Combination Treatment with AZT, Lamivudine Reduces Vertical HIV Transmission, But Raises Concerns About Side Effects, Resistance

Combining zidovudine (AZT) with lamivudine (3TC) prevents vertical HIV transmission five times more effectively than zidovudine alone, but the combination therapy yields more side effects in newborns than the single drug treatment, according to a study published in today's issue of the Journal of the American Medical Association. Researchers at Paris, France-based Cochin Hospital compared women given a zidovudine-lamivudine combination with women given only zidovudine to evaluate the safety of the combination, its effects on viral load, acquisition of drug resistance and maternal-infant transmission of HIV. The open-label, non-randomized study was conducted within the context of an ongoing study, called the French Perinatal Study, in which 899 HIV-positive pregnant women received zidovudine monotherapy -- the standard treatment for pregnant women -- between May 1994 through February 1997. In the study cohort, 445 HIV-positive pregnant women received lamivudine in addition to the standard zidovudine regimen between February 1997 and September 1998. Zidovudine was administered to women in both groups according to standard AIDS Clinical Trial Group 076 recommendations. Zidovudine therapy commenced at a median of 23 weeks' gestation, was administered for a median of 15 weeks during the pregnancy and was administered intravenously during delivery in 95% of women. Women in the study group also began lamivudine therapy at 32 weeks, at 150 mg twice per day orally, until delivery. Newborns then continued lamivudine therapy at 2mg/kg twice per day for six weeks. At six weeks after delivery, one-third of the women in the study group were still receiving the two drug combination, 65% were not receiving therapy and 5% were receiving another antiretroviral combination.

Study Results
The vertical HIV transmission rate among those in the combination drug cohort was 1.6%, which the researchers describe as the "lowest rate reported to date in a large prospective study." The vertical transmission rate with zidovudine monotherapy was 6.8%, "significantly higher than in the study group." After taking into account the mode of delivery (Caesarean vs. vaginal), history of antiretroviral therapy and maternal HIV disease progression, researchers determined that the rate of vertical HIV transmission in the study cohort was five times lower than in the control group (Mandelbrot et al., JAMA, 4/25). However, while blood abnormalities such as decreased white blood cell count and anemia were detected in newborns in both groups, they were "more severe" in the combined therapy group (Associated Press, 4/24). "Another potential drawback" to the combined drug therapy, researchers write, is that HIV strains in women taking both drugs showed signs of resistance to lamivudine, which may "compromise the future efficacy of lamivudine" for those women. Researchers conclude that the "implications of our findings for prevention of maternal-infant HIV transmission are not clear. Adding lamivudine to standard zidovudine prophylaxis in the third trimester may be a means to further reduce risk of infection. However, the precise relationship between incremental benefit and incremental risk remain to be determined, and compared with those of alternative prevention strategies." The authors add, "The increasing use of combination antiretroviral therapies as prophylaxis or as maternal therapy underscores the need for further clinical, animal and laboratory studies to determine safety in the perinatal period" (JAMA, 4/25).

Solution for Developing Countries
In an accompanying editorial, Dr. Nathan Shaffer, an epidemiologist with the Global AIDS Program at the CDC, writes that the "efficacy findings for the lamivudine-zidovudine combination are impressive," noting that the study's "safety and toxicity data emphasize the need for close monitoring during the administration of the combination therapy." Shaffer adds that the study data "will be extremely useful to the Public Health Service Task Force and other consensus bodies charged with making recommendations regarding new perinatal regimens." In addition, the study findings "may also have implications for developing countries focusing on the use of short-course antiretroviral regimens initiated in late third trimester. ... In developed countries, additional interventions that enhance the [standard zidovudine regimen], such as combination lamivudine-zidovudine and zidovudine plus Caesarean delivery, offer the possibility of virtually eliminating perinatal HIV transmission" (Shaffer, JAMA, 4/25). However, Dr. Lynne Mofenson, a pediatric infectious disease specialist at NIH, told HealthScout that the study "may be misleading." She said, "This isn't new information. It was first reported back in February 1999. Our current guidelines call for the use of highly active antiretroviral therapy with three drugs. AZT/3TC is not recommended for treatment without the third drug. We would never use that combination alone" (Berger, HealthScout, 4/24).