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2 Antiretroviral Drugs: Fuzeon and Reyataz


Trade Name Drug: Fuzeon

Generic Name Drug: Enfuvirtide

Company: Roche

Indication / Use: AIDS antiviral

Approval Date / FDA Class: 13 03 2003 / 1P



Trade Name Drug: Reyataz

Generic Name Drug: Atazanavir sulfate

Company: Bristol Myers Squibb

Indication / Use: AIDS antiviral

Approval Date / FDA Class:  20 06 2003 / 1P


Development and Mechanisms of Action

Since the introduction of zidovudine (AZT, Retrovir) in 1987, a relatively large number of drugs have been developed for the treatment of HIV-induced AIDS. Currently available antiretroviral drugs are subclassified based on their chemical structure and site of action as nucleoside reverse transcriptase inhibitors (NRTIs: zidovudine, didanosine, zalcitabine, stavudine, lamivudine and abacavir), non­nucleoside reverse transcriptase inhibitors (NNRTIs: nevirapine, delavirdine and efavirenz) and protease inhibitors (PIs: saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, and lopinavir).

The use of these and all antiretrovirals as monotherapy is limited largely by the rapid development of viral resistance. Thus current Public Health Service HIV treatment guidelines recommend the use of drug combinations consisting of three or four anti-AIDS drugs.

These combinations, now referred to as highly active antiretroviral therapy (HAART), typically include a combination of two NRTIs with one or two protease inhibitors, or two NRTIs with an NNRTI. These HAART approaches have proven to be more effective than the use of single agents in providing prolonged reductions in HIV and have contributed significantly to the reduction of mortality associated with AIDS since 1995.

Atazanavir, an azapeptide, is the newest PI to be introduced in the United States. Like other members of this therapeutic class, it functions as a selective HIV-1 protease inhibitor and thereby blocks the virus-specific processing of viral Gag and Gag-Pol polyproteins in virally infected cells, which prevents formation of mature virions.

Atazanavir exhibits anti­HIV-1 activity with a mean 50% effective concentration (EC50) of 2 to 5 nM against a variety of laboratory and clinical HIV-1 isolates grown in peripheral blood mononuclear cells, macrophages, CEM-SS cells, and MT-2 cells.

Furthermore atazanavir displays additive antiviral activity in vitro with NRTIs, NNRTIs, and other PIs without enhanced cytotoxicity. HIV-1 isolates with reduced susceptibility to atazanavir (93- to 183-fold resistant) have been isolated from viral strains in vitro and from patients experiencing virologic failure while on atazanavir therapy. While there are multiple HIV-1 mutations that may produce resistance, many isolates resistant to atazanavir are resistant to other PIs as well.

The introduction of the polypeptide derivative enfuvirtide represents a novel approach for the treatment of HIV infection. Unlike the NRTIs, NNRTIs, and PIs, enfuvirtide functions as an inhibitor of the fusion of HIV-1 with CD4+ cells. It does so by binding to the first heptad-repeat (HR1) in the gp41 subunit of the HIV viral envelope glycoprotein and thereby prevents the conformational changes required for the fusion of viral and cellular membranes.

In cell culture studies enfuvirtide exhibits additive to synergistic effects when combined with NRTIs, NNRTIs, and PIs. In clinical trials to date isolates resistant to NRTIs, NNRTIs, and PIs have remained suscept ible to enfuvirtide. However, HIV-1 isolates with reduced susceptibility to enfuvirtide have been isolated from patients treated with this drug in clinical trials.


Atazanavir is rapidly absorbed with a Tmax of approximately 2.5 hours. Atazanavir demonstrates nonlinear pharmacokinetics with greater than dose-proportional increases in AUC and Cmax values over the dose range of 200 to 800 mg once daily. Administration of a single 400-mg dose of Reyataz with a high-fat meal (721 kcal, 37.3 g fat, 29.4 g protein) resulted in a mean increase in AUC of 35% with no change in Cmax relative to the fasting state. Atazanavir is 86% bound to human serum proteins and protein binding is independent of concentration. Atazanavir binds to both alpha-1-acid glycoprotein (AAG) and albumin to a similar extent (89% and 86%, respectively).

The cerebrospinal fluid/plasma ratio for atazanavir ranged between 0.0021 and 0.0226 and seminal fluid/plasma ratio ranged between 0.11 and 4.42. Atazanavir is extensively metabolized with the primary biotransformation pathways consisting of monooxygenation and dioxygenation by CYP3A. Other minor metabolic pathways for atazanavir or its metabolites include glucuronidation, N-dealkylation, hydrolysis, and oxygenation with dehydrogenation.

