Chapter 28. Antiviral Agents

Viruses are obligate intracellular parasites. That is, unlike bacteria, viruses depend on living host cells to replicate and function. Since viruses rely on the synthetic machinery of host cells, viruses can be extremely small. In many cases, the entire viral particle, or virion, consists only of nucleic acids (deoxyribonucleic acid [DNA] or ribonucleic acid [RNA]) surrounded by a protein shell, or capsid. Some viruses have an additional glycoprotein coat called an envelope.

Viral infections range from common minor illnesses, such as the common cold and cold sores, to life-threatening diseases, such as AIDS, Ebola, and severe acute respiratory syndrome (SARS). In addition, some viruses can cause certain types of cancer. For example, human papillomavirus is the primary causative agent of cervical cancer.

Viral transmission can occur in many ways. The most common ways that virions enter the body are via inhaled droplets (e.g., rhinovirus, the causative agent of the common cold), contaminated food or water (e.g., hepatitis A), direct contact from infected hosts (e.g., HIV), or direct inoculation by bites of infected vectors (e.g., dengue fever, transmitted by mosquitoes).

Viruses are complicated chemotherapy targets for several reasons. Since viruses rely on host cells’ machinery to function, the selective pharmacologic destruction of a virus without destroying human cells is difficult. Early treatment is critical, but frequently not possible because viral replication often peaks before clinical symptoms develop. Many antiviral agents also rely on a normal immune system to destroy the virus. Thus, immune suppression often lengthens viral illnesses. Finally, mutations that cause changes in viral structure and enzymes often lead to the emergence of drug-resistant viral strains. Some viruses (influenza A and B, hepatitis B virus [HBV]) can be effectively controlled by vaccines (see section Vaccines and Immune Globulins: Active and Passive Immunizations below).

Antiviral drugs can potentially exert their actions at several stages of viral replication, including (1) viral attachment and entry into the host cell; (2) uncoating of viral nucleic acid; (3) synthesis of early viral regulatory proteins; (4) synthesis of RNA or DNA nucleic acids; (5) late protein synthesis and processing; (6) viral packaging and assembly, and (7) virion release (Figure 28–1).

One of the most important trends in viral chemotherapy, especially in the management of HIV infection, has been the introduction of combination drug therapy, in which more than one stage of viral replication is inhibited. The benefits of combination antiviral therapy include greater clinical effectiveness and the prevention or delay of drug resistance.

The antiviral agents covered in this chapter include drugs against herpes, HIV, influenza, HBV, and hepatitis C (HCV) (Figure 28–2).

Second to flu (influenza) and common cold viruses, herpes viruses are among the leading causes of human viral disease. The term herpes is derived from the Greek word herpein, which means to creep. This refers to the creeping or spreading quality of skin lesions caused by many herpes viruses. Although eight types of human herpes viruses have been identified, the most common herpes viruses are herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2 (HSV-2), varicella-zoster virus (VZV), Epstein-Barr virus (EBV), and cytomegalovirus (CMV).

Once infected by any herpes virus, the infection remains for the life of the individual. Herpes infections are well-known for remaining silent—or latent—for months or even years. Then, in response to some trigger (e.g., sun exposure, concurrent viral illness, immunosuppression), the virus is reactivated and the patient once again becomes symptomatic.

Most adult Americans harbor HSV-1, the HSV strain primarily responsible for orofacial (e.g., cold sores) and ocular infections. It is estimated that one in five Americans over the age of 12 years carries HSV-2, which generally causes genital infections. Notably, HSV-1 and HSV-2 can cause outbreaks at either body site by direct contact with infectious secretions or mucous membranes. During the primary infection, HSV spreads from infected epithelial and mucosal cells to nearby sensory nerve endings and is transported along the axon to the cell body. The virus enters the nucleus of a neuron, where it persists indefinitely in a latent state. Recurrent HSV infection occurs as a result of reactivation of the virus in the sensory ganglion. The virus migrates down the nerve axon and produces vesicular lesions, as well as intermittent asymptomatic viral shedding. Lesions usually heal within 2 weeks. Relapsing episodes are often physically and psychologically distressing. Pregnant women who are shedding the virus may transmit it during delivery, with severe and potentially fatal consequences to the neonate.

In its primary infection, VZV causes chickenpox (herpes varicella) in children and is rapidly spread via airborne droplets and contact with lesions. Herpes zoster, also known as shingles, is a reactivation of a previous infection with VZV. Roughly 2 to 3 days before vesicular skin lesions appear, the patient often experiences pain along affected dermatomes. The area generally remains painful until lesions heal in 2 to 3 weeks. Herpes zoster cannot be contracted from someone who has herpes zoster because the infection always comes from latent VZV infection in the patient’s own spinal cord ganglia. However, the primary infection—chickenpox can be transmitted from a person with herpes zoster to someone who has not already had chickenpox (or the chickenpox vaccine). Vaccines are currently available for both chickenpox and shingles (see section Vaccines and Immune Globulins: Active and Passive Immunizations).

Cytomegalovirus (CMV) may be acquired congenitally, perinatally, or postnatally. It is the most common congenital (present at birth) infection in the United States, and its incidence increases with age. Indeed, CMV is estimated to infect the majority of adults by 40 years of age. While multiple organs can be affected, CMV is usually asymptomatic in healthy adults. However, in immunocompromised individuals, especially those with AIDS, CMV infections cause various illnesses. In individuals with AIDS, the most common manifestation is an eye infection called CMV retinitis.

Most drugs active against herpes viruses inhibit viral DNA polymerases, enzymes that assist in viral replication. Often, antiviral drugs are bioactivated by virus-specific or host enzymes to active drug forms. It is important to note that anti-herpes agents act against the replicating virus by incorporating into the viral DNA, and therefore are ineffective against latent (nonreplicating) virus. Three oral antiherpes drugs are licensed for the treatment of HSV and VZV infections: acyclovir, valacyclovir, and famciclovir. They share similar mechanisms of action and indications for clinical use, and all are fairly well tolerated.

