a disease of the human immune system that is caused by the human immunodeficiency virus (HIV) and characterized by a reduction in the numbers of certain immune system cells, thereby rendering the person highly vulnerable to life-threatening opportunistic infections secondary to reduced immune function.
DNA (deoxyribonucleic acid)
the genetic blueprint for all living organisms typically found on chromosomes within the nucleus of human cells but also incorporated into some types of virus particles.
RNA (ribonucleic acid)
a nucleic acid concerned with the synthesis of protein and occurring in the nucleus and cytoplasm of cells but also incorporated into some types of virus particles.
a microscopic infectious agent, classified as parasitic because it is incapable of reproduction outside an infected living host cell.
After completing this chapter, you should be able to
Define the following:
Describe common types of viral infections.
Differentiate between viral infections treated with antiviral therapy and those whose treatment is restricted to supportive care.
Describe the different types of antiviral medications and the targets of action of each.
List the major adverse effects, cautions, and drug interactions for antiviral medications.
Viruses are the smallest parasites, ranging from 0.01–0.8 microns (about one tenth the average size of bacteria) and 100–1,000 times smaller than the cells they infect.1 Unlike bacteria, viruses are not living organisms. They are capsules of genetic material depending completely on living cells (bacterial, plant, or animal) to reproduce, so they are called obligate parasites. Viruses have an outer cover of protein and sometimes lipid (fat), referred to as a capsid, and an RNA (ribonucleic acid) or DNA (deoxyribonucleic acid) core. For infection to occur, the virus first attaches to the host cell, then fuses with its cell membrane and enters the cell. The viral DNA or RNA then separates from the outer cover (uncoating) and uses the enzymes and cellular machinery of the host cell to make copies (replicate) of the virus. Most RNA viruses replicate their nucleic acid in the cytoplasm (the material within the cell that is outside the nucleus), whereas most DNA viruses do so in the host cell nucleus. The host cell typically dies, releasing new viruses that infect other host cells. Some infections are asymptomatic or latent. In latent infection, viral RNA or DNA remains in host cells but does not cause disease unless some trigger causes symptoms. This is the case in disease states such as hepatitis. Latency may facilitate person-to-person spreading, as infected individuals do not show signs of illness. Some viruses alter normal cellular machinery, leading to abnormal cellular growth and cancer. These viruses are known as oncogenic viruses.
Charles Black is a 74-year-old man who had chills 3 days ago but has since developed a fever, which has lasted more than 48 hours. He complains that he has a terrible headache and is coughing and congested.
The most common types of human viral infections are those affecting the nose, throat, and upper airways, commonly known as upper airway (respiratory) infections (URIs). These include but are not limited to sore throat, the common cold, and sinusitis. Additionally, influenza is a viral infection. Small children often experience croup and inflammation of the windpipe or deeper airways in the lungs. As with other infectious diseases viral respiratory infections are more severe in older patients, infants, and those with lung or heart disorders. Viruses that affect the gastrointestinal (GI) system are known as enteroviruses. Some viruses (such as rabies, West Nile virus, and several different encephalitis viruses) infect the nervous system. Viral infections also develop in the skin, sometimes resulting in warts or other blemishes. Some viral infections are transmitted sexually and through the transfer of blood, whereas others may be inhaled or ingested through the GI tract.
Another group of common viral infections are caused by herpesviruses. Three of them—herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2 (HSV-2), and varicella zoster virus (VZV)—cause infections that produce blisters on the skin or mucus membranes. Another herpesvirus, Epstein-Barr virus (EBV), causes infectious mononucleosis. Cytomegalovirus (CMV) is a cause of serious infections in newborns and in people with weakened immune systems. It can also produce symptoms similar to infectious mononucleosis in people with a healthy immune system. Human herpesviruses 6 and 7 cause a childhood infection called roseola infantum. Human herpesvirus 8 has been implicated as a cause of cancer (Kaposi’s sarcoma) in people with AIDS (acquired immunodeficiency syndrome). All of the herpesviruses cause lifelong infection because the virus remains within its host cell in a dormant (latent) state even after the acute (symptomatic) phase of the infection. Sometimes the virus reactivates and produces further episodes of disease. Reactivation may occur rapidly or many years after the initial infection. See Table 28-1.
Viral infections cause a broad constellation of symptoms. The immune responses they elicit are similar to those discussed in Chapter 27 for bacterial infection, including fever and leukocytosis. As with bacterial infections, many viral diseases have a characteristic set of symptoms (eg, chickenpox, measles, influenza). Viral infection presents very similarly to bacterial infection and in many cases it is difficult if not impossible to differentiate based on symptoms alone. For infections that occur in epidemics (such as influenza), the presence of other similar cases may help doctors identify a particular infection. For other viral illnesses, blood tests and cultures (sampling blood, body fluid, or other material taken from an infected area and incubating it to see if anything grows from it) may be done. Blood may be tested for antibodies to viruses or for antigens (proteins on or in viruses that trigger the body’s defenses). Techniques known as polymerase chain reaction (PCR) may be used to make many copies of the viral genetic material, enabling doctors to rapidly and accurately identify the virus. Tests must sometimes be done quickly; for instance, when the infection is a serious threat to public health or when symptoms are severe. A sample of blood or other tissues is sometimes examined with an electron microscope, which provides high magnification with clear resolution (as viruses, unlike bacteria, are difficult or impossible to identify through a regular light microscope).
