Farmacs Efectes2aris Gens

1 DRUGS, ADVERSE EFFECTS AND GENES

Nucleoside Reverse Transcriptase Inhibitors...............................................................................2

Abacavir...................................................................................................................................2

Didanosine...............................................................................................................................2

Emtricitabine............................................................................................................................2

Lamivudine...............................................................................................................................2

Stavudine.................................................................................................................................2

Zidovudine................................................................................................................................2

Nonnucleoside Reverse Transcriptase Inhibitors.........................................................................2

Delavirdine...............................................................................................................................2

Efavirenz...................................................................................................................................2

Etravirine..................................................................................................................................2

Nevirapine................................................................................................................................2

Rilpivirine.................................................................................................................................2

Protease Inhibitors.......................................................................................................................2

Atazanavir................................................................................................................................2

Darunavir..................................................................................................................................2

Fosamprenavir.........................................................................................................................2

Indinavir...................................................................................................................................2

Lopinavir...................................................................................................................................2

Nelfinavir..................................................................................................................................2

Saquinavir.................................................................................................................................2

Tipranavir.................................................................................................................................2

Ritonavir...................................................................................................................................2

Fusion Inhibitors...........................................................................................................................2

Enfuvirtide................................................................................................................................2

Entry Inhibitors.............................................................................................................................2

Maraviroc.................................................................................................................................2

Integrase Inhibitors......................................................................................................................2

Raltegravir................................................................................................................................2


Nucleoside Reverse Transcriptase InhibitorsRedistribution or accumulation of body fat, lipodystrophy, may occur in people taking antiviral medications giving rise to central obesity, facial arm, leg, and/or buttock wasting, breast enlargement, and fat accumulation in the base of the neck (buffalo hump). NRTIs are associated with lactic acidosis, hepatic steatosis, and body fat redistribution (lipodystrophy).

AbacavirAvailable under the trade name Ziagen (ViiV) and in the combination formulations Trizivir (abacavir, zidovudine and lamivudine) and Kivexa/Epzicom (abacavir and lamivudine). It has been well tolerated; the main side effect is hypersensibility, which can be severe, and in rare cases, fatal. Genetic testing can indicate whether an individual will be hypersensible. However, in a separate study, the risk of heart attack increased by nearly 90%.

Abacavir is given orally and has a high bioavailability (83%). It is metabolized primarly through alcohol dehydrogenase or glucuronyl transferase. It is capable of crossing the blood-brain barrier.

Not dosage adjustment requires, but should be avoided in those with end-stage renal disease or liver disease.

Adverse Events: Hypersensitivity syndrome

o Rash occurs in aboout half of the caseso Usually occurs in the first 6 weeks of treatmento May be more severe with once-daily dosingo Risk factor > HLA B*5701

Rash Headache Nausea Vomiting Diarrhea

Genes:Abacavir is primarily metabolized by the liver.

P450 does not play a major role in abacavir metabolism. Primary pathways of metabolism in man are by alcohol dehydrogenase and by glucuronidation.

Metabolyzed by: XXX Inhibitor of: BCRP, MRP1 and MRP2. Does not inhibit CYP3A4, CYP2C9 or CYP2D6 at

clinically relevant concentrations. Transported by: P-gp and BCRP1


DidanosineAvailable under trade names Videx and Videx EC (BMS). Didanosine has weak acid stability and is easily damaged by stomach acid. Therefore, the original formula approved by the FDA used chewable tablets that included an antacid buffering compound to neutralize stomach acid and would cause diarrhea. After patent expiration they reformulated in a smaller capsule containing coated microspheres (EC) instead of the buffering compound.

Within the cells, ddI is phosphorilated to the active metabolite by cellular enzymes.

Food substantially reduces ddI bioavailability and should be administered in an empty stomach. The half life in plasma is only 1.5 hours, but in the intracellular environment more than 12 hours. Elimination is predominantly renal; the kidneys actively secrete ddI, the amount being 20% of the oral dose.

Interactions: ddI interacts with allopurinol and could not be coadministered. Indinavir and delavirdine show reduced in plasma, they should be administered at different times. Ketoconazole, itraconazole, ciprofloxacin should be administered at a different time due to interactions with the buffering agent. Administration with drugs with overlapping toxicity (zalcitabine and stavudine) is not recomended. Alcohol cal exacerbate ddI's toxicity, so it should be avoided.

Half-life of ddI after oral administration increased from an average of 1.4 hours in subjects with normal renal function to 4.1 hours in subjects with severe renal impairment requiring dialysis. Patients with a creatinine clearance <60 ml/min may be at greater risk of ddI toxicity due to decreased drug clearance. A dose reduction is recommended for these patients.

Metabolism of ddI may be altered in patients with severe hepatic impairment. No specific dose adjustment can be recommended.

Adverse Events: Pancreatitis > Concomitant alcohol use may increase its risk Peripheral neurophaty > Increased risk when combined with stavudine Nausea Diarrhea > Low frequency with enteric-coated capsules

Increased risk of lactic acidosis and hepatic steatosis when combined with stavudine.

Adjusted dosage for renal insufficiency or failure.

