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New Treatments Winning Against HIV

Yvette C. Terrie, BSPharm, RPh
Published Online: Tuesday, July 1, 2008   [ Request Print ]


Ms. Terrie is a clinical pharmacy writer based in Haymarket, Virginia.


Currently, the classes of pharmacologic agents used in the treatment of HIV include nonnucleoside reverse transcriptase inhibitors (NNRTIs), nucleoside reverse transcriptase inhibitors (NRTIs), protease inhibitors (PIs), entry/fusion inhibitors, and integrase inhibitors. In addition, various agents are available, known as fixed-dose combinations, that contain 2 or more HIV medications that come from one or more drug classes.1 In 2007, the FDA approved 2 new treatments for HIV: maraviroc (Selzentry), manufactured by Pfizer Inc, in August, and raltegravir (Insentress) manufactured by Merck & Co Inc, in October. In 2008, the FDA approved etravirine (Intelence), manufactured by Tibotec Therapeutics. This article will review the 3 recently approved pharmacologic agents for the treatment of HIV infection.

Maraviroc

Maraviroc, in combination with other antiretroviral agents, is indicated for treatment-experienced adult patients infected with only chemokine receptor 5 (CCR5)?tropic HIV-1 detectable who have evidence of viral replication and HIV-1 strains resistant to multiple antiretroviral agents.2 It is classified as a selective, slowly reversible, small molecule antagonist of the interaction between human CCR5 and HIV-1 gp120.2 The blocking of this interaction prohibits CCR5-tropic entry into cells.1

The agent must be used in conjunction with other antiretroviral agents. According to manufacturer recommendations, the recommended dose of maraviroc varies based on which agent it will be used in conjunction with due to drug interactions (Table).

Maraviroc may be taken without regard to food and is available in 150- and 300-mg tablets. The most common adverse effects associated with the use of maraviroc twice a day include cough, pyrexia, upper respiratory tract infections, rash, musculoskeletal symptoms, abdominal pain, and dizziness.2 Other adverse effects reported with once-aday and twice-daily dosing were diarrhea, edema, influenza, esophageal candidiasis, sleep disorders, rhinitis, parasomnias, and urinary abnormalities.1 Pharmacists should remind patients to immediately seek medical attention if they experience a rash, jaundice, dark urine, vomiting, or abdominal pain. Discontinuation of maraviroc should be considered in any patient showing signs or symptoms of hepatitis, or with increased liver transaminases combined with rash or other systemic symptoms.2

Patients also should be reminded to adhere to the prescribed medication regimen, and if a dose is missed, to take it as soon as possible. If the missed dose is remembered less than 6 hours before the next scheduled dose, however, patients should not take the missed dose, but should wait and take the next scheduled dose. Patients also should be reminded to avoid driving or operating machinery if they experience any episodes of dizziness. Patients also should be advised that the concomitant use of maraviroc and St. John's wort, or products containing St. John's wort, is not recommended. Maraviroc should not be used in individuals younger than 16 years of age and is classified by the FDA as pregnancy category B.2

Table
Recommended Dosage Information for Maraviroc

Agents

Recommended Dosage and Administration

When given with strong CYP3A inhibitors (with or without CYP3A inducers), including PIs (except tipranavir/ritonavir), delavirdine

150 mg twice a day

With NRTIs, tipranavir/ritonavir, nevirapine, and other drugs that are not strong CYP3A inhibitors or CYP3A inducers

300 mg twice a day

With CYP3A inducers including efavirenz (without a strong CYP3A inhibitor)

600 mg twice a day

PIs = protease inhibitors; NRTIs = nucleoside reverse transcriptase inhibitors.
Adapted from reference 2.


Raltegravir

Raltegravir is an oral agent and the first agent to be approved in a new class of antiretroviral drugs known as integrase inhibitors. Raltegravir exerts its mechanism of action by inhibiting the insertion of HIV DNA into human DNA by the integrase enzyme.3 By inhibiting integrase from performing this essential function, it limits the ability of the virus to replicate and infect new cells.3 While other available agents inhibit 2 other enzymes critical to the HIV replication process—protease and reverse transcriptase—raltegravir is the only drug approved that inhibits the integrase enzyme.3

It is indicated for use in combination with other antiretroviral agents for the treatment of HIV-1 infection in treatment-experienced adults who have evidence of viral replication and HIV-1 strains resistant to multiple antiretroviral agents. Raltegravir is available as 400-mg tablets and is to be administered as 400 mg twice a day without regard to food. Because the safety and efficacy of raltegravir have not been determined, its use is not recommended in treatment-na?ve adult patients or pediatric patients younger than 16 years of age.3 The most common adverse effects reported include nausea, headache, diarrhea, and pyrexia. The plasma concentration of raltegravir may be decreased when given in conjunction with strong inducers of uridine diphosphate glucuronosyltransferase such as rifampin. Raltegravir is classified by the FDA as a pregnancy category C drug. Pharmacists should remind patients that if a dose is missed, it should be taken as soon as possible. If patients do not remember until the time for the next dose, however, patients should be instructed to skip the missed dose and resume the regular schedule. Patients should be reminded to never take 2 tablets at the same time.

