Australasian Society for HIV Medicine

The Swiss Federal AIDS Commission has released a report that has raised international concerns about safe sex practices. The statement, on behalf of the Swiss Federal Commission for HIV/AIDS was authored by four of Switzerland's foremost HIV experts: Prof Pietro Vernazza, of the Cantonal Hospital in St. Gallen, and President of the Swiss Federal Commission for HIV / AIDS; Prof Bernard Hirschel from Geneva University Hospital; Dr Enos Bernasconi of the Lugano Regional Hospital; and Dr Markus Flepp, president of the Swiss Federal Office of Public Health's Sub-committee on the clincal and therapeutic aspects of HIV/AIDS (1).

The report, published in the January issue of the Bulletin of Swiss Medicine (2), states that after review of the medical literature and extensive discussion with experts an HIV-infected person on antiretroviral therapy with completely suppressed viraemia (effective ART) is not sexually infectious, i.e. cannot transmit HIV through sexual contact. The authors clarify the statement indicating that it is only valid while the following strict conditions and someone infected with HIV meets narrow constraints:

• They must be undergoing antiretroviral therapy
• The virus must have been suppressed for at least six months and viral load levels regularly monitored
• They must be free of any other sexually transmitted disease.
  The Commission states that although available medical and biological evidence does not rule out the possibility of HIV transmission they feel that there is nonetheless enough information to support its statement (1).

The report was based on studies with heterosexual couples (3,4,5) with data confirming the current view that when the viral load (VL) is undetectable in blood the risk of HIV transmission is significantly reduced.

Q. Does an undetectable VL completely eliminate the risk of transmitting the virus?
Antiretroviral therapy has been shown to reduce the prevalence of HIV-1 in the male and female genital tracts resulting in a lower rate of sexual transmission of the virus (3,6,7,8,9,10,11). The analysis of semen samples from patients receiving Zidovudine monotherapy (11,15) was the first to show the decreased frequency of HIV-1 in compartments other than blood with antiretroviral treatment. This effect appeared to be associated with a significant reduction of HIV-1 positive white blood cells (seminal polynuclear cells), the principal HIV-1 cell hosts in semen. Subsequent studies on individuals receiving highly active antiretroviral treatment (HAART) continued to show a significant fall in the viral load in semen (RNA and culture), which paralleled the reduction of viral load in blood. More pronounced reductions of HIV RNA in semen have been observed as the effectiveness of ART on blood HIV RNA levels increases (6,7,8,9,10).

However, it is noteworthy that replication-competent viruses can be recovered from seminal cells of HIV-1-infected men who are receiving HAART and who have undetectable levels of HIV-1 RNA in blood plasma. Zhang et al (12) showed that despite the long-term suppression of HIV-1 RNA in the plasma proviral DNA could be detected in seminal cells in patients on triple therapy for more than 2 years. Further, these virus were macrophage-tropic, a feature that is characteristic of HIV-1 strains that are capable of being sexually transmitted. Choudhury et al (13) isolated infectious HIV from semen cells, but not from blood cells, of an individual on triple antiretroviral therapy. The absence of major resistance-conferring mutations in the semen virus isolate from this patient indicated that it was replicating in isolation from the antiviral agents. The compartmentalisation of blood and semen infection was further supported by genetic analysis of several infectious HIV clones isolated from semen cells and peripheral blood cells of another donor not on antiretroviral therapy (17). Protease gene sequence analyses revealed significant divergence of the two viral populations. These findings again suggesting distinct compartmentalisation of HIV in the semen, and support the concept that semen HIV arises from an isolated reservoir of infection that may function independently in the pathobiology of HIV disease. Leruez-Ville et al (9) analysed 39 HIV-1-infected men in a prospective study for HIV seminal shedding after the initiation of HAART. HIV RNA drastically decreased in the semen of all men, but low levels remained detectable in three men at month 18. Proviral HIV DNA became undetectable in the seminal cells of all men after 18 months. The authors suggested that HIV-infected cells in the male genital compartment might come from the intermittent passage of blood lymphocytes, rather than constituting a major local reservoir.

