scholarly journals Decreased Tenofovir Diphosphate Concentrations in a Transgender Female Cohort: Implications for Human Immunodeficiency Virus Preexposure Prophylaxis

2019 ◽  
Vol 69 (12) ◽  
pp. 2201-2204 ◽  
Author(s):  
Mackenzie L Cottrell ◽  
Heather M A Prince ◽  
Amanda P Schauer ◽  
Craig Sykes ◽  
Kaitlyn Maffuid ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Clinical Trials ◽  
Hormone Therapy ◽  
Transgender Women ◽  
Active Metabolites ◽  
Preexposure Prophylaxis ◽  
Immunodeficiency Virus ◽  
Female Cohort ◽  
Tenofovir Diphosphate

Abstract Feminizing hormone therapy (FHT) may interact with human immunodeficiency virus preexposure prophylaxis (PrEP). We found that transgender women who took FHT exhibited a 7-fold lower rectal tissue ratio of PrEP’s active metabolites vs competing deoxynucleotides compared to cisgender women and men (P = .03) that inversely correlated with estradiol (ρ = –0.79; P < .05). Thus, FHT may negatively impact PrEP efficacy. Clinical Trials Registration . NCT02983110.

scholarly journals Preexposure Prophylaxis for Mitigating Risk of HIV Transmission During HIV Cure–Related Clinical Trials With a Treatment Interruption

2019 ◽  
Vol 220 (Supplement_1) ◽  
pp. S16-S18 ◽  
Author(s):  
Jean-Daniel Lelièvre
Keyword(s):  
Human Immunodeficiency Virus ◽  
Clinical Trials ◽  
Hiv Transmission ◽  
Treatment Interruption ◽  
Sex Partners ◽  
Hiv Cure ◽  
Analytical Treatment ◽  
Secondary Transmission ◽  
Preexposure Prophylaxis ◽  
Immunodeficiency Virus

AbstractAnalytical treatment interruption performed during human immunodeficiency virus (HIV) cure–related clinical trials exposes sex partners of participants in these trials to a risk of HIV transmission. Preexposure prophylaxis (PrEP), which emerged in recent years as a key strategy for preventing HIV transmission, is often considered a useful tool to prevent this risk. This article supports offering PrEP to the stable sex partners of participants in these trials but also notes limitations that must be addressed. It concludes that PrEP cannot on its own eliminate the risk of secondary transmission in this context.

scholarly journals Biochemical Studies on the Mechanism of Human Immunodeficiency Virus Type 1 Reverse Transcriptase Resistance to 1-(β-d-Dioxolane)Thymine Triphosphate

2007 ◽  
Vol 51 (6) ◽  
pp. 2078-2084 ◽  
Author(s):  
Johan Lennerstrand ◽  
Chung K. Chu ◽  
Raymond F. Schinazi
Keyword(s):  
Human Immunodeficiency Virus ◽  
Reverse Transcriptase ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Nucleoside Analogs ◽  
Nucleotide Analogs ◽  
Immunodeficiency Virus ◽  
Large Panel ◽  
Tenofovir Diphosphate

ABSTRACT A large panel of drug-resistant mutants of human immunodeficiency virus type 1 reverse transcriptase (RT) was used to study the mechanisms of resistance to 1-(β-d-dioxolane)thymine triphosphate (DOT-TP) and other nucleotide analogs. RT containing thymidine analog-associated mutations (TAM) or RT with a T69S-SG insertion in combination with TAM removed 3′-azido-3′-deoxythymidine-5′-monophosphate or tenofovir more efficiently than DOT-monophosphate from chain-terminated DNA primer/template through ATP-mediated pyrophosphorolysis. For non-ATP-dependent discrimination toward DOT-TP, high levels of resistance were found for RT bearing the Q151M mutation with family mutations, while RT bearing only the M184V or the Y115F mutation conferred no resistance to DOT-TP. A lower degree of resistance to DOT-TP than to tenofovir diphosphate or carbovir-TP was found for RT containing the K65R mutation. In the present studies, 1-(β-d-dioxolane)guanine triphosphate, another nucleotide with a dioxolane sugar moiety, showed a resistance profile similar to that of DOT-TP. The results suggest that DOT, compared with other approved nucleoside analogs, is overall more resilient to mutations such as TAM, M184V, and K65R, which are commonly found in viruses derived from subjects failing multinucleoside therapy.

scholarly journals Impact of Next-generation Sequencing Defined Human Immunodeficiency Virus Pretreatment Drug Resistance on Virological Outcomes in the ANRS 12249 Treatment-as-Prevention Trial

