Antiviral Agent (HIV and AIDs)
Agents for HIV and AIDS Loss of helper T cell function causes acquired immune deficiency syndrome (AIDS) and AIDS-related complex (ARC), diseases that are characterized by the emergence of a variety of opportunistic infections and cancers that occur when the immune system is depressed and unable to function properly. The HIV mutates over time, presenting a slightly different configuration with each new generation. Treatment of AIDS and ARC has been difficult for two reasons: (1) the length of time the virus can remain dormant within the T cells (i.e., months to years), and (2) the adverse effects of many potent drugs, which may include further depression of the immune system.
A combination of at least three different antiviral drugs is used to attack the virus at various points in its life cycle to achieve maximum effectiveness with the least amount of toxicity. The types of antiviral agents that are used to treat HIV infections are the nonnucleoside and NRTIs, the protease inhibitors, and three newer classes of drugs—the fusion inhibitors, CCR5 (C-C chemokine receptor type 5) coreceptor antagonists, and integrase inhibitors. Collectively, these drugs are known as antiretroviral agents. The HIV virus poses a serious health risk. The patient and the family of the patient diagnosed with HIV infection will need tremendous support and teaching to cope with the disease and its treatment.
Agents for HIV and AIDS Nonnucleoside Reverse Transcriptase Inhibitors - delavirdine - efavirenz - etravirine * nevirapine - rilpivirine Nucleoside Reverse Transcriptase Inhibitors - abacavir - didanosine - emtricitabine - lamivudine - stavudine - tenofovir * zidovudine
Agents for HIV and AIDS Protease Inhibitors - atazanavir - darunavir * fosamprenavir - indinavir - lopinavir - nelfinavir - ritonavir - saquinavir - tipranavir Fusion Inhibitor * enfuvirtide CCR5 Coreceptor Antagonist * maraviroc Integrase Inhibitor - dolutegravir * raltegravir
Protease Inhibitors Clinically Significant Drug-Drug Interactions Fosamprenavir should not be used in patients who are receiving ritonavir if they have used protease inhibitors to treat their disease because of a risk of serious adverse effects. If nelfinavir is combined with pimozide, rifampin, triazolam, or midazolam, severe toxic effects and life-threatening arrhythmias may occur. Such combinations should be avoided. Indinavir and nevirapine interact to cause severe toxicity. If these two drugs are given in combination the doses should be adjusted and the patient should be monitored closely. Tipranavir, darunavir, and fosamprenavir have been shown to interact with many other drugs.
Before administering these drugs, it is important to check a drug guide to assess for potential interactions with other drugs being given. Many potentially serious toxic effects can occur when ritonavir is taken with nonsedating antihistamines, sedatives/hypnotics, or antiarrhythmics because of the activity of ritonavir in the liver. Patients with hepatic dysfunction are at increased risk for serious effects when taking ritonavir and require a reduced dose and close monitoring.