Genes:Didanosine is thought to follow the same pathways responsible for elimination of endogenous purines.

Metabolyzed by: Xanthine oxidase Inducer of: N/A Inhibitor of: N/A


Transported by: Unknown

EmtricitabineAvailable under trade names Emtriva (formerly Coviracil) (Gilead). Emtricitabine is also marketed in a fixed-dose combination with tenofovir (Viread) under the brand name Truvada. A fixed-dose triple combination of emtricitabine, tenofovir and efavirenz (Sustiva - BMS) is administered under the name Atripla.

Emtricitabine exhibits clinical activity against Hepatitis B virus (HBV), but it is not approved by FDA for treatment of HBV infection.

Adjust dosage for renal insufficiency or failure.

Adverse Events:In clinical practice, toxicity associated with emtricitabine is unusual. The most common treatment-related adverse events are diarrhea, headache, nausea, and rash. These symptoms are generally mild to moderate in severity, but they caused 1% of clinical trial patients to give up treatment. Skin discoloration, which is typically reported as hyperpigmentation and usually affects either the palms of the hands or the soles of the feet, is reported in less than 2% of individuals and is almost exclusive to patients of African origin.

Among the more severe side effects patients may experience are a hepatotoxicity or a lactic acidosis.

Headache Nausea Insomnia Hyperpigmentation of palms and soles > More frequent in dark-skinned people

Genes: Metabolyzed by: Limited metabolism, excreted via glomerular filtration and active

tubular secretion. Inducer of: Low potential for CYP450 involvement Inhibitor of: MRP1, MRP2, MRP3. Low potential for CYP450 involvement; may compete

with other drugs for active tubular secretion. Transported by: Inhibitors of anion and cation renal transport pathways have been

shown not to affect emtricitabine disposition.

LamivudineIt is marketed by GSK with the brand name Zeffix, Heptovir, Epivir and Epivir-HBV. Lamivudine has been used for treatment of HBV at a lower dose than for treatment of HIV. It improves the seroconversion of e-antigen positive hepatitis B and also improves histology staging of the liver. Long term use of lamivudine unfortunately leads to emergence of resistance HBV mutant. Despite this, lamivudine is still used widely as it is well tolerated.

It is usually used with Zidovudine (AZT). Tablets: Combivir (with zidovudine); Epzicom / Kivexa (with abacavir) and Trizivir (with zidovudine and abacavir).


It is phosphorilated to active metabolites that compete for incorporation into viral DNA.

Lamivudine is administered orally, and it is rapidly absorbed with a bio-availability of over 80%. Some research suggest that lamivudine can cross the blood-brain barrier. Lamivudine treatment has been shown to restore zidovudine sensitivity of previously resistant HIV.

Lamivudine concentrations are increased in patients with moderate - severe renal impairment due to decreased clearance. The dose should therefore be adjusted, using oral solution presentation, for patients whose creatinine clearance falls below 30 ml/min. Lamivudine pharmacokinetics are not significantly affected by hepatic dysfunction.

Adverse Events:Adverse effects occur infrequently. Active against HBV. In patients with HIV and HBV coinfection, hepatitis may flare upon discontinuation of lamivudine.

Adjust dosage for renal insufficiency or failure.

Headache Dry mouth

Genes: Metabolyzed by: Predominantly cleared unchanged by renal excretion. Hepatic

metabolism is low (5-10%). Inducer of: N/A Inhibitor of: MRP1, MRP2, MRP3 Transported by: Possibly MRP4, MRP8

StavudineIt is d4T (Zerit).

It is phosphorylated by cellular kinases into active triphosphate. Simultaneous use of zidovudine is not recommended, as it can inhibit the intracellular phosphorylation of stavudine.

The oral absorption rate is over 80%. Approximately half of stavudine is actively secreted unchanged into the urine and the other half is eliminated through endogenic pathways.

For optimal absorption, stavudine should be taken on an empty stomach (at least 1h prior to meals).

Adverse Events:The main adverse effect is peripheral neuropathy, which can be corrected by reducing dosage. Stavudine has been shown in laboratory test to be genotoxic, but with clinical doses its carcinogenic effects are non-existent. It is also one of the most likely antiviral drugs to cause lipodystrophy, and for this reason it is no longer considered an appropriate treatment for most patients in developed countries.


It is still used as a first choice in first line therapy in resource poor settings such as in India. Only in case of decelopment of peripheral neuropathy or pregnancy is changed to next choice - Zidovudine.

Clearance of stavudine decreases as creatinine clearance decreases; the manofacturers recommend that dosage is adjusted in patients with reduced renal function. Stavudine pharmacokinetics in patients with hepatic impairment were similar to those in patients with normal hepatic function.

Peripheral neuropathy > Consider dosage adjustment Pancreatitis Dyslipidemia Diarrhea Of the NRTIs, stavudine appears to convey the greatest risk of lipodystrophy and other

mithocondrial toxicity. Increased risk of lactic acidosis and hepatic steatosis when combined with didamosine;

this combination should be avoided when possible, especially during pregnancy. Adjust dosage for renal insufficiency or failure.