2018 ◽  
Vol 69 (2) ◽  
pp. 207-214 ◽  
Author(s):  
Anne Derache ◽  
Collins C Iwuji ◽  
Kathy Baisley ◽  
Siva Danaviah ◽  
Anne-Geneviève Marcelin ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Clinical Trials ◽  
Transcriptase Inhibitor ◽  
Hiv Positive ◽  
Treatment As Prevention ◽  
Kwazulu Natal ◽  
Immunodeficiency Virus ◽  
Virological Outcomes ◽  
Reverse Transcriptase Inhibitor ◽  
Generation Sequencing

Abstract Background Previous studies in human immunodeficiency virus (HIV)-positive individuals on thymidine analogue backbone antiretroviral therapy (ART) with either nevirapine or efavirenz have suggested poorer virological outcomes in the presence of pretreatment drug resistance (PDR). We assessed the impact of PDR on virological suppression (VS; <50 copies/mL) in individuals prescribed primarily tenofovir/emtricitabine/efavirenz in rural KwaZulu-Natal within a treatment-as-prevention trial. Methods Among 1557 HIV-positive individuals who reported no prior ART at study entry and provided plasma samples, 1328 individuals with entry viral load (VL) >1000 copies/mL had next-generation sequencing (NGS) of the HIV pol gene with MiSeq technology. Results were obtained for 1148 individuals, and the presence of PDR was assessed at 5% and 20% detection thresholds. Virological outcome was assessed using Cox regression in 837 of 920 ART initiators with at least 1 follow-up VL after ART initiation. Results PDR prevalence was 9.5% (109/1148) and 12.8% (147/1148) at 20% and 5% thresholds, respectively. After a median of 1.36 years (interquartile range, 0.91–2.13), mostly on fixed-dose combination tenofovir/emtricitabine/efavirenz, presence of both nonnucleoside reverse transcriptase inhibitor (NNRTI)/nucleoside reverse transcriptase inhibitor PDR vs no PDR was associated with longer time to VS (adjusted hazard ratio [aHR], 0.32; 95% confidence interval [CI], 0.12–0.86), while there was no difference between those with only NNRTI PDR vs no PDR (aHR, 1.05; 95% CI, 0.82–1.34) at the 5% threshold. Similar differences were observed for mutations detected at the 20% threshold, although without statistical significance. Conclusions NGS uncovered a high prevalence of PDR among participants enrolled in trial clinics in rural KwaZulu-Natal. Dual-class PDR to a mainly tenofovir/emtricitabine/efavirenz regimen was associated with poorer VS. However, there was no impact of NNRTI PDR alone. Clinical Trials Tegistration NCT01509508; South African National Clinical Trials Register: DOH-27-0512-3974.

scholarly journals A human immunodeficiency virus 1 (HIV-1) clade A vaccine in clinical trials: stimulation of HIV-specific T-cell responses by DNA and recombinant modified vaccinia virus Ankara (MVA) vaccines in humans

2004 ◽  
Vol 85 (4) ◽  
pp. 911-919 ◽  
Author(s):  
Matilu Mwau ◽  
Inese Cebere ◽  
Julian Sutton ◽  
Priscilla Chikoti ◽  
Nicola Winstone ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Clinical Trials ◽  
Vaccinia Virus ◽  
Mononuclear Cells ◽  
Vaccine Development ◽  
Cell Mediated Immunity ◽  
Phase I Clinical Trials ◽  
Modified Vaccinia Virus Ankara ◽  
Immunodeficiency Virus ◽  
Hiv 1

The immunogenicities of candidate DNA- and modified vaccinia virus Ankara (MVA)-vectored human immunodeficiency virus (HIV) vaccines were evaluated on their own and in a prime–boost regimen in phase I clinical trials in healthy uninfected individuals in the United Kingdom. Given the current lack of approaches capable of inducing broad HIV-neutralizing antibodies, the pTHr.HIVA DNA and MVA.HIVA vaccines focus solely on the induction of cell-mediated immunity. The vaccines expressed a common immunogen, HIVA, which consists of consensus HIV-1 clade A Gag p24/p17 proteins fused to a string of clade A-derived epitopes recognized by cytotoxic T lymphocytes (CTLs). Volunteers' fresh peripheral blood mononuclear cells were tested for HIV-specific responses in a validated gamma interferon enzyme-linked immunospot (ELISPOT) assay using four overlapping peptide pools across the Gag domain and three pools of known CTL epitopes present in all of the HIVA protein. Both the DNA and the MVA vaccines alone and in a DNA prime–MVA boost combination were safe and induced HIV-specific responses in 14 out of 18, seven out of eight and eight out of nine volunteers, respectively. These results are very encouraging and justify further vaccine development.

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