Antiviral Agents II: drug for HIV infection

Goal for treatment

(1) maximal and long-lasting suppression of viral load (2) restoration and preservation of immune function (3) improved quality of life (4) reduction of HIV-related morbidity and mortality (5) prevention of HIV transmission.

Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

-Differ from NRTIs in structure and mechanism of action, no structural relationship with naturally occurring nucleosides. -Classifications: efavirenz [Sustiva], nevirapine [Viramune], delavirdine [Rescriptor], etravirine [Intelence], and rilpivirine [Edurant]. MOA: NNRTIs bind to active center of reverse transcriptase and causes stereochemical changes (i.e., changes in the spatial arrangement of atoms forming the structure of molecules). This hampers the ability of nucleosides to bind, which inhibits DNA replication and promotes premature termination of the growing DNA strand. Therapeutic use: -active as they are administered -Only against HIV-1. -usually combined with an NRTI. Adverse Effects -Unlike NRTIs, there are no adverse effects shared by all NNRTIs. -Two of the NNRTIs, efavirenz and rilpivirine, can both cause CNS effects. Drug Interactions -The NNRTIs have multiple drug interactions with commonly used drugs across many drug classes..

Human Immunodeficiency Virus (HIV)

-Human immunodeficiency virus is a retrovirus (HIV-1 and HIV-2) ---HIV-1 is found worldwide, whereas HIV-2 is found mainly in West Africa. ---Although HIV-1 and HIV-2 differ with respect to genetic makeup and antigenicity, they both cause similar disease syndromes. Not all drugs that are effective against HIV-1 are also effective against HIV-2. HIV promotes immunodeficiency by killing CD4 T lymphocytes (CD4 T cells), which are key components of the immune system. As a result of HIV-induced immunodeficiency, patients are at risk for opportunistic infections and certain neoplasms. HIV has RNA as genetic material Uses reverse transcriptase to convert RNA into DNA and integrase to insert its DNA into ours Target cells: CD4 T cells (helper lymphocytes) Transmission via blood and body fluids -Virus is present in all body fluids -by sexual contact, transfusion, sharing IV needles, and accidental needle sticks; transmitted to the fetus by an infected mother, usually during the perinatal period. -Breast feeding should avoid -The central core contains two separate but identical single strands of RNA, each with its own molecule of reverse transcriptase attached. -The RNA serves as the template for DNA synthesis. -The outer envelope of HIV contains glycoproteins that are needed for attachment to host cells. -Each glycoprotein (gp) consists of two subunits, known as gp41 and gp120. The smaller protein (gp41) is embedded in the lipid bilayer of the viral envelope; the larger protein (gp120) is connected firmly to gp41. Global epidemic in the United States, approximately 1.2 million people are now infected and about 50,000 more become infected each year. More than 658,000 have died since the epidemic began

HIV Drug Resistance

-In most cases, resistance emerges over the course of treatment as a result of nonadherence to the prescribed regimen -Rarely, resistance results from primary infection with a drug-resistant HIV variant -Resistance tests can be used to guide drug selection, especially when changing a regimen that has failed Two major types of resistance assays are employed: phenotypic assays and genotypic assays. ---Phenotypic assays measure the ability of HIV to grow in the presence of increasing concentrations of antiretroviral drugs. (The ability to grow in high concentrations indicates resistance.) ---Genotypic assays are designed to detect resistance-conferring mutations in HIV genes that code for the targets that drugs attack (e.g., reverse transcriptase and protease). --Drawbacks: Expensive turnaround is slow (2 to 4 weeks) sensitivity is low phenotypic assays can produce false-negative results genotypic assays are difficult to interpret

Standard antiretroviral therapy (ART)

-Often referred to as HAART (for highly active antiretroviral therapy), can decrease plasma HIV to levels that are undetectable with current technology and can thus delay or reverse loss of immune function, decrease certain AIDS-related complications, preserve health, prolong life, and decrease HIV transmission. -Reduced AIDS deaths by 72% but cannot fully eliminate HIV -HIV can rapidly mutate from a drug-sensitive form into a drug-resistant form. To minimize the emergence of resistance, patients must be treated with a combination of antiretroviral drugs. usually consists of three or four drugs

HIV Treatment in Pregnancy

-Same principles that guide antiretroviral therapy in nonpregnant adults -the goal is to balance the benefits of treatment Reducing viral load, thereby promoting the health of the mother and decreasing the risk for vertical HIV transmission (i.e., transmission to the fetus) Against the risks of drug-induced fetal harm (e.g., teratogenesis, lactic acidosis, death). -Mother-to-child transmission HIV ---Rate of perinatal transmission in the United States is 25%. A high viral load increases risk. ---Risk for transmission can be greatly reduced by ART, which minimizes maternal viral load ---The risk for vertical transmission can be reduced by giving antiretroviral drugs to the mother during gestation and labor, and to the infant for 4 to 6 weeks postpartum. --Delivery by cesarean section at 38 weeks is recommended for patients with a viral load above 1000 copies/mL. To further prevent perinatal HIV transmission, an intravenous (IV) zidovudine infusion should be initiated 3 hours prior to surgery and concluded after birth -The same general principles apply to children

Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

-The first drugs used against HIV infection Classifications: abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, and zidovudine. MOA: inhibit HIV replication by suppressing synthesis of viral DNA. --First, undergoing intracellular conversion to their active (phosphate) form and acting as substrates for reverse transcriptase. --Then, they prevent reverse transcriptase from adding more bases and block growth of the DNA. --Also, for causing premature strand termination, the activated NRTI competes with natural nucleoside triphosphates for binding to the active site of reverse transcriptase. Therapeutic use: combine with other class of drug to treat HIV -The fixed-dose combinations are shown in Table 94.1 -Didanosine and Stavudine are used rarely because of their adverse effect. Adverse Effects: a core of adverse effects associated with mitochondrial toxicity. NRTIs can disrupt synthesis of mitochondrial DNA and can thereby impair mitochondrial function. 1. Lactic Acidosis: A major consequence of mitochondrial impairment is lactic acidosis. Lactic acid accumulates because dysfunctional mitochondria cannot break down lactic acid. --Symptoms include nausea, malaise, fatigue, anorexia, and hyperventilation (blowing off carbon dioxide can reduce acidosis). --Left untreated, the syndrome can be fatal. Diagnosis is based on lactic acid measurement in arterial blood. --Those for which this is most likely to occur are didanosine and stavudine. 2. Hepatic Steatosis (fatty degeneration of the liver) and hepatomegaly (enlarged liver) -associated with mitochondrial impairment because there is decreased breakdown of fatty acids by mitochondria leading to fatty deposits in the liver. 3. Other Adverse Effects: pancreatitis and myopathies, which are likely tied to lactic acidosis. Drug Interactions NRTIs have fewer drug interactions than most antiretroviral drugs, in part because most are not metabolized by the P450 enzymes.

Principal Laboratory Tests Used to Guide Therapy

-The principal laboratory tests employed to monitor HIV infection and guide therapy: plasma HIV RNA (viral load) and CD4 T-cell counts. -Plasma HIV RNA (viral load) assays: --Ongoing treatment of HIV infection is guided primarily by monitoring viral load, which is determined by measuring HIV RNA in plasma --the best measurement for predicting clinical outcome: if HIV RNA is high, the prognosis is poor; if HIV RNA is low, the risk for disease progression and death is greatly reduced. --Thus, the goal of antiretroviral therapy (ART) is to decrease plasma HIV RNA to levels that are undetectable (20 to 75 copies/mL, depending on the assay employed). --Reducing plasma HIV RNA to undetectable levels does not mean that HIV has been eradicated. It means only that there is too little HIV to measure. Nonetheless, patients still harbor HIV and are still infectious. Accordingly, treatment should continue indefinitely, and patients should be warned to avoid behaviors that can transmit HIV to others. -CD4 T-cell counts: Principal indicator of how much immunocompetence remains -HLA-B*5701 Screening: to assess the risk of hypersensitivity reaction to abacavir If the test is positive, abacavir should not be used -CCR5 Tropism: a CCR5 tropism assay should be performed when considering the therapy of CCR5 antagonist

Protease Inhibitors (PIs)

