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• W2044321160 abstract "In 2007, nearly 7000 new cases of HIV infection occurred each day. There is a constant increase in the proportion of women newly infected with HIV in the global population; this increase is particularly high in some areas of the world such as sub-Saharan Africa. Microbicides are products that are being developed to empower women against HIV. First- and second-generation microbicides are broad-spectrum products that include surface active agents, vaginal defense enhancers, and blocking agents. Third-generation microbicides are HIV-specific and include replication and entry inhibitors formulated as gels or as vaginal rings. However, there is a concern that antiretroviral-based microbicides could lead to drug resistance if they are used by HIV-positive women who are unaware of their HIV status. To reach the highest number of women possible, microbicides should be available over-the-counter, which might not be the case with antiretroviral-based formulations. In contrast, non-antiretroviral-based microbicides will have the advantage of being initiated and controlled by women themselves and they will not jeopardize the use of life-saving drugs. In 2007, nearly 7000 new cases of HIV infection occurred each day. There is a constant increase in the proportion of women newly infected with HIV in the global population; this increase is particularly high in some areas of the world such as sub-Saharan Africa. Microbicides are products that are being developed to empower women against HIV. First- and second-generation microbicides are broad-spectrum products that include surface active agents, vaginal defense enhancers, and blocking agents. Third-generation microbicides are HIV-specific and include replication and entry inhibitors formulated as gels or as vaginal rings. However, there is a concern that antiretroviral-based microbicides could lead to drug resistance if they are used by HIV-positive women who are unaware of their HIV status. To reach the highest number of women possible, microbicides should be available over-the-counter, which might not be the case with antiretroviral-based formulations. In contrast, non-antiretroviral-based microbicides will have the advantage of being initiated and controlled by women themselves and they will not jeopardize the use of life-saving drugs. In 2007, 33 million people were living with HIV/AIDS worldwide, 67% of whom were in Africa.1UNAIDS/WHO. 2008 Report on the global AIDS epidemic. Geneva: World Health Organization; 2008. Available at: http://www.unaids.org/en/KnowledgeCentre/HIVData/GlobalReport/2008/2008_Global_report.asp. (accessed May 2010).Google Scholar Since the mid-1990 s, women have represented half of all adults living with HIV/AIDS.2Quinn T.C. Overbaugh J. HIV/AIDS in women: an expanding epidemic.Science. 2005; 308: 1582-1583Crossref PubMed Scopus (307) Google Scholar In sub-Saharan Africa, three times more 15- to 24-year-old women than men of the same age are now infected with HIV. Women, and especially adolescents and younger women, are biologically more susceptible to HIV infection than men.3Padian N.S. Shiboski S.C. Glass S.O. Vittinghoff E. Heterosexual transmission of human immunodeficiency virus (HIV) in northern California: results from a ten-year study.Am J Epidemiol. 1997; 146: 350-357Crossref PubMed Scopus (297) Google Scholar In addition, infection in women is driven by social, cultural, and economic gender inequalities that limit their ability to protect themselves from infection.4Dunkle K.L. Jewkes R.K. Brown H.C. Gray G.E. McIntryre J.A. Harlow S.D. Gender-based violence, relationship power, and risk of HIV infection in women attending antenatal clinics in South Africa.Lancet. 2004; 363: 1415-1421Abstract Full Text Full Text PDF PubMed Scopus (941) Google Scholar, 5Ojikutu B.O. Stone V.E. Women, inequality, and the burden of HIV.N Engl J Med. 2005; 352: 649-652Crossref PubMed Scopus (36) Google Scholar Condoms, when used correctly and consistently, provide a high level of protection against HIV,6Weller S.C. Davis-Beaty K. Condom effectiveness in reducing heterosexual HIV transmission.Cochrane Database Syst Rev. 2002; (CD003255)Crossref PubMed Google Scholar but many women lack the social and/or economic power to persuade their partners to use them. To confront the vulnerability of women and to empower them against HIV/AIDS, the scientific community and advocacy groups have promoted the development of microbicides.7Stein Z.A. HIV prevention: the need for methods women can use.Am J Public Health. 