scholarly journals Deciphering the Effects of Injectable Pre-exposure Prophylaxis for Combination Human Immunodeficiency Virus Prevention

2016 ◽  
Vol 3 (3) ◽  
Author(s):  
Robert L. Glaubius ◽  
Urvi M. Parikh ◽  
Greg Hood ◽  
Kerri J. Penrose ◽  
Eran Bendavid ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Drug Resistance ◽  
Scale Up ◽  
Cross Resistance ◽  
Human Immunodeficiency Virus Prevention ◽  
Reference Scenario ◽  
Drug Resistant ◽  
Kwazulu Natal ◽  
Immunodeficiency Virus ◽  
Exposure Prophylaxis

Abstract Background.  A long-acting injectable formulation of rilpivirine (RPV), under investigation as antiretroviral pre-exposure prophylaxis (PrEP), may facilitate PrEP adherence. In contrast, cross-resistance between RPV and nonnucleoside reverse-transcriptase inhibitors comprising first-line antiretroviral therapy (ART) could promote human immunodeficiency virus (HIV) drug resistance and reduce PrEP's effectiveness. Methods.  We use novel mathematical modeling of different RPV PrEP scale-up strategies in KwaZulu-Natal, South Africa, to investigate their effects on HIV prevention and drug resistance, compared with a reference scenario without PrEP. Results.  Pre-exposure prophylaxis scale-up modestly increases the proportion of prevalent drug-resistant infections, from 33% to ≤37%. The change in the number of prevalent drug-resistant infections depends on the interplay between PrEP factors (coverage, efficacy, delivery reliability, and scale-up strategy) and the level of cross-resistance between PrEP and ART. An optimistic scenario of 70% effective RPV PrEP (90% efficacious and 80% reliable delivery), among women aged 20–29 years, prevents 17% of cumulative infections over 10 years while decreasing prevalent resistance; however, prevention decreases and resistance increases with more conservative assumptions. Uncertainty analysis assuming 40%–70% cross-resistance prevalence predicts an increase in prevalent resistance unless PrEP's effectiveness exceeds 90%. Conclusions.  Prioritized scale-up of injectable PrEP among women in KwaZulu-Natal could reduce HIV infections, but suboptimal effectiveness could promote the spread of drug resistance.

scholarly journals In Vitro Antiviral Activity and Cross-Resistance Profile of PL-100, a Novel Protease Inhibitor of Human Immunodeficiency Virus Type 1

2007 ◽  
Vol 51 (11) ◽  
pp. 4036-4043 ◽  
Author(s):  
Serge Dandache ◽  
Guy Sévigny ◽  
Jocelyn Yelle ◽  
Brent R. Stranix ◽  
Neil Parkin ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Antiviral Activity ◽  
Highly Active Antiretroviral Therapy ◽  
Cross Resistance ◽  
Drug Resistant ◽  
Resistance Profile ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Despite the success of highly active antiretroviral therapy, the current emergence and spread of drug-resistant variants of human immunodeficiency virus (HIV) stress the need for new inhibitors with distinct properties. We designed, produced, and screened a library of compounds based on an original l-lysine scaffold for their potentials as HIV type 1 (HIV-1) protease inhibitors (PI). One candidate compound, PL-100, emerged as a specific and noncytotoxic PI that exhibited potent inhibition of HIV-1 protease and viral replication in vitro (Ki , ∼36 pM, and 50% effective concentration [EC50], ∼16 nM, respectively). To confirm that PL-100 possessed a favorable resistance profile, we performed a cross-resistance study using a panel of 63 viral strains from PI-experienced patients selected for the presence of primary PI mutations known to confer resistance to multiple PIs now in clinical use. The results showed that PL-100 retained excellent antiviral activity against almost all of these PI-resistant viruses and that its performance in this regard was superior to those of atazanavir, amprenavir, indinavir, lopinavir, nelfinavir, and saquinavir. In almost every case, the increase in the EC50 for PL-100 observed with viruses containing multiple mutations in protease was far less than that obtained with the other drugs tested. These data underscore the potential for PL-100 to be used in the treatment of drug-resistant HIV disease and argue for its further development.