Drugs in Focus: Agents for HIV and AIDS Protease Inhibitors Drug Name: atazanavir (Reyataz) Dosage/Route: Adult: 400 mg PO, q8h Usual Indications: Treatment of adults with HIV as part of combination therapy Drug Name: darunavir (Prezista) Dosage/Route: Adult: 600 mg PO b.i.d with ritonavir 100 mg PO b.i.d Usual Indications: Treatment of adults with advanced HIV disease with progression following standard treatment, used as part of combination therapy that must contain ritonavir Drug Name: fosamprenavir (Lexiva) Dosage/Route: Adult: 1,400 mg/d PO with 100 mg/d ritonavir PO or 700 mg PO b.i.d. with ritonavir 100 mg PO b.i.d. Pediatric: 18-30 mg/kg b.i.d oral suspension, based on weight with ritonavir 3 mg/kg PO b.i.d Usual Indications: Part of combination therapy for the treatment of HIV Drug Name: indinavir (Crixivan) Dosage/Route: Adult: 800 mg PO q8h Usual Indications: Treatment of adults with HIV as part of combination therapy
Drug Name: lopinavir (Kaletra) Dosage/Route: Adult: 3 capsules or 5 mL PO b.i.d. Pediatric (6 mo-12 y): 10-12 mg/kg PO b.i.d. Usual Indications: Treatment of adults and children with HIV in combination with other antiretroviral agents Drug Name: nelfinavir (Viracept) Dosage/Route: Adult: 750 mg PO t.i.d. Pediatric (2-13 y): 20-30 mg/kg per dose PO t.i.d. Usual Indications: Combination therapy for the treatment of adults and children with HIV Drug Name: ritonavir (Norvir) Dosage/Route: Adult and pediatric (>2 y): 600 mg PO b.i.d. Usual Indications: Part of combination therapy for the treatment of adults and children with HIV Drug Name: saquinavir (Invirase) Dosage/Route: Adult: 1,000 mg PO b.i.d with ritonavir 100 mg PO b.i.d Usual Indications: Treatment of adults with HIV as part of combination therapy Drug Name: tipranavir (Aptivus) Dosage/Route: Adult: 500 mg/d PO with 200 mg ritonavir Usual Indications: Treatment of adults with HIV in combination with ritonavir
Drugs in Focus: Agents for HIV and AIDS Nonnucleoside Reverse Transcriptase Inhibitors Drug Name: delavirdine (Rescriptor) Dosage/Route: Adult: 400 mg PO t.i.d. Usual Indications: Part of combination therapy regimens for treatment of HIV in adults Drug Name: efavirenz (Sustiva) Dosage/Route Adult: 600 mg/d PO Pediatric: Dose determined by age and weight Usual Indications: Treatment of adults and children with HIV in combination with other antiretroviral agents Drug Name: etravirine (Intelance) Dosage/Route: Adult: 200 mg PO b.i.d after a meal Pediatric: Based on weight, 100-200 mg PO b.i.d Usual Indications: Treatment of HIV in adults with treatment experience who have evidence of viral replication and HIV strains resistant to standard therapy
Drug Name: nevirapine (Viramune) Dosage/Route: Adult: 200 mg/d PO for 14 d, then 200 mg PO b.i.d. Pediatric: 4 mg/kg PO for 14 d, then 4-7 mg/kg PO b.i.d. Usual Indications: Treatment of adults or children with HIV in combination with other antiretroviral agents Drug Name: Rilpivirine (Edurant) Dosage/Route: Adult: 25 mg/d PO with food Usual Indications: Combination treatment of adults with HIV-1 infection
Drugs in Focus: Agents for HIV and AIDS Nucleoside Reverse Transcriptase Inhibitors Drug Name: abacavir (Ziagen) Dosage/Route: Adult: 300 mg PO b.i.d. Pediatric: 8 mg/kg PO b.i.d. Usual Indications: Combination therapy for the treatment of adults and children with HIV Drug Name: didanosine (Videx) Dosage/Route: Adult: 250-400 mg/d PO or 125- 200 mg PO b.i.d. Pediatric: 120 mg/m2 PO b.i.d. Usual Indications: Treatment of advanced infections in adults and children with HIV as part of combination therapy Drug Name: emtricitabine (Emtriva) Dosage/Route: Adult: 200 mg/d PO or 240 mg oral solution/d Pediatric (3 mo-17 y): 6 mg/kg/d PO to a maximum 240 mg Usual Indications: Part of combination therapy for treatment of HIV-1 infection Drug Name: lamivudine (Epivir) Dosage/Route: Adult: 150 mg PO b.i.d.; for chronic hepatitis B, 100 mg PO q.d. Pediatric (3 mo-16 y): 4 mg/kg PO b.i.d. Usual Indications: With other antiretroviral agents for the treatment of adults and children with HIV; as an oral solution for the treatment of chronic hepatitis B