Types of Viruses
Many human respiratory infections are caused by adenoviruses, which are DNA viruses commonly acquired by contact with secretions (including finger transmission) from an infected person or by contact with a contaminated object (eg, towel, instrument). Infection may be airborne (particles released by coughing and sneezing) or waterborne. Respiratory or GI viral shedding (transmission of infectious viral particles by the infected host) may continue for months, even if infection is asymptomatic, as most are. When infection is symptomatic, many clinical manifestations are possible. The most common syndrome, especially in children, involves fever that tends to be greater than 39°C (102°F) and last more than 5 days. Sore throat, cough, runny nose, or other respiratory symptoms may occur. A separate syndrome involves conjunctivitis (an inflammation in the eye), pharyngitis (sore throat), and fever (pharyngoconjunctival fever). Eye inflammation involving both the conjunctiva and the cornea, termed epidemic keratoconjunctivitis, is sometimes severe and occurs both sporadically and in epidemics. Conjunctivitis is frequently bilateral (affecting both eyes). Periauricular adenopathy—swollen glands in the ear area—may develop. Systemic symptoms and signs are mild or absent. Epidemic keratoconjunctivitis usually resolves within 3 or 4 weeks, although corneal lesions may persist much longer.
Common Cold (Upper Respiratory Infection)
The common cold is an acute, self-limiting viral infection involving upper respiratory symptoms, such as rhinorrhea (runny nose), cough, and sore throat. Most colds are caused by a group of small RNA viruses termed rhinoviruses, which are spread in ways similar to those described for adenoviruses. Others may be due to infection by coronaviruses. URIs and their treatment are considered in detail in Chapter 36.
The most potent deterrent to viral URIs is the presence of specific antibodies in the serum and body fluids, induced by previous exposure to the same or a closely related virus. Susceptibility to colds is not affected by exposure to cold temperature, host health and nutrition, or upper respiratory tract abnormalities (eg, enlarged tonsils or adenoids). Treatment of the cold is supportive, including antihistamines, decongestants, and antipyretics.
Rhinovirus infections are most common during the fall and spring and are less common during the winter months. These infections are most efficiently spread by direct person-to-person contact, although spread may also occur via large-particle aerosols (released by coughing and sneezing).
Antiviral medications are not used to treat URIs, and there are currently no vaccines to prevent them.
Lower Respiratory Tract Infection
Most children suffer from an acute viral infection of the lower respiratory tract resulting in inflammation of the bronchioles (see Figure 18-1) at least once during their early years, frequently in the winter or early spring.2 Symptoms are nonspecific and may include irritability and fever, vomiting, and diarrhea, along with cough and breathing difficulties that may resemble asthma. While these infections may be caused by adenoviruses or influenza viruses, among others, the most common agent is respiratory syncytial virus, known as RSV. The infection is usually self-limiting and treatment is symptomatic, using antipyretics to reduce the fever and making sure there is adequate fluid intake to prevent dehydration. Children with more severe symptoms may be hospitalized and treated with oxygen therapy and intravenous (IV) fluids. A few, especially those with underlying heart or lung conditions, may require an aerosol (inhaled) antiviral medication.
What common viral illness does Mr. Black most likely have?
Influenza is an infection caused by a respiratory virus, influenza A or B. It is characterized by fever, head congestion, cough, headache, and malaise. Symptoms start 1–4 days after infection and can begin suddenly. Chills or a chilly sensation is often the first indication. Fever is common during the first few days, sometimes reaching 39°C (102–103°F). People frequently feel debilitated to the extent they remain in bed for days. Aches and pains are experienced throughout the body, particularly in the back and legs. Headache is often severe, with aching around and behind the eyes. Bright light may make the headache worse. At first, respiratory symptoms may be relatively mild, including a scratchy sore throat, a burning sensation in the chest, a dry cough, and a runny nose. These symptoms may progress and develop into pneumonia, either viral or bacterial. When bacterial pneumonia develops following influenza, it is known as a superinfection. Most symptoms subside after 2 or 3 days; however, they may last for weeks. Pneumonia is most commonly seen among the elderly and those with a heart or lung disorder.
Mortality is possible during epidemics, particularly among high-risk patients (eg, infants; the elderly; or those who are institutionalized, have cardiopulmonary insufficiency, or are in late pregnancy). Diagnosis is usually clinical and depends on local epidemiologic patterns. High-risk patients, their caregivers and household contacts, healthcare practitioners, and all children aged 6–24 months should receive annual influenza vaccination. Antiviral treatments include zanamivir and oseltamivir, as well as amantadine and rimantadine, which will be discussed in the drug therapy section of this chapter.
After 5 days of getting little relief from taking acetaminophen, Mr. Black has felt increasingly short of breath for the past couple of days. He has a past medical history significant only for chickenpox as a child. In the emergency room, his temperature is 103°F, heart rate = 110 (increased), respiratory rate = 20 (increased), oxygen saturation = 87% (low), chest x-ray demonstrates left lower lobe infiltrate, white blood cell (WBC) count = 21 (increased), and rapid nasal swab for influenza is positive for influenza A. Additionally, he has a rash that developed yesterday. It is located in a band across his lower back and is associated with sharp shooting pains. What common secondary infection does Mr. Black likely have as a result of his influenza infection?
Hemagglutinin (HA) is a protein on the influenza virus surface that allows it to fuse with the host cell membrane. Neuraminidase (NA), another surface protein, promotes viral dispersion from the infected cell. Relatively minor mutations in HA and NA of influenza A and B result in the frequent emergence of new viral strains (antigenic drift). The result is decreased protection by the antibody generated to the previous strain. In contrast to antigenic drift, a major change in NA or HA occurs in influenza A (antigenic shift) at infrequent intervals (10–40 years during the last century); as a result, the population has no immunity to the new virus, and pandemic (widespread epidemic) influenza may occur.
