The AIDS Beacon™

Brand Name:	Sustiva
Generic Name:	efavirenz
Company:	Bristol-Myers Squibb
FDA Clinical Phase:	Capsule formula approved in 1998 in combination with other HIV drugs for the treatment of HIV.  Tablet formula approved in 2002

Description

Sustiva is a Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI) approved by the U.S. Food and Drug Administration for HIV-1-positive adults and children older than 3 years of age.  For patients beginning antiretroviral therapy for the first time, the U.S. Department of Health and Human Services lists Sustiva as the preferred NNRTI option for use with at least two other HIV medications.  Sustiva must be taken in combination with other antiretroviral drugs, usually two or three, in drug regimens known as Highly Active Anti-Retroviral Treatment (HAART).

In addition, Sustiva is combined with Viread (tenofovir) and Emtriva (emtricitabine) in one pill under the brand name Atripla.  This combination is appealing to many patients because an entire HAART regimen can be administered once a day in the form of one pill.

Sustiva has not been adequately tested in patients older than 65 years of age, and dosage recommendations and side effects are not established for these patients.

Mechanism of Action

Sustiva prevents HIV from replicating in infected cells by blocking the reverse transcriptase enzyme.  This enzyme is responsible for transcribing the virus’s RNA into DNA to insert into the genetic material of an infected cell.  By blocking the enzyme, the HIV copy cannot inject its genetic material into the cell, preventing CD4 cells from creating more copies of the virus.

History

Sustiva was originally produced by DuPont Pharmaceuticals, but is currently manufactured by Bristol-Myers Squibb.  The drug is marketed in the U.S., Canada, and a few European countries.  Stocrin (efavirenz), the brand name of the drug in Europe, is manufactured by Merck Sharp & Dohme.

Use in HIV

Sustiva is most effective when taken early in a patient’s treatment plan.  The drug is recommended both for patients beginning therapy for the first time as well as for treatment-experienced patients who have not developed resistance to other NNRTIs.

Patients who have developed resistance to other NNRTIs such as Viramune (nevirapine) or Rescriptor (delavirdine) are more likely to have resistance to Sustiva as well.  Similarly, patients with developed resistance to Sustiva are more likely to show resistance toward other NNRTIs.

Dosage and Administration

For adults and children weighing more than 40 kilograms, the recommended dosage of Sustiva is one 600 milligram (mg) tablet taken once a day on an empty stomach before sleeping.  Eating food before taking Sustiva may increase the intensity of side effects.  HIV-positive children who are three years of age or older can take the drug, but must take the appropriate amount based on the child’s age and weight.

Sustiva is administered through 600 mg tablets or capsules with 50 mg and 200 mg doses.  Researchers are currently developing an oral solution of the drug for patients (especially children) who have problems swallowing pills.  Bristol-Myers Squibb offers the oral solution through an expanded access program designed for patients who are unable to receive treatment because of problems of administering or swallowing pills.

Like other medications, Sustiva should be stored at room temperature away from moisture and heat to ensure the drug’s effectiveness.

If a patient forgets to take a dose of Sustiva, he or she should take the missed dose as soon as possible.  The next dose should still be taken at the regularly scheduled time.  On the other hand, if a patient misses a dose but realizes it within a few hours of the next scheduled dose, he or she should not take the missed dose, but should instead take Sustiva at the next scheduled time.

A physician should be notified immediately if a patient is suspected to have overdosed on Sustiva.  Symptoms of over-dosage include severe confusion, lack of balance or coordination, severe behavioral changes, or thoughts of suicide.

Side Effects

Common side effects associated with Sustiva occur more frequently during the first two weeks of use.  Because of reported psychotic side effects including hallucinations, delusions, and confused speech or behavior, researchers highly recommend Sustiva be taken before bed.  In most patients, the majority of side effects clear up within a few weeks of starting the drug.  Patients should notify their physicians if any side effects persist past a few weeks or if any side effects worsen.  Additionally, using alcohol or the use of recreational drugs can significantly worsen side effects associated with Sustiva.