Bujan et al (14) found that although HAART may reduce blood RNA to undetectable levels, this does not mean that there are no viral genomes in semen. Results of paired blood and semen samples from this study showed that where seminal plasma results were always negative, 6-10% of sperm cell samples contained HIV-1 genomes due to the presence of seminal polynuclear cells. Persistent HIV type 1 infection has also been observed in semen and blood compartments in patients after long-term potent antiretroviral therapy (16).

Clearly research to date shows that when the viral load is undetectable it results in a significantly reduced risk of HIV transmission. However, data from studies where infectious virus can be isolated from blood as well as in male and female genital tracts even after extensive HAART suggests a continued and significant risk of virus transmiission.

Q. Do antiretroviral drug concentrations differ between body compartments?
There is recent evidence that certain antiretroviral drugs of key HAART components are found in differing concentrations in cervicovaginal fluid and blood plasma. Drumond et al (20) stratified antiretroviral drugs according to the female genital tract concentrations achieved relative to blood plasma. Lamivudine (concentrations achieved were 411% greater than blood plasma), emtricitabine (395%), zidovudine (235%) tenofovir (75%), ritonavir (26%), didanosine (21%), atazanavir (18%), lopinavir (8%), abacavir (8%), stavudine (5%), and efavirenz (0.4%). More recently Kwara et al (19) published data in the March issue of Clinical Infectious Diseases looking at the antiretroviral drug concentrations and HIV RNA in the genital tract of HIV-infected women receiving long-term highly active antiretroviral therapy. The group found that the concentrations of tenofovir in cervicovaginal fluid were five times those in the blood. High concentrations of 3TC in cervicovaginal fluids were also observed, with levels of the drug in the genital tract being three times higher than those seen in the blood. In addition, levels of FTC (emtricitabine, Emtriva) were 50% higher in the genital tract than blood and those of ddI some nine times higher. But concentrations in the genital tract of efavirenz (Sustiva) were only 1% of those achieved in the blood, and concentrations of protease inhibitors in cervicovaginal fluid were between 3%-33% of those in the blood. Although both NNRTIs and protease inhibitors had poor concentrations in the genital tract compared to blood sustained suppression of HIV RNA levels were observed in the genital tract compartment.

This data provides good evidence for use of specific drug combinations for post exposure prophylaxis (PEP) and NPEP. However variation of drug concentrations over time and in varying body compartments means that there is potential for viral load to rise and go undetected in these areas. Drug concentrations of the positive discordant partner would need regular monitoring as they could vary considerably even if blood VL remains below the level of detection. Therefore, promoting unprotected sex practices in monogamous discordant relationships would still be associated with a risk of infection, i.e. it will not be 100% safe.

Q. What are other organisations recommending in light of the Swiss Report?
Despite the line being suggested by the Swiss Report most AIDS researchers insist safe sex is the only way to prevent HIV spread. UNAIDS and the World Health Organization have come out strongly in favour of recommending a continued use of a comprehensive package of HIV prevention approaches, including correct and consistent use of condoms (21). The Centers for Disease Control and Prevention (CDC) continues to underscore its recommendation that people living with HIV who are sexually active use condoms consistently and correctly with all sex partners (22).

In light of the literature which indicates suppression of HIV on one hand but also indicates continued presence of replication-competent viruses in some patients receiving HAART, ASHM supports the UNAIDS, WHO and CDC recommendations. For the present, and in light of our current knowledge safe sex is the only way to prevent HIV spread. Safer sex includes correct and consistent male and female condom use, and early and effective treatment for sexually transmitted infections.

Further research on the dynamics of viral suppression after the initiation of HAART in male and female genital tract, the mucosa of colorectal and cervicovaginal tissue, the degree to which latently infected lymphocytes are sequestered in the prostate or in the seminal vesicles compartments are required. Studies on viral kinetics in the genital tract should assess the impact of different antiretroviral regimens, and monitor changes in cellular proviral DNA and replication-competent virus over a longer period of time. Researchers also need to consider other related factors that contribute to HIV transmission including co-infection with other sexually transmitted diseases. Finally, analysis also needs to consider homosexual as well as heterosexual modes of transmission.