Influenza is typically diagnosed or at least suspected based on clinical symptoms. Laboratory tests are available to test blood and respiratory secretions for confirmation of influenza infection. These are available in physician offices and hospitals.
Coronaviruses have been identified as the cause of multiple respiratory infections, including severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and, most notably, coronavirus disease 2019 (COVID-19), resulting in a pandemic. Coronaviruses may affect nonhuman hosts and can be seen in avian hosts. SARS-COV-2 is the virus associated with the COVID-19 pandemic and it is postulated that this virus may be from bats or pangolins. COVID-19 symptoms range broadly, and the severity of the disease can vary heavily from one person to another, from a complete absence of symptoms to severe syndromes requiring hospitalization. Some symptoms associated with COVID-19 include fever, chills, cough, shortness of breath, fatigue, body aches, loss of taste or smell, diarrhea, and rashes. Symptoms may appear anywhere from 2–14 days after exposure to the virus. The COVID-19 pandemic at the time of writing has infected more than 150 million people with more than 3 million deaths worldwide, and more than 500,000 in the United States.
Due to the high transmissibility and mortality of the SARS-COV-2 virus, many different types of medications were tested to help in the treatment of COVID-19. Some of the agents that have been studied include antiviral medications (remdesivir, lopinavir/ritonavir), antimalarial medications (hydroxychloroquine), monoclonal antibodies (tocilizumab, bamlanivimab/etesevimab, casirivimab/imdevimab), and immunomodulators (corticosteroids). The only current medication that is approved by the U.S. Food and Drug Administration (FDA) for the treatment of COVID-19 is remdesivir, an adenosine nucleotide, which is indicated for patients who require hospitalization or have mild to moderate COVID-19 and are at high risk for progression to severe COVID-19. Other therapies to note are dexamethasone, a corticosteroid, which has been studied to reduce mortality in those requiring supplemental oxygen, and tocilizumab, a monoclonal interleukin-6 receptor antagonist, which has shown benefit in patients who exhibit rapid deterioration in their respiratory status.
Remdesivir may only be administered in healthcare settings in which healthcare providers have immediate access to medications to treat a severe infusion or hypersensitivity reaction, such as anaphylaxis, and the ability to activate the emergency medical system, as necessary.
Accelerated vaccine development for COVID-19 was determined to be instrumental in the fight against the pandemic, and in December 2020, nearly a year after the virus was first noted, a two-shot vaccine was approved by the FDA for the prevention of COVID-19. Clinical trials demonstrated that the vaccine was 95% effective at prevention of COVID-19 after both doses had been given. There are currently strong global efforts to vaccinate all individuals who are willing and able to receive vaccinations. The treatment recommendations for the pandemic are constantly in flux, because of new evidence emerging frequently. Organizations such as the Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO) are excellent resources for the most up-to-date information on treatment recommendations.
Eight different types of herpesviruses infect humans. After initial infection, all herpesviruses remain latent (inactive) within specific host cells and may subsequently reactivate or be shed. Herpesviruses do not survive long outside a host; thus, transmission usually requires contact with blood or sexual fluid, although varicella zoster virus (VZV) may spread by contact with respiratory secretions. Because the virus remains latent, transmission sometimes occurs from asymptomatic infected people.
Herpes simplex virus types 1 and 2 (HSV-1 and HSV-2) are widespread throughout most human populations and cause painful sores and blisters. Cold sores or fever blisters in the mouth or on the lips are most often caused by HSV-1, transmitted by close contact with an infected individual or an object that is contaminated by fluids from that individual. Genital herpes is among the most common sexually transmitted diseases in the United States and, while most often caused by HSV-2 infection, may also be associated with HSV-1. After the initial symptoms (painful blisters that break and become ulcers), the infection becomes latent and can recur throughout the patient’s lifetime.
While transmission is more likely to occur while the disease is symptomatic, infected individuals may be continuously contagious even while the disease is latent and no sores or blisters are evident.
One of the most commonly encountered herpesviruses is human herpesvirus type 3 or VZV, the causative organism of chickenpox and shingles. Chickenpox is predominantly a childhood disease caused by initial exposure to the virus. Shingles, also known as herpes zoster, typically presents in older patients. It is caused by reactivation of the VZV contracted at an earlier date. Chickenpox is extremely contagious and spread by droplet contact with an infected individual. Patients typically experience headache, fever, and fatigue as the initial symptoms up to 2 weeks prior to the development of a rash. The rash begins as teardrop-shaped, fluid-filled pouches, known as vesicles, on the face and trunk, and it is extremely itchy. The vesicles erupt (break) and crust over after a couple of days, with new vesicle formation ceasing after 5 days and crusting of vesicles complete by the sixth day. The disease is contagious from 48 hours prior to the development of the rash until final crusting of the rash. Chickenpox is typically a mild disease; however, in adults, newborns, and immunocompromised patients, it can progress to pneumonia and septic shock.
What childhood infection may likely be the original cause of Mr. Black’s rash?
Shingles, as mentioned earlier, is a reactivation of VZV. When latent, the virus resides in the roots of nerves. Upon reactivation the patient experiences sharp shooting pain in the affected region, followed in 2–3 days by the development of red vesicular lesions (vesicles). Lesions develop for up to 5 days. Typically patients experience only one outbreak of zoster; however, the pain may persist for months to years.
Infection with human herpesvirus type 8 (HHV-8) and EBV are linked to the development of malignancy (cancer). HHV-8 is also known as Kaposi’s sarcoma–associated herpesvirus (KSHV) and infections with this agent are most often seen in immunosuppressed patients, especially those with AIDS.
