Skip to main content

Antivirals and Male Reproduction

  • Chapter
  • First Online:
Impacts of Medications on Male Fertility

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1034))

Abstract

The use of antiviral medications has increased with the recognition and treatment of HIV infections, and these drugs are the main focus of this chapter. HIV has become a chronic disease, and many men with HIV desire children. The disease itself has profound negative effects on semen quality, as does infection with hepatitis C virus (HCV), so treatment with antivirals generally improves semen quality in men with longer duration of infection and/or greater symptoms. Several changes in medical practice have allowed studies of pharmacopathology of antiviral medications and brought focus on medication effects in asymptomatic men: (1) the successful practice of specialized sperm washing of asymptomatic men with HIV infection for insemination of their HIV-negative partner; (2) the recommendation that men begin anti-retroviral treatment before HIV symptoms appear; and (3) the recommendation that men without HIV infection who have HIV-seropositive partners take HIV prophylaxis. Early cases of HIV infection were generally treated by monotherapy with the nucleoside analog reverse transcriptase inhibitor (NRTI) zidovudine (AZT). Currently, men with HIV infections take combination anti-retroviral therapy (cART), involving three or more medications, making it difficult to assess the toxicity of individual medications. In general, zidovudine alone or cART have minimal negative effects on semen quality; the most common being decreased rapid swimming of motile sperm. We review studies with other outcomes and animal studies in this chapter. Peginterferon-α, which is utilized together with ribavirin to treat HCV, does appear to decrease testosterone levels and semen quality although studies showing these effects have been small. Antiviral medications used to treat viral infections other than HIV and HCV have received little experimental attention for male reproductive effects, even in experimental species.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Institutional subscriptions

References

  • Adaramoye OA, Akanni OO, Adewumi OM, Owumi SE. Lopinavir/ritonavir, an antiretroviral drug, lowers sperm quality and induces testicular oxidative damage in rats. Tokai J Exp Clin Med. 2015;40:51–7. PMID: 26150184.

    CAS  PubMed  Google Scholar 

  • Bairy KL, Kumar G, Rao Y. Effect of acyclovir on the sperm parameters of albino mice. Indian J Physiol Pharmacol. 2009;53:327–33. PMID: 20509324.

    CAS  PubMed  Google Scholar 

  • Barboza JM, Medina H, Doria M, Rivero L, Hernandez L, Joshi NV. Use of atomic force microscopy to reveal sperm ultrastructure in HIV-patients on highly active antiretroviral therapy. Arch Androl. 2004;50:121–9. PMID: 14761843.

    Article  CAS  PubMed  Google Scholar 

  • Pavili L, Daudin M, Moinard N, Walschaerts M, Cuzin L, Massip P, Pasquier C, Bujan L. Decrease of mitochondrial DNA level in sperm from patients infected with human immunodeficiency virus-1 linked to nucleoside analogue reverse transcriptase inhibitors. Fertil Steril. 2010;94:2151–6. https://doi.org/10.1016/j.fertnstert.2009.12.080.

    Article  CAS  PubMed  Google Scholar 

  • Pecou S, Moinard N, Walschaerts M, Pasquier C, Daudin M, Bujan L. Ribavirin and pegylated interferon treatment for hepatitis C was associated not only with semen alterations but also with sperm deoxyribonucleic acid fragmentation in humans. Fertil Steril. 2009;91:933.e17–22. https://doi.org/10.1016/j.fertnstert.2008.07.1755.

    Article  Google Scholar 

  • Politch JA, Mayer KH, Abbott AF, Anderson DJ. The effects of disease progression and zidovudine therapy on semen quality in human immunodeficiency virus type 1 seropositive men. Fertil Steril. 1994;61:922–8. PMID: 8174732.

    Article  CAS  PubMed  Google Scholar 

  • Rahim S, Ortiz O, Maslow M, Holzman R. A case-control study of gynecomastia in HIV-1-infected patients receiving HAART. AIDS Read. 2004;14:23–4, 29–32, 35–40. PMID: 14959701.