Dizziness, trouble sleeping, drowsiness, trouble concentrating, unusual dreams, cough, blurred vision, muscle or joint pain, fat redistribution, rash, upset stomach, vomiting, constipation, and diarrhea are common side effects of Sustiva.  These side effects usually disappear after a few weeks of treatment.

Patients with the following side effects should notify their physician:

• Severe depression
• Strange or hallucinogenic thoughts
• Suicidal thoughts
• Physical aggressiveness
• The combination of a headache, fever, or sore throat with a severe skin rash
• The combination of nausea, stomach pain, yellowing of the skin or eyes (jaundice), dark urine, and clay-colored stools
• The combination of fever, flu-like symptoms, and body chills
• Any signs of new infection
• Immune reconstitution syndrome, or an inflammation response to opportunistic infections (infections that do not occur in individuals with healthy immune systems) not previously felt or visible.

After Sustiva became available for public use, some patients committed suicide while taking Sustiva.  The FDA reported these cases, but cannot establish a causal relationship between suicide and taking the drug.  Patients should be aware of the psychotic effects of the drug and discuss any strange or suicidal thoughts with a health care professional.

Rashes can pose greater health threats to children than adults, so any rash developments in children taking Sustiva should be reported to a physician immediately.

Drug Interactions

Patients considering taking Sustiva should discuss all medications with their physician before starting the drug.  This includes all prescribed, over-the-counter, and herbal medications.  Sustiva can cause some medications to be less effective or can increase the severity of some side effects.  Likewise, certain medications can increase or decrease the amount of Sustiva in the bloodstream, altering the effectiveness of the drug.

Sustiva should not be taken with other NNRTIs or Atripla, which already contains Sustiva.  Administering these combinations will increase the risk of resistance or overdosing.

The following medications should not be taken with Sustiva:

• Hismanal (astemizole) or terfenadone (Seldane), two antihistamines
• Intelence (etravirine), another NNRTI
• midazolam or triazolam (Halcion), two sedatives
• Orap (pimozide), an antipsychotic
• Priftin (rifapentine), an antibiotic
• Propulsid (cisapride), an acid reflux medication
• Vascor (bepridil), a heart medication
• Vfend (voriconazole), an antifungal
• Wigraine (ergotamine and caffeine) or Cafergot (ergotamine tartrate and caffeine), two ergot (fungus) medications

The following medications interact with Sustiva, altering the effectiveness of both drugs:

• Biaxin (clarithromycin), an antibiotic
• Channel blockers including diltiazem, felodipine (Plendil), nicardipine hydrochloride (Cardene), nifedipine, verapamil
• ketoconazole (Perkhotal and Nizoral), an antifungal
• Mycobutin (rifabutin), an antibacterial used to prevent prevent Mycobacterium avium complex (MAC) disease
• Rifadin (rifampin), an antibiotic used to treat tuberculosis
• Sporanox (itraconazole), an antifungal used for yeast infections and other fungal infections
• Viagra (sildenafil citrate) and Levitra (Vardenafil hydrochloric acid), two erectile dysfunction medications

All Nucleoside Reverse Transcriptase Inhibitors (NRTIs), which also block the reverse transcriptase enzyme, can be taken safely with Sustiva.

Sustiva can reduce the amount of Protease Inhibitors (antiretroviral drugs that target the enzyme protease) in the bloodstream.  Sustiva can reduce amounts of Agenerase (amprenavir), Crixivan (indinavir sulfate), Invirase (saquinavir mesylate), Kaletra (liponavir and ritonavir), Lexiva (fosamprenavir) or Reyataz (atazanavir) in the blood stream.

Sustiva can also increase the amount of Kaletra, Viracept (nelfinavir), and Norvir (ritonavir) in the bloodstream.  In addition, taking Sustiva with Norvir can increase the amount of Sustiva in a patient’s bloodstream.

Patients should discuss these interactions with their physician to adjust dosages of other antiretrovirals (if needed).

