scholarly journals Long-Acting Anti-HIV Drugs Targeting HIV-1 Reverse Transcriptase and Integrase

2019 ◽  
Vol 12 (2) ◽  
pp. 62 ◽  
Author(s):  
Kamal Singh ◽  
Stefan G. Sarafianos ◽  
Anders Sönnerborg
Keyword(s):  
Drug Resistance ◽  
Clinical Trials ◽  
Reverse Transcriptase ◽  
Treatment Regimens ◽  
Drug Concentrations ◽  
The Status ◽  
Long Acting ◽  
Major Factors ◽  
Hiv Drugs ◽  
Hiv 1

One of the major factors contributing to HIV-1 drug resistance is suboptimal adherence to combination antiretroviral therapy (cART). Currently, recommended cART for HIV-1 treatment is a three-drug combination, whereas the pre-exposure prophylaxis (PrEP) regimens consist of one or two antivirals. Treatment regimens require adherence to a once or twice (in a subset of patients) daily dose. Long-acting formulations such as injections administered monthly could improve adherence and convenience, and thereby have potential to enhance the chances of expected outcomes, although long-lasting drug concentrations can also contribute to clinical issues like adverse events and development of drug resistance. Globally, two long-acting antivirals have been approved, and fifteen are in clinical trials. More than half of investigational long-acting antivirals target HIV-1 reverse transcriptase (HIV-1 RT) and/or integrase (HIV-1 IN). Here, we discuss the status and potential of long-acting inhibitors, including rilpivirine (RPV), dapivirine (DPV), and 4-ethynyl-2-fluoro-2-deoxyadenosine (EFdA; also known as MK-8591), which target RT, and cabotegravir (CAB), which targets IN. The outcomes of various clinical trials appear quite satisfactory, and the future of long-acting HIV-1 regimens appears bright.

scholarly journals Patterns of acquired HIV-1 drug resistance mutations and predictors of virological failure in Moshi, northern Tanzania

2020 ◽  
Author(s):  
Shabani Ramadhani Mziray ◽  
Happiness H Kumburu ◽  
Hellen B Assey ◽  
Tolbert B Sonda ◽  
Michael J Mahande ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Reverse Transcriptase ◽  
Virological Failure ◽  
Health Concern ◽  
Resistance Mutations ◽  
Hiv Drug Resistance ◽  
Drug Resistance Mutations ◽  
Northern Tanzania ◽  
Hiv Drugs ◽  
Hiv 1

AbstractDrug resistance is a public health concern. Profiles of HIV drug resistance mutations (HIVDRM) and virological failure (VF) are not extensively studied in Tanzania. This study aimed to determine HIVDRM and predictors of VF in HIV-infected individuals failing first-line HIV drugs in Moshi, northern Tanzania. A case-control study was conducted at KCMC, Mawenzi, Pasua and Majengo health facilities with HIV-care and treatment clinics in Moshi from October, 2017 to August, 2018. Cases and controls were HIV-infected individuals with VF and viral suppression (VS) respectively. HIV-1 reverse transcriptase and protease genes were amplified and sequenced. Stanford University’s HIV drug resistance database and REGA HIV-1 Subtyping tool 3.0 determined HIVDRM and HIV-1 subtypes respectively. Odds ratios with 95% confidence intervals investigated predictors of VF. P-value <5% was considered statistically significant. A total of 124 participants were recruited, of whom 63 (50.8%) had VF and 61 (49.2%) had VS. Majority (66.1%) were females. Median [IQR] age and duration on ART were 45 [35-52] years and 72 [48-104] months respectively. Twenty five out of 26 selected HIV-1 RNA samples from cases were successively sequenced. Twenty four samples (96%) had at least one major mutation conferring resistance to HIV drugs, with non-nucleoside reverse transcriptase inhibitor (NNRTI) associated mutations as the majority (92%). Frequent NNRTI resistance mutations were K103N (n=11), V106M (n=5) and G190A (n=5). Prevalent nucleoside reverse transcriptase inhibitors mutations were M184V (n=17), K70R (n=7) and D67N (n=6). Dual-class resistance was observed in 16 (64%) samples. Thirteen samples (52%) had at least one thymidine analogue-associated resistance mutation (TAM). Three samples (12%) had T69D mutation with at least 1 TAM. Age was independently associated with VF [aOR 0.94 (0.90-0.97) p<0.001]. In conclusion, HIV drug resistance is common among people failing antiretroviral therapy and resistance testing will help to guide switching of HIV drugs.