    Google Scholar 

  • Schilsky RL, Davidson HS, Magid D, Daiter S, Golomb HM. Gonadal and sexual function in male patients with hairy cell leukemia: lack of adverse effects of recombinant alpha 2-interferon treatment. Cancer Treat Rep. 1987;71:179–81. PMID: 3100036.

    CAS  PubMed  Google Scholar 

  • Semprini AE. Insemination of HIV-negative women with processed semen of HIV-positive partners. Lancet. 1993;341(8856):1343–4. PMID: 8098468.

    Article  CAS  PubMed  Google Scholar 

  • Shevchuk MM, Pigato JB, Khalife G, Armenakas NA, Fracchia JA. Changing testicular histology in AIDS: its implication for sexual transmission of HIV. Urology. 1999;53:203–8. PMID: 9886613.

    Article  CAS  PubMed  Google Scholar 

  • Sikka SC, Gogu SR, Agrawal KC. Effect of zidovudine (AZT) on reproductive and hematopoietic systems in the male rat. Biochem Pharmacol. 1991;42:1293–7. PMID: 1909529.

    Article  CAS  PubMed  Google Scholar 

  • Szczech GM, Wang LH, Walsh JP, Rousseau FS. Reproductive toxicology profile of emtricitabine in mice and rabbits. Reprod Toxicol. 2003;17:95–108. PMID: 12507664.

    Article  CAS  PubMed  Google Scholar 

  • Bezemer G, Van Gool AR, Fekkes D, Vrolijk JM, Hansen BE, Janssen HL, de Knegt RJ. Psychiatric side effects and fluctuations in serotonergic parameters in the treatment of chronic hepatitis C infection. Neuropsychobiology. 2012;65:126–32. https://doi.org/10.1159/000330585. PMID: 22378062.

    Article  CAS  PubMed  Google Scholar 

  • United States Food and Drug Administration. Reference ID: 3438539. Highlights of prescribing information Victrelis® (boceprevir) capsules for oral use. 2014. http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/202258s012lbl.pdf. Accessed 28 Dec 2015.

  • van Leeuwen E, Wit FW, Repping S, Eeftinck Schattenkerk JK, Reiss P, van der Veen F, Prins JM. Effects of antiretroviral therapy on semen quality. AIDS. 2008a;22:637–42. https://doi.org/10.1097/QAD.0b013e3282f4de10.

    Article  PubMed  Google Scholar 

  • van Leeuwen E, Wit FW, Prins JM, Reiss P, van der Veen F, Repping S. Semen quality remains stable during 96 weeks of untreated human immunodeficiency virus-1 infection. Fertil Steril. 2008b;90:636–41. PMID: 18023441.

    Article  PubMed  Google Scholar 

  • Biglia A, Blanco JL, Martínez E, Domingo P, Casamitjana R, Sambeat M, Milinkovic A, Garcia M, Laguno M, Leon A, Larrousse M, Lonca M, Mallolas J, Gatell JM. Gynecomastia among HIV-infected patients is associated with hypogonadism: a case-control study. Clin Infect Dis. 2004;39:1514–9. PMID: 15546089.

    Article  PubMed  Google Scholar 

  • Wang D, Li L, Xie Q, Hou Z, Yu X, Ma M, Huang T. Factors affecting sperm fertilizing capacity in men infected with HIV. J Med Virol. 2014;86:1467–72. https://doi.org/10.1002/jmv.23991. PMID: 24898681.

    Article  CAS  PubMed  Google Scholar 

  • Were EO, Heffron R, Mugo NR, Celum C, Mujugira A, Bukusi EA, Baeten JM, Partners PrEP Study Team. Pre-exposure prophylaxis does not affect the fertility of HIV-1-uninfected men. AIDS. 2014;28:1977–82. https://doi.org/10.1097/QAD.0000000000000313.