Acyclovir

Mechanism of Action and Pharmacokinetics

Acyclovir (acycloguanosine) is derived from the nucleoside guanosine. Acyclovir is activated first by virus-specific and then by host enzymes to form acyclovir triphosphate, which competes with deoxyguanosine triphosphate for the viral DNA polymerase. The drug then becomes incorporated into the viral DNA, but because acycloguanosine lacks the necessary position for nucleotide attachment, the DNA chain terminates. Resistance of HSV has been reported, mainly among immunocompromised patients. Resistance is often associated with mutations in the viral enzyme thymidine kinase, which is involved in the initial bioactivation of acyclovir. Strains resistant to acyclovir are crossresistant to similar drugs such as ganciclovir, valacyclovir, and famciclovir. Resistant infections are often managed by foscarnet, cidofovir, or trifluridine, which use a different mechanism of antiviral action, but these drugs are significantly more toxic than acyclovir.

Acyclovir is available in oral, topical, and intravenous forms. Because of its short half-life, oral acyclovir must be taken several times per day. Patients with renal impairment require reduced dosages because the kidneys are primarily responsible for eliminating acyclovir.

Clinical Uses and Toxicity

Oral acyclovir has multiple uses. It is most commonly used for the treatment of mucocutaneous and genital herpes lesions (Table 28–1) and prophylaxis in immunocompromised patients. Oral therapy is the most effective route of administration for treating primary HSV infection and recurrent genital herpes. In initial episodes of genital herpes, oral acyclovir shortens the duration of symptoms, the time for lesions to heal, and the duration of viral shedding. In recurrent genital herpes, the time course is also shortened. Daily oral suppressive therapy decreases the frequency of symptomatic genital herpes outbreaks and asymptomatic viral shedding. This latter point is especially important in decreasing the risk of transmission to sexual partners. Intravenous acyclovir is the treatment of choice for serious HSV infections such as herpes simplex encephalitis and neonatal HSV infections, serious VSV infections, and VSV infections in immunocompromised patients.

Oral administration of acyclovir is generally well tolerated, with headache and gastrointestinal distress occasionally reported. Toxic effects with intravenous administration include delirium, tremor, seizures, hypotension, and nephrotoxicity.

Acyclovir Congeners

Several antiherpes drugs, such as valacyclovir,famciclovir, and penciclovir, are congeners––drugs that share similar chemical structures and characteristics—of acyclovir. Consequently, acyclovir congeners share many of acyclovir’s clinical uses. After oral administration, valacyclovir is converted to acyclovir by the liver. Greater plasma levels can be achieved with valacyclovir than with acyclovir; thus, the duration of action is longer. Although valacyclovir is as effective as acyclovir in the cutaneous healing rate for herpes zoster (shingles), valacyclovir has been shown to be associated with a shorter duration of zoster-associated pain. Oral famciclovir is converted to penciclovir by the liver. It is well tolerated, and it is similar to acyclovir in its pharmacokinetic properties and clinical uses. Penciclovir is the active metabolite of famciclovir. Topical penciclovir is an effective treatment for recurrent genital herpes infection of the labia.

Ganciclovir

Mechanism of Action and Pharmacokinetics

Ganciclovir inhibits viral DNA polymerases of cytomegalovirus (CMV) and HSV. The first step in bioactivation of ganciclovir is a phosphorylation step catalyzed by virus-specific enzymes in both HSV-infected and CMV-infected cells. Ganciclovir is usually given intravenously and penetrates well into tissues, including the central nervous system (CNS) and the eye. It is also available as an intraocular implant. Valganciclovir, a prodrug of ganciclovir, has greater oral bioavailability than ganciclovir. Thus, valganciclovir has largely replaced oral ganciclovir because patients are required to take fewer pills per day.

Clinical Uses and Toxicity

Ganciclovir’s activity against CMV is about 100 times greater than that of acyclovir. It is often used in immunocompromised patients for the treatment and prophylaxis of CMV infections, especially CMV retinitis, a vision-threatening infection of the eye. The most common systemic toxic effect of ganciclovir (and valganciclovir) is myelosuppression, a decrease in the ability of bone marrow to produce blood cells. Rare side effects include neurotoxicity (confusion, seizures) and nephrotoxicity.

Cidofovir

Mechanism of Action and Pharmacokinetics

Cidofovir is bioactivated exclusively by host cell enzymes. It inhibits the DNA polymerases of HSV, CMV, adenovirus, and human papillomavirus. Cidofovir is active against many acyclovir and ganciclovir-resistant strains because its bioactivation does not require viral kinases. To date, clinical resistance to cidofovir is rare. Cidofovir is generally administered topically or intravenously. It has a long intracellular half-life of 17 to 65 hours, permitting long intervals between doses.

Clinical Uses and Toxicity

Intravenous cidofovir is used to treat CMV retinitis and mucocutaneous HSV infections, including strains resistant to acyclovir. It is also effective in treating genital warts. Cidofovir is dose-dependently nephrotoxic. Patients receiving cidofovir will also receive a drug that blocks active tubular secretion (probenecid) to decrease its nephrotoxicity. Concurrent administration of other potentially nephrotoxic drugs (e.g., nonsteroidal antiinflammatory drugs [NSAIDs]) should be avoided.

Foscarnet

Mechanism of Action and Pharmacokinetics

Foscarnet inhibits viral DNA polymerase, RNA polymerase, and HIV reverse transcriptase. It is only administered intravenously, and it penetrates well into tissues, including the CNS.

Clinical Uses and Toxicity

Foscarnet is an alternative drug for the prophylaxis and treatment of CMV infections, and it has activity against ganciclovir- and cidofovir-resistant strains. It is also effective against acyclovir-resistant HSV and VZV herpes strains, and may suppress resistant infections in AIDS patients. Toxic effects can be severe. These include nephrotoxicity, electrolyte imbalances (especially hypocalcemia), genitourinary ulcerations, and CNS effects (headache, hallucinations, seizures).

Idoxuridine, Trifluridine, and Vidarabine

Idoxuridine, trifluridine, and vidarabine are frequently used topically in the treatment of herpes keratitis, an eye infection that can be recurrent and may lead to blindness. Idoxuridine and trifluridine are too toxic for systemic use. Despite marked toxic potential, vidarabine has been used intravenously for severe HSV infections, especially those resistant to acyclovir. Toxic systemic effects include gastrointestinal irritation, hepatic dysfunction, and CNS toxicity (paresthesias, tremor, convulsions).