Drug Name: stavudine (Zerit XR) Dosage/Route: Adult ( ≥60 kg): 100 mg/d PO Adult (30-60 kg): 75 mg/d PO Pediatric: based on weight Usual Indications: Treatment of patients with HIV in combination with other antiretroviral agents Drug Name: tenofovir (Viread) Dosage/Route: Adult: 300 mg/d PO Pediatric: 8 mg/kg/day PO (for HIV, not recommended for hepatitis B) Usual Indications: Treatment of adults with HIV infection in combination with other antiretroviral drugs; treatment of chronic hepatitis B Drug Name: AZT (Retrovir, Aztec) Dosage/Route: Adult: 100 mg PO q4h Pediatric (6 wk-12 y): 90-180 mg/m2 PO q6h Maternal: 100 mg PO five times per day from 14-wk gestation until start of labor Usual Indications: Treatment of symptomatic HIV in adults and children as part of combination therapy; prevention of maternal transmission of HIV
Drugs in Focus: Agents for HIV and AIDS Fusion Inhibitor Drug Name: enfuvirtide (Fuzeon) Dosage/Route: Adult: 90 mg PO b.i.d. by subcutaneous injection Pediatric 6-16 y: 2 mg/kg b.i.d. by subcutaneous injection Usual Indications: Part of combination therapy in treatment of HIV patients with evidence of HIV replication despite antiretroviral therapy Drugs in Focus: Agents for HIV and AIDS CCR5 Coreceptor Antagonist Drug Name: maraviroc (Selzentry) Dosage/Route: Adult: 150 mg PO b.i.d. Usual Indications: Part of combination therapy for treatment of HIV-1 infections
Drugs in Focus: Agents for HIV and AIDS Integrase Inhibitor Drug Name: dolutegravir (Tivicay) Dosage/Route: Adult and children 12 and older: 50 mg/day PO in combination with other antiretrovirals Usual Indications: Part of combination therapy for treatment of HIV-1 infections Drug Name: raltegravir (Isentress) Dosage/Route: Adult: 400 mg PO b.i.d. Usual Indications: Part of combination therapy for treatment of HIV-1 infections
Nucleoside Reverse Transcriptase Inhibitors Adverse Effects Serious-to-fatal hypersensitivity reactions have occurred with abacavir, and it must be stopped immediately at any sign of a hypersensitivity reaction (fever, chills, rash, fatigue, GI upset, flu-like symptoms). Patients exhibiting any signs of hypersensitivity should be listed with the Abacavir Hypersensitivity Registry, a drug follow-up registry that is maintained by the drug company and reported to the U.S. Food and Drug Administration. Serious pancreatitis, hepatomegaly, and neurological problems have been reported with didanosine, which is why its use is limited to the treatment of advanced infections.
Emtricitabine has been associated with severe and even fatal hepatomegaly with steatosis. Severe hepatomegaly with steatosis has been reported with tenofovir, so it must be used with extreme caution in any patient with hepatic impairment or lactic acidosis. Patients also need to be alerted that the drug may cause changes in body fat distribution, with loss of fat from arms, legs, and face and deposition of fat on the trunk, neck, and breasts. Severe bone marrow suppression has occurred with zidovudine
Fixed Combination Drugs for Treatment of HIV Infection Patients who are taking combination drug therapy for HIV infection may have to take a very large number of pills each day. Keeping track of these pills and swallowing such a large number each day can be an overwhelming task. In an effort to improve patient compliance and make it easier for some of these patients, some anti-HIV agents are now available in combination products. Combivir is a combination of 150-mg lamivudine and 300-mg zidovudine. The patient takes one tablet twice a day. Because this is a fixed combination drug, it is not the drug of choice for patients who require a dose reduction owing to renal impairment or adverse effects that limit dose tolerance. Trizivir combines 300-mg abacavir, 150-mg lamivudine, and 300-mg zidovudine. The patient takes one tablet twice a day. Because this is a fixed combination drug, it is not the drug of choice for patients who require a dose reduction owing to renal impairment or adverse effects that limit dose tolerance. Patients taking Trizivir should be warned at the time the prescription is filled about the potentially serious hypersensitivity reactions associated with abacavir and should be given a written list of warning signs to watch for.