    Article  PubMed  PubMed Central  Google Scholar 

  • White DJ, Mital D, Taylor S, St John JC. Sperm mitochondrial DNA deletions as a consequence of long term highly active antiretroviral therapy. AIDS. 2001;15:1061–2. PMID: 11399991.

    Article  CAS  PubMed  Google Scholar 

  • Wong N, Levy M, Stephenson I. Hypogonadism in the HIV-Infected Man. Curr Treat Options Infect Dis. 2017;9:104. https://doi.org/10.1007/s40506-017-0110-3.

    Article  PubMed  PubMed Central  Google Scholar 

  • Wunder DM, Bersinger NA, Fux CA, Mueller NJ, Hirschel B, Cavassini M, Elzi L, Schmid P, Bernasconi E, Mueller B, Furrer H, Swiss HIV. Cohort Study. Hypogonadism in HIV-1-infected men is common and does not resolve during antiretroviral therapy. Antivir Ther. 2007;12:261–5. PMID: 17503668.

    CAS  PubMed  Google Scholar 

  • Brinkman K, ter Hofstede HJ, Burger DM, Smeitink JA, Koopmans PP. Adverse effects of reverse transcriptase inhibitors: mitochondrial toxicity as common pathway. AIDS. 1998;12:1735–44. PMID: 9792373.

    Article  CAS  PubMed  Google Scholar 

  • Bujan L, Sergerie M, Moinard N, Martinet S, Porte L, Massip P, Pasquier C, Daudin M. Decreased semen volume and spermatozoa motility in HIV-1-infected patients under antiretroviral treatment. J Androl. 2007;28:444–52. https://doi.org/10.2164/jandrol.106.001529. PMID: 17215546.

    Article  PubMed  Google Scholar 

  • Chernow B, Schooley RT, Dracup K, Napolitano LM, Stanford GG, Klibanski A. Serum prolactin concentrations in patients with the acquired immunodeficiency syndrome. Crit Care Med. 1990;18:440–1. PMID: 2318055.

    Article  CAS  PubMed  Google Scholar 

  • Collazos J, Mayo J, Martínez E, Ibarra S. Association between sexual disturbances and sexual hormones with specific antiretroviral drugs. AIDS. 2002;16:1294–5. PMID: 12045499.

    Article  CAS  PubMed  Google Scholar 

  • Crittenden JA, Handelsman DJ, Stewart GJ. Semen analysis in human immunodeficiency virus infection. Fertil Steril. 1992;57:1294–9. PMID: 1601153.

    Article  CAS  PubMed  Google Scholar 

  • D’Souza UJ, Narayana K. Mechanism of cytotoxicity of ribavirin in the rat bone marrow and testis. Indian J Physiol Pharmacol. 2002;46:468–74. PMID: 12683223.

    PubMed  Google Scholar 

  • Diehl S, Vernazza P, Trein A, Schnaitmann E, Grimbacher B, Setzer B, Walker UA. Mitochondrial DNA and sperm quality in patients under antiretroviral therapy. AIDS. 2003;17:450–1. https://doi.org/10.1097/01.aids.0000050834.06065.78. PMID: 12556705.

    Article  PubMed  Google Scholar 

  • Dobs AS, Dempsey MA, Ladenson PW, Polk BF. Endocrine disorders in men infected with human immunodeficiency virus. Am J Med. 1988;84:611–6. PMID: 3348269.

    Article  CAS  PubMed  Google Scholar 

  • Dondero F, Rossi T, D’Offizi G, Mazzilli F, Rosso R, Sarandrea N, Pinter E, Aiuti F. Semen analysis in HIV seropositive men and in subjects at high risk for HIV infection. Hum Reprod. 1996;11:765–8. PMID: 8671325.

    Article  CAS  PubMed  Google Scholar 

  • Douglas JM Jr, Davis LG, Remington ML, Paulsen CA, Perrin EB, Goodman P, Conner JD, King D, Corey L. A double-blind, placebo-controlled trial of the effect of chronically administered oral acyclovir on sperm production in men with frequently recurrent genital herpes. J Infect Dis. 1988;157:588–93. PMID: 2830348.

