To the Editor: The results of the trial of cellulose sulfateas a vaginal gel for the prevention of human immunodeficiencyvirus (HIV) infection, reported by Van Damme et al. (July 31issue),1 indicated that cellulose sulfate did not prevent sexualtransmission of HIV and may have increased the risk of HIV acquisition,as compared with placebo. The cellulose sulfate and placebogels had a pH of 7.5 and 4.4, respectively. The healthy humanvagina provides a low pH, diminishing HIV infectivity and transmissionof cell-associated HIV.2,3 Therefore, microbicides should havea pH of approximately 4.5.3 The apparently increased risk ofHIV acquisition among women using the cellulose sulfate gelmight be due to the disparity in pH between the active-treatmentand placebo gels.
The anti-HIV activity of anionic polymers (including cellulosesulfate) may be compromised by seminal fluid.4 This is expectedto be overcome by inclusion of acidic pH buffering systems.4Such combinations are currently in the microbicide pipeline.Langerhans' cells first encounter HIV during sexual transmissionof the virus and bind HIV by means of langerin. Captured virusis internalized and degraded.5 It remains to be establishedwhether candidate microbicides interfere with this defense mechanismand possibly increase the probability of HIV acquisition.
A. Robert Neurath, Ph.D. Virotech New York, NY 10003 arneurath{at}att.net
References
Van Damme L, Govinden R, Mirembe FM, et al. Lack of effectiveness of cellulose sulfate gel for the prevention of vaginal HIV transmission. N Engl J Med 2008;359:463-472. [Erratum, N Engl J Med 2008;359:877.] [Free Full Text]
Olmsted SS, Khanna KV, Ng EM, et al. Low pH immobilizes and kills human leucocytes and prevents transmission of cell-associated HIV in a mouse model. BMC Infect Dis 2005;5:79-79. [CrossRef][Medline]
Weber J, Desai K, Darbyshire J. The development of vaginal microbicides for the prevention of HIV transmission. PLoS Med 2005;2:e142-e142. [CrossRef][Medline]
Neurath AR, Strick N, Li Y-Y. Role of seminal plasma in the anti-HIV-1 activity of candidate microbicides. BMC Infect Dis 2006;6:150-150. [CrossRef][Medline]
de Witte L, Nabatov A, Pion M, et al. Langerin is a natural barrier to HIV-1 transmission by Langerhans cells. Nat Med 2007;13:367-371. [CrossRef][Web of Science][Medline]
To the Editor: The report that cellulose sulfate did not reducethe risk of HIV acquisition, and in fact increased it in womencompleting the protocol, is not surprising, given that clinicallyrelevant concentrations of this compound reproducibly increasethe in vitro infection rate of sexually transmissible R5-tropicstrains of HIV.1 Similar results were reported more than a decadeago for another sulfated polyanion, dextran sulfate, which increasedthe replication of primary isolates of HIV both in vivo2 andin vitro.3 Unfortunately, detailed titrations, which are essentialfor detecting enhancement by biphasic compounds such as celluloseand dextran sulfate, have not been published for the viral strainsthat were prevalent at the trial sites.
Chris Richards, B.S. Wang Tao, M.D., Ph.D. Dean Hamer, Ph.D. National Institutes of Health Bethesda, MD 20892 deanh{at}helix.nih.gov
References
Tao W, Richards C, Hamer D. Enhancement of HIV infection by cellulose sulfate. AIDS Res Hum Retroviruses 2008;24:925-929. [CrossRef][Web of Science][Medline]
Flexner C, Barditch-Crovo PA, Kornhauser DM, et al. Pharmacokinetics, toxicity, and activity of intravenous dextran sulfate in human immunodeficiency virus infection. Antimicrob Agents Chemother 1991;35:2544-2550. [Free Full Text]
Meylan PRA, Kornbluth RS, Zbinden I, Richman DD. Influence of host cell type and V3 loop of the surface glycoprotein on susceptibility of human immunodeficiency virus type 1 to polyanion compounds. Antimicrob Agents Chemother 1994;38:2910-2916. [Free Full Text]
The authors reply: In response to Neurath: the low pH of a formulationis not enough to inactivate HIV transported by semen (pH ofapproximately 7.9) unless it is accompanied by a strong acid-bufferingcapacity. Although the cellulose sulfate and hydroxyethylcellulose-basedplacebo gels have different pH values, neither has significantbuffering capacity. This is reinforced by the lack of anti-HIVactivity of the hydroxyethylcellulose placebo (pH of approximately4.5) in preclinical studies.1 We agree that seminal plasma reducesthe antiviral activity of anionic compounds; however, cellulosesulfate S was clinically administered at a concentration (60mg per milliliter) that is orders of magnitude higher than theseminal plasma–increased median effective concentrationreported by Neurath and colleagues.2
Regarding the comments by Richards et al., the statement thatclinically relevant concentrations of cellulose sulfate reproduciblyincrease the in vitro infection rate of R5 tropic strains ofHIV (R5-HIV) omits mention of the finding that all other testedconcentrations in the data reported by Tao et al.3 were eithernot effective (<0.3 µg per milliliter) or highly inhibitory(>3 µg per milliliter). Although we do not disputethe reported spike in infectivity between 0.3 and 3.0 µgper milliliter, we question its clinical relevance, given thatcellulose sulfate was applied intravaginally at 210 mg per dose.Furthermore, the CONRAD data presented by Tao et al.3 show areduction in R5-HIV infection between 1.0 and 3.0 µg permilliliter, a disparity in results that cannot be explainedby lack of statistical power. Although the results of the intravenousdextran sulfate study should be considered as a possible explanationfor our findings, its experimental protocol is considerablydifferent. In addition, cellulose sulfate did not induce a significantincrease in macrophage infection in vitro.4
The potential increased risk of infection observed in our per-protocolanalysis was driven by results from two sites (Benin and Uganda)where gel was reportedly used 20 times per week on average (9infections with cellulose sulfate and 1 with placebo). Thisfrequency of use was dramatically higher than the four-times-per-weekuse reported in South Africa, where there was essentially noevidence of an effect (12 infections with cellulose sulfateand 10 with placebo). Although not conclusive, these findingssuggest that a mechanism related to very frequent exposure tocellulose sulfate is a more likely explanation for our results.
Lut Van Damme, M.D. Doug Taylor, Ph.D. Family Health International Arlington, VA 22203 lvandamme{at}fhi.org
References
Tien D, Schnaare RL, Kang F, et al. In vitro and in vivo characterization of a potential universal placebo designed for use in vaginal microbicide clinical trials. AIDS Res Hum Retroviruses 2005;21:845-853. [CrossRef][Web of Science][Medline]
Neurath AD, Strick N, Li Y-Y. Role of seminal plasma in the anti-HIV-1 activity of candidate microbicides. BMC Infect Dis 2006;6:150-150. [CrossRef][Medline]
Tao W, Richards C, Hamer D. Enhancement of HIV infection by cellulose sulfate. AIDS Res Hum Retroviruses 2008;24:925-929. [CrossRef][Web of Science][Medline]
Scordi-Bello IA, Mosoian A, He C, et al. Candidate sulfonated and sulfated topical microbicides: comparison of anti-human immunodeficiency virus activities and mechanisms of action. Antimicrob Agents Chemother 2005;49:3607-3615. [Free Full Text]
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