Sustiva can also limit the effectiveness of birth control contraceptives.  Women taking Sustiva should use reliable forms of barrier contraception such as condoms or a diaphragm in addition to taking birth control to prevent transferring HIV to another individual.

Precautions

Because Sustiva causes mild to severe drowsiness and some psychotic side effects, patients taking the drug should not drive a car or operate heavy machinery immediately after taking a dose.  Patients taking Sustiva should also avoid medicines used for anxiety, the common cold or allergy, narcotic pain, muscles relaxation, severe depression, sedation, or seizures to avoid increased drowsiness.

Sustiva can take weeks to be entirely eliminated from a patient’s body, so patients considering switching from Sustiva to other medications should consult their physician about how to safely transition between two regimens without encountering drug interactions or increasing the possibility of developing resistance.  Patients taking Atripla should be cautious of these interactions as well.

Women who are pregnant or breastfeeding should talk to a doctor before taking Sustiva.  The FDA lists Sustiva as a “Category D” threat, which means there is evidence of human fetal risk based on reported experiences or studies in humans.  On the other hand, the potential benefits of Sustiva may warrant its use in some pregnant women despite the potential risks.  Pregnant women who are taking Sustiva can register for the Antiretroviral Pregnancy Registry through their physicians.  The registry is a voluntary study that allows researchers to collect data on the effects of antiretroviral treatments on pregnancies.  Participating in the registry can potentially help other pregnant, HIV-positive patients weigh their options.

Although it is not clear whether Sustiva can be transferred through breast milk, HIV-positive women should not breastfeed because of the possibility of the virus being transferred to the child.

Patients with HIV who also have a history of liver conditions like hepatitis B or C should discuss possible dosage adjustments or side effects of Sustiva.  Patients with serious skin hypersensitivity in the past have increased risks when taking Sustiva.

Also, patients taking Sustiva who undergo drug screening for employment should notify the hospital or nurse conducting the test about taking the drug.  In some cases, Sustiva causes a “false positive” drug test for marijuana.

Ongoing Clinical Trials

Open:

Phase Undefined

• University Hospital, Geneva: Patient preference, sleep quality, and anxiety/depression: a randomized comparison of Intelence and Sustiva (SWITCH-EE) (NCT00792584)
• National Institute of Allergy and Infectious Diseases (NIAID): Pharmacokinetic study of anti-HIV drugs during pregnancy (NCT00042289)

Phase 2/3:

• French National Agency for Research on AIDS and Viral Hepatitis: Comparison of Viramune and Sustiva for the treatment of HIV-TB co-infected patients (ANRS 12146 CARINEMO) (NCT00495326)

Phase 4:

• Oswaldo Cruz Foundation: Randomized clinical trial to assess the efficacy and safety of concomitant use of rifampicin and Sustiva 600 X 800mg (IPEC-EFV) (NCT00533390)
• 407 Doctors: Once daily Epivir (lamivudine), Sustiva and didanosine (Videx) for HIV infection (NCT00214435)

Closed:

Phase 1/2:

• National Institute of Allergy and Infectious Diseases (NIAID): Safety and effectiveness of Emtriva (emtricitabine), Sustiva, and didanosine  in HIV infected children who have taken few or no anti-HIV drugs (NCT00016718)

Phase 2:

• Gilead Sciences: Study of the safety and efficacy of elvitegravir/Emtriva /Viread (tenofovir disoproxil fumarate)/GS-9350 (QUAD) versus Atripla(R) in HIV infected, antiretroviral treatment-naive adults (NCT00869557)

Phase 3:

• National Institute of Allergy and Infectious Diseases (NIAID): Anti-HIV drugs for treating infants who acquired HIV infection at birth (NCT00102960)
• Merck: A study to evaluate the safety and antiretroviral activity of MK0518 versus Sustiva in treatment naive HIV-infected patients, each in combination with TRUVADA(TM) (emtricitabine/tenofovir) (NCT00369941)
• International Medical Center of Japan: Comparing the effectiveness between ritonavir boosted Reyataz and Sustiva for the first HIV treatment (NCT00280969)