Epzicom (600-mg abacavir with 300-mg lamivudine) is taken as one tablet once a day. Truvada (200-mg emtricitabine with 300-mg tenofovir) is also a once-a-day tablet. The patient should be stabilized on each antiviral individually before being switched to the combination form Atripla—600-mg efavirenz, 200-mg emtricitabine, and 300-mg tenofovir. Atripla is recommended for patients 18 years old and older who have already been stabilized on each antiviral individually. Complera combines 200-mg emtricitabine, 25-mg rilpivirine, and 300-mg tenofovir. It is also approved for patients who have taken the individual drugs before. Triumeq combines 50-mg dolutegravir, 600-mg abacavir, and 300-mg lamivudine and is recommended for adults who experience success with each of the drugs alone.
Fusion Inhibitor Prototype Summary: Enfuvirtide Indications: Treatment of HIV-1-infected patients who have experienced clinical or immunological deterioration after treatment with other agents, in combination with other antiretrovirals. Actions: Prevents the entry of the HIV-1 virus into cells by inhibiting the fusion of the virus membrane with the cellular membrane.
Fusion Inhibitor Prototype Summary: Enfuvirtide Pharmacokinetics: Route: Subcutaneous Onset: Slow Peak: 4-8 h T1/2: 3.2 to 4.4 hours; metabolized in the liver, tissues recycle the amino acids, not excreted. Adverse Effects: Headache, nausea, vomiting, diarrhea, rash, anorexia, pneumonia, chills, injection site reactions.
HIV Resistance In late 2003 Gilead Sciences, Inc. notified health care professionals of a high rate of early virological failure and the emergence of nucleoside reverse transcriptase inhibitor (NRTI) resistance-associated mutations. This was observed in a clinical study of HIV-infected, treatment-naive patients receiving a once-daily triple NRTI regimen containing didanosine enteric-coated beadlets (Videx EC), lamivudine (Epivir), and tenofovir disoproxil fumarate (Viread). Based on these studies, tenofovir in combination with didanosine and lamivudine is not recommended when considering a new treatment regimen for therapy-naive or experienced patients with HIV infection. Patients currently on this regimen should be considered for treatment modification.
In a similar study, patients receiving unboosted Reyataz (atazanavir sulfate) and Viread (tenofovir) showed less decrease in viral concentrations and loss of virological response, which could show a possible resistance to Reyataz. For patients taking atazanavir and tenofovir, the Food and Drug Administration advises that a boosted dose of atazanavir should be used to overcome a decrease in concentration of the drug that seems to occur when it is used with tenofovir.
Protease Inhibitors Pharmacokinetics (1/2) Atazanavir is rapidly absorbed from the GI tract and can be taken with food. After metabolism in the liver, it is excreted in the urine and feces with a half-life of 6.5 to 7.9 hours. It is not recommended for patients with severe hepatic impairment; for those with moderate hepatic impairment the dose should be reduced. Darunavir is well absorbed from the GI tract, reaching peak levels in 2.5 to 4 hours. It is metabolized in the liver and excreted in the urine and feces with a half-life of 15 hours. It is not recommended for patients with severe hepatic impairment. Fosamprenavir is rapidly absorbed after oral administration, reaching peak levels in 1.5 to 4 hours. It is metabolized in the liver and excreted in the urine and feces.
Indinavir is rapidly absorbed from the GI tract, reaching peak levels in 0.8 hour. Indinavir is metabolized in the liver by the cytochrome P450 system. It is excreted in the urine with a half-life of 1.8 hours. Patients with hepatic or renal impairment are at risk for increased toxic effects, necessitating a reduction in dose. Lopinavir is used as a fixed combination drug that combines lopinavir and ritonavir. The ritonavir inhibits the metabolism of lopinavir, leading to increased lopinavir serum levels and effectiveness. (Box 10.5 reviews the dose calculation with lopinavir.). It is readily absorbed from the GI tract, reaching peak levels in 3 to 4 hours, and undergoes extensive hepatic metabolism by the cytochrome P450 system.