1990; 80: 460-462Crossref PubMed Scopus (309) Google Scholar Microbicides are products that women can initiate and control to protect themselves against HIV.8Elias C.J. Heise L.L. Challenges for the development of female-controlled vaginal microbicides.AIDS. 1994; 8: 1-9Crossref PubMed Scopus (119) Google Scholar They can be developed in any form that is convenient to use such as gel, cream, foam, film, suppository, or vaginal ring. First- and second-generation microbicides tend to be broad-spectrum products that disrupt the viral envelope, maintain vaginal pH, and/or bind to the virus to inhibit entry. More recently, pharmaceutical companies have granted royalty-free licenses to develop, manufacture, and distribute some antiretrovirals (ARVs) as microbicides in resource-poor countries.9Klasse P.J. Shattock R. Moore J.P. Antiretroviral drug-based microbicides to prevent HIV-1 sexual transmission.Annu Rev Med. 2008; 59: 455-471Crossref PubMed Scopus (158) Google Scholar These third-generation microbicides may have implications regarding the emergence of drug-resistant HIV. Indeed, ARVs administered vaginally could be absorbed systemically and may select for resistance if used by HIV-positive women who are unaware of their HIV status.10Wilson D.P. Coplan P.M. Wainberg M.A. Blower S.M. The paradoxical effects of using antiretroviral-based microbicides to control HIV epidemics.Proc Natl Acad Sci U S A. 2008; 105: 9835-9840Crossref PubMed Scopus (54) Google Scholar Therefore, women using ARV-based microbicides should be monitored for HIV, leading to increased costs and reduced accessibility to these products, especially if in the future the Food and Drug Administration (FDA) or other health authorities require that they be prescribed. We believe that non-ARV-based microbicides available over-the-counter, for women to initiate and control by themselves, still need to be developed as a novel prevention technology to curb the number of new HIV infections, especially in low- and middle-income countries. Preclinical and clinical research on the most advanced microbicides currently in the pipeline have been extensively reviewed in several papers.11Dhawan D. Mayer K.H. Microbicides to prevent HIV transmission: overcoming obstacles to chemical barrier protection.J Infect Dis. 2006; 193: 36-44Crossref PubMed Scopus (41) Google Scholar, 12Madan R.P. Keller M.J. Herold B.C. Prioritizing prevention of HIV and sexually transmitted infections: first-generation vaginal microbicides.Curr Opin Infect Dis. 2006; 19: 49-54Crossref PubMed Scopus (24) Google Scholar, 13McGowan I. Microbicides: a new frontier in HIV prevention.Biologicals. 2006; 34: 241-255Crossref PubMed Scopus (70) Google Scholar, 14Nuttall J. Romano J. Douville K. Galbreath C. Nel A. Heyward W. et al.The future of HIV prevention: prospects for an effective anti-HIV microbicide.Infect Dis Clin North Am. 2007; 21: 219-239Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar, 15Nikolic D.S. Garcia E. Piguet V. Microbicides and other topical agents in the prevention of HIV and sexually transmitted infections.Expert Rev Anti Infect Ther. 2007; 5: 77-88Crossref PubMed Scopus (14) Google Scholar, 16Cutler B. Justman J. Vaginal microbicides and the prevention of HIV transmission.Lancet Infect Dis. 2008; 8: 685-697Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar, 17Moscicki A.B. Vaginal microbicides: where are we and where are we going?.J Infect Chemother. 2008; 14: 337-341Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar, 18Hendrix C.W. Cao Y.J. Fuchs E.J. Topical microbicides to prevent HIV: clinical drug development challenges.Annu Rev Pharmacol Toxicol. 2009; 49: 349-375Crossref PubMed Scopus (62) Google Scholar Briefly, first- and second-generation microbicides include surface active agents (e.g., nonoxynol-9 and C31G), vaginal defense enhancers (e.g., BufferGel), and blocking agents (e.g., cellulose sulfate, Carraguard®, and PRO 2000/5 gel). In addition to their effect on HIV, they may be effective against other sexually transmitted pathogens. Some of these products may also demonstrate a contraceptive efficacy, while others may not. Most phase I and phase II clinical trials completed to date have found these products to be safe and well-tolerated. However, phase III trials with nonoxynol-9 and cellulose sulfate have shown that they could be harmful to the vaginal mucosa and increased the risk of HIV acquisition in women.19Van Damme L. Ramjee G. Alary M. Vuylsteke B. Chandeying V. Rees H. et al.Effectiveness of COL-1492, a nonoxynol-9 vaginal gel, on HIV-1 transmission in female sex workers: a randomised controlled trial.Lancet. 