scholarly journals Demonstration of Sustained Drug-Resistant Human Immunodeficiency Virus Type 1 Lineages Circulating among Treatment-Naïve Individuals

2009 ◽  
Vol 83 (6) ◽  
pp. 2645-2654 ◽  
Author(s):  
Stéphane Hué ◽  
Robert J. Gifford ◽  
David Dunn ◽  
Esther Fernhill ◽  
Deenan Pillay
Keyword(s):  
Human Immunodeficiency Virus ◽  
Drug Resistance ◽  
United Kingdom ◽  
Phylogenetic Analyses ◽  
Antiretroviral Drugs ◽  
Cross Resistance ◽  
Transmitted Drug Resistance ◽  
The United Kingdom ◽  
Immunodeficiency Virus

ABSTRACT Transmission of human immunodeficiency virus (HIV) drug resistance is well-recognized and compromises response to first-line therapy. However, the population dynamics of transmitted resistance remains unclear, although previous models have assumed that such transmission reflects direct infection from treated individuals. We investigated whether population-based phylogenetic analyses would uncover lineages of resistant viruses circulating in untreated individuals. Through the phylogenetic analysis of 14,061 HIV type 1 (HIV-1) pol gene sequences generated in the United Kingdom from both treatment-naïve and -experienced individuals, we identified five treatment-independent viral clusters containing mutations conferring cross-resistance to antiretroviral drugs prescribed today in the United Kingdom. These viral lineages represent sustainable reservoirs of resistance among new HIV infections, independent of treatment. Dated phylogenies reconstructed through Bayesian Markov chain Monte Carlo inference indicated that these reservoirs originated between 1997 and 2003 and have persisted in the HIV-infected population for up to 8 years. Since our cohort does not represent all infected individuals within the United Kingdom, our results are likely to underestimate the number and size of the resistant reservoirs circulating among drug-naïve patients. The existence of sustained reservoirs of resistance in the absence of treatment has the capacity to threaten the long-term efficacy of antiretroviral therapy and suggests there is a limit to the decline of transmitted drug resistance. Given the current decrease in resistance transmitted from treated individuals, a greater proportion of resistance is likely to come from drug-naïve lineages. These findings provide new insights for the planning and management of treatment programs in resource-rich and developing countries.

scholarly journals Revealing the Mutation Patterns of Drug-Resistant Reverse Transcriptase Variants of Human Immunodeficiency Virus through Proteochemometric Modeling

Biomolecules ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 1302
Author(s):  
Jingxuan Qiu ◽  
Xinxin Tian ◽  
Jiangru Liu ◽  
Yulong Qin ◽  
Junjie Zhu ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Drug Resistance ◽  
Reverse Transcriptase ◽  
External Validation ◽  
Drug Resistant ◽  
Dominant Mutation ◽  
Pcm Model ◽  
Immunodeficiency Virus ◽  
Frequent Mutations ◽  
Hiv 1

Drug-resistant cases of human immunodeficiency virus (HIV) nucleoside reverse transcriptase inhibitors (NRTI) are constantly accumulating due to the frequent mutations of the reverse transcriptase (RT). Predicting the potential drug resistance of HIV-1 NRTIs could provide instructions for the proper clinical use of available drugs. In this study, a novel proteochemometric (PCM) model was constructed to predict the drug resistance between six NRTIs against different variants of RT. Forty-seven dominant mutation sites were screened using the whole protein of HIV-1 RT. Thereafter, the physicochemical properties of the dominant mutation sites can be derived to generate the protein descriptors of RT. Furthermore, by combining the molecular descriptors of NRTIs, PCM modeling can be constructed to predict the inhibition ability between RT variants and NRTIs. The results indicated that our PCM model could achieve a mean AUC value of 0.946 and a mean accuracy of 0.873 on the external validation set. Finally, based on PCM modeling, the importance of features was calculated to reveal the dominant amino acid distribution and mutation patterns on RT, to reflect the characteristics of drug-resistant sequences.

scholarly journals Integrating Antiretroviral Strategies for Human Immunodeficiency Virus Prevention: Post- and Pre-Exposure Prophylaxis and Early Treatment