Genes: Metabolyzed by: Not elucidated in humans Inducer of: N/A Inhibitor of: Does not inhibit the major CYP450 isoforms CYP1A2, CYP2C9, CYP2C19,

CYP2D6, and CYP3A4 Transported by: Unknown

ZidovudineSold under the names Retrovir and Retrovis. It used as an ingredient in combivir and trizivir, among others.

Zidovudine is phosphorylated in both infected and uninfected cells to the monophosphate and subsequently to the diphosphate, and then the active triphosphate form.

Adverse Events:Chronic, high dose therapy with AZT is associated with significant side effects, including anemia, neutropenia, hepatotoxicity, cardiomyopathy, and myopathy. Damage to muscle cells is reversible upon cessation of AZT treatment. It has been attributed to several possible causing including depletion of mitochondrial DNA, sensitivity of the γ-DNA polymerase in the cell mitochondria, the depletion of thymidine triphosphate, oxidative stress, reduction of intracellular L-carnitine or apoptosis of the muscle cells. Anemia due to AZT can be treated using erythropoietin to stimulate red blood cell production. Drugs that inhibit hepatic glucuronidation, such as Aspirin and tripethoprim, decrease the elimination rate and increase the toxicity of the drug. Minor side effects include nausea and vomiting, headache, changes in the distribution of body fat, sleep disruption and loss of appetite while less common but potientally serious side effects include discoloration of fingernails and toenails, mood changes,


tingling or numbness of the hands or feet, easy bruising or bleeding and seizures. Serious allergic reactions are rare.

Anemia Neutropenia Fatigue (with nausea, headache and myalgia, usually resolved 2-4 weeks after

initiation) Malaise Headache Nausea Vomiting Myalgia Myopathy

Adjust dosage for renal insufficiency or failure

Genes: Metabolyzed by: Hepatic conjugation to an inactive glucuronidated metabolite. No

P450 involvement. Inducer of: N/A Inhibitor of: BCRP (in vitro) Transported by: BCRP1

Nonnucleoside Reverse Transcriptase InhibitorsNNRTIs are associated with rash, and may cause Stevens-Johnson syndrome and toxic epidermal necrolysis. All of them may have significant interactions with other drugs; dosage adjustment of interacting agents may be required

DelavirdineAvailable under the trade name Rescriotor (ViiV), its efficacy is lower than other NNRTIs, especially efavirenz, and it also has an inconvenient schedule; is not recommended as a part of initial therapy. The risk of cross-resistance across the NNRTIs class, as well as its complex set of drug interactions, make the place of delavirdine in second-line and salvage therapy unclear, and it is currently rarely used.

Like ritonavir, delavirdine is an inhibitor of cytochrome P450 isoenzyme CYP3A4, and interacts with many medications. It should not be administered with a wide range of drugs, including amprenavir, fosamprenavir, simvastatin, lovastatin, rifampin, rigabutin, rifapentine, St John's wort, astemizole, midazolam, triazolam, ergot medications, and several medications for acid reflux.

Adverse Events:The most common adverse event is moderate to severe rash, which occurs in up to 20% of patients. Other common adverse events include fatigue, headache and nausea. Liver toxicity has also been reported.


Fatigue Elevations in liver function test Hepatitis Nausea Diarrhea

Genes:Pharmacokinetics of delavirdine in patients with hepatic or renal impairment have not been investigated. Delavirdine is metabolized primarily by the liver; caution should be exercised in patients with impaired hepatic function.

Metabolyzed by: Primarily CYP3A4; in vitro data suggests involvement of CYP2D6. Inducer of: Unknown Inhibitor of: CYP3A4 (in vivo and in vitro); CYP2C9 (in vitro); CYP2D6 (in vitro); CYP2C19

(in vitro); BCRP (in vitro); MRP1, MRP2, and MRP3 Transported by: Unknown

EfavirenzAvailable under the trade name Sustiva and Stocrin. Antiretroviral guidelines recommends the use of efavirenz in combination with lamivudine/zidovudine (Combivir) or tenofovir/emtricitabine (Truvada) as the prefered NNRTI-based regimens. Efavirenz is also used in combination with other antiretroviral agents as part of an expanded postexpousure prophylaxis regimen to reduce risk in people exposed to a significant risk. It is usually taken on an empty stomach at bedtime to reduce neurological and psychiatric adverse effects.

Efavirenz is not affective against HIV-2, as the pocket of the HIV-2 reverse transcriptase has a different structure which confers intrinsic resistance to the NNRTI class.

Adverse Events:Psychiatric symptoms, including insomnia, nightmares, confusion, memory loss, and depression, are common, and more serious symptoms such as psychosis may occur in patients with compromised liver or kidney function.

Rash, nausea, dizziness and headache may occur.

A general guideline about efavirenz and pregnancy states that efavirenz can cause birth defects and should not be used in women who might become pregnant. A later study, however, found no increased risk of overall birth defects among women exposed ti efavirenz during the first trimester of pregnancy compared with exposure to other antiretroviral drugs.