Among the most effective antiretroviral drugs Classification: Lopinavir/ritonavir , Ritonavir , Indinavir , Saquinavir , Nelfinavir, Fosamprenavir , Atazanavir , Tipranavir , Darunavir MOA: prevent HIV maturation by blocking the HIV enzyme protease to block HIV infect CD4 cells Therapeutic use: -Used in combination with NRTIs; can reduce viral load to an undetectable level -active against both HIV-1 and HIV-2 Elimination: Feces (primary), urine for all of PIs family Resistance: -Mutant strains of HIV that are resistant to one PI are likely to be cross-resistant to other PIs. -Since PIs do not share the same mechanism as other antiretroviral drugs, cross-resistance between PIs and these drugs does not occur. -To reduce the risk for resistance, PIs should never be used alone; rather, they should always be combined with at least one reverse transcriptase inhibitor, and preferably two. Adverse effects -There are several adverse effects that all protease inhibitors have in common including hyperglycemia and the development of diabetes, lipodystrophy (fat redistribution), elevation of serum transaminases, and decreased cardiac conduction velocity. They can also increase bleeding in patients with hemophilia. -Hyperglycemia, new-onset diabetes, abrupt exacerbation of existing diabetes, and diabetic ketoacidosis. Onset typically occurs after 2 months of drug use but can also develop much earlier. can be managed with insulin and oral antidiabetic agents (e.g., metformin). Patients should report signs of the disease, such as polydipsia, polyphagia, and polyuria In patients with existing diabetes, monitor blood glucose closely. Monitor blood glucose at baseline, every 3 to 4 months during the first year of treatment and less frequently thereafter. Although withdrawing PIs may restore normal glucose metabolism, discontinuation is not recommended. -Lipodystrophy, redistribution of body fat or pseudo-Cushing's syndrome (cushingoid appearance). Fat accumulates in the abdomen, in the breasts of men and women, and between the shoulder blades at the base of the neck but lost from the face, arms, buttocks, and legs. The underlying mechanism has not been determined; Drug withdrawal may cause symptoms to resolve but is not recommended. -Hyperlipidemia. All PIs can elevate plasma levels of cholesterol and triglycerides. occur with or without redistribution of fat. Elevation of cholesterol can lead to atherosclerosis and associated cardiovascular events. Elevation of triglycerides can lead to pancreatitis. Monitor lipid levels every 3 to 4 months. Potential interventions for hyperlipidemia include diet, exercise, and lipid-lowering drugs. However, benefits of these interventions have not been established. If lipid-lowering drugs are employed, lovastatin and simvastatin should be avoided because cytochrome P450 inhibition by PIs can cause lovastatin and simvastatin to accumulate to dangerous levels. -Increased Bleeding in People With Hemophilia. Bleeding typically occurs in the joints and soft tissues, where danger is lower. However, serious bleeds in the brain and GI tract have also occurred. The mean time to increased bleeding is 22 days after the onset of treatment. Patients may need to increase their dosage of coagulation factors. -Elevation of Serum Transaminases indicating injury to the liver. Caution in patients with chronic liver disease (e.g., hepatitis B or C, cirrhosis). Monitor serum transaminases at baseline and periodically thereafter. -Decreased Cardiac Conduction Velocity. The most common effect is prolongation of the PR interval; may also lead to bundle branch blocks. This effect may be worsened if patients are taking other drugs that promote this effect, such as beta blockers. -Reduced bone density Drug interactions -All PIs are metabolized by cytochrome P450 enzymes, and all PIs can inhibit selected cytochrome P450 enzymes. PIs can interact with drugs that inhibit or induce P450 enzymes and with drugs that are substrates for P450 enzymes. -Not all interactions are harmful By inhibiting selected P450 enzymes one PI can increase the level of another PI and can thus intensify therapeutic effects. Example: Ritonavir [Norvir] is routinely combined with other PIs with the specific purpose of increasing the therapeutic effects of the other PI. Unfortunately, most interactions with PIs are not beneficial.

Overall drug interaction issue of anti-HIV drugs

Drug interactions are common and significant with these drugs. Many are inducers or inhibitors of one or more (and sometimes many) CYP450 enzymes. Some drugs share the same adverse effects; therefore, giving them together can intensify an effect so that it becomes dangerous. Moreover, patients with HIV infection, especially those with advanced infection and AIDS, often take drugs for multiple other illnesses and infections. When we consider all the various combinations of these drugs, the possibility of dangerous drug interactions increases dramatically. Everyone with the responsibility for medication administration needs access to a reliable drug interaction software that is capable of simultaneously checking for interactions among multiple drugs. This is critical when administering drugs to patients with HIV infection and AIDS.

Classification of Antiretroviral Drugs

Five types of antiretroviral drugs Inhibit enzymes required for HIV replication -Reverse transcriptase inhibitors ----Nucleoside Reverse Transcriptase Inhibitors (NRTIs) ----Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) -Integrase strand transfer inhibitors -Protease inhibitors Block viral entry into cells Fusion inhibitors CCR5 antagonists

CCR5 antagonist: Maraviroc [Selzentry]

MOA: CCR5 is a co-receptor that some strains of HIV must bind with to enter CD4 cells. Maraviroc binds with CCR5 and thereby blocks viral entry. -HIV strains that require CCR5 for entry are referred to as being CCR5 tropic. Between 50% and 60% of patients are infected with this type of HIV. Therapeutic Use: combined use with other antiretroviral drugs to treat patients age 16 years or older who are infected with CCR5-tropic HIV-1 strains Elimination: unclear Adverse Effects -most common: cough, dizziness, pyrexia, rash, abdominal pain, musculoskeletal symptoms, and upper respiratory tract infections. Intensity is generally mild to moderate. -Liver injury preceded by signs of an allergic reaction (e.g., eosinophilia, pruritic rash, elevated immunoglobulin E). -Patients should be informed about signs of an evolving reaction (itchy rash, jaundice, vomiting, and/or abdominal pain) and instructed to stop maraviroc and seek medical attention. -Rare: cardiovascular events, including myocardial ischemia and MI. Maraviroc should be used with caution in patients with cardiovascular risk factors. Drug Interactions -Because maraviroc is metabolized by CYP3A4, drugs that inhibit or induce this enzyme will affect maraviroc levels. Levels will be raised by strong CYP3A4 inhibitors, including protease inhibitors (except tipranavir/ritonavir) and delavirdine. levels will be lowered by strong CYP3A4 inducers, including etravirine and efavirenz.