scholarly journals Low Frequency of Drug-Resistant Variants Selected by Long-Acting Rilpivirine in Macaques Infected with Simian Immunodeficiency Virus Containing HIV-1 Reverse Transcriptase

2015 ◽  
Vol 59 (12) ◽  
pp. 7762-7770 ◽  
Author(s):  
Kevin Melody ◽  
Sarah McBeth ◽  
Christopher Kline ◽  
Angela D. M. Kashuba ◽  
John W. Mellors ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Simian Immunodeficiency Virus ◽  
Prolonged Exposure ◽  
Peak Plasma ◽  
Antiretroviral Drugs ◽  
Drug Resistant ◽  
Drug Concentrations ◽  
Immunodeficiency Virus ◽  
Long Acting ◽  
Hiv 1

ABSTRACTPreexposure prophylaxis (PrEP) using antiretroviral drugs is effective in reducing the risk of human immunodeficiency virus type 1 (HIV-1) infection, but adherence to the PrEP regimen is needed. To improve adherence, a long-acting injectable formulation of the nonnucleoside reverse transcriptase (RT) inhibitor rilpivirine (RPV LA) has been developed. However, there are concerns that PrEP may select for drug-resistant mutations during preexisting or breakthrough infections, which could promote the spread of drug resistance and limit options for antiretroviral therapy. To address this concern, we administered RPV LA to macaques infected with simian immunodeficiency virus containing HIV-1 RT (RT-SHIV). Peak plasma RPV levels were equivalent to those reported in human trials and waned over time after dosing. RPV LA resulted in a 2-log decrease in plasma viremia, and the therapeutic effect was maintained for 15 weeks, until plasma drug concentrations dropped below 25 ng/ml. RT mutations E138G and E138Q were detected in single clones from plasma virus in separate animals only at one time point, and no resistance mutations were detected in viral RNA isolated from tissues. Wild-type and E138Q RT-SHIV displayed similar RPV susceptibilitiesin vitro, whereas E138G conferred 2-fold resistance to RPV. Overall, selection of RPV-resistant variants was rare in an RT-SHIV macaque model despite prolonged exposure to slowly decreasing RPV concentrations following injection of RPV LA.

scholarly journals Drug Susceptibility and Viral Fitness of HIV-1 with Integrase Strand Transfer Inhibitor Resistance Substitution Q148R or N155H in Combination with Nucleoside/Nucleotide Reverse Transcriptase Inhibitor Resistance Substitutions

2015 ◽  
Vol 60 (2) ◽  
pp. 757-765 ◽  
Author(s):  
Kristen N. Andreatta ◽  
Michael D. Miller ◽  
Kirsten L. White
Keyword(s):  
Drug Resistance ◽  
Reverse Transcriptase ◽  
Viral Fitness ◽  
Strand Transfer ◽  
Wild Type ◽  
Drug Concentrations ◽  
Multiple Drugs ◽  
Inhibitor Resistance ◽  
Hiv 1

ABSTRACTIn clinical trials of coformulated elvitegravir (EVG), cobicistat (COBI), emtricitabine (FTC), and tenofovir disoproxil fumarate (TDF), emergent drug resistance predominantly involved the FTC resistance substitution M184V/I in reverse transcriptase (RT), with or without the tenofovir (TFV) resistance substitution K65R, accompanied by a primary EVG resistance substitution (E92Q, N155H, or Q148R) in integrase (IN). We previously reported that the RT-K65R, RT-M184V, and IN-E92Q substitutions lacked cross-class phenotypic resistance and replicative fitness compensation. As a follow-up, thein vitrocharacteristics of mutant HIV-1 containing RT-K65R and/or RT-M184V with IN-Q148R or IN-N155H were also evaluated, alone and in combination, for potential interactions. Single mutants displayed reduced susceptibility to their corresponding inhibitor classes, with no cross-class resistance. Viruses with IN-Q148R or IN-N155H exhibited reduced susceptibility to EVG (137- and 40-fold, respectively) that was not affected by the addition of RT-M184V or RT-K65R/M184V. All viruses containing RT-M184V were resistant to FTC (>1,000-fold). Mutants with RT-K65R had reduced susceptibility to TFV (3.3- to 3.6-fold). Without drugs present, the viral fitness of RT and/or IN mutants was diminished relative to that of the wild type in the following genotypic order: wild type > RT-M184V ≥ IN-N155H ≈ IN-Q148R ≥ RT-M184V + IN-N155H ≥ RT-M184V + IN-Q148R ≥ RT-K65R/M184V + IN-Q148R ≈ RT-K65R/M184V + IN-N155H. In the presence of drug concentrations approaching physiologic levels, drug resistance counteracted replication defects, allowing single mutants to outcompete the wild type with one drug present and double mutants to outcompete single mutants with two drugs present. These results suggest that during antiretroviral treatment with multiple drugs, the development of viruses with combinations of resistance substitutions may be favored despite diminished viral fitness.