2002; 360: 971-977Abstract Full Text Full Text PDF PubMed Scopus (697) Google Scholar, 20Halpern V. Ogunsola F. Obunge O. Wang C.H. Onyejepu N. Oduyebo O. et al.Effectiveness of cellulose sulfate vaginal gel for the prevention of HIV infection: results of a Phase III trial in Nigeria.PLoS One. 2008; 3: e3784Crossref PubMed Scopus (129) Google Scholar, 21Van Damme L. Govinden R. Mirembe F.M. Guédou F. Solomon S. Becker M.L. et al.Lack of effectiveness of cellulose sulfate gel for the prevention of vaginal HIV transmission.N Engl J Med. 2008; 359: 463-472Crossref PubMed Scopus (375) Google Scholar Phase III trials with Carraguard® and BufferGel have not demonstrated efficacy in preventing HIV transmission.22Skoler-Karpoff S. Ramjee G. Ahmed K. Altini L. Plagianos M.G. Friedland B. et al.Efficacy of Carraguard for prevention of HIV infection in women in South Africa: a randomised, double-blind, placebo-controlled trial.Lancet. 2008; 372: 1977-1987Abstract Full Text Full Text PDF PubMed Scopus (427) Google Scholar, 23Abdool Karim S, Coletti A, Richardson B, Ramjee G, Hoffman I, Chirenje M, et al., Safety and effectiveness of vaginal microbicides BufferGel and 0.5% PRO 2000/5 Gel for the prevention of HIV infection in women: results of the HPTN 035 trial. 16th Conference on Retroviruses and Opportunistic Infections, Montreal, Canada, February 8–11, 2009.Google Scholar Moreover, two phase III trials with C31G did not produce meaningful results due to lower-than-expected HIV incidence in the study populations.24Peterson L. Nanda K. Opoku B.K. Ampofo W.K. Owusu-Amoako M. Boakye A.Y. et al.SAVVY (C31G) gel for prevention of HIV infection in women: a Phase 3, double-blind, randomized, placebo-controlled trial in Ghana.PLoS One. 2007; 2: e1312Crossref PubMed Scopus (163) Google Scholar, 25Feldblum P.J. Adeiga A. Bakare R. Wevill S. Lendvay A. Obadaki F. et al.SAVVY vaginal gel (C31G) for prevention of HIV infection: a randomized controlled trial in Nigeria.PLoS One. 2008; 3: e1474Crossref PubMed Scopus (231) Google Scholar More interestingly, a phase II/IIB trial with PRO 2000/5 gel (a naphthalene sulfonate polymer) involving 3099 participants showed that it might have some effectiveness for the prevention of HIV infection.23Abdool Karim S, Coletti A, Richardson B, Ramjee G, Hoffman I, Chirenje M, et al., Safety and effectiveness of vaginal microbicides BufferGel and 0.5% PRO 2000/5 Gel for the prevention of HIV infection in women: results of the HPTN 035 trial. 16th Conference on Retroviruses and Opportunistic Infections, Montreal, Canada, February 8–11, 2009.Google Scholar Women in the PRO 2000/5 gel arm had a 30% lower rate of HIV infection compared with those in the no gel at all, universal placebo gel, and BufferGel arms, but this effect was not statistically significant. Unfortunately, the phase III clinical trial with PRO 2000/5 gel which involved a larger number of women (9395) found no evidence that this product reduced the risk of HIV infection. Other promising first- and second-generation microbicides that are at an earlier stage of preclinical and clinical investigation include the Invisible Condom® (a physical/chemical barrier; phase II/III planned),26Mbopi-Keou F.X. Trottier S. Omar R.F. Nkele N.N. Fokoua S. Mbu E.R. et al.A randomized, double-blind, placebo-controlled safety and acceptability study of two Invisible Condom formulations in women from Cameroon.Contraception. 2009; 80: 484-492Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar, 27Mbopi-Keou F.X. Trottier S. Omar R.F. Nkele N.N. Fokoua S. Mbu E.R. et al.A randomized, double-blind, placebo-controlled Phase II extended safety study of two Invisible Condom formulations in Cameroonian women.Contraception. 