NNRTIs Efavirenz [Sustiva]

MOA: binds directly to HIV reverse transcriptase and thereby disrupts the active center of the enzyme. As a result, replication is suppressed. Therapeutic use: -Only NNRTI recommended for first-line therapy of HIV-1 infection and serve as the prototype for the NNRTIs -the combination of efavirenz plus two NRTIs (zidovudine and lamivudine) was at least as effective as indinavir (a protease inhibitor) combined with the same two NRTIs. -The efavirenz-based regimen was better tolerated. Because efavirenz crosses the blood-brain barrier, it can reduce HIV levels in the CNS, making it particularly useful in patients with CNS complications. Elimination: Feces (primary), urine Adverse effects 1. Transient adverse CNS effects in 50% of patients dizziness, insomnia, impaired consciousness, drowsiness, vivid dreams, and nightmares. Delusions, hallucinations, and severe acute depression may also occur, primarily in patients with a history of mental illness or drug abuse. Patients who experience these severe reactions should discontinue the drug. CNS symptoms are prominent at the onset of treatment, but generally resolve within 2 to 4 weeks, despite continuous drug use. 2. Rash developed in 27% of adults and 40% of children. Rash can range in severity from mild (erythema, pruritus) to moderate (diffuse maculopapular rash, dry desquamation) to severe (vesiculation, moist desquamation, ulceration). Very rarely, rash evolves into potentially fatal Stevens-Johnson syndrome, erythema multiforme, or toxic epidermal necrolysis. Accordingly, if severe rash occurs, efavirenz should be withdrawn immediately. Mild rash may respond to antihistamines and topical glucocorticoids. 3. Teratogenicity high incidence of fetal malformation in animal studies. Women using the drug must avoid getting pregnant. A barrier method of birth control (e.g., condom) should be used in conjunction with a hormonal method (e.g., oral contraceptive). Pregnancy must be ruled out before efavirenz is used. 4. Other Adverse Effects. liver damage. Liver enzymes should be monitored, especially in patients with hepatitis B or C. Hyperlipidemia may occur. Interestingly, drug screens of people taking efavirenz may show a false positive result for cannabinoids and benzodiazepines. Drug Interactions. - Efavirenz is a substrate, inhibitor, and inducer of several cytochrome P450 enzymes. it has many drug interactions. -Example: efavirenz can decrease the effects of hormonal contraceptives, including oral contraceptives and the etonogestrel contraceptive implant. Contraceptive failure can result. Since efavirenz is teratogenic, it is essential that women of childbearing potential use a barrier contraceptive in addition to any hormonal contraceptive. -Efavirenz is metabolized by CYP2B6 (primarily), CYP3A4, and CYP2A6. Thus, drugs that are inducers of these enzyme systems may decrease efavirenz levels, and drugs that are inhibitors of these enzyme systems may increase efavirenz levels. -Example: If efavirenz is combined with indinavir, the dosage of indinavir should be increased. Combined use with saquinavir, a drug with low bioavailability, should be avoided. Combining with ritonavir (a protease inhibitor that inhibits CYP3A4) can increase levels of efavirenz. Toxicity may result. -Efavirenz is also a CYP2C9 and CYP2C19 inhibitor. Drugs that are substrates for these enzymes may have increased serum levels—and increased adverse effects—if dosage adjustments are not made.

Nucleoside Reverse Transcriptase Inhibitors (NRTIs) Lamivudine (3TC)

MOA: converted to its active form, lamivudine triphosphate to suppresses viral DNA synthesis Therapeutic use: Combine with other drugs to treat HIV Elimination: urine Adverse effects: (best tolerate) -lactic acidosis and hepatic steatosis: small risk -Pancreatitis: 0.3% of patients. -Others: fatigue, insomnia, and headache, but these effects usually fade in a few weeks. -In patients co-infected with HBV, withdrawal of lamivudine may result in severe acute exacerbation of hepatitis. If lamivudine is discontinued in a patient with HBV, it is essential to monitor for signs and symptoms as well as laboratory evidence of liver dysfunction for several months. Drug Interactions. should not be combined with the NRTI emtricitabine. Emtricitabine has significant toxic effects that may be enhanced by coadministration with lamivudine.