Human immunodeficiency virus (HIV) strikes the immune system, specifically targeting CD4 T lymphocytes. Depletion of CD4 cells ultimately leads to profound immunosuppression. Acquired immune deficiency syndrome (AIDS) is symptomatic disease, characterized by the development of a wide spectrum of opportunistic infections and malignancies either acquired or reactivated as a result of the immunosuppression caused by HIV. Worldwide, HIV/AIDS is a global health problem, affecting over 40 million people, with over 70% of infected individuals living in sub-Saharan Africa. In the United States, it is estimated that 1 million people are currently living with HIV/AIDS. While primary routes of infection in developed countries include male homosexual intercourse and intravenous drug use, primary routes of infection in developing countries include heterosexual contact and vertical transmission from mother to child.

To understand the drugs used in the treatment of HIV, the life cycle of HIV must be briefly examined (Figure 28–3). HIV is a retrovirus, meaning that it is an enveloped virus with a single-stranded RNA, not DNA, genome. Before HIV can enter CD4 cells, viral glycoproteins in the envelope bind to CD4 and chemokine receptors. Next, the virus fuses with the host cell membrane and uncoats as it enters the host cell. After uncoating, viral replication depends on the viral reverse transcriptase enzyme, which transcribes the viral genome from RNA into DNA. This newly formed double-stranded DNA is integrated into the human host’s genome by an integrase enzyme. Integrated viral DNA is then transcribed by a host polymerase enzyme into messenger RNA, which is translated into proteins that assemble into immature noninfectious virions that bud from the host cell membrane. Proteolytic cleavage allows maturation into fully infectious virions.

As we mark the completion of the first 25 years of the HIV/AIDS epidemic, there is no cure for HIV infection or AIDS. However, pharmacologic therapy can dramatically improve the length and quality of life for infected individuals, and can delay the onset of AIDS. Without pharmacologic treatment, most patients die within a few years after the onset of symptoms. Currently, the standard of care in treating HIV infection involves initiating highly active antiretroviral therapy (HAART) that requires three to four antiretroviral drugs. If possible, HAART is initiated before symptoms appear. The goal of combination regimens is to inhibit or stop viral replication at a number of different steps (Figure 28–3). Compared with the administration of a single antiretroviral agent, combination therapy increases the efficacy of drug therapy, decreases the risk of developing drug resistance, and reduces viral load. Six classes of antiretroviral agents are currently available: nucleoside reverse transcriptase inhibitors (NRTIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), a fusion inhibitor, an integrase inhibitor, and an entry receptor blocker (Table 28–2).

Drug combinations are tailored to each patient depending on many variables, including potency and susceptibility, patient tolerance, convenience, and adherence to drug regimen. With the exception of the fusion inhibitor, the anti-HIV agents are all available as oral formulations. Drug management of HIV/AIDS is subject to change as newer agents become available. New pharmacotherapies are being sought that offer the advantages of once-daily dosing, smaller pill size, lower incidence of adverse effects, new viral targets, and activity against virus that is resistant to other agents.

Nucleoside Reverse Transcriptase Inhibitors

The NRTIs were the first group of drugs used to treat HIV infection. NRTIs selectively inhibit the HIV viral reverse transcriptase (Figure 28–3). The reverse transcriptase incorporates the phosphorylated NRTI (instead of a natural nucleotide) into the growing DNA chain, thus preventing complete conversion of viral RNA into DNA. If used as single agents to treat HIV, resistance emerges rapidly. However, resistance is rare in combination regimens. The NRTIs include zidovudine, didanosine, zalcitabine, lamivudine, stavudine, and abacavir. Details about each of these drugs follow.

Severe toxic effects are associated with most NRTIs, with the exception of lamivudine (3TC). All of the NRTIs have the potential to cause a rare, but serious, lactic acidosis and severe hepatic steatosis, likely due to mitochondrial damage in liver cells. Risk factors include obesity, prolonged treatment with NRTIs, and preexisting liver dysfunction. Symptoms include severe nausea, vomiting, and persistent abdominal pain. NRTI administration will often be suspended in these cases.

Zidovudine (ZDV), formerly called azidothymidine, or AZT, was the first antiretroviral drug approved for HIV treatment. Zidovudine is still frequently used in combination drug regimens. It is also used in prophylaxis against HIV infection through accidental needle sticks and via vertical transmission from mother to fetus. Zidovudine is active orally and is distributed to most tissues, including the CNS. The primary adverse effect is myelosuppression, which may be severe enough to require transfusions. Gastrointestinal distress, headaches, myalgia, agitation, and insomnia may also occur, but tend to decrease or resolve during therapy.

Didanosine (ddI) should be taken on an empty stomach to maximize bioavailability. The major clinical toxicity of didanosine (and to a lesser extent zalcitabine and stavudine) is dose-dependent pancreatitis. This occurs more frequently in alcoholic patients and those with hypertriglyceridemia. Other adverse effects include painful peripheral distal neuropathy, diarrhea, and CNS toxicity (headache, irritability, insomnia). Patients on didanosine also must have frequent retinal examinations because of reports of retinal changes and optic neuritis.

Zalcitabine (ddC) has relatively high oral bioavailability, but plasma levels decrease significantly when the drug is taken with food or antacids. The major adverse effect is peripheral neuropathy, which can be treatment limiting in 10 to 20% of patients. The neuropathy appears to be slowly reversible if treatment is discontinued promptly. Other major toxicities include oral and esophageal ulcerations and pancreatitis. Headache, arthralgias, myalgias, nausea, and rash may occur, but tend to resolve during therapy.

Unlike didanosine and zalcitabine, the bioavailability of lamivudine (3TC) is high and not food-dependent. It is commonly used as a component in HAART, as well as in the treatment of hepatitis B infections (see discussion below). Lamivudine is one of the best-tolerated NRTIs. Potential adverse effects are generally mild and include headache, fatigue, and gastrointestinal discomfort.

Stavudine (d4T) also has good oral bioavailability that is not food dependent. The major adverse effect of stavudine is dose-related peripheral sensory neuropathy. The incidence of these symptoms increases with coadministration of other neuropathy-inducing NRTIs such as didanosine and zalcitabine. Symptoms usually resolve completely if stavudine is discontinued. Other potential adverse effects include pancreatitis and arthralgias. As discussed above, all NRTIs have the potential to cause lactic acidosis with hepatic steatosis. However, these toxicities tend to occur more frequently in patients receiving stavudine than in those receiving other NRTIs.

Abacavir has good oral bioavailability that is unaffected by food. In a small percentage of patients taking abacavir, potentially fatal hypersensitivity reactions can occur. Symptoms usually occur in the first 6 weeks of therapy and include fever, malaise, vomiting, diarrhea, and anorexia.