In addition to symptomatic treatment, some antiviral medications (detailed later in this chapter) are active against herpesviruses. Drugs that have activity against herpesviruses include acyclovir, cidofovir, famciclovir, fomivirsen, foscarnet, ganciclovir, idoxuridine, penciclovir, trifluridine, valacyclovir, valganciclovir, and vidarabine. While antiviral therapy can reduce the severity of symptoms, frequency of recurrence, and, possibly, disease transmission, it does not cure the infection.2 Additionally, vaccines have been developed to protect patients from herpesvirus infections; these are discussed in Chapter 30.
Hepatitis is an inflammation of the liver characterized by the widespread death of cells. Noninfectious hepatitis is covered in Chapter 23. Major infectious causes are specific hepatitis viruses A, B, and C. Less common causes include other viral infections (eg, infectious mononucleosis, yellow fever, CMV infection) and leptospirosis (a nonviral parasitic infection). Hepatitis A is spread through the GI tract. It is a self-limiting disease, usually resolving within 2–6 months, and is seldom chronic or fatal.2 There is no recommended drug treatment for hepatitis A.
Sharing of personal supplies, including toothbrushes, razors, towels, and needles, as well as the use of nonsterile instruments for tattooing and ear piercing, have been implicated in the spread of hepatitis B.1
Hepatitis B and C are transmitted via blood or other body fluids. Hepatitis B can even be transmitted from an infected mother to her child during childbirth, as well as sexual activity with an infected partner, which accounts for up to 50% of new cases in the United States.2
Hepatitis B infections can be asymptomatic and undetectable except with tests for serum antibodies and may resolve completely in 6 months. Some patients (especially those infected in infancy), however, can progress to a chronic infection, which can be controlled with antivirals but not cured. Patients with chronic infections can be contagious even when they are showing no symptoms. Chronic hepatitis B can result in fatal liver disease and malignancy. Hepatitis C may be the most common blood-borne disease in the United States.2 Many patients are asymptomatic (but contagious) for long periods, but over 20–30 years develop fatal liver damage. This disease can be controlled and even cured by a combination of antiviral medications.
Vaccines (discussed inChapter 30) are available to prevent hepatitis A and B. There is currently no vaccination against hepatitis C.
Enteroviruses are picornaviruses (pico = small, so these are small RNA viruses). This group includes the poliovirus, coxsackievirus, echovirus, and enterovirus D. Coxsackieviruses and echoviruses are shed in oral secretions, stool, blood, and cerebrospinal fluid and have wide geographic distribution. Enteroviruses cause various diseases, including poliomyelitis and meningitis. Epidemic pleurodynia, hand-foot-and-mouth disease, and herpangina are other diseases caused almost exclusively by enteroviruses.
Enteroviral diseases/epidemics in the United States occur in the summer and early fall. Antivirals are not used in their therapy, but vaccines are available to prevent some enterovirus infections, such as poliomyelitis.
Rubella (German measles) is caused by an RNA virus, which is spread by respiratory droplets through close contact or through the air. It is a contagious viral infection that may produce adenopathy (swollen glands), rash, and sometimes constitutional symptoms, which are usually mild and brief. Infection during early pregnancy can cause spontaneous abortion, stillbirth, or congenital defects, including but not limited to hearing loss, ophthalmologic defects, most commonly cataracts, cardiac abnormalities, and neurologic defects. Diagnosis is clinical and treatment is rarely necessary. Vaccination is effective; hence, only sporadic cases are seen in the United States.
A patient can transmit rubella from asymptomatic infection or from 10 days before until 15 days after the onset of the rash. Congenitally infected infants may transmit rubella for many months after birth. Rubella is less contagious than measles. Immunity appears to be lifelong after natural infection.
Measles is a viral infection rendered very uncommon in the United States and other developed countries by effective vaccination. It is a highly contagious viral infection most common in children. It is characterized by fever, cough, nasal congestion, conjunctivitis, and a rash consisting of red elevated bumps that usually spreads from the head downward over the body. Koplik’s spots, which appear as a dot of white sand on a slightly elevated reddened surface inside the mouth, are also seen. Diagnosis is based on clinical symptoms and treatment is supportive, consisting of acetaminophen or ibuprofen for fever and antihistamines for rash.
Human Immunodeficiency Virus
Human immunodeficiency virus (HIV) infection results from one of two similar agents (HIV-1 and HIV-2) called retroviruses because of the way their RNA works as a template for new DNA in infected host cells. These viruses destroy CD4 lymphocytes (important immune system cells) and impair cell-mediated immunity, increasing the risk of certain infections and cancers.
HIV is spread primarily through sexual contact, although other modes of transmission include parenteral (shared needles or accidental needle sticks, blood transfusion) and childbirth (from mother to child). Initial infection may cause nonspecific febrile illness. The risk of developing subsequent infections is proportional to the level of remaining CD4 lymphocytes. Clinical manifestations range from asymptomatic carriage to AIDS, which is defined by serious opportunistic infections or cancers or a CD4 count of <200/μL. HIV infection can be diagnosed by antibody or antigen testing. Screening should be routinely offered to all adults and adolescents. Treatment aims to suppress HIV replication by using combinations of drugs that inhibit viral enzymes and replication.
Medications targeting viral infection are aimed at numerous different pathways in the viral replication cycle: viral attachment and entry, penetration, uncoating, early protein synthesis, nucleic acid synthesis, late protein synthesis, packaging and assembly of virus, release of virus, viral replication, assimilation of viral particles, and viral shedding. See Figure 28-1 for a description of the actions of various antivirals.