These metabolites are devoid of antiviral activity. Unchanged drug accounts for approximately 20% and 7% of the administered dose in the feces and urine, respectively. The mean half-life of atazanavir in moderately to severely hepatically impaired patients is nearly doubled (from 6.5 to 12 hours) and the AUC significantly increased (average 42%). Thus increased concentrations of atazanavir are expected in patients with moderately or severely impaired hepatic function. At present there are no pharmacokinetic data available on patients with impaired renal function. No clinically important pharmacokinetic differences have been observed due to age or gender. At present there are insufficient pharmacokinetic studies to recommend an atazanavir dose in pediatric patients.

The bioavailability of enfuvirtide is 89% following sc administration with a mean absorption time of about seven hours following a 45-mg sc dose and 10 hours following a 180-mg sc dose. The mean steady-state volume of distribution after intravenous administration of a 90-mg dose of enfuvirtide is estimated to be 5.5 L. Enfuvirtide is approximately 92% bound to plasma proteins in HIV-infected plasma over a concentration range of 2 to 10 mg/mL.

It is bound predominantly to albumin and to a lower extent to a-1 acid glycoprotein. As a peptide, enfuvirtide is expected to undergo catabolism to its constituent amino acids, with subsequent recycling of the amino acids in the body pool. The terminal half-life is about four hours following standard doses. Formal pharmacokinetic studies of enfuvirtide have not been conducted in patients with hepatic or renal impairment.

Clinical Profile

The efficacy of atazanavir has been demonstrated in a number of controlled, comparative trials. In one study involving 420 patients, three doses of atazanavir (200, 400, or 500 mg once daily) were compared with nelfinavir (750 mg three times daily), as both monotherapy and in combination with didanosine (400 mg once daily) plus stavudine (40 mg twice daily) in treatment-naive HIV patients.

These patients had a baseline viral load greater than 2,000 copies/mL. With monotherapy, a decrease in HIV RNA by approximately 1.5 log copies/mL was seen with nelfinavir and all atazanavir dose groups.

During combined therapy with nelfinavir or atazanavir plus didanosine/stavudine, similar reductions in HIV RNA from baseline were seen in all groups, and a similar number of patients achieved reductions to less than 400 copies/mL and 50 copies/mL. In the atazanavir plus didanosine/stavudine group at 48 weeks, HIV RNA levels had fallen by about 2.5 log copies/mL, with increases in CD4+ counts by approximately 220/cubic mm. In a second study involving 467 patients, nelfinavir (1,250 mg twice daily) was compared to atazanavir (400 or 600 mg once daily), combined with lamivudine (150 mg twice daily) plus stavudine (40 mg twice daily).

Patients included were treatment-naive adults with baseline HIV RNA levels of at least 2,000 copies/mL and CD4+ counts of at least 100/mm. At week 24, a viral load of less than 400 copies/mL was achieved in 67% of the 400-mg atazanavir group, 70% of the 600-mg atazanavir groups, and 63% of the nelfinavir group. A viral load of less than 50 copies/mL was observed in 31%, 36%, and 38% of these respective groups by week 48. Increases in CD4+ counts were similar among all groups at week 48 (about 235/mm), but the mean log reduction in viral load was significantly greater in the 600-mg atazanavir group (2.6 log copies/mL) and 400-mg atazanavir group (2.5) versus the nelfinavir group (2.3). In a third study with 85 patients who experienced virologic failure on a prior protease-inhibitor regimen (baseline HIV RNA of 1,000 to 100,000 copies/mL and CD4+ count of at least 100 cells/mm), once-daily atazanavir (400 or 600 mg) plus saquinavir (1,200 mg) was compared to ritonavir (400 mg) plus saquinavir (400 mg twice daily).

All of these patients were also receiving two nucleoside analogues. At 24 weeks of therapy, mean changes from baseline in HIV RNA were ­1.28, ­1.17, and ­1.5 log copies/mL in patients receiving atazanavir 400 mg/saquinavir, atazanavir 600 mg/saquinavir, and ritonavir/saquinavir, respectively. Mean increases in CD4+ counts in these groups were 55, 67, and 98 cells/mm. Based on the results of these and comparable trials, atazanavir is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection.

Data from clinical trials to date suggest that enfuvirtide added to an optimized, combination antiretroviral regimen provided greater improvement in virologic and immunologic responses than an optimized, combination antiretroviral regimen alone. In a randomized, open-label, multicenter, phase III trial (TORO 1), 491 HIV-infected individuals were randomized to receive enfuvirtide 90 mg sc twice a day plus an optimized, combination antiretroviral regimen or an optimized, combination antiretroviral regimen alone, for 48 weeks.