    Article  PubMed  Google Scholar 

  • Dove LM, Rosen RC, Ramcharran D, Wahed AS, Belle SH, Brown RS, Hoofnagle JH; Virahep-C Study Group. Decline in male sexual desire, function, and satisfaction during and after antiviral therapy for chronic hepatitis C. Gastroenterology. 2009;137:873–84, 884.e1. https://doi.org/10.1053/j.gastro.2009.05.060. PMID: 19527724.

  • Dubé MP, Parker RA, Mulligan K, Tebas P, Robbins GK, Roubenoff R, Grinspoon SK. Effects of potent antiretroviral therapy on free testosterone levels and fat-free mass in men in a prospective, randomized trial: A5005s, a substudy of AIDS Clinical Trials Group Study 384. Clin Infect Dis. 2007;45:120–6. PMID: 17554712.

    Article  PubMed  Google Scholar 

  • Dulioust E, Du AL, Costagliola D, Guibert J, Kunstmann JM, Heard I, Juillard JC, Salmon D, Leruez-Ville M, Mandelbrot L, Rouzioux C, Sicard D, Zorn JR, Jouannet P, De Almeida M. Semen alterations in HIV-1 infected men. Hum Reprod. 2002;17:2112–8. PMID: 12151446.

    Article  CAS  PubMed  Google Scholar 

  • Durazzo M, Premoli A, Di Bisceglie C, Bertagna A, Faga E, Biroli G, Manieri C, Bo S, Pagano G. Alterations of seminal and hormonal parameters: An extrahepatic manifestation of HCV infection? World J Gastroenterol. 2006;12:3073–6. https://doi.org/10.3748/wjg.v12.i19.3073. PMID: 16718790.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Faqi AS, Klug A, Merker HJ, Chahoud I. Ganciclovir induces reproductive hazards in male rats after short-term exposure. Hum Exp Toxicol. 1997;16:505–11. PMID: 9306137.

    Article  CAS  PubMed  Google Scholar 

  • Frapsauce C, Grabar S, Leruez-Ville M, Launay O, Sogni P, Gayet V, Viard JP, De Almeida M, Jouannet P, Dulioust E. Impaired sperm motility in HIV-infected men: an unexpected adverse effect of efavirenz? Hum Reprod. 2015;30:1797–806. https://doi.org/10.1093/humrep/dev141. PMID: 26085581.

    Article  CAS  PubMed  Google Scholar 

  • Garrido N, Meseguer M, Remohí J, Simón C, Pellicer A. Semen characteristics in human immunodeficiency virus (HIV)- and hepatitis C (HCV)-seropositive males: predictors of the success of viral removal after sperm washing. Hum Reprod. 2005;20:1028–34. PMID: 15608027.

    Article  PubMed  Google Scholar 

  • Gorman JM, Warne PA, Begg MD, Cooper TB, Novacenko H, Williams JB, Rabkin J, Stern Y, Ehrhardt AA. Serum prolactin levels in homosexual and bisexual men with HIV infection. Am J Psychiatry. 1992;149:367–70. https://doi.org/10.1176/ajp.149.3.367. PMID: 1346949

    Article  CAS  PubMed  Google Scholar 

  • Graef AS, Gonzalez SS, Baca VR, Ramirez ML, Daza LB, Blanco FF, Ortiz OA, Lavalle CM. High serum prolactin levels in asymptomatic HIV-infected patients and in patients with acquired immunodeficiency syndrome. Clin Immunol Immunopathol. 1994;72:390–3. PMID: 8062450.

    Article  CAS  PubMed  Google Scholar 

  • Hofer H, Donnerer J, Sator K, Staufer K, Scherzer TM, Dejaco C, Sator M, Kessler H, Ferenci P. Seminal fluid ribavirin level and functional semen parameters in patients with chronic hepatitis C on antiviral combination therapy. J Hepatol. 2010;52:812–6. https://doi.org/10.1016/j.jhep.2009.12.039. PMID: 20399525.