Nonnucleoside Reverse Transcriptase Inhibitors Clinically Important Drug-Drug Interactions
Life-threatening effects can occur if delavirdine is combined with antiarrhythmics, clarithromycin, dapsone, antituberculosis drugs, calcium-channel blockers, warfarin, quinidine, indinavir, saquinavir, or dapsone. These combinations should be avoided if at all possible. There is a risk of serious adverse effects if efavirenz is combined with midazolam, rifabutin, triazolam, or ergot derivatives; these combinations should be avoided. There may be a lack of effectiveness if nevirapine is combined with hormonal contraceptives or protease inhibitors. St. John's wort should not be used with these drugs; a decrease in antiviral effects can occur.
Nonnucleoside Reverse Transcriptase Inhibitors Pharmacokinetics Delavirdine: is rapidly absorbed from the GI tract, with peak levels occurring within 1 hour. Delavirdine is extensively metabolized by the cytochrome P450 system in the liver and is excreted through the urine. Efavirenz: is absorbed rapidly from the GI tract, reaching peak levels in 3 to 5 hours. Efavirenz is metabolized in the liver by the cytochrome P450 system and is excreted in the urine and feces with a half-life of 52 to 76 hours. Etravirine: is rapidly absorbed from the GI tract, reaching peak levels in 2.5 to 4 hours. Etravirine is metabolized in the liver by the cytochrome P450 system and is excreted in feces and urine with a half-life of 21 to 61 hours.
Nevirapine: is recommended for use in adults and children older than 2 months. After rapid GI absorption with a peak effect occurring at 4 hours, nevirapine is metabolized by the cytochrome P450 system in the liver. Excretion is through the urine with a half-life of 45 hours. Box 10.4 provides information about the emergence of resistance to certain reverse transcriptase inhibitor combinations. Rilpivirine (Edurant): is the newest drug in this class. It is rapidly absorbed from the GI tract, reaching peak levels in 4 to 5 hours. It is metabolized in the liver and excreted in feces and urine with a half-life of 50 hours.
Nonnucleoside Reverse Transcriptase Inhibitors Contraindications and Cautions There are no adequate studies of nonnucleoside reverse transcriptase inhibitors in pregnancy, so use should be limited to situations in which the benefits clearly outweigh any risks. It is suggested that women not breastfeed if they are infected with HIV. Safety for the use of delavirdine in children has not been established.
Nonnucleoside Reverse Transcriptase Inhibitors Adverse Effects The adverse effects most commonly experienced with these drugs are GI related—dry mouth, constipation or diarrhea, nausea, abdominal pain, and dyspepsia. Dizziness, blurred vision, and headache have also been reported. A flu-like syndrome of fever, muscle aches and pains, fatigue, and loss of appetite often occurs with the anti-HIV drugs, but these signs and symptoms may also be related to the underlying disease.
Nonnucleoside Reverse Transcriptase Inhibitors The nonnucleoside reverse transcriptase inhibitors have direct effects on the HIV virus activities within the cell. The nonnucleoside reverse transcriptase inhibitors available include delavirdine (Rescriptor), efavirenz (Sustiva), etravirine (Intelence), nevirapine (Viramune), and rilpivirine (Edurant).
Nonnucleoside Reverse Transcriptase Inhibitors Therapeutic Actions and Indications The nonnucleoside reverse transcriptase inhibitors bind directly to HIV reverse transcriptase, blocking both RNA- and DNA-dependent DNA polymerase activities. They prevent the transfer of information that would allow the virus to carry on the formation of viral DNA. As a result, the virus is unable to take over the cell and reproduce. These antiviral agents are indicated for the treatment of patients with documented AIDS or ARC who have decreased numbers of helper T cells and evidence of increased opportunistic infections in combination with other antiviral drugs
Nucleoside Reverse Transcriptase Inhibitors The nucleoside reverse transcriptase inhibitors (NRTIs) (Table 10.3) were the first class of drugs developed to treat HIV infections. These are drugs that compete with the naturally occurring nucleosides within a human cell that the virus would need to develop. The NRTIs include the following agents: abacavir (Ziagen), didanosine (Videx), emtricitabine (Emtriva), lamivudine (Epivir), stavudine (Zerit XR), tenofovir (Viread), and zidovudine (Retrovir).