Abnormal dreams, drowsiness, dizziness, confusion > CNS symptoms are common, severity usually decreases within 2-4 weeks

Mood changes Elevations in liver function tests Hyperlipidemia


Genes:Efavirenz is metabolized by the liver, and is both a substrate and inducer of the 2B6 and 3A4 isoforms of the cytochrome P450 system. This means efavirenz may interact with other drugs metabolized in the liver, requiring either increase or decrease dosages.

Efavirenz lowers blood levels of most protease inhibitors. Dosages of amprenavir, atazanavir, or indinavir may need to be increased. The blood levels of saquinavir are dramatically lowered. This can result in incomplete inhibition of viral replication, which can allow multidrug resistant virus to evolve. This condition can potentially be fatal.

St John's wort and garlic supplements may decrease efavirenz blood levels.

Pharmacokinetics of efavirenz have not been studied in renal insufficiency. Less than 1% of a dose is excreted unchanged in the urine; impact of renal impairment on efavirenz elimination should be minimal. Because of extensive CYP450 mediated metabolism and limited clinical experience, caution is recommended in patients with mild/moderate liver disease. Safety and efficacy of efavirenz has not been established in patients with significant underlying liver disorders. It is contraindicated in patients with severe hepatic impairment.

Metabolyzed by: CYP3A4, CYP2B6 (in vitro) Inducer of: CYP3A4 Inhibitor of: CYP2C9, CYP2C19, CYP3A4, BCRP (in vitro), MRP1, MRP2, MRP3. Transported by: Unknown

EtravirineAvailable under the trade name Intelence (formerly TMC125) (J&J). Unlike currently available agents in the class, resistance to other NNRTIs does not seem to confer resistance to etravirine.

Each 100mg etravirine tablet contains 160mg of lactose; patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Etravirine is a flexible molecule; it has some conformational isomerism than can bind the enzyme RT in multiple conformations, allowing for a more robust interaction between etravirine and the enzyme, even in the presence of mutations.

Adverse Events: Elevations in liver function tests Has significant interactions with many other drugs (may differ from those of first

generation NNRTIs); screen carefully for drug interactions before prescriving. Does not interact with methadone.

Genes: Metabolyzed by: CYP3A4, CYP2C9, CYP2C19 Inducer of: CYP3A4 Inhibitor of: CYP2C9, CYP2C19


Transported by: Unknown

NevirapineAvailable under the trade name Viramune (Boehringer Ingelheim). HIV rapidly develops resistance to nevirapine if administered alone.

Nevirapine is not effective against HIV-2, as the pocket of the HIV-2 RT has a different structure.

Significant lowering levels of nevirapine levels occur with the anti-tuberculosis drug, rifampicin, and the drugs should not be administered together.

Nevirapine is an inducer of cytochrome P450 isoenzymes CYP3A4 and CYP2B6. It reduces the levels of several co-administered drugs including the antiretrovirals efavirenz, indinavir, lopinavir, nelfinavir and saquinavir, as well as clarithromycin, ketoconazole, forms of hormonal contraception and methadone.

Renal impairment (mild, moderate and severe) has been found to result in no significant change in the pharmacokinetics of nevirapine. Safety and efficacy has not been established in patients with significant underlying liver disorders. Nevirapine is contraindicated in patients with severe hepatic impairment. Caution should be exercised in patients with moderate hepatic dysfunction.

Adverse Events:The most common adverse effect of nevirapine is the development of mild or moderate rash (13%). Severe or life-threatening skin reactions have been observed in 1.5% of patients, including Stevens-Johnsons syndrome, toxic epidermal necrolysis and hypersensitivity.

Nevirapine may cause severe or life-threatening liver toxicity, usually emerging in the first six weeks of treatment.

Elevations in liver function tests Hepatitis, liver failure > Hepatotoxicity may be life thratening. It is more common at

higher CD4 cell counts, in women and patients with HBV and HCV.

Genes: Metabolyzed by: CYP3A4, CYP2B6 Inducer of: CYP3A4, potentially CYP2B6 Inhibitor of: BCRP (in vitro); MRP1, MRP2, MRP3 Transported by: Unknown

RilpivirineAvailable under the trade name Edurant (J&J). It is a second generation NNRTI with higher potency, longer half-life and reduced side-effect profile compared with older NNRTIs.

A fixed-dose drug combining rilpivirine with emtricitabine and tenofovir is approved under the brand name Complera.


No dose adjustment is required in patients with mild or moderate renal impairement. However, in patients with severe renal imapirement or end-stage renal disease, rilpivirine should be used with caution and with increased monitoring for adverse effects, as rilpivirine concetrations may be increased due to alteration of drug absorption, distribution, and metabolism secondary to renal dysfunction. As rilpivirine is highly bound to plasma proteins, it is unlikely that it will be significantly removed by haemodialysis or peritoneal dialysis.

No dose adjustment is required in patients with mild or moderate hepatic impairement. Rilpivirine has not been studied in subjects with severe hepatic impairment.

Adverse Events: Insomnia Depression Elevations in liver function tests Elevations in serum creatinine

May be less potent if HIV VL>100.000 cop/ml

Requires acid gastric involvement for adequate absorption: Must be taken with food, contraindicated with proton pump inhibitors and other antacid medications and H2 blockers require specific timing if used by persons taking rilpivirine.