Protease Inhibitors Atazanavir

MOA: inhibits HIV protease in the same manner of all PIs. Therapeutic use: combine with other drug to treat HIV-1 & 2; Dosing is done just once a day, with or without boosting with ritonavir. Adverse Effects. -shares the same adverse effects as all PIs. -The prolongation of the PR interval is more common with this drug. It causes asymptomatic first-degree AV block in 5% to 9% of patients. the drug should be used with caution in patients with structural heart disease, pre-existing cardiac conduction disturbances, or ischemic heart disease, and in those taking other drugs that prolong the PR interval. -Interferes with normal processing of bilirubin, and thereby raises levels of unconjugated bilirubin in plasma (indirect hyperbilirubinemia). about 11% of patients develop jaundice (yellowing of the skin) and scleral icterus (yellowing of the eyes), which reverse following drug withdrawal. If it will be given to patients with hepatic impairment, dosage adjustment is needed. Drug Interactions. Atazanavir is subject to numerous interactions with other drugs. It is a CYP3A4 inhibitor and substrate and a weak CYP2C8 inhibitor.

Protease Inhibitors Lopinavir/Ritonavir

MOA: inhibits HIV protease, and thereby prevents maturation of HIV. Therapeutic use: -Lopinavir and ritonavir are available in a fixed-dose combination under the brand name Kaletra. -Lopinavir is the active antiretroviral component. Ritonavir is present only to boost lopinavir's effects; -lopinavir/ritonavir was effective against some HIV strains that had become resistant to other PIs. Adverse Effects. -The most common: diarrhea (13.8%). -The remainder (occur in less than 10%): nausea, headache, and weakness or tiredness -Most serious one and not shared by all Pis: pancreatitis. -Of the shared PI adverse effects, prolongation of both the PR and QT intervals can be significant with lopinavir/ritonavir. By prolonging the PR interval, the drug increases the risk for second- or third-degree atrioventricular (AV) block. should be used with caution in patients with structural heart disease, pre-existing cardiac conduction disturbances, or ischemic heart disease, and in those taking other drugs that prolong the PR interval. By prolonging the QT interval, lopinavir/ritonavir increases the risk for torsades de pointes and other severe dysrhythmias. Accordingly, the drug should be avoided in patients with congenital long QT syndrome and in those taking other drugs that prolong the QT interval. Drug Interactions. --Lopinavir/ritonavir strongly inhibits two drug-metabolizing enzymes: CYP3A4 and CYP2D6—and can thereby raise levels of drugs that are substrates for these enzymes. Serious toxicity can result. To avoid toxicity, certain drugs must be used in greatly reduced dosage and others must not be used at all. --lopinavir/ritonavir can induce metabolism of some drugs, including methadone and ethinyl estradiol, a component of many oral contraceptives. As a result, the plasma level of these drugs may fall to subtherapeutic levels. --Agents that induce CYP3A4 can accelerate metabolism of lopinavir/ritonavir and can thereby decrease antiretroviral effects. --Because of its alcohol content, the oral solution of lopinavir/ritonavir should not be combined with disulfiram [Antabuse] or metronidazole because both drugs will cause accumulation of acetaldehyde, a toxic metabolite of alcohol.

Protease Inhibitors Ritonavir

MOA: inhibits HIV protease, and thereby prevents maturation of HIV. Therapeutic use: Because of its ability to inhibit CYP3A4 and CYP2D6 enzymes, which are enzymes that metabolize PIs, ritonavir is often combined with other PIs to boost their effects. Nearly one-third of HIV patients use this drug. Adverse Effects. -In addition to the shared adverse effects, ritonavir can cause circumoral (around the mouth) paresthesias and paresthesias of the extremities. It can also alter taste sensation. -Nausea, vomiting, and diarrhea are common during the initial weeks of therapy and then tend to fade. - Adverse effects can be reduced by initiating therapy at a low dosage and then gradually titrating up to the maintenance dosage. Drug Interactions: Ritonavir has a role in affecting metabolism by numerous P450 enzymes: CYP3A4 and CYP2D6 inhibitor and inducer of CYP1A2, CYP2C8, CYP2C9, and CYP2C19. There are also minor (typically nonconsequential) actions on other enzyme systems.

HIV Integrase Strand Transfer Inhibitors Elvitegravir

MOA: stops HIV replication by preventing insertion of HIV DNA Therapeutic use: -Used in combination with other drugs to treatment HIV -It is incapable of achieving therapeutic levels when given alone, owing to extensive metabolism by the P450 enzyme system, especially CYP3A isoenzymes. HIV resistance is common. Elimination: Feces (95%), urine Adverse Effects: diarrhea (7%) and nausea (4%). because it is given in combination with drugs from other HIV drug classes, those adverse effects must be considered, as well, when monitoring patients for complications of therapy. Drug Interactions As mentioned, elvitegravir is a substrate of CYP3A enzyme systems. Drugs that are CYP3A inducers (especially CYP3A4) can decrease serum levels.