Nucleoside Reverse Transcriptase Inhibitors Therapeutic Actions and Indications NRTIs compete with the naturally occurring nucleosides within the cell that the virus would use to build the DNA chain. These nucleosides, however, lack a substance needed to extend the DNA chain. As a result, the DNA chain cannot lengthen and cannot insert itself into the host DNA. Thus the virus cannot reproduce. They are used as part of combination therapy for the treatment of HIV infection. See Table 10.3 for usual indications for each of these agents.
Protease Inhibitors Contraindications and Cautions Of the protease inhibitors listed, saquinavir is the only agent that has not been shown to be teratogenic; however, its use during pregnancy should be limited. Saquinavir crosses into breast milk, and women are advised not to breastfeed while taking this drug. For the other agents, there are no adequate studies in pregnancy, so use should be limited to situations in which the benefits clearly outweigh any risks. It is suggested that women not breastfeed if they are infected with HIV. Patients with mild to moderate hepatic dysfunction should receive a lower dose of fosamprenavir, and patients with severe hepatic dysfunction should not receive this drug or darunavir because of their toxic effects on the liver. Patients receiving tipranavir must have liver function monitored regularly because of the possibility of potentially fatal liver dysfunction. Saquinavir must also be used cautiously in the presence of hepatic dysfunction.
Patients receiving darunavir may also be at risk for developing diabetes mellitus or hyperglycemia and may require dosage adjustments if being treated with antidiabetic drugs. Darunavir is also associated with mild to severe dermatologic reactions including Stevens-Johnson syndrome and the drug should be stopped if a severe reaction develops. The safety of indinavir for use in children younger than 12 years has not been established. Darunavir should not be used in children younger than 3 years of age because of the potential for toxic effects.
Protease Inhibitors The protease inhibitors block protease activity within the HIV virus. The protease inhibitors that are available for use include atazanavir (Reyataz), darunavir (Prezista), fosamprenavir (Lexiva), indinavir (Crixivan), lopinavir (Kaletra), nelfinavir (Viracept), ritonavir (Norvir), saquinavir (Fortovase), and tipranavir (Aptivus).
Protease Inhibitors Therapeutic Actions and Indications Protease is essential for the maturation of an infectious virus; without it an HIV particle is immature and noninfective, unable to fuse with and inject itself into a cell. All of these drugs are used as part of combination therapy for the treatment of HIV infection (see Table 10.3).
Protease Inhibitors Prototype Summary: Fosamprenavir Indications: Management of adults with symptomatic HIV infection in combination with other antiretrovirals. Actions: Inhibits protease activity, leading to the formation of immature, noninfectious virus particles.
Protease Inhibitors Prototype Summary: Fosamprenavir Pharmacokinetics: Route: Oral Onset: Varies Peak: 1.5-4 min T1/2: 7.7 hours; metabolized in the liver and excreted in the feces and urine. Adverse Effects: Headache, mood changes, nausea, diarrhea, fatigue, rash, Stevens-Johnson syndrome, redistribution of body fat (buffalo hump, thin arms and legs).
Prototype Summary: Nevirapine Indications: Treatment of HIV-1-infected patients who have experienced clinical or immunological deterioration, in combination with other antiretrovirals. Actions: Binds to HIV-1 reverse transcriptase and blocks replication of the HIV by changing the structure of the HIV enzyme.
Prototype Summary: Nevirapine Pharmacokinetics: Route: Oral Onset: Rapid Peak: 4h T1/2: 45 hours, then 25 to 30 hours; metabolized in the liver and excreted in the urine. Adverse Effects: Headache, nausea, vomiting, diarrhea, rash, liver dysfunction, chills, fever.