Genes:Less than 1% is eliminated through urine unchanged.

Metabolyzed by: Primarly CYP3A. Potential contribution from CYP2A19 Inducer of: At the recommended dose of 25mg once daily, rilpivirine is not likely to

have a clinically relevant effect on the exposure of medicinal products metabolized by CYP enzymes.

Inhibitor of: At the recommended dose of 25mg once daily, rilpivirine is not likely to have a clinically relevant effect on the exposure of medicinal products metabolized by CYP enzymes. Based on in vitro results with 25mg once daily, rilpivirine may act as a P-gp inhibitor.

Transported by: Not significantly transported by P-gp

Protease InhibitorsAll PIs are associated with metabolic abnormalities including dyslipidemia, hyperglycemia, insulin resistance, and lipodystrophy. They may increase the bleeding risk in hemophiliacs and may have significant ineractions with other drugs; dosage adjustment of interacting agents may be required.

AtazanavirAvailable under the trade name Reyataz (BMS). It is distinguished from other PIs in that it can be given once-daily and has lesser effects on the patient's lipid profile. When boosted with ritonavir it is more potent but reduces the metabolic advantages.


Atazanavir should not be used with proton pump inhibitors, such as omeprazole, esomeprazole, or rabeprazole because they reduce the plasma concetrations. Other antacid medications and H2 blockers also interfere with absorption of atazanavir and should be used with caution in patients receiving atazanavir.

There is no pharmacokinetic data available on patients with renal insufficiency; the impact of renal impairment on atazanavir elimination is anticipated to be minimal. Atazanavir with ritonavir should be used with caution in mild hepatic impairment and should not be used in patients with moderate to severe hepatic impairment.

Adverse Events:Bilirubin levels in the blood are normally asymptomatically raised with atazanavir.

Hyperbilirubinemia, jaundice > Indirect hyperbilirubinemia does not require discontinuation of atazanavir.

Elevations in liver function tests PR interval prolongation

Genes: Metabolyzed by: CYP3A4 Inducer of: P-gp expression and function, MRP1 expression Inhibitor of: CYP3A4, UGT1A1, CYP2C8, BCRP (in vitro), P-gp, MRPs, OATPs Transported by: P-gp, MRPs, BCRP

DarunavirAvailable under the trade name Prezista (formerly TMC114) (Tibotec). It is a second-generation PI, designed specifically to overcome problems with older agents in this class. Early PIs often have severe side effects and drug toxicities, require a high therapeutic dose, are costly to manofacture, and show a disturbing susceptibility to drug resistant mutations. Such mutations can develop as little as a year of use, and effectively render the drugs useless. Darunavir was designed to form robust interactions with the protease enzyme from many strains of HIV, including strains from treatment-experienced patients with multiple resistance mutations to PIs.

Darunavir is predominantly metabolized by the liver. No dose adjustment is required in patients with renal impairment. Darunavir should be used with caution in patients with hepatic impairment. No dose adjustment is recomended in mild or moderate hepatic impairment, however, it should be used with caution. No pharmacokinetic data are available in patients with severe hepatic impairment, darunavir should not be used in patients with severe hepatic impairment.

Adverse Events:Is generally well tolerated. Mild to moderate rash was seen in 7% of patients. Some patients developed severe rash (0.3% discontinued due to rash). The most common severe side effects associated with darunavir include diarrhea (2.3%), headache (3.8%), abdominal pain (2.3%),


constipation (2.3%), and vomiting (1.5%). 4% of patients discontinued treatment due to adverse events.

There are few relevant drug-drug interactions with other medications commonly used in HIV populations, such as other antiretroviral medications, proton pump inhibitors, and H2 receptor agonists. St John's Wort may reduce its effectiveness by interaction with CYP3A.

High blood sugar, diabetes or worsening of diabetes, muscle pain, tenderness or weakness, and increase bleeding in people with hemophilia have been reported in patients taking PIs.

Rash Elevations in liver function tests Increase pravastatin (and other statins) levels; no significant interaction with

atorvastatin.

Genes: Metabolyzed by: CYP3A4 Inducer of: CYP2C9, CYP2C19 (with darunavir/ritonavir, possibly ritonavir effect),

CYP2C8 (in vitro, darunavir/ritonavir) Inhibitor of: CYP3A4, CYP2D6 (with darunavir/ritonavir, possibly ritonavir effect), P-

glycoprotein (with ritonavir), OATPs Transported by: P-glycoprotein (in vitro)

FosamprenavirAvailable under the trade name Lexiva or Telzir (ViiV). Is a pro-drug inhibitor of the protease inhibitor and antiretroviral drug amprenavir. The human body metabolizes fosamprenavir in order to form amprenavir, which is the active ingredient. That metabolization increases de duration that amprenavir is available, marking fosamprenavir a slow-release version of amprenavir and thus reducing the number of pills required versus standard amprenavir.

It is usually given with ritonavir.

It has comkparable potency of lopinavir, but patients on fosamprenavir tended to have higher serum cholesterol.

