Reporting in the Jan. 19 issue of The New England Journal of Medicine, the researchers showed that after one year of treatment, a regimen of antiretroviral pills, called tenofovir DF (Viread) and emtricitabine (Emtriva), plus efavirenz (Sustiva), led to 14 percent more patients able to suppress levels of the virus, with fewer problems of anemia, fatigue and nausea than another widely used combination of antiretrovirals, zidovudine and lamivudine (AZT and 3TC, or Combivir), plus efavirenz.
"The implications are quite clear for patients with HIV who are about to start therapy: The simple combination of tenofovir and emtricitabine, plus efavirenz, is likely to be highly potent with minimal side effects or long-term toxicity," says the study's lead author, Joel Gallant, M.D., M.P.H., associate professor and associate director of the AIDS Service at The Johns Hopkins University School of Medicine. Gallant notes that this regimen became even simpler in 2004, when tenofovir and emtricitabine were combined into a single pill, called Truvada.
The U.S. Centers for Disease Control and Prevention estimate that 40,000 Americans are newly infected each year with the virus that causes AIDS. Another quarter- million people already have HIV and are unaware of their infection and need for treatment.
Gallant cautions that the latest results may not apply to those patients already on zidovudine-lamivudine therapy and experiencing no problems. However, he points out that after the first year of the study, expected to continue for another two years, data already show early evidence of lipoatrophy (fat loss) in patients taking this regimen. Lipoatrophy is a known complication of some HIV medications that can lead to disfiguring changes in body shape. The researcher says that if fat loss gets worse during the remainder of the study in patients taking the zidovudine-lamivudine regimen, this would support switching to the tenofovir-emtricitabine regimen.
Tenofovir DF and emtricitabine are relatively new drugs, approved by the U.S. Food and Drug Administration (FDA) in 2001 and 2003 respectively. Zidovudine was the first antiretroviral drug, approved in 1987, and lamivudine became available in 1995. Since 1998, zidovudine and lamivudine have been available in a single-pill formulation called Combivir, which is prescribed as one pill taken twice daily.
In this study, both combinations included efavirenz, which, like the other drugs, prevents the genetic material, or RNA, in HIV from being turned into DNA. Efavirenz has been widely used for initial therapy since its approval in 1998.
Gallant's study results are believed to be the first to demonstrate superiority of any regimen over the combination of zidovudine, lamivudine and efavirenz, which has been a popular and recommended combination for many years. The latest guidelines from the U.S. Department of Health and Human Services, released in 2005, recommend either combination as preferred initial treatments for HIV disease.
The study, known as Study 934, involved 517 patients from 67 sites across the United States, France, Germany, Italy, Spain and the United Kingdom. Participants included both men and women of all races, with an average age of 36, none of whom had been treated for their HIV infection. Half had viral loads in excess of 100,000 copies per milliliter of blood. Each participant was randomly assigned to start treatment with either the tenofovir-emtricitabine or zidovudine-lamivudine regimen, each in combination with efavirenz. Their progress was monitored through blood tests, pill counts and regular check-ups at their medical clinic.
Researchers found at the end of the first year of treatment that 80 percent of patients receiving the tenofovir-emtricitabine combination were able to suppress viral loads to undetectable levels (less than 50 copies per milliliter of blood), compared to 70 percent in the zidovudine-lamivudine group.
As viral levels dropped, the immune systems of patients who received the tenofovir-emtricitabine regimen also rebounded most, as measured by the increase in CD4 cells, which help fight infection. Their CD4 counts increased by an average of 190 cells per cubic millimeter of blood, while the average increase in the zidovudine-lamivudine group was 158 cells per cubic millimeter of blood.
"Both treatments are effective," adds Gallant. "But this study shows that we can do better, with fewer side effects and greater simplicity."
More side effects were reported in the zidovudine-lamivudine group, with 9 percent having to withdraw from the study, compared to just 4 percent in the tenofovir-emtricitabine group. The most common reason for stopping therapy in the zidovudine-lamivudine group was anemia, or loss of red blood cells. Discontinuation due to nausea, fatigue and dizziness, other side effects of zidovudine, was also more common with this regimen.
A subgroup of 100 patients had specialized tests to measure the amount of fat in the limbs at the end of the study. Patients in the zidovudine-lamivudine group had significantly less fat in their limbs by an average of more than 4 pounds, which may be a result of lipoatrophy, a recognized long-term side effect of zidovudine.
Study 934 quickly follows the results of previous research, Study 903, published by Gallant in July 2004 in The Journal of the American Medical Association, which showed that tenofovir DF was equally effective but had fewer side effects than another antiretroviral drug called stavudine (d4T, Zerit).
Adherence to taking pills as prescribed in Study 934 was also better in the tenofovir-emtricitabine group, at 90 percent, than for the zidovudine-lamivudine group, at 87 percent. Gallant attributes some of this difference to the fact that the former regimen could be taken once daily and was less likely to cause nausea than the latter combination, which had to be taken twice daily.
While Gallant notes that antiretroviral drug regimens have dramatically decreased in complexity in the last 10 years, he says that it would not have been unusual in 1996 for patients to have been taking combinations of up to 24 pills per day, in as many as five daily doses, and often with complicated food restrictions. However, the drug regimen in Study 934, he adds, required that patients take just two pills per day without any food restrictions. The three drugs should be available in a single-pill formulation within the year.
"The steady progress we have seen in simplifying antiretroviral therapy should make it a lot easier for patients to be adherent, which is critical to having a prolonged response and avoiding drug resistance," the researcher says.
Drug resistance was not a significant factor for either drug combination in the study. However, Gallant notes that 22 patients in the study were later found to have been resistant to efavirenz before starting medications, and these patients did not do as well on therapy as the overall group.
"This highlights the importance of testing for drug resistance before choosing a drug regimen, so the initial combination can be tailored based on the patient's resistance results," he says.
Tenofovir is the only nucleotide reverse transcriptase inhibitor, but it is closely related to emtricitabine, zidovudine and lamivudine, which belong to a class of medications called nucleoside reverse transcriptase inhibitors. These drugs are combined with other AIDS drugs, either non-nucleoside reverse transcriptase inhibitors, such as efavirenz, or with protease inhibitors, which were not used in this study.
Funding for this research was provided by Gilead Sciences, of Foster City, Calif., the makers of the drugs tenofovir DF and emtricitabine. Gallant is a paid consultant to Gilead as well as to GlaxoSmithKline, which manufacturers the zidovudine-lamivudine combination. He is also a paid consultant to other drug manufacturers, including Bristol-Myers Squibb, which manufactures efavirenz. The terms of these arrangements are being managed by The Johns Hopkins University in accordance with its conflict of interest policies.
Besides Gallant, other senior researchers involved in Study 934 were Edwin DeJesus, M.D., in Orlando, Fla.; José Arribas, M.D., in Madrid, Spain; Anton Pozniak, M.D., and Brian Gazzard, M.D., in London, England; Raphael Campo, M.D., in Miami, Fla.; and, from Gilead Sciences, Biao Lu, Ph.D.; Damian McColl, Ph.D.; Steven Chuck, M.D.; Jeffrey Enejosa, M.D.; John Toole, M.D., Ph.D.; and Andrew Cheng, M.D., Ph.D., in Foster City, Calif.