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: 11.54).
12/2009; 31(2):74-81. DOI: 10.1016/j.tips.2009.10.009
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.
Available from: Christopher Destache
- "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.
Available from: ncbi.nlm.nih.gov
- "Oral administration of antiretroviral (ARV) drugs before exposure to HIV (pre-exposure prophylaxis [PrEP]) is a novel prevention strategy to protect high-risk HIV-1-negative people from becoming infected . Two recently completed trials with daily Truvada (a combination of emtricitabine [FTC] and tenofovir disoproxil fumarate [TDF]) have provided the first indication that oral PrEP reduces HIV transmission [2,3]. "
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ABSTRACT: Pre-exposure prophylaxis (PrEP) with daily Truvada [a combination of emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF)] is a novel HIV prevention strategy recently found to prevent HIV transmission among men who have sex with men and heterosexual couples. Acute infection in adherent persons who fail PrEP will inevitably occur under concurrent antiretroviral therapy, thus raising questions regarding the potential impact of PrEP on early viral dynamics. We investigated viral evolution dynamics in a macaque model of PrEP consisting of repeated rectal exposures to SHIV162P3 in the presence of PrEP.
Four macaques were infected during daily or intermittent PrEP with FTC or FTC/TDF, and five were untreated controls. SHIV env sequence evolution was monitored by single genome amplification with phylogenetic and sequence analysis. Mean nucleotide divergence from transmitted founder viruses calculated 17 weeks (range = 12-20) post peak viremia was significantly lower in PrEP failures than in control animals (7.2 × 10-3 compared to 1.6 × 10-2 nucleotide substitutions per site per year, respectively, p < 0.0001). Mean virus diversity was also lower in PrEP failures after 17 weeks (0.13% vs. 0.53% in controls, p < 0.0001).
Our results in a macaque model of acute HIV infection suggest that infection during PrEP limits early virus evolution likely because of a direct antiviral effect of PrEP and/or reduced target cell availability. Reduced virus diversification during early infection might enhance immune control by slowing the selection of escape mutants.
Available from: Ae S Youngpairoj
- "Clinical trials are currently underway or are being completed to evaluate the efficacy of pre-exposure prophylaxis (PrEP) with anti-retroviral (ARV) drugs for the prevention of HIV infection , , , . It is possible that HIV exposure during prophylaxis can stimulate the immune system and induce adaptive immunity in the absence of productive infection. "
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ABSTRACT: Pre-exposure prophylaxis (PrEP) with anti-viral drugs is currently in clinical trials for the prevention of HIV infection. Induction of adaptive immune responses to virus exposures during anti-viral drug administration, i.e., a "chemo-vaccination" effect, could contribute to PrEP efficacy. To study possible chemo-vaccination, we monitored humoral and cellular immune responses in nine rhesus macaques undergoing up to 14 weekly, low-dose SHIV(SF162P3) rectal exposures. Six macaques concurrently received PrEP with intermittent, oral Truvada; three were no-PrEP controls. PrEP protected 4 macaques from infection. Two of the four showed evidence of chemo-vaccination, because they developed anti-SHIV CD4(+) and CD8(+) T cells; SHIV-specific antibodies were not detected. Control macaques showed no anti-SHIV immune responses before infection. Chemo-vaccination-induced T cell responses were robust (up to 3,940 SFU/10(6) PBMCs), predominantly central memory cells, short-lived (≤22 weeks), and appeared intermittently and with changing specificities. The two chemo-vaccinated macaques were virus-challenged again after 28 weeks of rest, after T cell responses had waned. One macaque was not protected from infection. The other macaque concurrently received additional PrEP. It remained uninfected and T cell responses were boosted during the additional virus exposures. In summary, we document and characterize PrEP-induced T cell chemo-vaccination. Although not protective after subsiding in one macaque, chemo-vaccination-induced T cells warrant more comprehensive analysis during peak responses for their ability to prevent or to control infections after additional exposures. Our findings highlight the importance of monitoring these responses in clinical PrEP trials and suggest that a combination of vaccines and PrEP potentially might enhance efficacy.
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