FDA reinforces use of Sustiva in first-line HIV combination therapy

Aug 26 2004

Bristol-Myers Squibb has announced that Sustiva® (efavirenz) has received approval from the U.S. Food and Drug Administration to include new long-term virologic and clinical data from BMS Study 006 in its prescribing information.

The new data demonstrate the long-term durability of virologic response in people living with HIV-1 who are naïve to protease inhibitors, lamivudine (3TC) and non-nucleoside reverse transcriptase inhibitors (NNRTI) through more than three years of treatment on a combination regimen containing Sustiva.

"The new data from Study 006 provide valuable information to health care professionals supporting first-line use of Sustiva-based combination therapy," said Karen Tashima, M.D., associate professor of medicine, Brown Medical School, Miriam Hospital, Providence, Rhode Island. "The long-term data suggest that patients who stay on Sustiva as part of their combination therapy may experience durable viral suppression for more than three years reinforcing its use in first-line HIV combination therapy."

BMS Study 006 was a randomized, open-label, multicenter, multinational study of 1,266 HIV-1 positive people in the United States, Europe and Canada who were naïve to protease inhibitors, lamivudine and NNRTIs and who had a viral load greater than or equal to 10,000 copies/mL and a CD4+ cell count greater than or equal to 50 cells/mm3. Patients were given one of three treatment regimens: Sustiva+zidovudine+lamivudine (EFV 600 mg once-daily+ZDV 300 mg every 12 hours+LAM 150 mg every 12 hours; n=422), or Sustiva+indinavir (EFV 600 mg once-daily+IDV 1,000 mg every 8 hours; n=429), or indinavir+zidovudine+lamivudine (IDV 800 mg every 8 hours+ZDV 300 mg every 12 hours+LAM 150 mg every 12 hours; n=415).

Through 168 weeks, the percentage of patients who achieved and maintained HIV-1 RNA less than 400 copies/mL was 48 percent (EFV+ZDV+LAM), 40 percent (EFV+IDV) and 29 percent (IDV+ZDV+LAM) using an intent-to-treat, time-to-loss of virologic response analysis. The response rate for achieving viral load less than 50 copies/mL through 168 weeks was 43 percent (EFV+ZDV+LAM), 31 percent (EFV+IDV) and 23 percent (IDV+ZDV+LAM). A Kaplan-Meier analysis of time to loss of virologic response (HIV-1 RNA less than 400 copies/mL) suggests that both the trends of virologic response and differences in response continue through four years. Kaplan-Meier is a method of statistical analysis commonly used by biomedical researchers to predict the probability of a particular outcome over a given period of time.

Patients who remained on therapy through 168 weeks demonstrated mean CD4+ cell count increases (from a median baseline of 320 cells/mm3) of 329 cells/mm3 (EFV+ZDV+LAM; n=205), 319 cells/mm3 (EFV+IDV; n=158), and 329 cells/mm3 (IDV+ZDV+LAM; n=129).

"This sNDA approval represents another important addition to the support for combination therapy containing Sustiva in treating people living with HIV-1 infection," said Anthony Hooper, president, U.S. Pharmaceuticals, Bristol-Myers Squibb Company. "Since it first became available in 1998, Sustiva has been administered to thousands of patients in combination therapy to treat their HIV-1 infection. With this new labeling, health care professionals now have additional information to draw on when creating a durable antiretroviral regimen for their treatment-naïve patients."

