Biomedical Engineering – From Theory to Applications

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30 Biomedical Engineering – From Theory to Applications the ARV MIV-150 has shown some efficacy in preventing SHIV-RT infection in macaques (Aravantinou et al., 2010). Recently, there has been a major leap forward in the microbicide field, with the use of ARVbased agents for HIV prevention. The Centre for the AIDS Programme of Research In South Africa (CAPRISA) 004 safety and effectiveness study compared 1% tenofovir gel with a placebo, and found that the active gel reduced HIV infections by 39% overall, and by 54% in highly adherent trial participants (Abdool Karim et al., 2010). This result is at the forefront of a major sea change in the microbicide field away from non-specific compounds and towards the use of specific ARV drugs for application prior to exposure to HIV. Trials are currently planned to confirm the effect of 1% tenofovir gel, and several trials are ongoing to test the safety and/or efficacy of other ARVs such as dapivirine and UC781 (see table 2 below). Study /Phase Location Population Candidate substance VOICE (MTN 003) Phase IIb, safety and effectiveness IPM 014A Phase I/II, safety IPM 014B Phase I/II, safety IPM 020 Phase I/II, safety IPM 015 Phase I/II, safety IPM 013 Phase I, P/K Pilot Study Phase I Malawi, South Africa, Uganda, Zimbabwe 5,000 heterosexual women Tenofovir gel; oral TDF; oral TDF/FTC Kenya, Malawi, 320 women Dapivirine vaginal gel Rwanda, South Africa South Africa 320 women Dapivirine vaginal gel United States 180 women Dapivirine vaginal gel South Africa (ongoing), Kenya, Malawi, Rwanda, Tanzania, Zambia (planned) 280 women Belgium 48 women Dapivirine vaginal ring Dapivirine vaginal ring United States 15 women UC-781 gel Table adapted from Alliance for AIDS Vaccine Advocacy Coalition website at www.avac.org accessed March 29, 2011 FTC - emtricitabine; TDF - tenofovir disoproxil fumarate Table 2. Ongoing ARV-based microbicide trials The ARV-based microbicides in Table 2 are all reverse transcriptase inhibitors (RTIs), although of two different classes. Tenofovir is a nucleoside reverse transcriptase inhibitor or “chain terminator” which interferes with the synthesis of the viral DNA by interpolation into the growing strand. Both dapivirine and UC-781 are non-nucleoside reverse transcriptase inhibitors (NNRTIs) which bind to a non-active site on reverse transcriptase, inducing a conformational change which prevents further activity of the enzyme (D'Cruz & Uckun, 2006). Other prospective ARV-based microbicides may include maraviroc (a cell entry inhibitor) (Fletcher et al., 2010; Herrera et al., 2010), protease inhibitors (Evans et al., 2010) and other NNRTIs such as MIV-150 (Kenney et al., 2011). Recent innovations in microbicide delivery have included the development of intravaginal rings (IVRs). These rings are similar to those currently marketed for contraceptive use, but
Biomedical HIV Prevention have instead as their active ingredient an antiretroviral agent. The rings have been formulated in two ways – as matrix or reservoir types. In the matrix type, the active ingredient is homogenously distributed throughout the ring material, while in the reservoir type, a central core containing the ARV is surrounded by an unmedicated outer layer (Malcolm et al., 2010). Matrix type IVRs may have a less favourable drug release profile than the reservoir type, since the release of the drug is less controlled, resulting in an early spike in concentration. The addition of rate controlling layers may assist in minimising this characteristic (Malcolm et al., 2010). Most IVRs are made of silicone elastomer (eg. polydimethylsiloxane) or thermoplastic elastomer (eg. poly[ethylene vinyl acetate] and segmented polyurethane) (Malcolm et al., 2010). Formulation of IVRs both with and without contraceptives will provide women with the option of preventing acquisition/transmission of HIV without affecting fertility – a feature which is particularly important in contexts where fertility is highly valued. Although microbicides were initially proposed for vaginal use, there has recently been an increase in research on microbicides for rectal application, since it is recognised that this is a significant route of exposure to HIV infection for both women and men who have sex with men (Ramjee et al., 2010). The development of microbicides for application to the rectum has resulted in research comparing the effect of microbicides on the vaginal and rectal mucosa which has shown that the rectal mucosa may be relatively more delicate (Patton et al., 2009). Vaginal microbicides should not be assumed to be safe for rectal use. Future work on rectal microbicides will require specific in vitro and animal models to assess the impact of the products on the target tissue type. Challenges in the clinical trials of microbicides have included lack of appropriate animal models to assess safety prior to human trials, high pregnancy rates (women are taken off the product when pregnant), products with low HIV specificity, and achieving high adherence to the product by trial participants (Ramjee et al., 2010). The promising effectiveness demonstrated by an ARV-based microbicide has re-invigorated the field (Abdool Karim et al., 2010). However, these products remain unlikely to be 100% effective, hence correct and consistent use of additional prevention options may be required. 2.5 Oral antiretroviral therapy for prevention Development and use of ARV agents has had a significant impact on improving lifespan and quality of life of people living with HIV. These agents have also played a groundbreaking role in prevention of mother to child transmission (MTCT) (Connor et al., 1994) with MTCT in the developed world almost eradicated owing to this success. The use of ARVs for prevention of MTCT has been shown to be both feasible and cost effective (Chigwedere et al., 2008) - but treatment may not be available to women living in less developed countries. The success of prevention of MTCT suggests that antiretroviral therapy (ART) could be used as a chemoprophylactic method to prevent sexual HIV transmission due to its ability to suppress viral load and viral replication both prior to and post exposure to HIV. There is evidence that post-exposure prophylaxis (PEP) can reduce the risk of acquisition of HIV (Mackie & Coker, 2000). Research into ART for pre-exposure prophylaxis (PrEP) has gained momentum recently with several trials in various population groups under way in many countries. All these trials (see Table 3) have used the drug tenofovir disoproxil fumarate (TDF) or tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) due to its good safety profile and infrequent side effects (Paxton et al., 2007). Tenofovir disoproxil fumarate is the 31
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180 16. Acknowledgments Biomedical
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190 R* M M M M MR*M O O O O M O R*
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