Many different factors come into play in determining the appropriate antiviral medication. As with bacterial infection, knowledge of the most likely pathogens guides empiric choice of antiviral medications. Unlike bacterial infections, treatment for many viral infections (including the common cold, viral gastroenteritis, measles, mild cases of the flu) is supportive. Physicians choose an appropriate antiviral regimen based on patient allergies, age, kidney and liver function, infection site, pregnancy/lactation status, and other disease states and/or drug therapy.
Antiviral medications are divided into the following categories: adamantines, interferons, monoclonal antibodies, NA inhibitors, nucleosides, and nucleotides. These are listed in Medication Table 28-1 (Medication Tables are located at the end of the chapter). An additional category, antiretrovirals, includes medications used mainly against HIV, listed in Medication Table 28-2.
Amantadine (Symmetrel) and its derivative, rimantadine (Flumadine), are cyclic compounds of the adamantine family that inhibit uncoating of the viral RNA within infected host cells, thus preventing replication. These medications have been used for influenza treatment and prophylaxis. The most common side effects are GI and central nervous system (CNS) disturbances (difficulty concentrating, dizziness, insomnia), and in the case of rimantadine, hepatic dysfunction. These are more pronounced in the elderly and in patients with renal insufficiency. Though these medications have activity against influenza A, they are not recommended for treatment or prophylaxis due to high resistance rates. They are only warranted for resistant influenza virus, in conjunction with an NA inhibitor.
Does Mr. Black need treatment with either amantadine or rimantadine?
Zanamivir and oseltamivir are inhibitors of NA, which is responsible for the release of influenza virus from infected cells. The release of virus from infected cells is stopped, halting the spread of virus within the respiratory tract. These agents have activity against both influenza A and influenza B. Oseltamivir and zanamivir are easy to administer: zanamivir is a nasal spray and oseltamivir is given orally. They are well tolerated and duration of therapy is 5 days. Peramivir is only available as a solution and is given as an IV infusion. Peramivir may be given as a single dose for patients without complications, or for up to 10 days in higher-risk patients. Unfortunately, these agents require use within 48 hours of symptom onset to be effective and duration of illness is decreased by only 1–2 days even when they are started appropriately.
Endonuclease Inhibitor (Baloxavir)
Baloxavir Marboxil is an oral pro-drug (must be converted to an active form) of baloxavir, which is an inhibitor of endonuclease. This agent has activity against both influenza A and influenza B by inhibiting viral replication. Baloxavir is a well-tolerated medication and only one dose needs to be given in the treatment of influenza. Like the neuraminidase inhibitors, this medication should be given within 48 hours of influenza symptoms.
Should Mr. Black be treated with oseltamivir now?
Interferons are cellular messengers responsible for antiviral, immunomodulatory, and antiproliferative activities in the body. Interferon (IFN)-alfa appears to function by inhibiting viral penetration, translation, transcription, protein processing, maturation, and release, as well as enhancing the ability of the body’s immune system to eliminate viral particles (virions). Interferons are used to treat chronic hepatitis B, D, and acute hepatitis C. They have also been used experimentally against human papilloma virus (responsible for warts) and West Nile virus.
Comparison of Interferon Forms
Interferon is available in various formulations. Interferon alfa-2b can be administered either subcutaneously or intramuscularly. Interferon alfacon-1 is administered subcutaneously only. The pegylated interferons alfa-2a and alfa-2b are newer agents with longer half-lives suitable for once-weekly dosing. Alfa interferons are eliminated by the kidney, so dosage adjustment is required in patients with renal insufficiency. Liver metabolism is minimal, so dose adjustments are seldom necessary for hepatic insufficiency. Side effects are common, most routinely flu-like syndrome, and/or neuropsychiatric symptoms and immunosuppressive effects (occasionally aplastic anemia).
Nucleosides and Nucleotides
Nucleosides and nucleotides are antiviral medications that interfere with nucleic acid (DNA and/or RNA) synthesis. By inhibiting viral nucleic acid synthesis, they interfere with or prevent viral replication and spread. Acyclovir, ganciclovir, and valganciclovir are all analogs of the nucleoside guanosine. They require a viral enzyme for activation, so they are selectively activated and accumulate in infected cells. Their antiviral activity is accomplished by two mechanisms: competitive inhibition of viral DNA polymerase (where they take the place of the guanosine that is normally used by the virus) and chain termination following assimilation into the viral genome. These medications have activity against herpesvirus, VZV, EBV, and CMV. Intravenous acyclovir is associated with reversible renal toxicity. The main toxicity associated with ganciclovir and valganciclovir is myelosuppression.
Acyclovir was the first agent in this group to be developed. It is active against the herpesviruses, including genital herpes, varicella (chickenpox), and zoster (shingles). It has also been investigated for use in CMV and HSV. Administered by IV or oral routes, it must be given frequently (five times daily or every 4 hours) when used for acute infection. Acyclovir is also available alone or in combination with hydrocortisone as an ointment or cream for the treatment of genital herpes and cold sores.
IV acyclovir is dosed based on ideal body weight not actual body weight.