2010; 81: 79-85Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar praneem polyherbal vaginal tablet (unknown mechanism of action; phase II completed),28Joshi S.N. Dutta S. Kumar B.K. Katti U. Kulkarni S. Risbud A. et al.Expanded safety study of Praneem polyherbal vaginal tablet among HIV-uninfected women in Pune, India: a phase II clinical trial report.Sex Transm Infect. 2008; 84: 343-347Crossref PubMed Scopus (27) Google Scholar VivaGel (a dendrimer-based entry inhibitor; phase I/II ongoing),29Jiang Y.H. Emau P. Cairns J.S. Flanary L. Morton W.R. McCarthy T.D. et al.SPL7013 gel as a topical microbicide for prevention of vaginal transmission of SHIV89.6P in macaques.AIDS Res Hum Retroviruses. 2005; 21: 207-213Crossref PubMed Scopus (145) Google Scholar, 30Patton D.L. Cosgrove Sweeney Y.T. McCarthy T.D. Hillier S.L. Preclinical safety and efficacy assessments of dendrimer-based (SPL7013) microbicide gel formulations in a nonhuman primate model.Antimicrob Agents Chemother. 2006; 50: 1696-1700Crossref PubMed Scopus (94) Google Scholar ACIDFORM (a buffering agent; phase I ongoing),31Williams D.L. Newman D.R. Ballagh S.A. Creinin M.D. Barnhart K. Weiner D.H. et al.Phase I safety trial of two vaginal microbicide gels (Acidform or BufferGel) used with a diaphragm compared to KY jelly used with a diaphragm.Sex Transm Dis. 2007; 34: 977-984Crossref PubMed Scopus (32) Google Scholar and SAMMA (a mandelic acid condensation polymer; in preclinical studies).32Chang T.L. Teleshova N. Rapista A. Paluch M. Anderson R.A. Waller D.P. et al.SAMMA, a mandelic acid condensation polymer, inhibits dendritic cell-mediated HIV transmission.FEBS Lett. 2007; 581: 4596-4602Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar Bioengineered lactobacilli are also being developed to express proteins (such as CD4,33Chang T.L. Chang C.H. Simpson D.A. Xu Q. Martin P.K. Lagenaur L.A. et al.Inhibition of HIV infectivity by a natural human isolate of Lactobacillus jensenii engineered to express functional two-domain CD4.Proc Natl Acad Sci U S A. 2003; 100: 11672-11677Crossref PubMed Scopus (167) Google Scholar a derivative of gp41,34Rao S. Hu S. McHugh L. Lueders K. Henry K. Zhao Q. et al.Toward a live microbial microbicide for HIV: commensal bacteria secreting an HIV fusion inhibitor peptide.Proc Natl Acad Sci U S A. 2005; 102: 11993-11998Crossref PubMed Scopus (124) Google Scholar or cyanovirin35Lagenaur L.A. Berger E.A. An anti-HIV microbicide comes alive.Proc Natl Acad Sci U S A. 2005; 102: 12294-12295Crossref PubMed Scopus (17) Google Scholar) that bind to HIV and block either viral–host cell fusion or viral entry into host cells. Third-generation microbicides include HIV replication and entry inhibitors.9Klasse P.J. Shattock R. Moore J.P. Antiretroviral drug-based microbicides to prevent HIV-1 sexual transmission.Annu Rev Med. 2008; 59: 455-471Crossref PubMed Scopus (158) Google Scholar In contrast to earlier generations, they are not effective against other sexually transmitted pathogens and are not contraceptive. The most advanced compounds include ARV medications such as a nucleotide reverse transcriptase inhibitor (NtRTI) (tenofovir; Gilead) and two non-nucleoside reverse transcriptase inhibitors (NNRTI) (dapivirine (Tibotec/Virco) and UC781). These products formulated as vaginal gels are presently in the early phases of clinical investigation.36Mayer K.H. Maslankowski L.A. Gai F. El-Sadr W.M. Justman J. Kwiecien A. et al.Safety and tolerability of tenofovir vaginal gel in abstinent and sexually active HIV-infected and uninfected women.AIDS. 2006; 20: 543-551Crossref PubMed Scopus (155) Google Scholar, 37Jespers V.A. Van Roey J.M. Beets G.I. Buvé A.M. Dose-ranging phase 1 study of TMC120, a promising vaginal microbicide, in HIV-negative and HIV-positive female volunteers.J Acquir Immune Defic Syndr. 2007; 44: 154-158Crossref PubMed Scopus (56) Google Scholar, 38Schwartz J.L. Kovalevsky G. Lai J.J. Ballagh S.A. McCormick T. Douville K. et al.A randomized six-day safety study of an antiretroviral microbicide candidate UC781, a non-nucleoside reverse transcriptase inhibitor.Sex Transm Dis. 2008; 35: 414-419Crossref PubMed Scopus (50) Google Scholar The NNRTI MIV-150 suspended in Carraguard® gel base (PC-815; Population Council) is in advanced pre-clinical testing. Third-generation microbicides could also inhibit HIV infection by interfering with the binding of the virus to cellular receptors.39Reeves J.D. Piefer A.J. Emerging drug targets for antiretroviral therapy.Drugs. 