The impact of renal impairment on amprenavir and ritonavir elimination is expected to be minimal. Fosamprenavir with ritonavir should be used with caution and at reduced doses in adults with mild or moderate hepatic impairment and is contraindicated in patients with severe hepatic impairment.

Adverse Events:Parameters refer to amprenavir. Fosamprenavir is rapidly and almost completely hydrolysed to amprenavir and inorganic phosphate as it is absorbed thrrough the gut epithelium, following oral administration.

Diarrhea Nausea


Vomiting Elevations in liver function tests Rash > May cause rash in patients sensitive or intolerant of sulfonamides Hyperlipidemia

Genes: Metabolyzed by: Primarly CYP3A4 Inducer of: Possibly CYP3A4 (net inhibition when administered with ritonavir) Inhibitor of: CYP3A4, BCRP (in vitro), P-gp, MRP1, OATPs Transported by: P-glycoprotein

IndinavirAvailable under the trade name Crixivan (Merk). Indinavir wears off quickly after dosing and therefore requires dosing very precisely every 8 hours in order to thwart HIV from forming drug resistant mutations. It has restrictions on what sorts of food may be eaten currently.

Safety in patients with impaired renal function has not been studied; less than 20% of indnavir is excreted in the urine as unchanged drug or metabolites. Safety and efficacy of indinavir has not been established in patients with significant undelying liver disorders and should be used with caution.

Adverse Events:Include kidney stones, kidney failure, metabolic abnormalities (hyperlipidemia > Cholesterol or triglyceride elevations) and alterations in body shape (lypodistrophy).

Indinavir inhibits urinary nitrous oxide production and may inhibit nitric oxide production. Treatment with this drug is usually associated with renal abnormalities, sterile leukocyturia, and reduced creatinine clearance. Indinavir impairs endothelial function in helathy HIV-negative men and may accelerate atherosclerotic disease.

Nephrolitiasis > To reduce risk patients should drink at least 1.5 l of fluid daily Fank pain Hyperbilirubineima Elevations in liver function tests Alopecia Dry skin Ingrown nails Insomnia Taste perversion

Genes: Metabolyzed by: CYP3A4 Inducer of: N/A Inhibitor of: CYP3A4, P-glycoprotein, MRP1, OATP-C Transported by: P-glycoprotein, MRP1


LopinavirIt is used as a fixed-dose combination with ritonavir under the trade name Kaletra or Aluvia. It is highly bound to plasma proteins. There are contradictory reports regarding to penetration into CSF.

Pharmacokinetics have not been studied in patients with renal insufficiency; since the renal clearance of lopinavir is negligible, a decrease in total body clearance is not expected. In mild to moderate hepatic impairment, an increase of approx. 30% in lopinavir exposure has been observed, but is not expected to be clinically relevant. No data are available in patients with severe hepatic impairment; Kaletra should not be given to these patients.

Adverse Events: Diarrhea Nausea Vomiting Dyslipidemia Elevations in liver function tests Taste perversion

Genes: Metabolyzed by: CYP3A Inducer of: N/A Inhibitor of: CYP3A, BCRP (in vitro) Transported by: P-glycoprotein, MRP1, MRP2, hOATPs

NelfinavirAvailable under the trade name Viracept. It is a potent and orally bioavailable, bioavailavility is increased 2.5 to 5 times when taken with food and decreases the risk of diarrhea as a side effect.

It's active against HIV-1 and HIV-2. The precise mode of binding of nelfinavir to the enzyme may be suffiently unique to reduce cross-resistance between it and other PIs.

No special precautions or dose adjustments are required in renal impairment. An increase in nelfinavir AUC has been observed in hepatically impaired patients. Specific dose recommendations for nelfinavir cannot be made.

Adverse Events:Nelfinavir can produce a range of adverse effects. Common (more 1%) are flatulence, diarrhea or abdominal pain. Infrequent (less 0.1%) are fatigue, urination, rash, mouth ulcers or hepatitis. Rarely (les 0.01%) nephrolitiasis, arthralgia, leukopenia, pancreatitis or allergic reactions.

Diarrhea > Is very common and usually con be managed with antidiarrheals Nausea Vomiting


Elevations in liver function tests Fatigue

Genes:Nelfinavir's interaction profile is similar to that of other PIs. Most interactions occur at the level of the Cytochrome P450 isoenzymes 3A4 and CYP2C19, by which nelfinavir is metabolized.

Metabolyzed by: CYP3A, CYP2C19, also CYP2C9 and CYP2D6 Inducer of: N/A Inhibitor of: CYP3A, MRP1, BCRP (in vitro), OATP-C Transported by: P-gp, MRP1, MRP2

SaquinavirTwo formulations have been marketed:

a hard-gel capsule formulation of the mesylate, with trade name Invirase which requires combination with ritonavir to increase bioavailability.

a soft-gel capsule formulation of saquinavir, with trade name Fortovase

As Invirase, a poolry-absorbed hard gel capsule which quickly led to viral resistance. it inhibits HIV-1 and HIV-2.

The bioavailability of both forms increases when mixed with ritonavir. Unlike other PIs, the absorption of saquinavir seems to be improved by omeprazole.