HIV Integrase Strand Transfer Inhibitors (INSTIs) Dolutegravir

MOA: stops HIV replication by preventing insertion of HIV DNA Therapeutic use: approved for both treatment-naïve and treatment-experienced patients. It has a significant advantage over raltegravir and elvitegravir. HIV resistance is less likely to develop to dolutegravir than to the other INSTIs. Elimination: Feces (primary), urine Adverse Effects: elevated liver enzymes (up to 18%) and hyperglycemia (14%), insomnia (7%). Neutropenia (4%) Drug Interactions -Efavirenz, etravirine, fosamprenavir, nevirapine, and tipranavir can decrease dolutegravir level -Minerals such as iron, calcium, and magnesium can also decrease serum levels. -When patients take drugs containing these products, including multivitamins with minerals, dolutegravir should be administered at least 2 hours before or 6 hours after these agents.

Nucleoside Reverse Transcriptase Inhibitors (NRTIs) Abacavir (ABC)

MOA: suppresses HIV replication by (1) causing premature termination of the growing DNA strand and (2) competing with natural nucleoside triphosphates for binding to reverse transcriptase Therapeutic use: combination with other antiretroviral drugs to decrease HIV viral load, increase CD4 T-cell counts, delay onset of disease symptoms, and reduce symptom severity. Elimination: Urine (primary), feces Adverse effect: Lactic Acidosis and Hepatomegaly With Steatosis: relatively small Hypersensitivity Reactions: 5-8% develop during the first 6 weeks of treatment multiorgan failure and anaphylaxis Symptoms: fever, rash, myalgia, arthralgia, and GI disturbances (i.e., nausea, vomiting, diarrhea, abdominal pain). manifest initially as respiratory symptoms (e.g., pharyngitis, dyspnea, cough). Myocardial Infarction: controversy regarding an association between abacavir and myocardial infarction, may not use in patients with history of MI Others: 10% of patients experience fatigue and headache. Lipodystrophy with redistribution of adipose tissue Contraindications. Patients with HLA-B*5701 (+) should never receive abacavir. Increase the change of allergy Drug Interactions. Alcohol can compete with abacavir for metabolism by alcohol dehydrogenase. This can thereby increase abacavir levels substantially.

HIV Integrase Strand Transfer Inhibitors (INSTIs)

MOA: terminating the integration of HIV into DNA. -Integrase is one of three viral enzymes needed for HIV replication. -Integrase inserts HIV genetic material into the DNA of CD4 cells. By inhibiting integrase, these drugs prevent insertion of HIV DNA and thereby stop HIV replication. -They are effective against both HIV-1 and HIV-2. Therapeutic use: combined use with other antiretroviral agents to treat adults infected with HIV-1. Classification: raltegravir, dolutegravir, and elvitegravir

Nucleoside Reverse Transcriptase Inhibitors (NRTIs) Emtricitabine

MOA: uptake by cells and converted to emtricitabine triphosphate to inhibits viral DNA synthesis. Emtricitabine has a long intracellular half-life, and hence dosing can be done just once a day. Therapeutic use: combination with other drug to treat HIV Elimination: Urine (primary), feces Adverse Effects (generally well tolerate) -has the fewest adverse effects of the NRTIs. -Hyperpigmentation of the palms and soles This effect may extend to other regions, such as the arms, lips, and tongue. This unusual reaction is not associated with other complications. -The most common: headache, dizziness, insomnia, nausea, vomiting, diarrhea, and rash. -small risk for lactic acidosis and hepatomegaly with steatosis.

HIV prevention

Prophylactic drugs can reduce the risk for infection following accidental exposure to HIV (e.g., from a needle stick). Prophylaxis is most effective when initiated within 1 or 2 hours, and it may be ineffective if initiated after 72 hours. Pre-exposure Prophylaxis --tenofovir/emtricitabine --For (1) people who have sexual partners with known HIV-1 infection or are sexually active with people who belong to social networks with high HIV-1 prevalence and (2) people who have one or more of the following risk factors: Do not regularly use condoms Have sexually transmitted infections Engage in sex for money, drugs, or other supplies Use recreational drugs or are dependent on alcohol Postexposure Prophylaxis --Nonoccupational Postexposure Prophylaxis *Preferred: Tenofovir DF 300 mg plus emtricitabine 200 mg (or the combination Truvada) once daily with raltegravir 400 mg twice daily or dolutegravir 50 mg once daily • *Alternate: Tenofovir DF 300 mg plus emtricitabine 200 mg (or the combination Truvada) once daily with darunavir 800 mg and ritonavir 100 mg once daily --Occupational Postexposure Prophylaxis *Tenofovir DF 300 mg plus emtricitabine 200 mg (or the combination drug Truvada) with Raltegravir 400 mg twice daily

Difference between HIV and AIDS: HIV ≠ AIDS

The definition of AIDS, established by the CDC, is a syndrome in which the individual is HIV-positive and has either (1) CD4 T-cell counts below 200 cells/mL or (2) an AIDS-defining illness. Included in the CDC's long list of AIDS-defining illnesses are Pneumocystis pneumonia, cytomegalovirus retinitis, disseminated histoplasmosis, tuberculosis, and Kaposi's sarcoma.

