The effects of the human immunodeficiency virus on semen parameters and intrauterine insemination outcome

E. van Leeuwen1, J.M. van Weert, F. van der Veen and S. Repping

Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Academic Medical Center, Amsterdam

1 To whom correspondence should be addressed at: Academic Medical Center, Obstetrics and Gynecology, H4-205, Meibergdreef 9, 1100 DD Amsterdam, The Netherlands. Email: e.vanleeuwen{at}amc.uva.nl

Sir,

We have read with great interest the paper about the effects of the human immunodeficiency virus (HIV) on semen parameters by Nicopoullos et al. (2004)Go.

The authors performed a case–control study, comparing semen parameters of 106 asymptomatic HIV-1 infected men with semen parameters of 234 HIV negative men requiring IVF, because of a partner with tubal infertility. In addition, the study compared 133 pre-wash semen parameters on the day of intrauterine insemination (IUI) of HIV positive men with 222 pre-wash semen parameters on the day of IUI of non-infected men. Finally, the authors attempted to analyse which factors predict IUI outcome in HIV-infected men. Based on their analysis, the authors conclude that semen parameters are impaired in the presence of HIV infection and that both viral load and antiretroviral therapy predict IUI outcome in HIV infected men. However, there are several problems with the study that make us question whether these conclusions are justified.

First, the conclusions are based on a comparison between a group of HIV positive men with an unmatched group of HIV negative men. It is thus unclear if differences other than the presence of an HIV infection exist in these cases and controls that could explain the observed differences in semen quality. Furthermore, the variability of semen parameters between individuals limits the conclusions of a case–control study design (Guzick et al., 2001Go). The ideal situation to study the effects of HIV infection on semen parameters is a comparison of semen parameters before and after infection with HIV. Interestingly, we recently described semen parameters before and after infection with HIV from a sperm donor, who became seropositive (Van Leeuwen et al., 2004Go). However, this represents a unique case and larger studies of this kind are not feasible. The best study design feasible for larger patient numbers is a longitudinal cohort study, describing semen parameters during the course of an HIV infection.

Second, only the first semen analyses from the HIV positive men were used, to avoid the bias of repeated sampling according to the authors. However, most studies investigating semen parameters and fertility use the average of all available semen analyses, mainly because of the well-established high variability of semen parameters between different ejaculates from the same individual (Alvarez et al., 2003Go).

Third, the group of HIV positive men undergoing IUI examined by Nicopoullos et al. was extremely heterogeneous, consisting for instance of both men with and without antiretroviral therapy. The authors conclude that no effect of antiretroviral therapy on semen parameters was seen. This is not surprising since normozoospemia was an inclusion criterion for men to enter the IUI programme. It remains unclear how many HIV positive men were refused entry to the IUI programme because of poor semen quality, possibly due to the use of antiretroviral therapy. Furthermore, it is also unclear how many of the original 105 HIV positive men provided the 133 samples that were analysed.

Finally, although the idea itself is innovative, we question the methods used to analyse which HIV characteristics can predict IUI success in an HIV-infected population. The continuous variables such as year since diagnosis, viral load and CD4 count were not analysed as continuous variables by the authors, but instead were dichotomized with apparently randomly chosen thresholds. Such dichotomization is only appropriate if a spline analysis has demonstrated that this represents a proper correlation of the two variables. The authors then demonstrate by univariate analysis that the outcome of IUI is dependent on both viral load and antiretroviral therapy. However, parameters such as duration of infection, CD4 count, viral load and antiretroviral therapy are well-established dependent variables. Therefore, one should analyse the predictive capacity of these individual variables using a multivariable approach.

In conclusion, we have identified several flaws in the study design that make us question the conclusions of this study. In our opinion, a longitudinal study in a cohort of HIV-infected men is necessary to determine whether HIV infection itself and/or antiretroviral therapy affect semen quality. Furthermore, a multivariable approach is needed to determine which factors independently predict IUI outcome for HIV-infected men desiring genetically own offspring.

References

Alvarez C, Castilla JA, Martinez L, Ramirez JP, Vergara F and Gaforio JJ (2003) Biological variation of seminal parameters in healthy subjects. Hum Reprod 18, 2082–2088.[Abstract/Free Full Text]

Guzick DS, Overstreet JW, Factor-Litvak P, Brazil CK, Nakajima ST, Coutifaris C, Carson SA, Cisneros P, Steinkampf MP, Hill JA et al. (2001) Sperm morphology, motility, and concentration in fertile and infertile men. New Engl J Med 345, 1388–1393.[Abstract/Free Full Text]

Nicopoullos JDM, Ramsay JWA, Almeida PA and Gilling-Smith C (2004) The effect of HIV on sperm parameters and the outcome of IUI following sperm-washing. Hum Reprod 19, 2289–2297.[Abstract/Free Full Text]

Van Leeuwen E, Cornelissen M, de Vries JW, Lowe SH, Jurriaans S, Repping S and van der Veen (2004) Semen parameters of a semen donor before and after infection with human immunodeficiency virus type 1: Case report. Hum Reprod 19, 2845–2848.[Abstract/Free Full Text]

Submitted on December 17, 2004; accepted on February 25, 2005.





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