Tenofovir (a nucleotide) inhibits the HIV reverse transcriptase and becomes incorporated into the DNA, causing chain termination. Its bioavailability increases after ingestion of a high-fat meal, so patients are advised to ingest tenofovir with a meal. Gastrointestinal irritation is the most common adverse effect, but this rarely requires discontinuation of therapy.

Nonnucleoside Reverse Transcriptase Inhibitors

The NNRTIs interrupt transcription of viral RNA into DNA by a different mechanism than the NRTIs. The NNRTIs bind directly to the viral reverse transcriptase (Figure 28–3), change the shape of the enzyme, and inhibit DNA synthesis. Thus, unlike the NRTIs, which become incorporated into the viral DNA, NNRTI agents inactivate the reverse transcriptase to prevent DNA formation. Like the NRTIs, resistance can occur rapidly if these drugs are used as monotherapy. As a class, adverse effects associated with NNRTI administration include varying levels of gastrointestinal distress and skin rashes. NNRTI agents are metabolized by the cytochrome P450 (CYP450) system, which increases the likelihood of drug-drug adverse interactions. Drugs in the NNRTI class include nevirapine, delavirdine, and efavirenz.

Oral bioavailability of nevirapine is good, and is not affected by food intake. Nevirapine is typically used as a component in HAART. It is also used prophylactically as a single dose to HIV-infected mothers at the onset of labor and to the neonate. Nevirapine can cause severe hypersensitivity reactions such as Stevens-Johnson syndrome and a life-threatening toxic epidermal necrolysis.

Delavirdine’s oral bioavailability is good, but it is reduced by antacids. Delavirdine causes rash in about 20% of patients, although the rash is not life-threatening. Other adverse effects include headache, nausea, fatigue, and diarrhea. Because it has been shown to cause birth defects in animals, women should take precautions against pregnancy while taking delavirdine.

Efavirenz is generally used in combination with two NRTIs. The bioavailability of efavirenz increases after a high-fat meal. Adverse effects include CNS dysfunction (dizziness, drowsiness, headache, confusion, agitation, delusions, nightmares), skin rash, and increases in plasma cholesterol. Dosing at bedtime may be helpful for decreasing perception of some of the CNS effects. Pregnancy should also be avoided in women taking efavirenz because of fetal abnormalities observed in animals.

Protease Inhibitors

Assembly of infectious HIV virions depends on HIV-1 protease (Figure 28–3). Protease inhibitors (PIs) result in production of immature, noninfectious virions. As a class, the PIs in HAART drug combinations lead to the development of carbohydrate and lipid metabolic dysregulation. This syndrome includes hyperglycemia, insulin resistance, and hyperlipidemia. A lipodystrophy, or selective redistribution of fat, also occurs. Thus, patients may acquire a cushingoid appearance: buffalo hump, gynecomastia, abdominal obesity, and peripheral wasting. Incidence of the syndrome is about 30 to 50% of those patients on a HAART regimen containing PIs, with a median onset time of about 1 year after onset of treatment. Owing to these side effects, AIDS patients receiving PIs within a HAART regimen often receive counseling about heart disease as a new complication. Like the NNRTI agents, PIs are metabolized by the CYP450 system, increasing the likelihood of drug-drug adverse interactions. Six PIs are available for HIV treatment, and these are used in combinations with NRTIs and NNRTIs.

Indinavir must be taken on an empty stomach for maximal absorption. To avoid renal damage (nephrolithiasis), patients should consume at least 48 oz of water daily. Other adverse effects include nausea, diarrhea, and thrombocytopenia.

Bioavailability of ritonavir increases when given with food. The most common adverse effects are gastrointestinal disturbances, paresthesias (peripheral and circumoral), altered (bitter) taste, and hypertriglyceridemia. During the first weeks of therapy, nausea, vomiting, and abdominal pain usually occur and patients should be warned to expect these symptoms.

Saquinavir should be taken with food to improve its bioavailability and to decrease gastrointestinal distress. Other adverse effects include rhinitis, headache, and neutropenia.

Nelfinavir has higher absorption when taken with food. Its primary adverse effect is dose-limiting diarrhea, although this symptom often responds to antidiarrheal medications.

Amprenavir is rapidly absorbed from the gastrointestinal tract, and it can be taken with or without food; however, high-fat meals may decrease absorption and should be avoided. Common side effects are gastrointestinal distress, perioral paresthesias, depression, and rash. In a small percentage of cases, amprenavir has caused life-threatening rashes, including Stevens-Johnson syndrome, severe enough for the drug to be discontinued.

Lopinavir is often administered with ritonavir because of enhanced efficacy and improved tolerability. Absorption is enhanced with food. Adverse effects include nausea, vomiting, diarrhea, pancreatitis, and asthenia (decrease in strength).

Fusion Inhibitor

Enfuvirtide represents a new class of antiretroviral agents. The drug binds to a portion of the viral envelope and prevents conformational changes required for fusion of the viral and human cellular membranes (Figure 28–3). Unlike other anti-HIV drugs, enfuvirtide is not available in oral formulations. It is administered subcutaneously in combination with other antiretrovirals in treatment-experienced patients with persistent HIV-1 replication despite current therapy. Injection site reactions and hypersensitivity may occur.

Integrase Inhibitor

Raltegravir is an inhibitor of viral integrase, the enzyme required for integration of the viral DNA with that of the host. Block of this step (Figure 28–3) prevents replication of the viral genome. The drug is active by the oral route and is not affected by food. The drug is well tolerated but headache and gastrointestinal disturbances have been reported.

HIV Entry Receptor Blocker

Maraviroc combines with a chemokine receptor on lymphocytes and prevents the binding of HIV to cell-surface receptors, a step required for entry into host cells (Figure 28–3). It is orally active and always used with other anti-HIV drugs. Toxicity includes hypersensitivity reactions and hepatotoxicity.

There are three types of influenza viruses: A, B, and C. Influenza A and B produce similar clinical infections, manifested by fever, chills, malaise, myalgia, headache, nasal congestion, nonproductive cough, and sore throat. Influenza C is usually a minor illness. Influenza A and B infections are typically self-limiting, and most patients recover within 7 days. Anti-influenza agents can decrease the duration and severity of fever and systemic symptoms. They can also be used for prophylaxis of clinical infection. Complications of influenza, including pneumonia, occur more frequently in older adults, residents of long-term health-care facilities, and individuals with chronic illnesses such as diabetes mellitus and pulmonary or cardiovascular diseases. Available vaccines for the most current influenza A and B viral strains are recommended before the beginning of influenza season (typically fall or winter) for susceptible individuals as well as health-care workers.