    Article  CAS  PubMed  Google Scholar 

  • Kehl S, Weigel M, Müller D, Gentili M, Hornemann A, Sütterlin M. HIV-infection and modern antiretroviral therapy impair sperm quality. Arch Gynecol Obstet. 2011;284:229–33. https://doi.org/10.1007/s00404-011-1898-6. PMID: 21448708.

    Article  PubMed  Google Scholar 

  • Kohler JJ, Lewis W. A brief overview of mechanisms of mitochondrial toxicity from NRTIs. Environ Mol Mutagen. 2007;48:166–72. https://doi.org/10.1002/em.20223. PMID: 16758472.

    Article  CAS  PubMed  Google Scholar 

  • Kraus MR, Schäfer A, Bentink T, Scheurlen M, Weissbrich B, Al-Taie O, Seufert J. Sexual dysfunction in males with chronic hepatitis C and antiviral therapy: interferon-induced functional androgen deficiency or depression? J Endocrinol. 2005;185:345–52. PMID: 15845927.

    Article  CAS  PubMed  Google Scholar 

  • Krieger JN, Coombs RW, Collier AC, Koehler JK, Ross SO, Chaloupka K, Murphy VL, Corey L. Fertility parameters in men infected with human immunodeficiency virus. J Infect Dis. 1991;164:464–9. PMID: 1869837.

    Article  CAS  PubMed  Google Scholar 

  • Kushnir VA, Lewis W. Human immunodeficiency virus/acquired immunodeficiency syndrome and infertility: emerging problems in the era of highly active antiretrovirals. Fertil Steril. 2011;96:546–53. https://doi.org/10.1016/j.fertnstert.2011.05.094. PMID: 21722892.

    Article  PubMed  PubMed Central  Google Scholar 

  • Lambert-Niclot S, Poirot C, Tubiana R, Houssaini A, Soulié C, Dominguez S, Schubert B, Prades M, Bonmarchand M, Calvez V, Flandre P, Peytavin G, Marcelin AG. Effect of antiretroviral drugs on the quality of semen. J Med Virol. 2011;83:1391–4. https://doi.org/10.1002/jmv.22119. PMID: 21678443.

    Article  CAS  PubMed  Google Scholar 

  • Lasheeb AS, King J, Ball JK, Curran R, Barratt CL, Afnan M, Pillay D. Semen characteristics in HIV-1 positive men and the effect of semen washing. Genitourin Med. 1997;73:303–5. PMID: 9389956.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Leandri RD, Dulious E, Benbrik E, Jouannet P, De Almeida M. Deficit in cytochrome c oxidase activity induced in rat sperm mitochondria by in vivo exposure to zidovudine. Int J Androl. 2003;26:305–9. PMID: 14511219.

    Article  CAS  PubMed  Google Scholar 

  • Lewis W, Day BJ, Copeland WC. Mitochondrial toxicity of NRTI antiviral drugs: an integrated cellular perspective. Nat Rev Drug Discov. 2003;2:812–22. PMID: 14526384.

    Article  CAS  PubMed  Google Scholar 

  • Lowe SH, van Leeuwen E, Droste JA, van der Veen F, Reiss P, Lange JM, Burger DM, Repping S, Prins JM. Semen quality and drug concentrations in seminal plasma of patients using a didanosine or didanosine plus tenofovir containing antiretroviral regimen. Ther Drug Monit. 2007;29:566–70. PMID: 17898645.

    Article  CAS  PubMed  Google Scholar 

  • Manfredi R, Calza L, Chiodo F. True gynecomastia in congenitally HIV-infected children treated with antiretroviral agents. J Chemother. 2004;16(3):303–5. https://doi.org/10.1179/joc.2004.16.3.303. PMID: 15330330.