The optimized regimen was based on phenotypic and genotypic resistance testing, and previous antiretroviral therapy and tolerance for each patient. The primary efficacy end point was the change from baseline in plasma HIV-1 RNA level at 24 weeks. Patients in the enfuvirtide group had a statistically significant greater decrease from baseline in plasma HIV-1 RNA levels than the control group (1.696 versus 0.764 log copies/mL).

Furthermore, the increase in CD4 cell counts was greater in the enfuvirtide group when compared with the control group at 24 weeks (76.2 versus 32.1 cells/mm). Virologic failure at week 8 and week 24 was greater in the control group than in the enfuvirtide group (week 8, 33.3% versus 16%, respectively; week 24, 64.2% and 41.7%, respectively).

At present there are few studies evaluating efficacy of enfuvirtide in children. One small pediatric trial evaluated enfuvirtide in 11 treatment-experienced children ages 6 to 12 years; median CD4 cell count was 509 cells/µL and median baseline HIV-1 RNA was 4.5 log copies/mL. At week 48 of therapy, 6 of 11 (55%) patients had a decline in HIV-1 RNA of 1 or greater log copies/mm (median change from baseline ­1.48 log copies/mL).

Median change from baseline in CD4 cell count was 122 cells/µL. Currently enfuvirtide in combination with other antiretroviral agents is indicated for the treatment of HIV-1 infection in treatment-experienced patients with evidence of HIV-1 replication despite ongoing antiretroviral therapy.

Adverse Reactions

In all clinical trials published to date the primary adverse reactions associated with atazanavir therapy included headache (8% to 14%), GI effects including nausea, vomiting, abdominal pain, and diarrhea (6% to 16%), rash (3% to 13%), cough (3% to 5%), arthralgia (2% to 4%) and miscellaneous CNS effects (3% to 8% including depression, insomnia, dizziness, and neuropathies).

While many PIs cause significant elevations of total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides, atazanavir appears to have minimal impact on lipid profiles.

For example, in the clinical trial cited above significantly greater median increases in all lipid parameters were seen in patients receiving nelfinavir versus atazanavir (25% versus 5% to 6% for total cholesterol, 23% versus 5% to 7% for LDL-cholesterol, 50% versus 7% to 8% for triglycerides). The most common laboratory abnormality observed in patients treated with atazanavir is hyperbilirubinemia due to inhibition of UDP-glucuronosyl transferase­mediated conjugation of bilirubin. This laboratory abnormality resulted in jaundice or scleral icterus in 15% to 24% of clinical trial subjects. Hyperbilirubinemia with atazanavir does not appear to be associated with an increased risk of liver injury and is reversible upon discontinuation of the drug.

Atazanavir has been shown to prolong the PR interval of the electrocardiogram in some patients (6%), but abnormalities in atrioventricular (AV) conduction were asymptomatic and limited to first-degree AV block with rare exceptions. Hyperglycemia as well as increased bleeding in hemophiliacs have been reported with other PIs, and therefore patients receiving atazanavir should be monitored for these reactions. Also lactic acidosis syndrome and symptomatic hyperlactemia have been reported in patients receiving atazanavir in combination with NRTIs, although the contribution of atazanavir to these adverse effects has not been established.

The adverse-effects profile of enfuvirtide is based on data from the two phase III clinical trials which involved nearly 1,200 patients who received at least one dose of the drug. This includes more than 1,100 adults, 608 of whom received the recommended dose for more than 24 weeks, and 35 pediatric subjects. The most common adverse events reported with enfuvirtide were local injection-site reactions including pain and discomfort, induration, erythema, nodules and cysts, pruritus, and ecchymosis. More than 90% of patients had local reactions that required analgesics or limited usual activities.

An increased incidence of bacterial pneumonia also was reported in patients treated with enfuvirtide. Therefore, patients receiving this drug should be monitored for signs and symptoms of pneumonia, especially if they have risk factors that may predispose them to infection (low initial CD4 cell count, high initial viral load, IV drug use, smoking, or a prior history of lung disease).

Hypersensitivity reactions reported rarely with enfuvirtide include rash, fever, nausea and vomiting, chills, rigors, hypotension, and elevated serum liver transaminases. Other enfuvirtide-associated adverse events that may be immune mediated include primary immune complex reaction, respiratory distress, glomerulonephritis, and Guillain-Barre syndrome. Patients developing signs and symptoms suggestive of a systemic hypersensitivity reaction should discontinue enfuvirtide and seek medical evaluation immediately.

