the virus. 2. The drug stops the virus from producing. 3. The drug increases the effectiveness of white blood cells. 4. The drug blocks reverse transcriptase. 9. Which of the following foods should be avoided in persons taking cART? 1. Oranges 2. Bananas 3. Sushi 4. Kale 10. Which drug can be taken only by people who are HIV negative but are at high risk for becoming infected? 1. tenofovir 300 mg/emtricitabine 300 mg 2. delavirdine 200 mg 3. lamivudine 300 mg/zidovudine 300 mg 4. abacavir 600 mg 11. Order: “acyclovir 5 mg/kg intravenous every 8 hours.” The patient weighs 165 lb. 1. How many kilograms does the patient weigh? 2. How many milligrams of acyclovir should be given with the first dose? 12. Order: “delavirdine 400 mg three times a day.” The patient has HIV. Supplied: delavirdine 200-mg tablets. How many tablets will the patient need for a 10-day supply? Case Study Mary Taft is a patient who has AIDS. She states that her symptoms include sharp, burning pains in her feet with numbness and sensitivity to touch. She has been receiving cART. 1. What disease process or syndrome does Mary's symptoms suggest? 2. If the symptoms are ignored, what might happen? 209