2005; 65: 1747-1766Crossref PubMed Scopus (117) Google Scholar Two inhibitors of the chemokine receptor CCR5 (CMPD167 (Merck) and PSC-RANTES) have been shown to protect rhesus macaques after intravaginal challenge with a simian human immunodeficiency virus.40Lederman M.M. Veazey R.S. Offord R. Mosier D.E. Dufour J. Mefford M. et al.Prevention of vaginal SHIV transmission in rhesus macaques through inhibition of CCR5.Science. 2004; 306: 485-487Crossref PubMed Scopus (336) Google Scholar, 41Veazey R.S. Klasse P.J. Schader S.M. Hu Q. Ketas T.J. Lu M. et al.Protection of macaques from vaginal SHIV challenge by vaginally delivered inhibitors of virus-cell fusion.Nature. 2005; 438: 99-102Crossref PubMed Scopus (275) Google Scholar Recently, maraviroc, the CCR5 inhibitor developed by Pfizer, entered the development pipeline as a candidate microbicide. It is suggested that fusion and integrase inhibitors could also be candidates. In addition to gel formulations, coitally-independent microbicides are being developed in the form of vaginal rings made of silicone elastomer, which allow a controlled sustained release of ARV drugs over a long period of time, eliminating the need to apply a formulation before each sexual intercourse.42Malcolm R.K. Woolfson A.D. Toner C.F. Morrow R.J. McCullagh S.D. Long-term, controlled release of the HIV microbicide TMC120 from silicone elastomer vaginal rings.J Antimicrob Chemother. 2005; 56: 954-956Crossref PubMed Scopus (149) Google Scholar However, there is a concern that ARV-based microbicides could lead to drug resistance if they are used by HIV-positive women unaware of their HIV status. Therefore, the protocols of clinical trials testing ARV-based microbicides have been redesigned to evaluate the risk of HIV-positive women developing resistance (e.g., the VOICE study – Vaginal and Oral Interventions to Control the Epidemic). The risk of developing resistance is more elevated with formulations or vaginal rings containing a single ARV agent compared with combinations of drugs with different targets in the viral lifecycle. All classes of ARV-based microbicides could be formulated alone or in combination. However, FDA regulations require that microbicides containing more than one active ingredient show the clinical superiority of combined active agents over each individual component before they can be approved.43Coplan P.M. Mitchnick M. Rosenberg Z.F. Public health. Regulatory challenges in microbicide development.Science. 2004; 304: 1911-1912Crossref PubMed Scopus (30) Google Scholar This will add enormously to the cost and duration of product development. Considerable work has been accomplished in making ARV therapy accessible to individuals living in low- and middle-income countries, though much remains to be done in order to attain universal coverage. In resource-poor countries, it is important to preserve first-line treatment regimens because second-line therapies are rare and expensive.44Gilks C.F. Crowley S. Ekpini R. Gove S. Perriens J. Souteyrand Y. et al.The WHO public-health approach to antiretroviral treatment against HIV in resource-limited settings.Lancet. 2006; 368: 505-510Abstract Full Text Full Text PDF PubMed Scopus (535) Google Scholar First-line regimens, usually zidovudine (Retrovir), lamivudine (Epivir), and nevirapine (Viramune), costs nearly $240 per year, whereas second-line regimens, which often include tenofovir (Viread), emtricitabine (Emtriva) and lopinavir (Kaletra), cost as much as $750 per year. Tenofovir is a highly desired ARV in these countries because it is safe, requires relatively limited toxicity monitoring, and is administered once daily.45Ford N. Gray A. Venter F. Tough choices: tenofovir, tenders and treatment.S Afr J HIV Med. 2008; 9: 8-10Google Scholar The systemic tenofovir absorption from a 1% vaginal gel suggests that the development of resistance is plausible.36Mayer K.H. Maslankowski L.A. Gai F. El-Sadr W.M. Justman J. Kwiecien A. et al.Safety and tolerability of tenofovir vaginal gel in abstinent and sexually active HIV-infected and uninfected women.AIDS. 2006; 20: 543-551Crossref PubMed Scopus (155) Google Scholar However, tenofovir is currently being evaluated in clinical trials as a gel-based microbicide and a vaginal ring-based microbicide, as well as an ‘anti-HIV pill’ in pre-exposure prophylaxis (PrEP).46Cohen M.S. Kashuba A.D. Antiretroviral therapy for prevention of HIV infection: new clues from