Correspondence

Shortened Zidovudine Regimens to Prevent Mother-To-Child Transmission of HIV-1

N Engl J Med 2001; 344:307January 25, 2001

Article

To the Editor:

In their study of simplified and less costly regimens of zidovudine to reduce mother-to-child transmission of the human immunodeficiency virus (HIV), Lallemant et al. (Oct. 5 issue)1 used an intention-to-treat analysis of the efficacy of the interventions. Intention-to-treat analyses are widely regarded as “conservative” because they tend to minimize differences among treatment groups and thus bias the results toward the conventional null effect of no difference between groups. However, because equivalency studies essentially flip the conventional null and alternative hypotheses, such a bias may produce a “false positive” outcome of equivalence when, in fact, one treatment is superior.

The authors, and all who conduct active-controlled equivalency studies, should therefore provide an analysis according to treatment received, which would tend to magnify the differences among treatments and therefore bias away from a finding of equivalence. If the groups remain statistically equivalent within the specified 6 percent margin, we could have greater confidence that the regimens are equivalent.

Scott D. Halpern, B.S.
University of Pennsylvania School of Medicine, Philadelphia, PA 19104

1 References

1. 1

   Lallemant M, Jourdain G, Le Coeur S, et al. A trial of shortened zidovudine regimens to prevent mother-to-child transmission of human immunodeficiency virus type 1. N Engl J Med 2000;343:982-991
   Full Text | Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: Intention-to-treat analysis of clinical trials respects the initial randomization and ensures comparability among groups. It does not take into account erroneous treatment assignments, poor compliance, and violations of the protocol that usually, but not always, minimize differences. Halpern points out that intention-to-treat analysis may lead to a bias toward equivalence in the results.

In this study, however, no important violations of the criteria for entry were seen. Deviations from the protocol were rare. Less than 0.3 percent of the mothers and 1 percent of the infants received a regimen different from that of the group to which they had been assigned. Compliance with treatment was monitored closely and was equally good in all groups; withdrawals and loss to follow-up were rare and occurred at equal rates in all groups. End points were available for 99.5 percent of the infants.

The results of this trial would not suggest regression toward equivalence. Nor do they indicate a lack of compliance in the groups assigned to long treatment of the mother, the infant, or both, which would have led to results similar to those with short treatment.

The short–short regimen, but not the short–long regimen, was stopped at the time of the first interim superiority analysis. If poor infant compliance had been found, the short–long regimen would have been stopped as well. The equivalence between the long–long regimen and the short–long regimen was found to be borderline, suggesting that the long treatment regimen for the infant can reduce the incidence of intrapartum transmission when the mother has had treatment for only a short time. If maternal compliance had been poor, we would not have observed the large difference in rates of infection at birth, which supports our recommendation that prophylaxis with zidovudine be started at 28 weeks of gestation.

Deviations from the treatment protocol and problems with compliance do occur in real life, which is why intention-to-treat analysis provides the results most pertinent for clinical application and policy. Even though this study indicates that prophylaxis with zidovudine should start at the beginning of the third trimester of pregnancy, it also provides a clear framework for making decisions in the real-life situations in many developing countries, where pregnant women may present with HIV too late to benefit from a long treatment regimen.

Marc Lallemant, M.D.
Institut de Recherche pour le Développement, Paris 93143, France

Gonzague Jourdain, M.D.
Harvard School of Public Health, Boston, MA 02115

Jean-Yves Mary, Ph.D.
INSERM Unité 444, Paris 75251, France

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