Amantadine and Rimantadine

Amantadine and rimantadine inhibit an early replication step of the influenza A virus (not influenza B). These agents prevent viral uncoating within infected host cells (Figure 28–1). Both drugs are about 70 to 90% effective in preventing clinical illness. If treatment begins about 1 to 2 days after the onset of clinical flu symptoms, both drugs reduce the duration of fever and systemic complaints by 1 to 2 days. Rapid development of resistance occurs in up to 50% of treated individuals, and transmission of resistant virus to household members has been documented. Although the mechanism of action is not clearly defined, amantadine is also used to alleviate motor abnormalities in Parkinson’s disease (Chapter 17). The most common adverse effects include gastrointestinal irritation, dizziness, ataxia, and slurred speech.

Oseltamivir and Zanamivir

These drugs inhibit neuraminidases produced by influenza A and B. By cleaving attachments between viral proteins and surface proteins of infected cells, viral neuraminidases promote virion release and prevent clumping of newly released virions. Thus, neuraminidase inhibitors hinder viral spread. Both drugs are approved for the treatment of acute uncomplicated influenza infection. Unlike amantadine and rimantidine, oseltamivir and zanamivir are active against both influenza A and influenza B. When a 5-day drug course is initiated within 36 to 48 hours after the onset of symptoms, use of either drug shortens the severity and duration of illness, and may also decrease the incidence of respiratory complications in children and adults. Oseltamivir is used orally, and zanamivir is used intranasally or by oral inhalation using the Diskhaler device provided. Taken prophylactically, oseltamivir significantly decreases the incidence of influenza. Gastrointestinal symptoms may occur with oseltamivir, which may be decreased by administration with food. Zanamivir may induce bronchospasm in asthmatic patients.

Each of the recognized hepatitis viruses (A to E) belongs to a distinct virus family, but all of them have a long incubation period between initial infection and onset of symptoms. Hepatitis can easily be spread before symptoms appear, and many cases are likely unreported because initial symptoms may be mild. Both HBV and HCV are bloodborne viral infections. Sharing of intravenous drug use equipment and sexual contact with an infected person are the most frequent sources of HBV transmission, whereas intravenous drug use is the primary means of HCV transmission. Treatment of these infections is critical because there are millions of chronic carriers of HBV and HCV. Untreated carriers are not only infectious to others, but they can also develop long-term complications such as chronic hepatitis, cirrhosis of the liver, and hepatocellular carcinoma.

All currently available agents for use in the treatment of HBV and HCV are suppressive rather than curative. In general, antihepatitis drugs are more effective at hindering disease progression in HBV infection than in HCV infection. Compliance with drug treatment is also problematic. Adverse effects may be intolerable, and dosing regimens are often rigorous, requiring injections once daily or three times weekly for several months in the case of interferons. Drugs used for treatment of viral hepatitis fall into two broad categories: immune modulators (interferons) and replication inhibitors (lamivudine, adefovir, ribavirin) (Table 28–1). Given the morbidity and mortality associated with these infections, improved chemotherapies are critically needed. Although a vaccine is available for HBV, none is yet available for HCV.

Interferon-α and Pegylated Interferon-α

Mechanism of Action and Pharmacokinetics

Interferons are endogenous cytokines that are part of the body’s innate immune defenses. These proteins act through host cell surface receptors to increase the formation of antiviral proteins. Interferons are classified according to the cell type from which they were derived. Each of the three distinct major classes of human interferons (α, β, γ) has unique physicochemical properties, biologic effects, and producer cells. The antiviral action of interferon-α (IFN-α) is primarily due to activation of a host cell ribonuclease that degrades viral RNA. In addition, IFN-α promotes formation of natural killer cells that destroy virally infected liver cells.

There are several preparations of IFN-α available for treatment of both HBV and HCV. The interferons are available as subcutaneous or intramuscular injections, which are given either daily or three times per week. The attachment of polyethylene glycol to IFN-α (termed pegylated IFN-α) extends its duration of action, allowing for less frequent dosing.

Clinical Uses and Toxicity

IFN-α is used in the treatment of chronic HBV as a monotherapy or in combination with lamivudine. IFN-α used with ribavirin for acute HCV infection reduces progression to chronic HCV. For chronic HCV, pegylated IFN-α with ribavirin is superior to nonpegylated IFN-α as monotherapy. IFN-α is also used in the treatment of Kaposi sarcoma, papillomatosis, and topically for genital warts. Interferons also prevent dissemination of herpes zoster in cancer patients. Typical adverse effects of IFN-α include a flu-like syndrome within 6 hours after dosing in about 30% of patients, which tends to resolve with continued administration. Gastrointestinal symptoms, profound fatigue, neutropenia, myalgia, rash, and hypotension can also occur. Severe neuropsychiatric symptoms (severe depression, mental confusion) have been reported.

Adefovir

Mechanism of Action, Pharmacokinetics, and Clinical Use

Although initially developed for treatment of HIV, adefovir is currently approved for treatment of HBV. Similar to tenofovir (see section on Anti-HIV Drugs), adefovir is a nucleotide analog. It competitively inhibits HBV DNA polymerase, causing chain termination after incorporation into viral DNA. It suppresses HBV replication and improves liver histology and fibrosis at 1 year. However, after cessation of therapy, HBV DNA reappears. Oral bioavailability is good, and it is unaffected by meals.

Toxicity

The primary toxicity is dose-dependent nephrotoxicity, which is more likely in patients with renal dysfunction and those receiving the drug for more than 1 year. As with the NRTIs, adefovir may cause lactic acidosis and hepatomegaly.

Lamivudine

Lamivudine is a NRTI agent used in treatment of HIV (see discussion above). At lower doses than those used for HIV, lamivudine is used for treatment of chronic HBV infection. Although lamivudine’s use as a monotherapy rapidly suppresses HBV replication and is relatively nontoxic, resistance emerges rapidly. If patients still have detectable levels of HBV DNA, they are often switched to IFN-α or adefovir.