Genetic Diversity and Drug Resistance of HIV-1 CRF55_01B in Guangdong, China

2020 ◽  
Vol 18 (3) ◽  
pp. 210-218
Author(s):  
Guolong Yu ◽  
Yan Li ◽  
Xuhe Huang ◽  
Pingping Zhou ◽  
Jin Yan ◽  
...  
Keyword(s):  
Genetic Diversity ◽  
Drug Resistance ◽  
Reverse Transcriptase ◽  
Phylogenetic Analyses ◽  
Resistance Mutations ◽  
Protease Inhibition ◽  
Subtype B ◽  
Primary Drug Resistance ◽  
Hiv 1 ◽  
Primary Drug

Background: HIV-1 CRF55_01B was first reported in 2013. At present, no report is available regarding this new clade’s polymorphisms in its functionally critical regions protease and reverse transcriptase. Objective: To identify the diversity difference in protease and reverse transcriptase between CRF55_01B and its parental clades CRF01_AE and subtype B; and to investigate CRF55_01B’s drug resistance mutations associated with the protease inhibition and reverse transcriptase inhibition. Methods: HIV-1 RNA was extracted from plasma derived from a MSM population. The reverse transcription and nested PCR amplification were performed following our in-house PCR procedure. Genotyping and drug resistant-associated mutations and polymorphisms were identified based on polygenetic analyses and the usage of the HIV Drug Resistance Database, respectively. Results: A total of 9.24 % of the identified CRF55_01B sequences bear the primary drug resistance. CRF55_01B contains polymorphisms I13I/V, G16E and E35D that differ from those in CRF01_AE. Among the 11 polymorphisms in the RT region, seven were statistically different from CRF01_AE’s. Another three polymorphisms, R211K (98.3%), F214L (98.3%), and V245A/E (98.3 %.), were identified in the RT region and they all were statistically different with that of the subtype B. The V179E/D mutation, responsible for 100% potential low-level drug resistance, was found in all CRF55_01B sequences. Lastly, the phylogenetic analyses demonstrated 18 distinct clusters that account for 35% of the samples. Conclusions: CRF55_01B’s pol has different genetic diversity comparing to its counterpart in CRF55_01B’s parental clades. CRF55_01B has a high primary drug resistance presence and the V179E/D mutation may confer more vulnerability to drug resistance.

Geographic and Temporal Trends of Transmitted HIV-1 Drug Resistance Among Antiretroviral-Naïve Subjects Screening for Two Clinical Trials in North America and Western Europe

2009 ◽  
Vol 10 (2) ◽  
pp. 94-103 ◽  
Author(s):  
Sibtain Rahim ◽  
Linda M. Fredrick ◽  
Barbara A. da Silva ◽  
Barry Bernstein ◽  
Martin S. King
Keyword(s):  
Drug Resistance ◽  
Clinical Trials ◽  
North America ◽  
Western Europe ◽  
Temporal Trends ◽  
Hiv 1

scholarly journals HIV-1 Phenotypic Reverse Transcriptase Inhibitor Drug Resistance Test Interpretation Is Not Dependent on the Subtype of the Virus Backbone

PLoS ONE ◽  
2012 ◽  
Vol 7 (4) ◽  
pp. e34708 ◽  
Author(s):  
Michelle Bronze ◽  
Kim Steegen ◽  
Carole L. Wallis ◽  
Hans De Wolf ◽  
Maria A. Papathanasopoulos ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Reverse Transcriptase ◽  
Transcriptase Inhibitor ◽  
Resistance Test ◽  
Test Interpretation ◽  
Inhibitor Drug ◽  
Reverse Transcriptase Inhibitor ◽  
Hiv 1
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