an animal model.PLoS Med. 2008; 5: e30Crossref PubMed Scopus (23) Google Scholar It cannot be excluded that, if marketed, an inconsistent use of these prevention options for long periods of time by populations at high risk of acquiring HIV could lead to resistance to tenofovir (such as the high level tenofovir mutation K65R), which could thereby compromise future use of this highly desired life-saving drug. Currently, in regions that are the most hard hit by the HIV/AIDS epidemic, there is insufficient laboratory capacity as well as personnel and financial resources to perform regular HIV viral load monitoring and detection of resistance mutations.47Hamers R.L. Derdelinckx I. van Vugt M. Stevens W. Rinke de Wit T.F. Schuurman R. et al.The status of HIV-1 resistance to antiretroviral drugs in sub-Saharan Africa.Antivir Ther. 2008; 13: 625-639PubMed Google Scholar The World Health Organization (WHO) is launching a public health strategy through the Global HIV Drug Resistance Surveillance Network (HIVResNet) and national governments, but the global implementation still needs the support of policymakers and money.48Bennett D.E. Bertagnolio S. Sutherland D. Gilks C.F. The World Health Organization's global strategy for prevention and assessment of HIV drug resistance.Antivir. Ther. 2008; 13: 1-13PubMed Google Scholar In these countries, viral load measurement costs $20 to $50 per test, which is four-times more than the CD4 cell count test. Therefore, patients put on ARV therapy are monitored on the basis of clinical and immunological parameters only, as recommended by the WHO.49Antiretroviral therapy for HIV infection in adults and adolescents: recommendations for a public health approach. Revision 1-134. Geneva: World Health Organization; 2006. Available at: http://www.who.int/hiv/pub/guidelines/artadultguidelines.pdf. (accessed May 2010).Google Scholar Clinical and immunological parameters are less reliable than viral load monitoring and detection of resistance mutations to evaluate therapy failure, leading to unnecessary switches to second-line regimens in the absence of treatment failure or to longer administration of a failing treatment regimen.50Moore D.M. Mermin J. Awor A. Yip B. Hogg R.S. Montaner J.S. Performance of immunologic responses in predicting viral load suppression: implications for monitoring patients in resource-limited settings.J Acquir Immune Defic Syndr. 2006; 43: 436-439Crossref PubMed Scopus (62) Google Scholar, 51Mee P. Fielding K.L. Charalambous S. Churchyard G.J. Grant A.D. Evaluation of the WHO criteria for antiretroviral treatment failure among adults in South Africa.AIDS. 2008; 22: 1971-1977Crossref PubMed Scopus (189) Google Scholar, 52Reynolds S.J. Nakigozi G. Newell K. Ndyanabo A. Galiwongo R. Boaz I. et al.Failure of immunologic criteria to appropriately identify antiretroviral treatment failure in Uganda.AIDS. 2009; 23: 697-700Crossref PubMed Scopus (158) Google Scholar This could create the conditions for an accelerated development of HIV resistance to ARV drugs.53Hosseinipour M.C. van Oosterhout J.J. Weigel R. Phiri S. Kamwendo D. Parkin N. et al.The public health approach to identify antiretroviral therapy failure: high-level nucleoside reverse transcriptase inhibitor resistance among Malawians failing first-line antiretroviral therapy.AIDS. 2009; 23: 1127-1134Crossref PubMed Scopus (245) Google Scholar This situation will be even more complicated if individuals, at high risk of infection, use microbicides containing ARVs inconsistently and for long periods of time without knowing their HIV status. Therefore, there should be laboratory capacity, personnel, and financial resources in place to perform HIV diagnostics and detection of resistance mutations before introducing ARV-based formulations in resource-poor countries. To reach the highest possible number of women, microbicides should be available over-the-counter, which might not be the case with ARV-based formulations. In contrast, women will not need to be tested for HIV or obtain a prescription from a physician in order to gain access to non-ARV-based microbicides. Therefore, these products could be made rapidly available over-the-counter to a large number of women in countries most in need of microbicides. It has been estimated that a microbicide with even a low effectiveness, but with a wide distribution could have a substantial