Enfuvirtide therapy should not be reinstituted following systemic signs and symptoms consistent with a hypersensitivity reaction.

Drug Interactions

Like most other PIs, atazanavir functions as an inhibitor of cytochrome isozymes CYP3A, CYP1A2, and CYP2C9 and the glucuronidating enzyme UGT1A1. Therefore concurrent administration of atazanavir and drugs primarily metabolized by CYP3A (eg, calcium channel blockers, HMG-CoA reductase inhibitors, immunosuppressants, and sildenafil) or UGT1A1 (eg, irinotecan) may result in increased plasma concentrations of the other drug that could increase or prolong both its therapeutic and adverse effects. Also, since atazanavir is metabolized by the cytochrome isozymes (primarily CYP3A), coadministration with drugs that induce these enzymes, such as rifampin, may result in decreased atazanavir plasma concentrations and reduced therapeutic efficacy.

Conversely, drugs that inhibit CYP3A may increase atazanavir plasma concentrations.

Atazanavir does not interact with substrates of CYP2D6 (eg, nortriptyline, desipramine, metoprolol). Detailed information regarding specific potential drug interactions with atazanavir and associated cautions and contraindications is provided in the manufacturer’s prescribing information. Since atazanavir solubility decreases as pH increases, reduced plasma concentrations may occur if antacids, buffered medications, H50-receptor antagonists, and proton-pump inhibitors are administered with atazanavir.

Atazanavir has the potential to prolong the PR interval of the electrocardiogram in some patients and therefore caution should be exercised when this drug is used with other agents known to induce PR interval prolongation (eg, atenolol, diltiazem).

Based on known metabolic profiles, clinically significant drug interactions are not expected between atazanavir and fluvastatin, pravastatin, dapsone, trimethoprim/sulfamethoxazole, azithromycin, erythromycin, itraconazole, or fluconazole.

Enfuvirtide is not a substrate or inhibitor of cytochrome isozymes CYP3A4, CYP2D6, CYP1A2, or CYP2C19 and therefore is not expected to interact with other drugs by cytochrome metabolic mechanisms. No drug interactions with other antiretroviral medications have been identified that would warrant alteration of either the enfuvirtide dose or the dose of the other antiretroviral drug.

Dosage and Administration

Atazanavir sulfate is supplied as 100-, 150-, and 200-mg capsules. The recommended dose of atazanavir in adults is 400 mg (two 200-mg capsules) once daily taken with food. When coadministered with efavirenz (600 mg), it is recommended that the atazanavir dose be reduced to 300 mg and 100 mg of ritonavir added; atazanavir should not be coadministered with efavirenz without ritonavir.

Also, atazanavir should be given two hours before or one hour after administration of buffered formulations of didanosine. A dose reduction to 300 mg of atazanavir once daily is recommended for patients with moderate hepatic insufficiency (Child-Pugh Class B) and this drug should not be used in patients with severe hepatic insufficiency (Child-Pugh Class C). At present there are insufficient data to recommend a dosage adjustment for patients with renal impairment.

Enfuvirtide is supplied as a lyophilized powder in a single-use clear glass vial containing 108 mg of drug for the delivery of approximately 90 mg/1 mL when reconstituted with 1.1 mL of Sterile Water for Injection. T

he drug product is provided as a Convenience Kit containing 60 single-use vials (two cartons of 30 each) of enfuvirtide (90-mg strength), 60 vials (two cartons of 30 each) of Sterile Water for Injection (1.1 mL per vial), 60 reconstitution syringes (3 cc), 60 syringes (1 cc), alcohol wipes, a Package Insert, Patient Package Insert, and an Injection Instruction Guide. In adults the recommended dose of enfuvirtide is 90 mg (1 mL) twice daily injected subcutaneously into the upper arm, anterior thigh, or abdomen.

Each injection should be given at a site different from the preceding injection site and only where there is no current injection site reaction from an earlier dose. The reconstituted drug should not be injected into moles, scar tissue, bruises, or the navel. In pediatric patients 6 through 16, the recommended dosage of enfuvirtide is 2 mg/kg twice daily up to a maximum dose of 90 mg twice daily.

At present no data are available to establish a dose recommendation of enfuvirtide in pediatric patients below the age of 6. Detailed instructions for reconstitution and administration are provided in the Injection Instruction Guide provided by the manufacturer. Patients should be familiar with these instructions in order to inject enfuvirtide appropriately and to monitor carefully for signs or symptoms of cellulitis or local infection.

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