Other nucleoside analogs that are active against HSV include famciclovir and valacyclovir (oral treatment for genital herpes, cold sores, and shingles) and penciclovir (administered as a cream for cold sores on the lips and face). Ganciclovir is indicated for the treatment of CMV retinitis. It is available in dosage forms administered directly into the eye. Adefovir dipivoxil was initially investigated for the treatment of HIV, but it eventually gained FDA approval for the treatment of hepatitis B infection. Adefovir dipivoxil is a prodrug requiring enzymes in the cell to become active. It inhibits hepatitis B DNA polymerase, resulting in chain termination (halts nucleic acid synthesis). Sixty percent of the drug is absorbed upon oral administration and is unaffected by the presence of food in the stomach (so it may be taken without regard to meals). In contrast to acyclovir, dosage is only once daily. It is renally eliminated, making it safe for patients with severe liver disease. Commonly encountered side effects are headache, diarrhea, abdominal pain, and dose-dependent renal toxicity. Less common, more severe side effects are lactic acidosis and hepatic steatosis. Entecavir is an orally administered guanosine analog that competitively inhibits hepatitis B virus (HBV) replication enzymes. Oral bioavailability approaches 100% but is decreased by food; therefore, entecavir should be taken on an empty stomach. It is excreted by the kidney, so doses are adjusted for patients with renal insufficiency and those on dialysis.
Medication guides for antivirals used in the treatment of hepatitis advise patients to avoid alcoholic beverages. Even when there is no drug interaction, alcohol can increase the liver damage caused by the hepatitis infection.
Cidofovir is a cytosine nucleotide analog with in vitro activity against a variety of viral agents. Unlike acyclovir and similar drugs, cidofovir is transformed to an active form without the need for viral enzymes. Common adverse effects associated with cidofovir are nephrotoxicity, neutropenia, and metabolic acidosis. At the time of this writing, its only approved indication is for the treatment of CMV retinitis in patients with AIDS.
Cidofovir is a hazardous drug and must be prepared and handled as such by pharmacy personnel. This includes reconstitution in a biological safety cabinet and the use of appropriate personal protective garb.
Even though it is indicated for an eye condition, cidofovir is administered only by IV infusion over 1 hour and never by intraocular injection.
Ribavirin is another guanosine analog that is phosphorylated intracellularly by host cell enzymes. Although its mechanism of action has not been fully explained, it shows antiviral activity against a wide range of viruses, including influenza A and B, parainfluenza, RSV, paramyxoviruses, hepatitis C virus (HCV), and HIV-1. The oral form, currently indicated only for treatment of HCV in combination with an interferon, should be taken with food (meals high in fat increase absorption). Elimination is primarily via the kidneys and dose reduction is needed in cases of renal insufficiency. Hemolytic anemia occurs in up to 20% of patients treated with oral ribavirin. It is associated with depression, fatigue, nausea, and rash.
For RSV infections in infants and children, only inhaled (aerosol) ribavirin (and not the oral form) is indicated. It is generally reserved for hospitalized patients, especially if they also suffer from chronic lung, heart, or immune system deficiencies or diseases. Administration is generally continuous over 12–18 hours daily for 3–7 days.
Aerosolized ribavirin may only be administered with a special aerosol generator supplied by the medication’s manufacturer.
Solutions of ribavirin for aerosol must be prepared in the original vial, and only with sterile water for injection or inhalation containing no preservatives, antimicrobials, or other additives.
Hepatitis exacerbations have been associated with abrupt discontinuation of entecavir and other anti-HBV therapy. Patients should be reminded to consult their physicians before stopping these medications.
Foscarnet (phosphonoformic acid) is an inorganic compound that inhibits viral enzymes directly without requiring activation. It has shown activity against HSV, VZV, CMV, EBV, HHV-6, KSHV, and HIV-1. Its major toxicity is renal function impairment, but it has also been associated with changes in plasma minerals and electrolytes resulting in seizures. Patients receiving this drug are subject to careful monitoring of kidney function and serum electrolytes. Foscarnet is currently indicated only in the treatment of immunocompromised patients with CMV retinitis or certain resistant HSV infections of the skin and mucous membranes. It is administered by IV infusion (not topically).
Letermovir is a viral terminase inhibitor approved for the prophylaxis of CMV.
Tecovirimat is an antiviral medication that has activity against the smallpox virus.
Foscarnet solutions are chemically incompatible with many IV admixtures, calcium-containing solutions such as Ringer’s lactate or total parenteral nutrition. It is physically incompatible with a long list of additional medications, including many anti-infectives, CNS drugs, and others. Pharmacy personnel should be alert to possible incompatibilities and review the package literature before foscarnet is mixed or dispensed.
Foscarnet solutions are administered using an infusion pump and must be diluted to half strength if being administered via peripheral rather than central vein.
Linda Thorson is a 33-year-old woman and has tested positive for HIV infection. She is 5'9" tall and weighs 112 kg. Her past medical history is notable only for obesity and hyperlipidemia.
Ms. Thorson’s physician has prescribed lamivudine and zidovudine. What actions do these drugs have on HIV? How long will she have to take them before she is cured?
Ms. Thorson has heard she must keep her HIV medications refrigerated. This will be very inconvenient for her, as she must plan to take her zidovudine capsules and lamivudine tablets while she is at work. What will the pharmacy technician tell her?
Antiretroviral medications are medications that have activity against HIV. They are categorized by their mechanisms of action. The expected outcome of antiretroviral therapy is not to cure HIV infection, but to improve the patients’ quality of life by reducing symptoms, maximize immune system functioning, and prevent transmission. This is currently best accomplished by suppression of viral replication, and treatment is generally aimed at that goal.