HIV fusion inhibitor: Enfuvirtide [Fuzeon]

Widely known as T-20; First and only HIV fusion inhibitor MOA: prevents the HIV envelope from fusing with the cell membrane of CD4 cells and thereby blocks viral entry and replication. Fusion inhibition results from binding of enfuvirtide to gp41, a subunit of the glycoproteins embedded in the HIV envelope Therapeutic use: -reserved for treating HIV-1 infection that has become resistant to other antiretroviral agents. -indicated for HIV-1 infection in patients who are treatment experienced and have evidence of HIV replication despite ongoing ART. -To delay emergence of resistance, enfuvirtide should always be combined with other antiretroviral drugs. -Twice-daily subQ dosing Elimination: unclear Resistance -Resistance to enfuvirtide has developed in cultured cells and in patients. -The cause is a structural change in gp41. -no cross-resistance to other types of HIV drugs -When the patient's other antiretroviral drugs are still effective, resistance to enfuvirtide develops relatively slowly. However, when there is significant resistance to the other drugs, resistance to enfuvirtide develops rapidly. Adverse effects 1. Injection-Site Reactions (ISR)(98%) within the first week of treatment. Principal manifestations: pain and tenderness, erythema and induration, nodules or cysts, pruritus, and ecchymosis (small hemorrhagic spots). Although generally mild to moderate, symptoms can also be severe. In 17% of patients, individual ISRs persisted more than 7 days. The intensity of ISRs can be reduced by rotating the injection site, avoiding sites with an active ISR, and avoiding unnecessarily deep injections. If a severe ISR occurs, or if local infection develops, patients should seek immediate medical attention. 2. Pneumonia. Increase the risk for bacterial pneumonia. Patients should be informed about signs of pneumonia (cough, fever, breathing difficulties) and instructed to report them immediately. used with caution in patients who have pneumonia risk factors: low initial CD4 cell counts, high initial viral load, IV drug use, smoking, and a history of lung disease. 3. Hypersensitivity Reactions. Symptoms: rash, fever, nausea, vomiting, chills, rigors, hypotension, and elevated serum transaminases. also been associated with respiratory distress, glomerulonephritis, Guillain-Barré syndrome, and primary immune complex reaction, all of which may be immune mediated. If a systemic hypersensitivity reaction occurs, enfuvirtide should be discontinued immediately and never used again. Drug Interactions Enfuvirtide appears devoid of significant drug interactions.

Nucleoside Reverse Transcriptase Inhibitors (NRTIs) Tenofovir disoproxil fumarate (TDF) [Viread]

a nucleotide reverse transcriptase inhibitor MOA: the same with MOA discussion in HCV treatment Therapeutic use: Combine with other drugs to treat HIV Elimination: urine Adverse Effects (well tolerate) 1. Decreased Bone Mineralization. Approximately one-fourth of patients experience some degree of decreased bone mineral density, thus increasing the risk for osteoporotic fractures. Symptoms: bone pain and arthralgias. Calcium and vitamin D supplementation are recommended. 2. Renal Toxicity (rarely) Elevated serum creatinine and proteinuria. Since tenofovir is excreted by the kidneys, renal damage increases the risk for drug accumulation to dangerous levels. Dosage adjustment is necessary when prescribed to patients with renal impairment. 3. Other Adverse Effects. Because tenofovir can suppress HBV, patients co-infected with HBV may experience a severe exacerbation of hepatitis when tenofovir is withdrawn. For those patients with HBV, it is essential to monitor for evidence of liver dysfunction for several months. small risk for potentially fatal lactic acidosis with hepatic steatosis. More common adverse effects are nausea, vomiting, diarrhea, weakness, and headache; occur at the onset of therapy. Drug Interactions. -It is essential to consult drug interaction software capable of simultaneously checking for interactions of multiple drugs for patient safety. -Tenofovir can raise plasma levels of the NRTI didanosine and serum levels of adefovir and darunavir -Tenofovir decreases serum levels of atazanavir -Some protease inhibitors used to treat HIV infection (atazanavir, darunavir, lopinavir), drugs used to treat hepatitis C (i.e., Ledipasvir, simeprevir, telaprevir, and velpatasvir), and drugs used to treat cytomegalovirus (i.e, cidofovir, ganciclovir, and valganciclovir) can increase serum levels of tenofovir. -Adefovir can decrease the serum level of tenofovir -Cobicistat, a pharmacokinetic enhancer may enhance the adverse effects of tenofovir. -Lopinavir can increase the risk for nephrotoxicity when combined with tenofovir.