impact against the global HIV epidemic.54Foss A.M. Vickerman P.T. Heise L. Watts C.H. Shifts in condom use following microbicide introduction: should we be concerned?.AIDS. 2003; 17: 1227-1237Crossref PubMed Scopus (111) Google Scholar In addition, infections by other sexually transmitted pathogens, especially those causing ulcerations to the vaginal mucosa, are important risk factors for HIV acquisition. Therefore, although HIV is the primary target for most microbicides, broad-spectrum products that have the ability to cover additional sexually transmitted pathogens may demonstrate enhanced protection against HIV.55Foss A.M. Vickerman P.T. Alary M. Watts C.H. How much could a microbicide's sexually transmitted infection efficacy contribute to reducing HIV risk and the level of condom use needed to lower risk?. Model estimates.Sex Transm Infect. 2009; 85: 276-282Crossref PubMed Scopus (13) Google Scholar The development of safe and effective microbicides has been delayed by limitations in understanding the mechanism of HIV transmission, the lack of validated animal models, the lack of established surrogate markers of safety, and the need to enroll and follow large cohorts of high-risk participants for several years in order to demonstrate efficacy. Clinical trial failures with the first candidate microbicides has underscored the urgency of identifying and validating biomarkers predictive of safety and efficacy.56van de Wijgert J.H. Shattock R.J. Vaginal microbicides: moving ahead after an unexpected setback.AIDS. 2007; 21: 2369-2376Crossref PubMed Scopus (68) Google Scholar Several biomarkers have been proposed for the preclinical evaluation of candidate microbicides, such as epithelial barrier disruption,57Mesquita P.M. Cheshenko N. Wilson S.S. Mhatre M. Guzman E. Fakioglu E. et al.Disruption of tight junctions by cellulose sulfate facilitates HIV infection: model of microbicide safety.J Infect Dis. 2009; 200: 599-608Crossref PubMed Scopus (100) Google Scholar efficacy in preventing HIV infection in human cervical explant tissue cultures,58Cummins Jr., J.E. Guarner J. Flowers L. Guenthner P.C. Bartlett J. Morken T. et al.Preclinical testing of candidate topical microbicides for anti-human immunodeficiency virus type 1 activity and tissue toxicity in a human cervical explant culture.Antimicrob Agents Chemother. 2007; 51: 1770-1779Crossref PubMed Scopus (133) Google Scholar and effect of seminal plasma on product efficacy,59Patel S. Hazrati E. Cheshenko N. Galen B. Yang H. Guzman E. et al.Seminal plasma reduces the effectiveness of topical polyanionic microbicides.J Infect Dis. 2007; 196: 1394-1402Crossref PubMed Scopus (85) Google Scholar as well as mucosal inflammation and susceptibility to genital herpes in mice.60Galen B.T. Martin A.P. Hazrati E. Garin A. Guzman E. Wilson S.S. et al.A comprehensive murine model to evaluate topical vaginal microbicides: mucosal inflammation and susceptibility to genital herpes as surrogate markers of safety.J Infect Dis. 2007; 195: 1332-1339Crossref PubMed Scopus (59) Google Scholar In addition, biomarkers such as evaluation of induction of inflammatory response or loss of host defence,61Cummins Jr., J.E. Doncel G.F. Biomarkers of cervicovaginal inflammation for the assessment of microbicide safety.Sex Transm Dis. 2009; 36: S84-91Crossref PubMed Scopus (46) Google Scholar altered vaginal microflora,62Myer L. Kuhn L. Stein Z.A. Wright Jr., T.C. Denny L. Intravaginal practices, bacterial vaginosis, and women's susceptibility to HIV infection: epidemiological evidence and biological mechanisms.Lancet Infect Dis. 2005; 5: 786-794Abstract Full Text Full Text PDF PubMed Scopus (158) Google Scholar and ex vivo assessment of microbicide efficacy63Keller M.J. Zerhouni-Layachi B. Cheshenko N. John M. Hogarty K. Kasowitz A. et al.PRO 2000 gel inhibits HIV and herpes simplex virus infection following vaginal application: a double-blind placebo-controlled trial.J Infect Dis. 2006; 193: 27-35Crossref PubMed Scopus (88) Google Scholar, 64Keller M.J. Guzman E. Hazrati E. Kasowitz A. Cheshenko N. Wallenstein S. et al.PRO 2000 elicits a decline in genital tract immune mediators without compromising intrinsic antimicrobial activity.AIDS. 2007; 21: 467-476Crossref PubMed Scopus (119) Google Scholar, 65Keller M.J. Herold B.C. Understanding basic mechanisms and optimizing assays to evaluate the efficacy of