HIV is a relatively new infection first identified in the last half of the 20th century, and its treatment continues to evolve. The earliest antiretrovirals were the nucleoside reverse transcriptase inhibitors (NRTIs), and the first of these was zidovudine (sometimes still abbreviated AZT for its original name, azidothymidine, which describes its structure). NRTIs, which also include abacavir, emtricitabine, lamivudine, and tenofovir disoproxil fumarate act by inhibition of HIV-1 reverse transcriptase, an enzyme vital to HIV replication. They can also be incorporated into the viral DNA chain to cause early termination (before it is complete). They require an intracellular chemical reaction to become active and have activity against both HIV-1 and HIV-2. The main adverse effects are lactic acidosis, hepatic steatosis (fatty liver), peripheral neuropathy, and pancreatitis. Telbivudine, mentioned among the general antivirals, is classified as an NRTI but is indicated only for chronic HBV (and not currently used for HIV).
NRTIs must be stored under controlled temperature conditions, with solid oral dosage forms and unreconstituted liquids at 77°F (no lower than 59°F or higher than 86°F). Liquid dosage forms must be refrigerated and unused portions discarded after 30 days.
Zidovudine is a hazardous drug and must be prepared and handled as such by pharmacy personnel. This includes reconstitution of the injection in a biological safety cabinet and use of appropriate personal protective garb.
Tenofovir has a mechanism of action similar to the NRTIs, but because of its chemical structure, it is termed a nucleotide analog reverse transcriptase inhibitor (NtARTI or NtRTI). It also differs because it can have weak effects on some human cell replication enzymes and because it is indicated not only in the treatment of HIV, but also for chronic HBV. Nausea, vomiting, diarrhea, and flatulence are the most frequently experienced adverse events. Lactic acidosis and hepatic steatosis are possible. It may also have effects on bone density and has been associated with kidney damage.
Tenofovir powder is a dosage form for adults unable to swallow solid food. It must be measured only with the scoop supplied in the manufacturer’s package and mixed with soft food (never liquid).
Non-nucleoside reverse transcriptase inhibitors (NNRTIs) bind directly to the HIV-1 enzyme reverse transcriptase, resulting in the blockade of viral protein synthesis. The binding site of NNRTIs is near to but distinct from that affected by NRTIs. Medications in this group include doravirine, efavirenz, etraverine, nevirapine, and rilpivirine. Unlike the NRTI agents, NNRTIs do not require intracellular activation and have little effectiveness against HIV-2. NNRTI resistance occurs rapidly when these drugs are used as monotherapy, so they are usually combined with other agents. Common adverse events are GI distress, elevated liver enzyme levels, skin rash, and occasionally Stevens-Johnson syndrome. They are metabolized by the liver and have many interactions with other medications metabolized in the same way, including anticonvulsants, antifungals, H2-receptor antagonists, and some antibiotics.
In addition to the lamivudine and zidovudine mentioned above, Ms. Thorson also has a prescription for Kaletra, a combination of lopinavir and ritonavir. Of the medications she is taking, which one(s) might cause the most immediate concerns about her health? Why?
Protease inhibitors (PIs) are a class of agents that interfere with an important step in the HIV maturation process, causing production of immature, noninfectious viral particles. This group includes atazanavir, darunavir, fosamprenavir, indinavir, nelfinavir, ritonavir, saquinavir, and tipranavir. Unfortunately, resistance is fairly common with these agents, so they are seldom (if ever) used as monotherapy.
The most common adverse reaction to the PIs is GI distress. This class of medications is also associated with a syndrome of central abdominal obesity, buffalo hump (accumulation of fat on back), and breast enlargement. Additionally many patients treated with PIs develop hypertriglyceridemia, hyperlipidemia, and insulin insensitivity. Metabolized via a major liver enzyme responsible for drug metabolism, the PIs have many drug interactions, similar to those listed with the NNRTIs.
Because ritonavir interferes with the liver’s metabolism of other PIs, it is prescribed along with darunavir, tipranavir, and saquinavir to increase their plasma levels, affording greater antiretroviral efficacy from a more tolerable dose.
Many NNRTIs and PIs, as well as the entry inhibitor maraviroc, interact with many other medications, sometimes requiring dosage adjustments or changes in drug choices to ensure efficacy and avoid toxicity. It is vital that the pharmacist has a complete list of the patient’s current medication therapy, including over-the-counter and herbal or “natural” remedies (especially St. John’s Wort).
Recall that, for infection to occur, a virus must first attach to the host cell, then fuse with its cell membrane and enter the cell. The antiretrovirals categorized as entry inhibitors act to prevent this step in the process, interfering with the spread of HIV throughout the immune system.
Enfuvirtide is the first representative of this class of antiretroviral agents. It binds to the viral protein envelope, preventing the changes required for fusion with human cellular membranes. It is well tolerated, has no drug interactions, and lacks cross-resistance to other classes of antiretroviral drugs but is only used as part of a multidrug antiretroviral regimen. It requires twice daily subcutaneous (SUBQ) administration and must be reconstituted before use.
Enfuvirtide is supplied to patients as a kit, which includes vials of lyophilized medication (90 mg), vials of sterile water (1.1 mL), and syringes for use in reconstitution and administration. Patients who have not received prior instruction in preparation and administration will require pharmacist counseling.
Each vial of enfuvirtide is for single use only and unused material (from doses less than 90 mg) must be discarded. If reconstituted in advance (some patients prepare both doses for the day at the same time), the solution must be refrigerated and used within 24 hours.
Maraviroc is unique among currently available antiretrovirals because it does not act on the virus itself, interfering with viral entry by binding with the human cell membrane. It is effective only against certain types of HIV-1 but does not require dose adjustment for renal and hepatic dysfunction. The major side effects of this medication are cough, muscle and joint pain, diarrhea, and increases in liver function tests. Some patients, however, have developed life-threatening liver toxicity, preceded by an allergic reaction. Maraviroc is metabolized by the liver and subsequently has many drug interactions similar to those mentioned with the NNRTIs and PIs.