Phase 4:

• The National Centre in HIV Epidemiology and Clinical Research: ALTAIR – alternative antiretroviral strategies : a comparison of three initial regimens (NCT00335322)
• GlaxoSmithKline: KIVEXA (abacavir/lamivudine) vs TRUVADA, both administered with Sustiva, in ART-naive subjects (ASSERT) (NCT00549198)

More a more detailed listing of clinical trials involving Sustiva, please see the U.S. government’s clinical trials Web site.

Clinical Trial Results

A Phase 3, multicenter, randomized, open-label study to compare antiretroviral activity and tolerability of three different combination regimens (Sustiva + Crixivan, Sustiva + zidovudine (Retrovir) + Epivir, Crixivan + zidovudine + Epivir) in HIV-infected patients (2002): In this study, researchers analyzed the safety and effectiveness of Sustiva in various antiretroviral regimens.  One thousand two hundred and sixty-six patients were randomly assigned one of the three drug regimens.  The study concluded that Sustiva in combination with zidovudine and Epivir was the most effective in reducing viral load and sustaining it over a 168-week period.  Although patients in all three groups experienced steady increases in CD4 cell levels, individuals in the Sustiva, zidovudine, and Epivir group tolerated the treatment better than the other two treatments containing Crixivan.  Results from this trial can be found at the Bristol-Myers Squibb Web site (pdf).

A Phase 4, open-label, randomized, multicenter study to determine the safety and duration of viral suppression of continued therapy with one or two protease inhibitors + two nucleoside analogue reverse transcriptase inhibitor regimen versus substitution therapy with Sustiva + the same two nucleoside analogue reverse transcriptase inhibitors in HIV-infected patients (2000):  This study compared the effectiveness of Sustiva combined with two NRTIs to a regimen containing two PIs and two NRTIs over a 48-week period in 346 patients.  In one group, researchers administered two PIs and NRTIs.  Patients already taking PIs were allowed to continue treatment with those drugs.  The second group received Sustiva in combination with two NRTIs.  Researchers concluded that patients taking Sustiva had a longer viral progression, or time to viral failure, than the other group taking protease inhibitors and NRTIs.  In addition, the group taking Sustiva tolerated the new regimen as well as the other group.  Overall, this study established Sustiva as an effective alternative to the use of protease inhibitors for HIV therapy.  Results from this trial can be found at the Bristol-Myers Squibb Web site (pdf).

ACTG 364: virologic efficacy of Viracept (NFV) and/or Sustiva (EFV) in combination with new nucleoside analogs in nucleoside experienced subjects (1998): Researchers looked at the effectiveness of Viracept and Sustiva in suppressing viral loads to undetectable levels (less the 500 copies per milliliter of blood) during and directly after a 16-week period.  One hundred and ninety six patients were assigned to one of three treatment groups.  In one group, Viracept, a Sustiva placebo, and RTIs were administered, whereas the second group received a Viracept placebo, Sustiva, and RTIs.  The third group received Viracept, Sustiva, and RTIs with no placebos.  The study concluded that the introduction of Viracept or Sustiva (issued separately and together) were effective in viral suppression when combined with RTIs.  The combination provided viral suppression at and beyond week 16 of the study.  An abstract of the study can be found at the National Library of Medicine’s Web site.

Patient Assistance Programs

Bristol-Myers Squibb Patient Assistance Programs
http://www.bms.com/products/Pages/programs.aspx

Bristol-Myers Squibb Access Virology Patient Assistance Program
Application PDF

Partnership For Prescription Assistance
http://www.pparx.org/

Links of Interest

Hightlights of Sustiva’s Prescribing Information
http://packageinserts.bms.com/pi/pi_sustiva.pdf

Managing Sustiva’s Side Effects
http://www.aidsmeds.com/articles/SustivaTips_7550.shtml