LETTERS TO THE EDITOR How Safe Is Unprotected Sex Between Discordant Couples to Conceive in the Highly Active Antiretroviral Therapy Era? To the Editor: Antiretrovirals have increased life expectancy in HIV-infected patients and have reduced the mother-to-child trans- mission rate. Many HIV-serodiscordant heterosexual couples ask for counseling to make decisions about the future of their reproductive lives, which should be based on the best available information. Barreiro et al 1 have addressed this issue, reporting the outcome of natural preg- nancies attained by HIV-serodiscordant couples in which the infected partner had undetectable plasma viremia while receiving highly active antiretroviral ther- apy (HAART). The authors concluded that there is negligible risk of HIV sexual transmission in this specific scenario. This conclusion, however, raises con- cern. The sample size of the study was too small, and it may not have enough power to evaluate properly the risk of sexual transmission in individuals with an undetectable viral load under HAART who are attempting natural conception. Also, the highly selected cases of HIV- discordant couples in this retrospective study, in which all participants main- tained a suppressed viral load during the pregnancy and labor, do not allow generalization for counseling all couples who wish to attain natural conception, even under HAART. It is well established that the viral load in the sperm or genital secretions of HIV-infected individuals does not always attain a high correlation with the plasma viral load. 2,3 HIV- positive women may present no risk of sexual transmission by self-insemination, and we see no excuse to encourage un- protected intercourse. HIV-positive men could lower the risk by sperm washing, although that is not feasible for most patients living in developing countries. 4 Unfortunately, results of studies using antiretrovirals shortly before or after HIV sexual exposure (PREP [pre-exposure prophylaxis] and PEP [post-exposure prophylaxis] studies) are not available at this point. Regarding vertical transmission, cau- ses of the fetal deaths and the HIV status were not reported; thus, the 4% vertical transmission rate might be undercounted. In conclusion, this first report describing a low risk of sexual trans- mission in serodiscordant couples with viral suppression attaining natural preg- nancy gives support to develop prospec- tive protocols with adequate numbers of patients that are likely to enroll a full spectrum of patients infected with HIV under HAART. Helena Barreto dos Santos, MD Mirela Foresti Jime ´nez, MD Regis Kreitchmann, MD Sandra Costa Fuchs, MD Postgraduate Course in Epidemiology Universidade Federal do rio Grande do Sul Porto Alegre, Brazil REFERENCES 1. Barreiro P, Romero J, Leal M, et al. Natural pregnancies in HIV-discordant couples receiving successful antiretroviral therapy. J Acquir Im- mune Defic Syndr. 2006;20:635–636. 2. Zhang H, Domadula G, Beumont M, et al. Human immunodeficiency virus type 1 in the semen of men receiving highly active antiretroviral therapy. N Engl J Med. 1998;339:1803–1809. 3. Cu-Uvin S, Caliendo AM, Reinert S, et al. Effect of highly active antiretroviral therapy in cervi- covaginal HIV-1 RNA. AIDS. 2000;14:415–421. 4. Gilling-Smith C, Nicopoullos J, Semprini A, et al. HIV and reproductive careda review of current practice. BJOG. 2006;113:869–878. Authors’ Reply to ‘‘How Safe Is Unprotected Sex Between Discordant Couples to Conceive in the Highly Active Antiretroviral Therapy Era?’’ In Reply: We appreciate the interest from and comments by Barreto and colleagues 1a regarding our article about natural preg- nancy in the HIV setting. Some impor- tant issues raised merit a few comments. Regarding the sample size of the study population, we agree that larger numbers of couples are needed to ascer- tain the safety of natural pregnancy; this limitation may also apply for assisted reproduction, although broader experi- ence has been published. As commented elsewhere, 1 given that the average risk for heterosexual HIV transmission has been estimated to be 0.001 to 0.0001 per sexual contact, 2 a series of 3000 to 30,000 pregnancies would, in theory, be needed to establish the safety of any reproductive option definitively. Some studies have shown that HIV RNA may be amplified in semen, even when undetectable in plasma, in 2% to 8% of patients receiving highly active antiretroviral therapy (HAART). 3,4 Re- viewing the data, these episodes of dis- cordance were explained by the use of suboptimal therapy, such as regimens with unboosted protease inhibitors, 4,5 low CD4 cell counts, or concomitant geni- tal infection. 3 According to our recom- mendations, 6 these factors, particularly genital infections 7 , should be assessed and corrected before any reproductive attempt. No information regarding causes of fetal death was provided because all corresponded to early miscarriages. The rate of vertical transmission found is in accordance with larger series published in the HAART era, however. 8 Finally, we also expect for our study to be the first step to examine repro- ductive counseling and natural preg- nancy in the HIV setting in future prospective protocols. This should be the best scientific response for what is a growing demand of HIV-infected patients in our clinics. Pablo Barreiro, MD, PhD Vincent Soriano, MD, PhD Pablo Labarga, MD, PhD Department of Infectious Diseases Hospital Carlos III Madrid, Spain REFERENCES 1a. Barreto dos Santos H, Jime ´nez MF, Kreitch- mann R, et al. How safe is unprotected sex between discordant couples to conceive in the 476 J Acquir Immune Defic Syndr  Volume 45, Number 4, August 1, 2007 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.