    Article  CAS  PubMed  Google Scholar 

  • Merenich JA, McDermott MT, Asp AA, Harrison SM, Kidd GS. Evidence of endocrine involvement early in the course of human immunodeficiency virus infection. J Clin Endocrinol Metab. 1990;70:566–71. https://doi.org/10.1210/jcem-70-3-566. PMID: 2155250.

    Article  CAS  PubMed  Google Scholar 

  • Mira JA, Lozano F, Santos J, Ramayo E, Terrón A, Palacios R, León EM, Márquez M, Macías J, Fernández-Palacin A, Gómez-Mateos J, Pineda JA, Grupo Andaluz para el Estudio de las Enfermedades Infecciosas. Gynaecomastia in HIV-infected men on highly active antiretroviral therapy: association with efavirenz and didanosine treatment. Antivir Ther. 2004;9:511–7. PMID: 15456082.

    CAS  PubMed  Google Scholar 

  • Monroe AK, Dobs AS, Xu X, Palella FJ, Kingsley LA, Witt MD, Brown TT. Sex hormones, insulin resistance, and diabetes mellitus among men with or at risk for HIV infection. J Acquir Immune Defic Syndr. 2011;58:173–80. https://doi.org/10.1097/QAI.0b013e3182278c09.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Montero A, Bottasso OA, Luraghi MR, Giovannoni AG, Sen L. Association between high serum prolactin levels and concomitant infections in HIV-infected patients. Hum Immunol. 2001;62:191–6. PMID: 11182231.

    Article  CAS  PubMed  Google Scholar 

  • Muller CH, Coombs RW, Krieger JN. Effects of clinical stage and immunological status on semen analysis results in human immunodeficiency virus type 1-seropositive men. Andrologia. 1998;30(Suppl 1):15–22. PMID: 9629438.

    PubMed  Google Scholar 

  • Narayana K. A purine nucleoside analogue-acyclovir [9-(2-hydroxyethoxymethyl)-9h-guanine] reversibly impairs testicular functions in mouse. J Toxicol Sci. 2008a;33:61–70. PMID: 18303185.

    Article  CAS  PubMed  Google Scholar 

  • Narayana K, D’Souza UJ, Seetharama Rao KP. Ribavirin-induced sperm shape abnormalities in Wistar rat. Mutat Res. 2002a;513:193–6. PMID: 11719104.

    Article  CAS  PubMed  Google Scholar 

  • Narayana K, D’Souza UJ, Rao KP. Effect of ribavirin on epididymal sperm count in rat. Indian J Physiol Pharmacol. 2002b;46:97–101. PMID: 12024964.

    CAS  PubMed  Google Scholar 

  • Narayana K, D’Souza UJ, Narayan P, Kumar G. The antiviral drug ribavirin reversibly affects the reproductive parameters in the male Wistar rat. Folia Morphol. 2005;64:65–71. PMID: 16121321.

    CAS  Google Scholar 

  • Nicopoullos JD, Almeida PA, Ramsay JW, Gilling-Smith C. The effect of human immunodeficiency virus on sperm parameters and the outcome of intrauterine insemination following sperm washing. Hum Reprod. 2004;19:2289–97. https://doi.org/10.1093/humrep/deh426. PMID: 15242991.

    Article  PubMed  Google Scholar 

  • Njuguna C, Swart A, Blockman M, Maartens G, Chisholm B, Stewart A, Uys A, Cohen K. Cases of antiretroviral-associated gynaecomastia reported to the National HIV & Tuberculosis Health Care Worker Hotline in South Africa. AIDS Res Ther. 2016;13:40. https://doi.org/10.1186/s12981-016-0121-z. PMID: 27891161.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer International Publishing AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Drobnis, E.Z., Nangia, A.K. (2017). Antivirals and Male Reproduction. In: Impacts of Medications on Male Fertility. Advances in Experimental Medicine and Biology, vol 1034. Springer, Cham. https://doi.org/10.1007/978-3-319-69535-8_11

Download citation

Publish with us

Policies and ethics