Ribavirin

Mechanism of Action and Pharmacokinetics

Ribavirin inhibits the replication of many DNA and RNA viruses, including influenza A and B, parainfluenza, HCV, and HIV. The precise mechanism of action is not known, but it inhibits the formation of viral DNA, prevents capping of viral mRNA, and blocks RNA-dependent RNA polymerases of some viruses. Ribavirin is available orally, intravenously, and as an aerosol. Oral bioavailability increases with high-fat meals and decreases with antacid consumption.

Clinical Uses and Toxicity

Ribavirin is used with IFN-α to treat patients with chronic HCV infection with liver disease. Monotherapy with ribavirin alone is not effective. In viral hemorrhagic fevers, early intravenous ribavirin decreases mortality. Ribavirin is also used in the treatment of respiratory syncitial virus (RSV) in children. Systemic use may cause a dose-dependent hemolytic anemia. Aerosolic formulations may cause conjunctival and bronchial irritation. Ribavirin is absolutely contraindicated in pregnancy because it is a human teratogen.

Vaccines consist of whole virions or virus fragments that are completely inactivated (dead) or partially inactivated (live attenuated). Active immunization consists of inoculation with a vaccine that triggers the host immune system to produce antibodies and cell-mediated immunity against this antigen. Thus, active immunization provides immunity to subsequent exposure to that particular virus. The ideal vaccine prevents the viral disease, prevents the virus carrier state, and produces long-lasting immunity with a minimum number of immunizations, absence of toxicity, and convenience for mass immunizations (e.g., inexpensive and easy to administer). Live attenuated products stimulate natural resistance and impart longer lasting immunity than dead antigens. However, the risk of contracting the viral disease is greater than with completely inactivated antigens. Examples of live attenuated vaccines include those for measles, mumps, and rubella (MMR), poliovirus (the oral vaccine), and varicella. Vaccines containing dead viral antigens include those for rabies, both hepatitis A and B viruses, and poliovirus (the parenteral vaccine). Currently, vaccines are available for many viral infections. Whereas some vaccinations are required by law (e.g., measles, poliomyelitis), others are only administered to high-risk populations (e.g., influenza). Selected examples of commonly used material for active immunization in the United States are given in Table 28–3.

Unlike active immunization, which requires time to develop because the individual’s immune system must produce its own antibodies, passive immunization allows an individual to gain immediate immunity because it consists of the transfer of preformed immunoglobulins to an individual. Since the recipient does not produce his/her own antibodies, passive immunization is temporary. Passive immunization products generally contain high titers of antibodieseither directed against a specific antigen, or may simplycontain antibodies found in most of the population. Passive immunization is used for (1) individuals who are unable to form antibodies (e.g., congenital agammaglobulinemia); (2) prevention of disease when time does not permit active immunization (e.g., postexposure); (3) treatment of certain diseases normally prevented by immunization (e.g., tetanus); and (4) treatment of conditions for which active immunization is unavailable or impractical (e.g., snakebite). Antibodies can be derived from animal or human sources. Immunizations derived from human antibodies have the advantages of avoiding the risk of hypersensitivity reactions and having a longer half-life than those from animal sources. Selected materials for passive immunization are presented in Table 28–4.

Although many antiviral agents limit the extent of systemic damage, especially when initiated early in the course of viral infection, very few completely cure viral infections. Patients taking antiviral agents face particular challenges in adhering to complicated drug regimens. HAART regimens generally require HIV/AIDS patients to take more than a dozen pills per day–some on an empty stomach, some with meals, and others with large quantities of water. Antihepatitis interferon compounds require injections one to three times per week, often for extended periods of time. In addition, the adverse effects of systemic antiviral agents may cause patients to abandon a complete course of treatment.

Physical therapists can assist patients’ compliance with drug regimens. Therapists can arrange drugs in a single readily accessible location, teach patients to use a timer to signal dosing times, develop a color-coded system with pill boxes to remind patients which drugs need to be taken separately from or with food, and remind and educate patients about the importance of adherence to the antiviral regimen.

In arranging therapy sessions, therapists must be sensitive to the profound impact that antiviral drugs have on patients’ ability to participate. Nausea, vomiting, diarrhea, or malaise may delay treatment sessions. In an inpatient setting, frequent brief sessions may be more effective and tolerable than a single longer session. Pain due to peripheral neuropathies or myalgia may alter a treatment plan toward pain alleviation, in which therapists can assist by adjunctive use of heat modalities and transcutaneous electrical nerve stimulation (TENS). Flexibly managing therapy sessions around patients’ best time optimizes their ability to reach rehabilitation goals.

Because HIV directly targets the immune system, AIDS patients are among the most immunocompromised individuals. In addition to HAART, AIDS patients are often taking prophylactic medications to prevent opportunistic infections from other viruses, bacteria, fungi, and miscellaneous pathogens. Therapists should be alert to new signs and symptoms of acute infections, and report these to the primary health-care provider immediately to facilitate aggressive treatment in early infectious stages. Physical therapists must vigilantly practice standard precautions when working with HIV/AIDS patients. This also includes staying home or avoiding patient care when illness strikes the therapist to prevent pathogen transmission.

Adverse Drug Reactions

Antiherpes Drugs

• • Ganciclovir may cause myelosuppression.
• • Cidofovir and foscarnet can cause nephrotoxicity.
• • Foscarnet (and less commonly, ganciclovir) can cause CNS toxicity including headache, hallucinations, and seizures.

Anti-HIV Drugs

• • Many anti-HIV drugs cause gastrointestinal distress (nausea, vomiting, diarrhea, abdominal pain), malaise, fatigue, and CNS dysfunction (headache, agitation, dizziness, confusion).
• • The NNRTIs and PIs are metabolized by the cytochrome P450 system, increasing likelihood of drug-drug interactions.
• • Food decreases bioavailability of some NRTIs (didanosine, zalcitabine) and the PI indinavir.
• • An empty stomach decreases bioavailability of some NNRTIs (efavirenz), and PIs (ritonavir, saquinavir, nelfinavir, lopinavir).
• • Antacids decrease bioavailability of zalcitabine, delavirdine, and amprenavir.

NRTIs

• • All NRTIs (especially stavudine) have the potential to cause serious lactic acidosis and severe hepatic steatosis.
  • • Zidovudine can cause severe myelosuppression.
  • • Didanosine, zalcitabine, and stavudine can cause dose-dependent pancreatitis.
  • • Didanosine, zalcitabine, and stavudine can cause peripheral neuropathy.
  • • Didanosine can produce retinal changes.

NNRTIs

• • Most NNRTIs tend to produce a rash, which can be life-threatening with nevirapine.