2015 ◽  
Vol 2 (4) ◽  
Author(s):  
Robert M. Grant ◽  
Dawn K. Smith
Keyword(s):  
Human Immunodeficiency Virus ◽  
Best Practices ◽  
Hiv Infection ◽  
Early Treatment ◽  
Research Evidence ◽  
Diagnostic Testing ◽  
High Impact ◽  
Human Immunodeficiency Virus Prevention ◽  
Immunodeficiency Virus ◽  
Exposure Prophylaxis

Abstract Best practices for integrating human immunodeficiency virus (HIV) testing and antiretroviral interventions for prevention and treatment are suggested based on research evidence and existing normative guidance. The goal is to provide high-impact prevention services during periods of substantial risk. Antiretroviral medications are recommended for postexposure prophylaxis (PEP), pre-exposure prophylaxis (PrEP), and treatment of HIV infection. We reviewed research evidence and current normative guidelines to identify best practices for integrating these high-impact prevention strategies. More sensitive HIV tests used for screening enable earlier diagnosis and treatment of HIV infection, more appropriate counseling, and help limit drug resistance. A fully suppressive PEP regimen should be initiated based on exposure history or physical findings when sensitive diagnostic testing is delayed or not available and antibody tests are negative. Transitions from PEP to PrEP are often warranted because HIV exposure events may continue to occur. This algorithmic approach to integrating PEP, PrEP, and early treatment decisions may increase the uptake of these interventions by a greater number and diversity of knowledgeable healthcare providers.

scholarly journals Combination of Drugs and Drug-Resistant Reverse Transcriptase Results in a Multiplicative Increase of Human Immunodeficiency Virus Type 1 Mutant Frequencies

2002 ◽  
Vol 76 (18) ◽  
pp. 9253-9259 ◽  
Author(s):  
Louis M. Mansky ◽  
Dennis K. Pearl ◽  
Lisa C. Gajary
Keyword(s):  
Human Immunodeficiency Virus ◽  
Drug Resistance ◽  
Reverse Transcriptase ◽  
Drug Resistant ◽  
Resistance Mutations ◽  
Drug Resistance Mutations ◽  
Immunodeficiency Virus ◽  
Hiv 1 ◽  
Mutant Frequency

ABSTRACT Replication of drug-resistant human immunodeficiency virus type 1 (HIV-1) in the presence of drug can lead to the failure of antiretroviral drug treatment. Drug failure is associated with the accumulation of drug resistance mutations. Previous studies have shown that 3′-azido-3′-deoxythymidine (AZT), (−)2′,3′-dideoxy-3′-thiacytidine (3TC), and AZT-resistant HIV-1 reverse transcriptase (RT) can increase the virus in vivo mutation rate. In this study, the combined effects of drug-resistant RT and antiretroviral drugs on the HIV-1 mutant frequency were determined. In most cases, a multiplicative effect was observed with AZT-resistant or AZT/3TC dually resistant RT and several drugs (i.e., AZT, 3TC, hydroxyurea, and thymidine) and led to increases in the odds of recovering virus mutants to over 20 times that of the HIV-1 mutant frequency in the absence of drug or drug-resistance mutations. This observation indicates that HIV-1 can mutate at a significantly higher rate when drug-resistant virus replicates in the presence of drug. These increased mutant frequencies could have important implications for HIV-1 population dynamics and drug therapy regimens.

scholarly journals Efficient Identification of Human Immunodeficiency Virus Type 1 Mutants Resistant to a Protease Inhibitor by Using a Random Mutant Library