Renal clearance is a minor elimination pathway. No dosage adjustment required in mild/moderate renal impairment; caution should be exercised in severe renal impairment. No dosage adjustment necessary in mild hepatic impairment; caution should be exercised in patients with moderate hepatic impairment. The use of saquinavir in decompensated hepatic impairment is contraindicated.

Adverse Events:The most frequent adverse events with saquinavir in either formulation are mild gastrointestinal symptoms, including diarrhea, nausea, loose stools and abdominal discomfort. Invirase is better tolerated than Fortovase.

Must be used in combination with low-dose ritonavir

Nausea Vomiting Diarrhea Elevations in liver function tests Headache Oral ulcerations


Genes:Saquinavir is metabolized by P450 3A4 isozyme to an inactive form; but with the ritonavir inhibiting this enzyme, the saquinavir blood levels increased. Additionally, ritonavir also inhibits multidrug transporters, although to a much lower extent.

Metabolyzed by: CYP3A4 Inducer of: N/A Inhibitor of: P-glycoprotein, MRP1, BCRP (in vitro), OATP-C Transported by: P-glycoprotein, MRP1, MRP2, hOATPs

TipranavirAvailable under the trade name Aptivus (Boehringer-Ingelheim). It is administered with ritonavir.

Has the ability to inhibit the replication of viruses that are resistant to other PIs. Tipranavir itself seems to require multiple mutations.

Since renal clearance is negligible, increased plasma concentrations are not expected in patients with renal impairment. No dosage adjustment is required. Tripanavir should be used with caution, and with increased monitoring frequency in mild hepatic impairments and should not be used in moderate or severe hepatic impairment.

Adverse Events:Side effects can be more severe than other antiretrovirals. Some side effects include intracranial hemorraging, hepatitis, and diabetes mellitus. The drug has also been shown to cause increases in total cholesterol and triglycerides.

Must be coadministered with ritonavir; should never be used without ritonavir boosting. Should be taken with food.

It has many drug-drug interactions.

Nausea Vomiting Diarrhea Elevations in liver function tests Increased total cholesterol and triglycerides Rash > In patients sensitive or intolerant of sulfonamides Intracranial hemorrhage > Not clear

Genes: Metabolyzed by: Predominantly CYP3A4 Inducer of: CYP3A and P-glycoprotein (when coadministered with ritonavir, net

induction is observed over time) Inhibitor of: Modest inhibition of CYP2C19 has been observed at first dosem byt there

was marked induction at steady state. CYP3A (when coadministered with ritonavir, net inhibition is observed). Potent inhibition of CYP2D6 and both hepatic and intestinal


CYP3A4/5 activities were observed after first dosage and steady state. P-glycoprotein, BCRP (in vitro)

Transported by: P-glycoprotein

RitonavirAvailable under the trade name Norvir (Abbott). It is frequently prescribed with HAART, not for its antiviral action, but as it inhibits the same host enzyme that metabolizes other PIs. This inhibition leads to higher plasma concentrations of these latter drugs, allowing the clinician to lower their dose and frequency and improving their clinical efficacy.

It is one of the most complex protease inhibitors. It is rarely used for its own antiviral activity, but remains widely used as a booster of other PIs. It is used to inhibit a particular liver enzyme that normally metabolizes PIs, cytochrome P450 - 3A4. The drug's molecular structure inhibits CYP3A4, so a low dose can be used to enhance other PIs. This has drastically reduced the adverse effects and improved the efficacy of PIs and HAART. This effect does come with a price, at also affects the efficacy of numerous other medications, marking it difficult to know how to administer them concurrently. In addition it can cause a large number of side-effects on its own.

Concomitant therapy of ritonavir with a variety of medications may result in serious and sometimes fatal drug interactions. These interactions can occur with strong inhibitors, strong or moderate inducers or substrates of hepatic cytochrome P450 CYP3A4 isoform. The list include: amiodarone (decreased metabolism, possible toxicity), midazolam and triazolam (contraindicated), carbamazepine (decreased metabolism, possible toxicity), cisapride (decreased metabolism, possible prolongation of Q-T interval and life-threatening arrythmias), disulfiram (decreased ritonavir metabolism), eplerenone, etravirine, flecainide (decreased metabolism, possible toxicity), MDMA, meperidine (build-up of toxic concentrations of a metabolite possible), nilotinib, nisoldipine, pimozide, quinidine, ranolazine, salmeterol, St John's wort, statins (decreased metabolism, without dosage modification increased risk of rhabomyolisis), thioridazine, topotecan, voriconazole (increased metabolism).

Renal clearance id negligible; a decrease in total body clearance is not expected in renal imairment. There are currently no data specific to this patient population. Pharmacokinetic data indicate that no dose adjustment is necessary in mild to moderate hepatic impairment. Ritonavir should not be given to patients with severe hepatic impairment. Ritonavir should not be given as a pharmacokinetic enhancer to patients with decompensated liver disease. In the absence of pharmacokinetic studies in patients with stable severe hepatic impairment without decompensation, caution should be exercised as increased levels of the co-administered PI may occur.