Nucleoside Reverse Transcriptase Inhibitors Prototype Summary: Zidovudine Indications: Management of adults with symptomatic HIV infection in combination with other antiretrovirals; prevention of maternal-fetal HIV transmission. Actions: A thymidine analogue that is activated to a triphosphate form, which inhibits the replication of various retroviruses, including HIV.
Prototype Summary: Zidovudine Pharmacokinetics: Route: oral Onset: vary Peak: 30-90 min Route: IV Onset: Rapid Peak: End of infusion T1/2: 30 to 60 minutes; metabolized in the liver and excreted in the urine. Adverse Effects: Headache, insomnia, dizziness, nausea, diarrhea, fever, rash, bone marrow suppression.
Public Education about AIDS
Public education is key for promoting the acceptance and support of patients with HIV infection or AIDS, who need a great deal of support and assistance. Nurses can be role models for dealing with HIV patients and can provide informal public education whenever the opportunity presents.
Protease Inhibitors Pharmacokinetics (2/2) Lopinavir is excreted in urine and feces. Tipranavir is used for the treatment of HIV infection in adults in combination with 200 mg of ritonavir. It is taken orally with food, two 250-mg capsules each day with the ritonavir. It is slowly absorbed, reaching peak levels in 2.9 hours. It is metabolized in the liver with a half-life of 4.8 to 6 hours; excretion is through urine and feces. Nelfinavir is well absorbed from the GI tract, reaching peak levels in 2 to 4 hours. Nelfinavir is metabolized in the liver using the cytochrome P450 CY3A system, and caution must be used in patients with any hepatic dysfunction. It is primarily excreted in the feces, with a half-life of 3.5 to 5 hours. Because there is little renal excretion, this is considered a good drug for patients with renal impairment.
Ritonavir is rapidly absorbed from the GI tract, reaching peak levels in 2 to 4 hours. Ritonavir undergoes extensive metabolism in the liver and is excreted in the feces and urine. Saquinavir is slowly absorbed from the GI tract and is metabolized in the liver by the cytochrome P450 mediator, so it must be used cautiously in the presence of hepatic dysfunction. It is primarily excreted in the feces with a short half-life. Because therapy for HIV infection involves the use of several different antiviral drugs, many are now available as combination drugs, which reduces the number of tablets a patient has to take each day. Box 10.6 discusses combination drugs.
Nucleoside Reverse Transcriptase Inhibitors Pharmacokinetics Abacavir is an oral drug that is rapidly absorbed from the GI tract. It is metabolized in the liver and excreted in feces and urine with a half-life of 1 to 2 hours. Didanosine is rapidly destroyed in an acid environment and therefore must be taken in a buffered form. It reaches peak levels in 15 to 75 minutes. Didanosine undergoes intracellular metabolism with a half-life of 8 to 24 hours. It is excreted in the urine. Emtricitabine has the advantage of being a one-capsule-a-day therapy. Emtricitabine has a rapid onset and peaks in 1 to 2 hours. It has a half-life of 10 hours, and after being metabolized in the liver is excreted in the urine and feces. Dose needs to be reduced in patients with renal impairment. It has been associated with severe and even fatal hepatomegaly with steatosis, a fatty degeneration of the liver. Lamivudine is rapidly absorbed from the GI tract and is excreted primarily unchanged in the urine. It peaks within 4 hours and has a half-life of 5 to 7 hours. Because excretion depends on renal function, dose reduction is recommended in the presence of renal impairment. The drug is available as an oral solution, Epivir-HBV; it is also recommended for the treatment of chronic hepatitis B.