2011 ◽  
Vol 55 (11) ◽  
pp. 5090-5098 ◽  
Author(s):  
Sanggu Kim ◽  
Yun-Cheol Kim ◽  
Hangfei Qi ◽  
Kunkai Su ◽  
Sherie L. Morrison ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Drug Resistance ◽  
Protease Inhibitor ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Drug Resistant ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACTEmergence of drug-resistant mutant viruses during the course of antiretroviral therapy is a major hurdle that limits the success of chemotherapeutic treatment to suppress human immunodeficiency virus type 1 (HIV-1) replication and AIDS progression. Development of new drugs and careful patient management based on resistance genotyping data are important for enhancing therapeutic efficacy. However, identifying changes leading to drug resistance can take years of clinical studies, and conventionalin vitroassays are limited in generating reliable drug resistance data. Here we present an efficientin vitroscreening assay for selecting drug-resistant variants from a library of randomly mutated HIV-1 strains generated by transposon-directed base-exchange mutagenesis. As a test of principle, we screened a library of mutant HIV-1 strains containing random mutations in the protease gene by using a reporter T-cell line in the presence of the protease inhibitor (PI) nelfinavir (NFV). Analysis of replicating viruses from a single round of infection identified 50 amino acid substitutions at 35 HIV-1 protease residue positions. The selected mutant viruses showed specific resistance to NFV and included most of the known NFV resistance mutations. Therefore, the new assay is efficient for identifying changes leading to drug resistance. The data also provide insights into the molecular mechanisms underlying the development of drug resistance.

Transmission of Drug-Resistant HIV After an Occupational Exposure Despite Postexposure Prophylaxis With a Combination Drug Regimen

2002 ◽  
Vol 23 (6) ◽  
pp. 345-348 ◽  
Author(s):  
Elise M. Beltrami ◽  
Chi-Cheng Luo ◽  
Nicolas de la Torre ◽  
Denise M. Cardo
Keyword(s):  
Human Immunodeficiency Virus ◽  
Drug Resistance ◽  
Infected Patient ◽  
Drug Regimen ◽  
Drug Resistant ◽  
Postexposure Prophylaxis ◽  
Combination Drug ◽  
Antiretroviral Drug Resistance ◽  
Antiretroviral Drug ◽  
Immunodeficiency Virus

Abstract We documented a case of occupational human immunodeficiency virus (HIV) despite postexposure prophylaxis (PEP) with a combination drug regimen after percutaneous injury with a needle from a sharps disposal container in the hospital room of an HIV-infected patient. This failure of PEP with a combination drug regimen may have been related to antiretroviral drug resistance, other factors, or both. This case highlights the importance of preventing injury to prevent occupational transmission of HIV.

scholarly journals Persistence of Transmitted Drug Resistance among Subjects with Primary Human Immunodeficiency Virus Infection

2008 ◽  
Vol 82 (11) ◽  
pp. 5510-5518 ◽  
Author(s):  
Susan J. Little ◽  
Simon D. W. Frost ◽  
Joseph K. Wong ◽  
Davey M. Smith ◽  
Sergei L. Kosakovsky Pond ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Drug Resistance ◽  
Antiretroviral Therapy ◽  
Transmitted Drug Resistance ◽  
Drug Resistant ◽  
Conservative Estimate ◽  
Resistant Virus ◽  
Wild Type ◽  
Immunodeficiency Virus ◽  
Drug Resistant Virus

ABSTRACT Following interruption of antiretroviral therapy among individuals with acquired drug resistance, preexisting drug-sensitive virus emerges relatively rapidly. In contrast, wild-type virus is not archived in individuals infected with drug-resistant human immunodeficiency virus (HIV) and thus cannot emerge rapidly in the absence of selective drug pressure. Fourteen recently HIV-infected patients with transmitted drug-resistant virus were followed for a median of 2.1 years after the estimated date of infection (EDI) without receiving antiretroviral therapy. HIV drug resistance and pol replication capacity (RC) in longitudinal plasma samples were assayed. Resistance mutations were characterized as pure populations or mixtures. The mean time to first detection of a mixture of wild-type and drug-resistant viruses was 96 weeks (1.8 years) (95% confidence interval, 48 to 192 weeks) after the EDI. The median time to loss of detectable drug resistance using population-based assays ranged from 4.1 years (conservative estimate) to longer than the lifetime of the individual (less conservative estimate). The transmission of drug-resistant virus was not associated with virus with reduced RC. Sexual transmission of HIV selects for highly fit drug-resistant variants that persist for years. The prolonged persistence of transmitted drug resistance strongly supports the routine use of HIV resistance genotyping for all newly diagnosed individuals.

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