References and links

Link to English translation of the report HIV-positive individuals without additional sexually transmissible diseases (STD) and on effective anti-retroviral therapy are sexually non-infectious:
http://www.ternyata.org/books/wisdom/swiss_english.pdf

(1) Bernard E, (2008) Swiss experts say individuals with undetectable viral load and no STI cannot transmit HIV during sex Link to report: Aidsmap Wednesday, January 30, 2008 http://www.aidsmap.org/en/news/4E9D555B-18FB-4D56-B912-2C28AFCCD36B.asp

(2) Vernazza P et al. (2008) Les personnes séropositives ne souffrant d'aucune autre MST et suivant un traitment antirétroviral efficace ne transmettent pas le VIH par voie sexuelle. Bulletin des médecins suisses 89 (5).

(3) Quinn CT et al. (2000) Viral load and heterosexual transmission of human immunodeficiency virus type 1. New England Journal of Medicine 342 (12): 921-929. Link to full text: http://content.nejm.org/cgi/content/full/342/13/921

(4) P Gupta, J Mellors, L Kingsley, S Riddler, MK Singh, S Schreiber, M Cronin and CR Rinaldo (1997) High viral load in semen of human immunodeficiency virus type 1-infected men at all stages of disease and its reduction by therapy with protease and nonnucleoside reverse transcriptase inhibitors. J Virol 71:6271-6275. Link to abstract: http://www.ncbi.nlm.nih.gov/pubmed/9223532?ordinalpos=13&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

(5) Castilla J et al. Effectiveness of highly active antiretroviral therapy in reducing heterosexual transmission of HIV. (2005) J Acquir Immune Defic Syndr 40: 96 - 101. Link to abstract http://www.ncbi.nlm.nih.gov/pubmed/16123689?ordinalpos=5&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

(6) Vernazza PL, Gilliam BL, Flepp M, Dyer JR, Frank AC, Fiscus SA, et al. Effect of antiviral treatment on the shedding of HIV-1 in semen. AIDS 1997, 11:1249 - 1254. 30.
Link to Full Text: http://www.aidsonline.com/pt/re/aids/pdfhandler.00002030-19971000000008.pdf;jsessionid=H66ppq1QM69w6DdvrJBzn9qTHTfSpTPsvG146LWL9h1rFPmTxzp8!383192544!181195628!8091!-1

(7) Auvert B, Males S, Puren A, Taljaard D, Caraël M, Williams B. (2004). Can highly active antiretroviral therapy reduce the spread of HIV?: A study in a township of South Africa. : J Acquir Immune Defic Syndr. May 1; 36(1): 613-21.
Link to abstract: http://www.ncbi.nlm.nih.gov/pubmed/15097305?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

(8) Gilliam BL, Dyer JR, Fiscus SA, Marcus C, Zhou S, Wathen L, et al. Effects of reverse transcriptase inhibitor therapy on the HIV-1 viral burden in semen. J Acquir Immune Defic Syndr Hum Retrovirol 1997, 15:54 - 60. Link to source: http://www.ncbi.nlm.nih.gov/pubmed/9215655?ordinalpos=3&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

(9) Leruez-Ville M, Dulioust E, Costabliola D, Salmon D, Tachet A, Finkielsztejn L, et al. Decrease in HIV-1 seminal shedding in men receiving highly active antiretroviral therapy: an 18 month longitudinal study (ANRS EP012). AIDS 2002, 16:486 - 488. Link to full text article: http://www.aidsonline.com/pt/re/aids/fulltext.00002030-200202150-00023.htm;jsessionid=H91cBZr2Y35HGvd2zgGcdGhhrRGbnnyvyKp1JgtvX6fjW1YpM694!-383192544!181195628!8091!-1

(10) Taylor S, Ferguson NM, Cane PA, Anderson RM, Pillay D. Dynamics of seminal plasma HIV-1 decline after antiretroviral treatment. AIDS 2001, 15:424 - 426. Link to full text article: http://www.aidsonline.com/pt/re/aids/fulltext.00002030-200102160-00022.htm;jsessionid=H91cBZr2Y35HGvd2zgGcdGhhrRGbnnyvyKp1JgtvX6fjW1YpM694!-383192544!181195628!8091!-1

(11) Politch JA, Mayer KH, Abbott AF, Anderson DJ. (2004) The effects of disease progression and zidovudine therapy on semen quality in human immunodeficiency virus type 1 seropositive men. Fertil Steril. 1994 May; 61(5): 922-8.
Link to abstract: http://www.ncbi.nlm.nih.gov/pubmed/8174732?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlusDrugs1