In the study, selected treatment-emergent adverse events of moderate or severe intensity reported in greater than or equal to 2 percent of patients treated in the EFV+ZDV+LAM (n=412) and IDV+ZDV+LAM (n=401) arms were: rash (11 percent for EFV+ZDV+LAM, 5 percent for IDV+ZDV+LAM), nausea (10 percent, 24 percent), dizziness (9 percent, 2 percent), tiredness (8 percent, 9 percent), headache (8 percent, 3 percent), trouble sleeping (7 percent, 2 percent), vomiting (6 percent, 14 percent), depression (5 percent, less than 1 percent), trouble concentrating (5 percent, less than 1 percent), upset stomach (4 percent, 6 percent), diarrhea (3 percent, 6 percent), abnormal dreams (3 percent, 0 percent), anxiety (2 percent, less than 1 percent), sleepiness (2 percent, less than 1 percent), stomach pain (2 percent, 5 percent) and nervousness (2 percent, 0 percent). More subjects discontinued the study prematurely due to adverse events in the IDV+ZDV+LAM (20 percent) arm than in either of the treatment regimens containing Sustiva (8 percent in each Sustiva arm).

Analysis of long-term data from Study 006 (median follow-up 180 weeks, 102 weeks, and 76 weeks for patients treated with EFV+ZDV+LAM, EFV+IDV, and IDV+ZDV+LAM, respectively) showed that, beyond 24 weeks of therapy, the incidence of new-onset nervous system symptoms among patients treated with Sustiva were generally similar to those in the indinavir-containing control arm.

The new labeling also indicates that Sustiva® should not be administered concurrently with voriconazole (better known as Vfend®, a drug indicated for treatment of certain fungal infections) because Sustiva significantly decreases voriconazole plasma concentrations while voriconazole significantly increases Sustiva plasma concentrations. In addition, when Sustiva is co-administered with Reyataz® (atazanavir sulfate) in treatment-naïve patients, the recommended dose of Reyataz is 300 mg with ritonavir 100 mg and Sustiva 600 mg ( all once daily). Dosing recommendations for Sustiva and Reyataz in treatment-experienced patients have not been established.

Sustiva is a medication for use in treating people infected with Human Immunodeficiency Virus type 1 (HIV-1), the virus that causes AIDS. It is a member of a class of medications known as non-nucleoside reverse transcriptase inhibitors (NNRTIs).

In July 2003, the U.S. Department of Health and Human Services (DHHS) revised their treatment guidelines to list Sustiva as the only NNRTI recommended as part of a preferred regimen when combined with certain nucleoside reverse transcriptase inhibitors (NRTIs) for the initial treatment of HIV-infected individuals. In March 2004, the DHHS updated the guidelines, and Sustiva continues to be the only NNRTI listed as part of a preferred regimen.

Sustiva is a prescription medicine used in combination with other medicines to treat people who are infected with the human immunodeficiency virus type 1 (HIV-1). Sustiva does not cure HIV or help prevent passing HIV to others. Sustiva should not be taken with the following medicines: Hismanal® (astemizole), Propulsid® (cisapride), Versed® (midazolam), Halcion® (triazolam), ergot medicines (for example, Wigraine® and Cafergot®), or Vfend® (voriconazole). This list of medicines is not complete. The use of all prescription and non-prescription medicines, vitamin and herbal supplements or other health preparations (particularly St. John's wort) should be discussed with a health care provider.

Any side effects or conditions should be discussed with a health care provider, including the following: severe depression, strange thoughts or angry behavior which have been reported by a small number of patients taking Sustiva -- there have been a few reports of suicide but it is not known if Sustiva was the cause; a history of mental illness or drug or alcohol use; dizziness, trouble sleeping or concentrating, drowsiness and/or unusual dreams are common -- these feelings tend to go away after taking Sustiva for a few weeks; pregnancy -- women should not become pregnant or breastfeed while taking Sustiva; rash is a common side effect that usually goes away without any change in medicines -- rash may be a serious problem in some children; health care providers may want to do tests to check the liver or drug levels in the blood in the presence of liver disease, a history of seizures, or in patients taking medicine for seizures.

Changes in body fat have been seen in some patients taking anti-HIV medicines. The cause and long-term effects are not known at this time. Other common side effects of Sustiva taken with other anti-HIV medicines include: tiredness, upset stomach, vomiting and diarrhea. Sustiva should be taken on an empty stomach, preferably at bedtime, which may make some side effects less bothersome.