Oral pre-exposure prophylaxis for HIV prevention

Division of HIV/AIDS Prevention, National Center for HIV, Hepatitis, STD, and Prevention, Centers for Disease Control and Prevention, 1600 Clifton Road, Atlanta, GA 30329, USA.
Trends in Pharmacological Sciences (Impact Factor: 9.99). 12/2009; 31(2):74-81. DOI: 10.1016/
Source: PubMed

ABSTRACT In the absence of an effective vaccine, HIV continues to spread worldwide, emphasizing the need for new biomedical interventions to limit its transmission. Appreciation of the challenges that HIV has to face to initiate an infection mucosally has spurred interest in evaluating the use of antiretroviral drugs to prevent infection. Recent animal studies using macaques or humanized mice models of mucosal transmission of SIV or HIV have shown that daily or intermittent pre-exposure prophylaxis (PrEP) with tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) can exploit early virus vulnerabilities and effectively prevent establishment of infection. These preclinical findings have fueled interest in evaluating the safety and efficacy of PrEP in humans. We provide an overview of the rationale behind PrEP and discuss the next steps in PrEP research, including the need to better define the ability of current drugs to reach and accumulate in mucosal tissues and protect cells that are primary targets during early HIV infection.

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    • "Prevention of HIV-1 infection to reduce the number of newly infected individuals is an international priority. Various modalities such as male circumcision (Warner et al., 2009), prophylactic HIV vaccines (Munier et al., 2011), vaginal microbicides (Kelly and Shattock, 2011) and oral pre-exposure prophylaxis (García-Lerma et al., 2010) have been explored to prevent sexual contraction of HIV. Prevention of HIV infection by using antiretroviral agents as vaginal microbicides has received more attention in recent years. "
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    ABSTRACT: The objective of this investigation was to develop a thermosensitive vaginal gel containing raltegravir+efavirenz loaded PLGA nanoparticles (RAL-EFV-NPs) for pre-exposure prophylaxis of HIV. RAL-EFV-NPs were fabricated using a modified emulsion-solvent evaporation method and characterized for size and zeta potential. The average size and surface charge of RAL-EFV-NP were 81.8±6.4nm and -23.18±7.18mV respectively. The average encapsulation efficiency of raltegravir and efavirenz was 55.5% and 98.2% respectively. Thermosensitive vaginal gel containing RAL-EFV-NPs was successfully prepared using a combination of Pluronic F127 (20% w/v) and Pluronic F68 (1% w/v). Incorporation RAL-EFV-NPs in the gel did not result in nanoparticle aggregation and RAL-EFV-NPs containing gel showed thermogelation at 32.5°C. The RAL-EFV-NPs were evaluated for inhibition of HIV-1(NL4-3) using TZM-bl indicator cells. The EC(90) of RAL-EFV-NPs was lower than raltegravir+efavirenz (RAL-EFV) solution but did not reach significance. Compared to control HeLa cells without any treatment, RAL-EFV-NPs or blank gel were not cytotoxic for 14days in vitro. The intracellular levels of efavirenz in RAL-EFV-NPs treated HeLa cells were above the EC(90) for 14days whereas raltegravir intracellular concentrations were eliminated within 6days. Transwell experiments of NPs-in-gel demonstrated rapid transfer of fluorescent nanoparticles from the gel and uptake in HeLa cells within 30min. These data demonstrate the potential of antiretroviral NP-embedded vagina gels for long-term vaginal pre-exposure prophylaxis of heterosexual HIV-1 transmission.
    Antiviral research 10/2012; 96(3). DOI:10.1016/j.antiviral.2012.09.015 · 3.94 Impact Factor
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    • "The concept of targeted systemic PrEP involves the continuous treatment of HIV-1-negative individuals at high risk for acquiring HIV-1 with antiretroviral drugs in an effort to prevent HIV-1 transmission (Garcia-Lerma et al., 2010). However, there are major concerns regarding the potential side effects of the drugs used because systemic PrEP entails the administration of antiretroviral drugs to large numbers of otherwise healthy individuals (Derdelinckx et al., 2006). "
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    ABSTRACT: An HIV vaccine capable of providing sterilizing immunity from vaginal infection would reduce the spread of HIV to women. Unfortunately, only one of the four HIV-1 vaccine clinical trials has demonstrated any level of protection (31%) against HIV-1 transmission. Additionally, only one topical microbicide clinical trial has reported an overall reduction in HIV transmission (39%). Developing even more effective vaccines and microbicides will require a better understanding of the key events involved in HIV infection and dissemination at the site of exposure. Novel immunodeficient mice capable of being systemically reconstituted with human hematopoietic stem cells have provided new systems where HIV transmission studies can be performed. Specifically, a humanized mouse model of vaginal HIV transmission has been developed that utilizes the humanized bone marrow-liver-thymus (BLT) mouse. The female reproductive tract (FRT) of humanized BLT mice is reconstituted with functional human immune cells rendering them susceptible to vaginal HIV-1 infection. In this review we focus on four aspects of BLT mice for the study of vaginal HIV-1 transmission: (1) we discuss methods for creating humanized BLT mice and their reconstitution with human hematopoietic cells, (2) we describe reconstitution of the BLT mouse FRT with human immune cells, (3) we highlight the work done regarding vaginal HIV-1 transmission and (4) we summarize the efficacy of systemic pre-exposure prophylaxis (PrEP) to prevent vaginal HIV-1 transmission in BLT mice. BLT mice are a highly relevant small animal model for studying vaginal HIV-1 transmission, prevention and therapy.
    Journal of Reproductive Immunology 03/2011; 88(2):195-203. DOI:10.1016/j.jri.2010.11.005 · 2.37 Impact Factor
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    ABSTRACT: Ultrasound contrast agent applications have expanded in recent years to the assessment of perfusion and microvascularity. A new system that measures the acoustic properties of single microbubbles can provide information that can shed new light on contrast enhanced imaging. A polymer shelled agent, BiSphere<sup>®</sup> (Point Biomedical, San Carlos, CA, USA) was used. A very diluted hydrodynamically focused flow of microbubbles was exposed to ultrasound beams of 1 to 4 MHz transmit frequency and 0.2 to 1 MPa peak negative pressure. RF data were captured using an ultrasound scanner (Sonos5500, Philips, Andover, MA, USA). The microbubbles were subjected to consecutive triggered pulses and their survival rate was also assessed. At 0.5 MPa fundamental scattering cross section (SCS) was maximum below 1.5 MHz, while the second harmonic SCS was constant up to 2.3 MHz and greater than the fundamental between 2 and 2.4 MHz. A strong ultraharmonic was present in the majority of the scattered echoes above 0.8 MPa. At 0.5 MPa the microbubble echoes disappeared after the first insonation, suggestive of rapid dissolution. In conclusion BiSphere<sup>TM</sup> displayed compatibility with myocardial perfusion requirements, but most importantly the investigated scattered pulses provided spectral and temporal characteristics that could be used to optimise ultrasound examinations.
    Ultrasonics, 2003 IEEE Symposium on; 11/2003
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