Protease Inhibitors: Darunavir

a second-generation PI, serve as our prototype for this class MOA: inhibits HIV protease, and thereby prevents maturation of HIV. Therapeutic use: activity against HIV strains that are resistant to other PIs. typically boosted with ritonavir and combined with other antiretroviral drugs. The combination can be especially useful in treatment-experienced patients infected with PI-resistant HIV strains. Adverse Effects: Same adverse effects shared with other PIs. Hyperlipidemia (23% to 25%): elevated cholesterol levels with associated increases in low-density lipoprotein cholesterol and triglycerides. Rash (10%). Other common: nausea, diarrhea, and headache. When administered with cobicistat, increases in serum creatinine have occurred. Drug Interactions. -Darunavir is both a CYP3A4 substrate and inhibitor. It is also a CYP2C9 inducer. Because these two enzyme systems are responsible for the metabolism of so many drugs, the number of drug interactions is extensive -Darunavir can increase serum levels of maraviroc and indinavir. -Darunavir can decrease serum levels of abacavir. -Indinavir increases darunavir levels; lopinavir/ritonavir and saquinavir decrease darunavir levels. -Coadministration with boceprevir decreases levels of both boceprevir and darunavir. -Coadministration with simeprevir increases levels of both drugs. -Darunavir increases levels of beta blockers, calcium channel blockers, amiodarone, lidocaine, disopyramide, flecainide, mexiletine, propafenone, and quinidine. This is significant because this can further worsen the decreased conduction velocity that can be an adverse effect of darunavir.

HIV Integrase Strand Transfer Inhibitors (INSTIs) Raltegravir [Isentress]

first HIV integrase strand transfer inhibitor to be developed MOA: stops HIV replication by preventing insertion of HIV DNA Therapeutic use: active against HIV strains resistant to some of the other drugs. combination with tenofovir plus either emtricitabine or lamivudine is considered a first-choice drug for HIV treatment. raltegravir demonstrated increased viral suppression when compared to protease inhibitors and the NNRTI efavirenz. Unfortunately, HIV resistance was also more likely to develop Elimination: Feces (primary), urine Adverse effects (generally well tolerate) --most common: elevation in liver enzymes (10%) and serum amylase and lipase (4%-5%). --Other common (2%-4%): insomnia and headache --Rare: Severe hypersensitivity reactions. Skin reactions include Stevens-Johnson syndrome and toxic epidermal necrolysis, which can be fatal. Organ dysfunction, including liver failure. signs of a hypersensitivity reaction: severe rash, or rash associated with blisters, fever, malaise, fatigue, oral lesions, facial edema, hepatitis, angioedema, muscle or joint aches Need to discontinue raltegravir immediately. -FDA pregnancy risk: Category C Drug Interactions -Because raltegravir is metabolized by glucuronidation, it does not have many interactions with other drugs -Atazanavir and other inhibitors of UGT can increase levels of raltegravir. -Inducers of UGT (e.g., efavirenz, fosamprenavir, rifabutin, tipranavir) can lower raltegravir levels.

Nucleoside Reverse Transcriptase Inhibitors (NRTIs) Zidovudine [Retrovir, AZT, ZDV]

first NRTI available MOA: converted to its active form zidovudine triphosphate (ZTP). This active form suppresses viral DNA synthesis Therapeutic use: HIV treatment --penetrates to the CNS better than most other drugs and be valuable for relieving cognitive symptoms. --also commonly used to prevent mother-to-infant HIV transmission during labor and delivery and as short-term (4-week) prophylaxis for their newborn infants. Elimination: urine Adverse effects 1. Hematologic toxicity: Severe anemia and neutropenia secondary to bone marrow suppression Monitor Hb and neutrophil before treatment and at least every 2 to 4 weeks thereafter patients who develop severe anemia or severe neutropenia, zidovudine should be interrupted until bone marrow recovery. If neutropenia and anemia are less severe, reduce dosage. Transfusions may permit some patients to continue drug use. If not, anemia and neutropenia may resolve following zidovudine withdrawal. 2. Lactic acidosis with hepatomegaly: especially concerning when combining two older NRTIs in the treatment of pregnant women because fatalities have occurred. 3. myopathy (damage to muscle fibers) may occur with prolonged use. Myositis (inflammation of muscle fibers) may also develop 4. Gastrointestinal effects: anorexia, nausea, vomiting, diarrhea, abdominal pain, stomach upset 5. Central nervous system (CNS) reactions: CNS depression, headache, insomnia, confusion, anxiety, nervousness, and seizures 6. Others: nail pigmentation, insulin resistance/diabetes, and hyperlipidemia. Drug interactions: 1. Severe anemia and neutropenia: ---with ganciclovir and valganciclovir (two antiviral drugs used to treat cytomegalovirus infection that may occur in patients with AIDs) --ribavirin (an antiviral drug used to treat hepatitis C, a common co-infection in patients with HIV infection) --any drugs that are myelosuppressive. --Canadian labeling contraindicates the use of zidovudine in patients with bone marrow suppression, --establishing that it should not be given if hemoglobin is less than 7.5 gm/dL or if the neutrophil count is less than 750/mm3.) 2. myopathy Combine with Raltegravir. Rhabdomyolysis may develop.