(12) Zhang H, Dornadula G, Beumont M, Livornese L, Jr, van Uitert B, Henning K, 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.
Link to Full Text: http://content.nejm.org/cgi/content/full/339/25/1803

(13) Choudhury B, Pillay D, Taylor S, Cane PA. (2002) Analysis of HIV-1 variation in blood and semen during treatment and treatment interruption. J Med Virol. 2002 Dec; 68(4): 467-72. Link to abstract: http://www.ncbi.nlm.nih.gov/pubmed/12376952?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlusDrugs1

(14) Bujan L, Daudin M, Matsuda T, Righi L, Thauvin L, Berges L, Izopet J, Berrebi A, Massip P, Pasquier C. (2004) Factors of intermittent HIV-1 excretion in semen and efficiency of sperm processing in obtaining spermatozoa without HIV-1 genomes. AIDS 18: 757-766
Link to Full Text: http://www.aidsonline.com/pt/re/aids/pdfhandler.00002030-20040326000006.pdf;jsessionid=H6bQjsrYQTBgyyRDnhGszlmyypHNwqgrjvGT3STB4MVh5Nb5HvCX!383192544!181195628!8091!-1

(15) Anderson DJ, O'Brien TR, Politch JA, Martinez A, Seage GR, III, Padian N, et al. Effects of disease stage and zidovudine therapy on the detection of human immunodeficiency virus type 1 in semen. JAMA 1992, 267:2769 - 2774. Link to abstract: http://www.ncbi.nlm.nih.gov/sites/entrez

(16) Craigo JK, Patterson BK, Paranjpe S, Kulka K, Ding M, Mellors J, Montelaro RC, Gupta P. (2004) Persistent HIV type 1 infection in semen and blood compartments in patients after long-term potent antiretroviral therapy. AIDS Res Hum Retroviruses. 2004 Nov; 20(11): 1196-209. Link to abstract: http://www.ncbi.nlm.nih.gov/pubmed/15588342?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlusDrugs1

(17) Kiessling AA, Fitzgerald LM, Zhang D, Chhay H, Brettler D, Eyre RC, et al. Human immunodeficiency virus in semen arises from a genetically distinct virus reservoir. AIDS Res Hum Retroviruses 1998, 14 Suppl 1:S33 - S41.
Link to abstract: http://www.ncbi.nlm.nih.gov/pubmed/9581882?ordinalpos=3&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

(18) Iversen AK, Larsen AR, Jensen T, Fugger L, Balslev U, Wahl S, Gerstoft J, Mullins JI, Skinhøj P. (1998) Distinct determinants of human immunodeficiency virus type 1 RNA and DNA loads in vaginal and cervical secretions. J Infect Dis 177:1214-1220, Link to abstract: http://www.ncbi.nlm.nih.gov/pubmed/9593006?dopt=Abstract

(19) Kwara A, Delong A, Rezk N, Hogan J, Burtwell H, Chapman S, Moreira CC, Kurpewski J, Ingersoll J, Caliendo AM, Kashuba A, Cu-Uvin S. (2008) Antiretroviral drug concentrations and HIV RNA in the genital tract of HIV-infected women receiving long-term highly active antiretroviral therapy. Clin Infect Dis. Mar 1; 46(5): 719-25. Link to abstract: http://www.ncbi.nlm.nih.gov/pubmed/18220480?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

(20) Dumond JB, Yeh RF, Patterson KB, Corbett AH, Jung BH, Rezk NL, Bridges AS, Stewart PW, Cohen MS, Kashuba AD. (2007) Antiretroviral drug exposure in the female genital tract: implications for oral pre- and post-exposure prophylaxis. : AIDS. 2007 Sep 12; 21(14): 1899-907. Link to abstract: http://www.ncbi.nlm.nih.gov/pubmed/17721097?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlusDrugs1

(21) Barton-Knott S and Abramov V (2008 | Antiretroviral therapy and sexual transmission of HIV UNAIDS and WHO statement. Link to statement: http://data.unaids.org/pub/PressStatement/2008/080201_hivtransmission_en.pdf

(22) National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention (2008) CDC Underscores Current Recommendation for Preventing HIV Transmission: Divisions of HIV/AIDS Prevention Link to source: http://www.cdc.gov/hiv/resources/press/020108.htm

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