Integrase inhibitors work by blocking integrase, an enzyme required for the HIV particle to combine its genetic material with that of the host cell to continue the replication process. This group includes raltegravir, dolutegravir, bictegravir, and elvitegravir. The most common side effects are diarrhea, nausea, dizziness, and headache. Because it is metabolized by different liver enzymes from those used by NNRTIs, PIs, and maraviroc, the potential for drug interactions is reduced (though not eliminated).
Patients receiving maraviroc should receive information (pamphlet and/or pharmacist counseling) advising them to seek immediate medical attention if they develop signs or symptoms of hepatitis (abdominal pain, dark urine, yellow-looking eyes or skin, vomiting) or allergic reaction (itching, rash).
Patients taking rifampin may be prescribed an unusually high dose of raltegravir because rifampin decreases blood levels of the drug.
Antiretroviral Treatment Regimens
The decision to initiate antiretroviral therapy (in some cases soon after diagnosis of HIV infection, in others, only after the patient becomes symptomatic) is one undertaken after serious discussion between the physician and the patient. In all cases, the possible benefits of added length and quality of life must be balanced against the near certainty of adverse effects. The patient must be able to commit to strict adherence to the treatment plan, as lapses can result in accelerated development of viral resistance and a decrease in the variety of treatment options later in the course of the disease. This is difficult to accomplish given the complexity of the regimens, frequency of side effects, cost of therapy, and in some cases changes in the availability of medications.
Ms. Thorson’s physician explained that her antiretroviral therapy will not cure the HIV infection. Ms. Thorson has read on the Internet that herbal remedies may help and she has asked the pharmacy technician to ring up a bottle of St. John’s Wort preparation along with her prescription refills. What should the technician do or say?
All recommended treatment regimens involve combinations of three or more drugs from at least two different categories (eg, two NNRTIs with an NRTI, or two PIs with two NRTIs), all administered on strict schedules over long periods of time (possibly for the rest of the patient’s life).3 Oversight of treatment efficacy by a specialist in HIV is extensive. HIV viral load, CD4 count, complete blood count, and signs and symptoms of opportunistic infection are routinely monitored. In many cases, testing to determine the type of viral mutations conferring resistance to treatment is indicated. To simplify scheduling and increase the patient’s ease in adherence, combination products (with two or more antiretrovirals) are sometimes prescribed. These are listed in Medication Table 28-3.
Recommended regimens for the treatment of patients infected with HIV are frequently referred to by the acronym HAART (highly active antiretroviral therapy).
For patients who do not have HIV but may be at high risk for contracting the virus, the use of pre-exposure prophylaxis (PrEP) can be used to reduce the probability of infection. The Centers for Disease Control and Prevention recommends that PrEP be considered in those without HIV who have vaginal or anal sex with a partner who has or may have HIV, those who may share needles or equipment with someone with HIV, and those who have had nonoccupational postexposure prophylaxis (PEP) and continue to engage in high-risk activities. PrEP works by having antiviral medication in the body if and when a person may be exposed to HIV, and helps to halt replication of HIV and stop the virus from spreading. For PrEP it is essential that a person take it every day, otherwise there may not be enough of the medication in their body to prevent the HIV from spreading.3
PrEP involves treatment with a combination of two or more antiviral medications with different mechanisms of action. As of this writing, the preparations approved for this type of therapy are oral fixed-dose combinations of emtricitabine and tenofovir. Emtricitabine with tenofovir alafenamide (Descovy) is approved for PrEP to reduce the risk of sexually acquired HIV infection. Emtricitabine with tenofovir disoproxil fumarate (Truvada) is indicated as PrEP for uninfected patients at high risk for acquiring HIV via sexual exposure.
Because infection with HIV is potentially fatal and there is currently no vaccine available to prevent it, those who have (or may have) been exposed to the virus should receive therapy to prevent infection. This is known as postexposure prophylaxis (PEP). The type of PEP prescribed usually depends on the nature of the exposure.
Occupational (workplace) exposure to HIV occurs when healthcare workers come in contact with materials (blood or body fluids) via needle stick, in the eyes or mouth, or on damaged skin (cuts, chapping, and dermatitis). Although the risk of actual transmission of the HIV virus by such events is very low, the potential harm is so great that PEP is often offered anyway, unless it can be verified that the potentially infective materials are HIV-free. If the source is unknown and the exposed person chooses, a two-drug regimen (usually a PI and an agent from a different class of antiretrovirals) is continued for 4 weeks. If the source of the exposure is known to be HIV-positive, a three-drug regimen (those from the two-drug plan plus an additional agent) is followed.3
Nonoccupational exposure to HIV can occur from sexual contact (including assault) with infected (or potentially infected) partners, injection drug use, or other contact with body fluids. PEP for individuals with this type of exposure is chosen on a case-by-case basis, but it generally involves a 4-week HAART regimen.3
A virus is a microscopic infectious agent, classified as parasitic because it is incapable of reproduction outside an infected living host cell. It reproduces by using the processes and materials in the cells it infects and spreads when the newly replicated viral particles repeat their infectious processes in new cells. Some viral infections are self-limiting and are treated only with supportive care. Others may be life threatening and require treatment with antiviral medications.
Antiviral medications act by interfering with the processes that allow viruses to enter and infect cells, replicate themselves, or distribute replicated particles to infect new cells. They are generally categorized by their mode of action and/or by the type of viral infections they are used to treat. Many of them have serious side effects, and the risks of these must be balanced against the benefits of therapy with them.