Etravirine

Etravirine is an NNRTI of HIV-1 and the first to be approved in over a decade. Etravirine is the first NNRTI to show antiviral activity in treatment-experienced adult patients with HIV resistant to an NNRTI and other antiretroviral agents.4

Etravirine is indicated for use in combination with other antiretroviral agents and is specifically indicated for the treatment of HIV-1 infection in treatment-experienced adult patients who have evidence of viral replication and HIV-1 strains resistant to an NNRTI and other antiretroviral agents.4 It exerts its mechanism of action by binding directly to reverse transcriptase and blocks the RNA-dependent and DNA-dependent DNA polymerase activities by causing a disruption of the enzyme's catalytic site. Etravirine does not inhibit the human DNA polymerases α, β, and γ.4

Etravirine is available in 100-mg tablets, and the recommended initial dosage is 200 mg (100 mg twice a day after a meal). It is classified by the FDA as a pregnancy category B drug. This agent should not be coadministered with the following antiretroviral agents: pranavir/ritonavir, fosamprenavir/ritonavir, atazanavir/ritonavir, full-dose ritonavir (600 mg twice a day), protease inhibitors administered without ritonavir, and other NNRTIs.4 In addition, it should not be coadministered with carbamazepine, phenobarbital, phenytoin, rifampin, rifapentine, rifabutin (when part of a regimen containing protease inhibitor/ritonavir), or products containing St. John's wort.4 More information on potential drug interactions can be found on the product Web site. Patients unable to swallow may disperse the tablet in a glass of water. The most common adverse effects associated with the use of etravirine include rash, diarrhea, nausea, fatigue, abdominal pain, peripheral neuropathy, headache, and hypertension.

Table
FDA-approved Medications to Treat HIV Infection Listed by Class

Brand Name (Generic Name)

Manufacturer

Approval Date

NNRTIs

Intelence (etravirine)

Tibotec Therapeutics

January 18, 2008

Rescriptor (delavirdine)

Pfizer Inc

April 4, 1997

Sustiva (efavirenz)

Bristol-Myers Squibb

September 17, 1998

Viramune (nevirapine)

Boehringer Ingelheim

June 21, 1996

NRTIs

Combivir (lamivudine and zidovudine)

GlaxoSmithKline

September 27, 1997

Emtriva (emtricitabine)

Gilead Sciences Inc

July 2, 2003

Epivir (lamivudine)

GlaxoSmithKline

November 17, 1995

Epzicom (abacavir and lamivudine)

GlaxoSmithKline

August 2, 2004

Hivid (zalcitabine)

Hoffmann-La Roche

June 19, 1992

Retrovir (zidovudine, azidothymidine)

GlaxoSmithKline

March 19, 1987

Trizivir (abacavir, zidovudine, and lamivudine)

GlaxoSmithKline

November 14, 2000

Truvada (tenofovir disoproxil fumarate and emtricitabine)

Gilead Sciences Inc

August 2, 2004

Videx EC (enteric-coated didanosine)

Bristol-Myers Squibb

October 31, 2000

Videx (didanosine, dideoxyinosine)

Bristol-Myers Squibb

October 9, 1991

Viread (tenofovir disoproxil fumarate)

Gilead Sciences Inc

October 26, 2001

Zerit (stavudine)

Bristol-Myers Squibb

June 24, 1994

Ziagen (abacavir)

GlaxoSmithKline

December 17, 1998

PIs

Agenerase (amprenavir)

GlaxoSmithKline

April 15, 1999

Aptivus (tipranavir)

Boehringer Ingelheim

June 22, 2005

Crixivan (indinavir)

Merck & Co Inc

March 13, 1996

Invirase (saquinavir mesylate)

Hoffmann-La Roche

December 6, 1995

Kaletra (lopinavir and ritonavir)

Abbott Laboratories

September 15, 2000

Lexiva (fosamprenavir calcium)

GlaxoSmithKline

October 20, 2003

Norvir (ritonavir)

Abbott Laboratories

March 1, 1996

Prezista (darunavir)

Tibotec Therapeutics

June 23, 2006

Reyataz (atazanavir sulfate)

Bristol-Myers Squibb

June 20, 2003

Viracept (nelfinavir mesylate)

Agouron Pharmaceuticals

March 14, 1997

Entry/Fusion Inhibitors

Fuzeon (enfuvirtide)

Hoffmann-La Roche

March 13, 2003

Selzentry (maraviroc)*

Pfizer Inc

August 6, 2007

Integrase Inhibitors

Isentress (raltegravir)

Merck & Co Inc

October 12, 2007

Multiclass Combination Products

Atripla (efavirenz, emtricitabine, tenofovir disoproxil fumarate)

Bristol-Myers Squibb and Gilead Sciences

July 12, 2006

* Entry inhibitor—CCR5 coreceptor antagonist.
NNRTIs = non-nucleoside reverse transcriptase inhibitors; NRTIs = nucleoside reverse transcriptase inhibitors; PIs = protease inhibitors.
Adapted from reference 1.


References

  1. Drugs Used in the Treatment of HIV Infection. FDA Web site. www.fda.gov/oashi/aids/virals.html.
  2. Selzentry [package insert]. New York, NY: Pfizer Inc; 2007.
  3. Isentress [package insert]. Whitehouse Station, NJ: Merck & Co Inc; 2007.
  4. Intelence [package insert]. Raritan, NJ: Tibotec Therapeutics, Division of Ortho Biotech Products LP; 2008.
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