PIs

• • The PIs often cause carbohydrate and lipid metabolic dysregulation.
  • • Indinavir can cause kidney damage.
  • • Ritonavir and amprenavir can cause paresthesias.
  • • Amprenavir can cause life-threatening rashes.
  • • Lopinavir can cause asthenia (weakness).

Anti-Influenza Drugs

• • Amantadine and oseltamivir can cause gastrointestinal upset.
• • Amantadine can cause dizziness and ataxia.
• • Zanamivir may induce bronchospasm in asthmatic patients.

Anti-Hepatitis Drugs

• • IFN-α can cause flu-like symptoms within six hours after parenteral dosing.
• • IFN-α can cause hypotension and severe neuropsychiatric symptoms.
• • Aerosolic ribavirin can cause conjunctival and bronchial irritation.

Effects Interfering with Rehabilitation

• • Myelosuppression (ganciclovir, zidovudine) can result in decreased resistance to nosocomial infections (due to leukopenia), increased fatigue and shortness of breath (due to anemia), and easy bruising or excessive bleeding from minor wounds (due to thrombocytopenia).
• • Concurrent use of NSAIDs for musculoskeletal pain and inflammation should be avoided when patients are taking nephrotoxic drugs (e.g., cidofovir, foscarnet).
• • Gastrointestinal and CNS effects can affect participation and functional performance of patients in rehabilitation programs.
• • HIV/AIDS patients on HAART who take over-the-counter drugs or supplements risk decreased or increased blood drug levels, resulting in either undermedication or increased adverse effects associated with overmedication.
• • Severe nausea, vomiting, abdominal pain, rapid respirations or shortness of breath in HIV/AIDS patients receiving NRTIs may indicate onset of lactic acidosis.
• • HIV/AIDS patients receiving NRTIs who complain of constant pain in the upper abdomen with possible radiation to the back may be experiencing acute pancreatitis.
• • Painful peripheral neuropathies (didanosine, zalcitabine, stavudine), paresthesias (ritonavir, amprenavir), dizziness and ataxia (amantadine), and asthenia (lopinavir) can affect mobility and gait, and limit participation in rehabilitation.
• • Retinal changes (didanosine) can affect vision, balance, and mobility.
• • Protease inhibitor-induced metabolic dysregulation increases patients’ risk profile for cardiovascular disease.
• • Patients taking zanamivir or ribavirin may have respiratory dysfunction.
• • Participation in therapies may be limited within the first hours after IFN-α administration.

Possible Therapy Solutions

• • If the patient has myelosuppression, physical therapists should practice excellent standard precautions to prevent infection transmission. Exercise intensity and duration should be reduced to account for decreased oxygen-carrying capacity of the blood. In addition, extreme caution should be taken to avoid inadvertent or sustained pressure on any area of the patient, due to decreased clotting ability.
• • If patients taking nephrotoxic drugs experience musculoskeletal pain after exercise or therapies, drug alternatives such as heat or ice should be used instead of NSAIDs.
• • Therapy should be timed to occur during periods when adverse effects are lowest. Therapists should discuss with the referring health-care provider or pharmacist whether certain drugs can be taken at night to decrease perception of some CNS effects and minimize their impact on patients’ functional performance and ability to participate in therapy.
• • Physical therapists can assist with reinforcing optimal drug dosing schedules for patients on HAART. For example, therapists can make pictures or tables in convenient locations, such as above the bedside or in the kitchen, to remind patients which pills should be taken on an empty stomach and which should be taken with meals. Didanosine, zalcitabine, and indinavir should be taken on an empty stomach. Efavirenz, tenofovir, ritonavir, saquinavir, nelfinavir, and lopinavir should be taken with meals. Antacids should not be taken with zalcitabine, delavirdine, and amprenavir.
• • Because of the large potential for drug-drug interactions with HIV/AIDS patients on HAART, physical therapists should take a complete drug history and educate the patient regarding the potential for any drug, including herbal supplements and cold medicines, to interfere with drug metabolism. Therapists should strongly encourage the patient to discuss all current drug use with the referring health-care provider.
• • Symptoms consistent with lactic acidosis or pancreatitis should be immediately reported to referring health-care provider, and therapy discontinued until symptoms resolve.
• • Patient reports of vision changes, peripheral neuropathy, and paresthesias should be reported to referring health-care provider to determine if dose reduction alleviates symptoms.
• • Any rash or progression or spread of a current rash should be immediately reported to the primary health-care provider because of the ability for many antiviral drugs to produce life-threatening rashes.
• • Patients taking PIs should be monitored for signs of cardiovascular disease. If tolerated, exercise prescriptions should be modified to increase participation in aerobic exercise.
• • Physical therapists should carefully monitor respiratory function during therapy with patients taking zanamivir or ribavirin, especially if patients have chronic obstructive pulmonary disease. Worsening of symptoms should be reported to the primary health-care provider. Short-acting bronchodilators should be immediately available in the case of bronchospasm.

Brief History: The patient is a 44-year-old male who has been HIV positive for 10 years. On his most recent physician visit, it was noted that he was hyperglycemic and hyperlipidemic. In addition, although his weight has not changed in the past year, he notes that his legs appear thinner and his waist is definitely larger.

Current Medical Status and Drugs: The patient’s HAART regimen includes two NRTIs, one NNRTI, and a protease inhibitor. Since the patient’s HIV infection has responded very well to this drug regimen, his physician is currently reluctant to switch to a protease inhibitor–sparing regimen. Instead, she has referred him to rehabilitation to assess the efficacy of a nonpharmacological approach to the hyperglycemia, hyperlipidemia, and lipodystrophy syndrome.

Rehabilitation Setting: The physical therapist prescribes an exercise program for the patient that includes aerobic and progressive resistance training. His exercise program includes 40 minutes of moderate aerobic activity and 20 minutes of resistance training three to four times per week. Larger muscle groups, especially the lower extremities, are targeted for strengthening. The therapist monitors his vital signs, and progresses exercises appropriately to his tolerance. The patient has been stringently following his exercise program for 4 months. He is quite pleased with the results, as he notes that his belt fits better now and he is noting more strength and mass in his legs. At his physician’s reassessment, his metabolic profile has also improved significantly: decreased lipidemia, decreased fasting blood glucose, and decreased resting blood pressure.