Adverse Events:The most common side effects of ritonavir are: asthenia, malaise, diarrhea, nause, vomiting, abdominal pain, dizziness, insomnia, sweating, taste abnormality, metabolic (hypercolesterolemia, hypertriglyceridemia, elevated transaminases, elevated CPK). One of ritonavir's side effects is hyperglycemia; it appears that ritonavir directly inhibits the GLUT4


insulin-regulated transporter, keeping glucose from entering fat and muscle cells. This can lead to insulin resistance and cause problems for type II diabetics.

Nausea Vomiting Diarrhea Abdominal pain Elevations in liver function tests Fatigue Circumoral or peripheral numbness Taste perversion Hyperuricemia

Genes: Metabolyzed by: CYP3A, CYP2D6 Inducer of: CYP1A2, CYP2C8, CYP2C9 and CYP2C19, MRP1 expression Inhibitor of: CYP3A, CYP2D6, P-glycoprotein, MRP1, OATP-C, BCRP Transported by: P-glycoprotein, MRP1

Fusion Inhibitors

EnfuvirtideAvailable under the trade name Fuzeon (Roche). Enfuvirtide works by disrupting the HIV molecular machinery at the final stage of fusion with the target cell, preventing uninfected cells from becoming infected. It is only active against HIV-1. Viral strains acquired resistance as a result of a mutated 10 aa motif in viral gp41; primary resistance has yet to be observed.

No dose adjustment is required for patients with renal impairment including those receiving dialysis. Data is limited in this patients. The pharmacokinetics of enfuvirtide have not been studied in patients with hepatic impairment; enfuvirtide should be used with caution in these patients.

Adverse Events:Common adverse drug reactions (>1%) associated with enfuvirtide therapy include: injection site reactions (pain, hardening of skin, erythema, nodules, cysts, itch), peripheral neuropathy, insomnia, depression, cough, dyspnoea, anorexia, arthralgia, infections (including bacterial pneumonia) and/or eosinophilia. Various hypersensitivity reactions occur infrequently (less 1%), symptoms of which include rash, fever, nausea, vomiting, chills, rigors, hypotension, elevated hepatic transaminases; and possibly more severe reactions including respiratory distress, glomerulonephritis, and/or anaphylaxis.

Injection site reactions: erythema, cysts and nodules Neutropenia Possible increased frequency of pneumonia Elevations in liver function tests


Fatigue

Genes: Metabolyzed by: As a peptide, enfuvirtide is expected to undergo catabolism to its

constituent aa, with subsequent recycling. No CYP450 involvement expected Inducer of: No CYP450 involvement expected Inhibitor of: No CYP450 involvement expected Transported by: Unknown

Entry Inhibitors

MaravirocAvailable under the trade name Selzentry or Celsentri (Pfizer). Maraviroc is a negative allosteric modulator of the CCR5 receptor. The drug binds to CCR5, thereby blocking de HIV protein gp120; so HIV is unable to enter human macrophages and T-cells. Because HIV can also use other coreceptors, such as CXCR4, an HIV tropism test must be performed to determine if the drug will be effective.

Safety and efficacy have not been specifically studied in patients with renal impairment, therefore maraviroc should be used with caution in this population. Dosage adjustment is only recommended in patients with renal impairment also receiving potent CYP3A4 inhibitors. Limited data are available in hepatic impairment; maraviroc should be used with caution.

Adverse Events:Many drug-drug interactions; dose adjustment needed with many other antiretrovirals and/or other medications.

Diarrhea Nausea Elevations in liver function tests Hepatitis Upper respiratory tract infections Cough Fatigue Dizziness Headache Joint pain Muscle pain

Genes: Metabolyzed by: CYP3A4 Inducer of: Unlikely at clinically relevant concentrations Inhibitor of: Unlikely at clinically relevant concentrations; potential inhibition of

CYP2D6 at higher doses. Effects on P-glycoprotein have not been evaluated, an inhibitory effect cannot be excluded


Transported by: P-glycoprotein

Integrase Inhibitors

RaltegravirAvailable under the trade name Isentress (Merck). Raltegravir targets integrase, an HIV enzyme that integrates the viral genetic material into human chromosomes, a critical step in pathogenesis of HIV. The drug is metabolized away via glucuronidation.

Raltegravir do not result in increased serum levels of total cholesterol, LDL cholesterol or triglycerides.

Renal clearance of unchanged medicinal product is a minor pathway of elimination. Clinically important pharmacokinetic differences between patients with severe renal insufficiency and healthy subjects have not been observed. No dosage adjustment is required for patients with renal imairment.

No dosage adjustment is required in mild to moderate hepatic impairment. The dafety and efficacy of raltegravir have not been established in severe underlying liver disorders and should be used with caution in these patients.

Adverse Events: Nausea Diarrhea Flatulence Elevations in amylase and liver function tests Headache Dizziness Abnormal dreams Pruritus Rash Fatigue Muscle pain

Genes: Metabolyzed by: Mainly via UGT1A1-mediated glucuronidation. No CYP450

involvement. Inducer of: No CYP450 or P-glycoprotein involvement expected. Inhibitor of: No CYP450 or P-glycoprotein involvement expected. Transported by: Unknown

Documents

Farmacs Efectes2aris Gens