vaginal microbicides.Sex Transm Dis. 2009; 36: S92-S95Crossref PubMed Scopus (17) Google Scholar could give information in early clinical trials about the safety and likely effectiveness of candidate microbicides. This would allow a better characterization of candidate microbicides and the detection of less promising products before they move to large phase IIB/III clinical trials. Finally, biomarkers of sexual behavior, such as vaginal exposure to semen66Mauck C.K. Biomarkers of semen exposure.Sex Transm Dis. 2009; 36: S81-S83Crossref PubMed Scopus (20) Google Scholar and adherence to product use67Mauck C.K. Straten A. Using objective markers to assess participant behavior in HIV prevention trials of vaginal microbicides.J Acquir Immune Defic Syndr. 2008; 49: 64-69Crossref PubMed Scopus (29) Google Scholar could help with interpretation of study results. With these new tools in hand, we suggest that the development of over-the-counter non-ARV-based microbicides should be reinvigorated. There are now new biomarkers of safety and efficacy to characterize the other promising first- and second-generation products that are in the pipeline for a more rationale selection of those that could enter into large and expensive phase IIB/III clinical trials. Non-ARV-based microbicides may have an important place in the arsenal of HIV preventive options that are urgently needed by women, especially those living in low- and middle-income countries, to control their sexual destiny without jeopardizing the use of life-saving drugs. Conflict of interest: No conflict of interest to declare." @default.
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• W2044321160 cites W1566538987 @default.
• W2044321160 cites W1834473277 @default.
• W2044321160 cites W1975920443 @default.
• W2044321160 cites W1982826681 @default.
• W2044321160 cites W1983160608 @default.
• W2044321160 cites W1986445745 @default.
• W2044321160 cites W1991703470 @default.
• W2044321160 cites W1994566416 @default.
• W2044321160 cites W1994842809 @default.
• W2044321160 cites W1999408038 @default.
• W2044321160 cites W1999846706 @default.
• W2044321160 cites W2002999110 @default.
• W2044321160 cites W2004948816 @default.
• W2044321160 cites W2008851079 @default.
• W2044321160 cites W2020228820 @default.
• W2044321160 cites W2020394552 @default.
• W2044321160 cites W2024213191 @default.
• W2044321160 cites W2029246165 @default.
• W2044321160 cites W2032195660 @default.
• W2044321160 cites W2032367420 @default.
• W2044321160 cites W2034212848 @default.
• W2044321160 cites W2050023514 @default.
• W2044321160 cites W2050080139 @default.
• W2044321160 cites W2050121349 @default.
• W2044321160 cites W2051528892 @default.
• W2044321160 cites W2053151515 @default.
• W2044321160 cites W2059780880 @default.
• W2044321160 cites W2064309577 @default.
• W2044321160 cites W2073889754 @default.
• W2044321160 cites W2075201634 @default.
• W2044321160 cites W2078191149 @default.
• W2044321160 cites W2078702893 @default.
• W2044321160 cites W2083205410 @default.
• W2044321160 cites W2087185133 @default.
• W2044321160 cites W2091180436 @default.
• W2044321160 cites W2096077458 @default.
• W2044321160 cites W2100206933 @default.
• W2044321160 cites W2100424501 @default.
• W2044321160 cites W2101188907 @default.
• W2044321160 cites W2106853491 @default.
• W2044321160 cites W2109302198 @default.
• W2044321160 cites W2123459861 @default.
• W2044321160 cites W2129351297 @default.
• W2044321160 cites W2129431697 @default.
• W2044321160 cites W2130644352 @default.
• W2044321160 cites W2130956363 @default.
• W2044321160 cites W2133166320 @default.
• W2044321160 cites W2139561917 @default.
• W2044321160 cites W2143649821 @default.
• W2044321160 cites W2144198686 @default.
• W2044321160 cites W2145718464 @default.
• W2044321160 cites W2150550553 @default.
• W2044321160 cites W2151842647 @default.
• W2044321160 cites W2155737863 @default.
• W2044321160 cites W2156761639 @default.
• W2044321160 cites W2159327723 @default.
• W2044321160 cites W2159835304 @default.
• W2044321160 cites W2160010002 @default.
• W2044321160 cites W2160780945 @default.
• W2044321160 cites W2166916078 @default.
• W2044321160 cites W2167246391 @default.
• W2044321160 cites W2168429913 @default.
• W2044321160 cites W2288781812 @default.
• W2044321160 cites W3196876339 @default.
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