Problem/Clinical Options: Without question, HAART has increased the lifespan and improved the quality of life of individuals with HIV infection. As HIV/AIDS patients live longer, other morbidities have emerged, including cardiovascular disease. Protease inhibitors traditionally included in HAART regimens are often associated with development of dyslipidemia, insulin resistance, and lipodystrophy. Similar to the management of these conditions in HIV-uninfected individuals, exercise can be used to help prevent potential cardiovascular and metabolic complications in HIV-infected people. Recommendations include smoking cessation, reduction in dietary fat, and increasing exercise. Specifically, resistance and aerobic exercises have been shown to help HIV-infected individuals gain lean body mass, decrease truncal adiposity, and decrease total cholesterol and triglyceride concentrations.

Abacavir (Ziagen)

Oral: 300-mg tablets; 20 mg/mL solution

Oral (Trizir): 300-mg tablets in combination with 150 mg lamivudine and 300 mg zidovudine

Acyclovir (Generic, Zovirax)

Oral: 200-mg capsules; 400-, 800-mg tablets; 200 mg/5 mL suspension

Parenteral: 50 mg/mL; powder to reconstitute for injection (500, 1000 mg/vial)

Topical: 5% ointment

Adefovir (Hepsera)

Oral: 10-mg tablets

Amantadine (Generic, Symmetrel)

Oral: 100-mg capsules, tablets; 50 mg/5 mL syrup

Amprenavir (Agenerase)

Oral: 50-, 150-mg capsules; 15 mg/mL solution

Cidofovir (Vistide)

Parenteral: 375 mg/vial (75 mg/mL) for IV injection

Delavirdine (Rescriptor)

Oral: 100-, 200-mg tablets

Didanosine (Dideoxyinosine, Ddi)

Oral (Videx): 25-, 50-, 100-, 150-, 200-mg tablets; 100-, 167-, 250-mg powder for oral solution; 2-, 4-g powder for pediatric solution

Oral (Videx-EC): 125-, 200-, 250-, 400-mg delayed-release capsules

Efavirenz (Sustiva)

Oral: 50-, 100-, 200-mg capsules; 600-mg tablets

Enfuvirtide (Fuzeon)

Parenteral: 90 mg/mL for injection

Famciclovir (Famvir)

Oral: 125-, 250-, 500-mg tablets

Fomivirsen (Vitravene)

Intravitreal: 6.6 mg/mL for injection

Foscarnet (Foscavir)

Parenteral: 24 mg/mL for IV injection

Ganciclovir (Cytovene)

Oral: 250-, 500-mg capsules

Parenteral: 500 mg/vial for IV injection

Intraocular implant (Vitrasert): 4.5 mg ganciclovir/implant

Idoxuridine (Herplex)

Ophthalmic: 0.1% solution

Imiquimod (Aldera)

Topical: 5% cream

Indinavir (Crixivan)

Oral: 100-, 200-, 333-, 400-mg capsules

Interferon Alfa‐2a (Roferon‐a)

Parenteral: 3-, 6-, 9-, 36-million IU vials

Interferon Alfa‐2b (Intron‐a)

Parenteral: 3-, 5-, 10-, 18-, 25-, and 50-million IU vials

Interferon Alfa-2b (Rebetron)

Parenteral: 3-million IU vials (supplied with oral ribavirin, 200-mg capsules)

Interferon Alfa-N3 (Alferon N)

Parenteral: 5-million IU/vial

Interferon Alfacon-1 (Infergen)

Parenteral: 9- and 15-mcg vials

Lamivudine (Epivir)

Oral (Epivir): 150-, 300-mg tablets; 10 mg/mL oral solution

Oral (Epivir-HBV): 100-mg tablets; 5 mg/mL solution

Oral (Combivir): 150-mg tablets in combination with 300 mg zidovudine

Oral (Trizir): 300-mg tablets in combination with 150 mg lamivudine and 300 mg zidovudine

Lopinavir/Ritonavir (Kaletra)

Oral: 133.3 mg/33.3 mg capsules; 400 mg/100 mg per 5 mL solution

Maraviroc (Selzentry)

Oral: 150, 300 mg tablets

Nelfinavir (Viracept)

Oral: 250-mg tablets; 50 mg/g powder

Nevirapine (Viramune)

Oral: 200-mg tablets; 50 mg/5 mL suspension

Oseltamivir (Tamiflu)

Oral: 75-mg capsules; powder to reconstitute as suspension (12 mg/mL)

Peginterferon Alfa-2a (Pegylated Interferon-Alfa 2a, Pegasys)

Parenteral: 180 mcg/mL

Peginterferon Alfa-2b (Pegylated Interferon-Alfa 2b, PEG-Intron)

Parenteral: powder to reconstitute as 100, 160, 240, 300 mcg/mL injection

Penciclovir (Denavir)

Topical: 1% cream

Raltegravir (Isentress)

Oral: 400-mg tablets

Ribavirin

Aerosol (Virazole): powder to reconstitute for aerosol; 6 g/100 mL vial

Oral (Rebetol): 200-mg capsules

Oral (Rebetron): 200 mg in combination with 3-million units interferon alfa-2b (Intron-A)

Rimantadine (Flumadine)

Oral: 100-mg tablets; 50 mg/5 mL syrup

Ritonavir (Norvir)

Oral: 100-mg capsules; 80 mg/mL oral solution

Saquinavir

Oral (Invirase): 200-mg hard gel capsules

Oral (Fortovase): 200-mg soft gel capsules

Stavudine (Zerit)

Oral: 15-, 20-, 30-, 40-mg capsules; powder for 1 mg/mL oral solution

Tenofovir (Viread)

Oral: 300-mg tablets

Trifluridine (Viroptic)

Topical: 1% ophthalmic solution

Valacyclovir (Valtrex)

Oral: 500-, 1000-mg tablets

Valgancyclovir (Valcyte)

Oral: 450-mg capsules

Zalcitabine (Dideoxycytidine, ddC) (Hivid)

Oral: 0.375-, 0.75-mg tablets

Zanamivir (Relenza)

Inhalational: 5 mg/rotadisk

Zidovudine (Azidothymidine, AZT) (Retrovir)

Oral: 100-mg capsules, 300-mg tablets, 50 mg/5 mL syrup

Oral (Combivir): 300-mg tablets in combination with 150 mg lamivudine

Oral (Trizir): 300-mg tablets in combination with 150 mg lamivudine and 300 mg zidovudine

Parenteral: 10 mg/mL