Stavudine is rapidly absorbed from the GI tract, reaching peak levels in 1 hour. Most of the drug is excreted unchanged in the urine, making it important to reduce dose and monitor patients carefully in the presence of renal dysfunction. It can be used for adults and children and is only available in an extended release form, allowing for once-a-day dosing. Tenofovir is a newer drug that affects the virus at a slightly different point in replication—a nucleotide that becomes a nucleoside. It is used only in combination with other antiretroviral agents. It is rapidly absorbed from the GI tract, reaching peak levels in 45 to 75 minutes. Its metabolism is not known, but it is excreted in the urine. Zidovudine was one of the first drugs found to be effective in the treatment of AIDS. It is rapidly absorbed from the GI tract, with peak levels occurring within 30 to 75 minutes. Zidovudine is metabolized in the liver and excreted in the urine, with a half-life of 1 hour.
Fusion Inhibitor A newer class of drug is the fusion inhibitor (Table 10.3). This agent acts at a different site than do other HIV antivirals. The fusion inhibitor prevents the fusion of the virus with the human cellular membrane, which prevents the HIV-1 virus from entering the cell. Enfuvirtide (Fuzeon) is used in combination with other antiretroviral agents to treat adults and children older than 6 years who have evidence of HIV-1 replication despite ongoing antiretroviral therapy. Enfuvirtide is given by subcutaneous injection and peaks in effect in 4 to 8 hours. After metabolism in the liver, it is recycled in the tissues and not excreted.
The half-life of enfuvirtide is 3.2 to 4.4 hours. Enfuvirtide is contraindicated with hypersensitivity to any component of the drug and in nursing mothers. It should be used with caution in the presence of lung disease or pregnancy. The drug has been associated with insomnia, depression, peripheral neuropathy, nausea, diarrhea, pneumonia, and injection site reactions. There are no reported drug interactions, but caution should be used when it is combined with any other drug.
Nucleoside Reverse Transcriptase Inhibitors Clinically Significant Drug-Drug Interactions Tenofovir can cause large increases in the serum level of didanosine. If both of these drugs are given, tenofovir should be given 2 hours before or 1 hour after didanosine. Lamivudine and zalcitabine inhibit the effects of each other and should not be used together. Severe toxicity can occur if abacavir is combined with alcohol; this combination should be avoided. Didanosine can cause decreased effects of several antibiotics and antifungals; any antibiotic or antifungal started with didanosine should be evaluated carefully.
There is an increased risk of potentially fatal pancreatitis if stavudine is combined with didanosine and increased risk of severe hepatomegaly if it is combined with other nonnucleoside antivirals; these combinations are often used, and the patient needs to be monitored very closely. There have been reports of severe drowsiness and lethargy if zidovudine is combined with cyclosporine; warn the patient to take appropriate safety precautions.
Agents for HIV and AIDS Human immunodeficiency virus (HIV) attacks the helper T cells [CD4 (cluster of differentiation 4) cells] within the immune system. This virus (an RNA strand) reacts with a receptor site on the CD cell, fuses with the membrane, and then enters the helper T cell, where it uses reverse transcriptase to copy the RNA and produce a double-stranded viral DNA. The virus uses various nucleosides found in the cell to synthesize this DNA strand. The DNA enters the host cell nucleus and slides into the chromosomal DNA to change the cell's processes to ones that produce new viruses.
This changes the cell into a virus-producing cell. As a result, the cell loses its ability to perform normal immune functions. The newly produced viruses mature through the action of various proteases and then are released from the cell. Upon release, they find a new cell to invade, and the process begins again. Eventually, as more and more viruses are released and invade more CD4 cells the immune system loses an important mechanism responsible for propelling the immune reaction into full force when the body is invaded.
Nucleoside Reverse Transcriptase Inhibitors Contraindications and Cautions Of the nucleosides, zidovudine is the only agent that has been proven to be safe when used during pregnancy. Of the other agents, there have been no adequate studies in pregnancy, so use should be limited to situations in which the benefits clearly outweigh any risks.
Women infected with HIV are urged not to breastfeed. Tenofovir, zidovudine, and emtricitabine should be used with caution in the presence of hepatic dysfunction or severe renal impairment because of their effects on the liver and kidneys. Zidovudine should also be used with caution with any bone marrow suppression because it could aggrevate the suppression.
