Safety and Pharmacokinetics of Intravaginal Rings Delivering Tenofovir in Pig-Tailed Macaques

ABSTRACTAntiretroviral-based microbicides applied topically to the vagina may play an important role in protecting women from HIV infection. Incorporation of the nucleoside reverse transcriptase inhibitor tenofovir (TFV) into intravaginal rings (IVRs) for sustained mucosal delivery may lead to increased microbicide product adherence and efficacy compared with those of conventional vaginal formulations. Formulations of a novel “pod IVR” platform spanning a range of IVR drug loadings and daily release rates of TFV were evaluated in a pig-tailed macaque model. The rings were safe and exhibited sustained release at controlled rates over 28 days. Vaginal secretion TFV levels were independent of IVR drug loading and were able to be varied over 1.5 log units by changing the ring configuration. Mean TFV levels in vaginal secretions were 72.4 ± 109 μg ml−1(slow releasing) and 1.84 ± 1.97 mg ml−1(fast releasing). The mean TFV vaginal tissue concentration from the slow-releasing IVRs was 76.4 ± 54.8 μg g−1and remained at steady state 7 days after IVR removal, consistent with the long intracellular half-life of TFV. Intracellular tenofovir diphosphate (TFV-DP), the active moiety in defining efficacy, was measured in vaginal lymphocytes collected in the study using the fast-releasing IVR formulation. Mean intracellular TFV-DP levels of 446 ± 150 fmol/106cells fall within a range that may be protective of simian-human immunodeficiency virus strain SF162p3 (SHIVSF162p3) infection in nonhuman primates. These data suggest that TFV-releasing IVRs based on the pod design have potential for the prevention of transmission of human immunodeficiency virus type 1 (HIV-1) and merit further clinical investigation.

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Human Immunodeficiency Virus Type 1 Reverse Transcriptase Mutation Selection during In Vitro Exposure to Tenofovir Alone or Combined with Abacavir or Lamivudine

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.48.4.1413-1415.2004 ◽

2004 ◽

Vol 48 (4) ◽

pp. 1413-1415 ◽

Cited By ~ 25

Author(s):

Chris Stone ◽

Mounir Ait-Khaled ◽

Charles Craig ◽

Philip Griffin ◽

Margaret Tisdale

Keyword(s):

Human Immunodeficiency Virus ◽

Reverse Transcriptase ◽

Transcriptase Inhibitor ◽

Wild Type Virus ◽

Virus Genotype ◽

Human Immunodeficiency Virus Strain ◽

Immunodeficiency Virus ◽

In The Wild ◽

Inhibitor Resistance

ABSTRACT Mutations selected or deselected during passage of human immunodeficiency virus strain HXB2 or resistant variants with tenofovir (TFV), abacavir (ABC), and lamivudine (3TC) differed depending on the drug combination and virus genotype. In the wild-type virus, TFV-ABC and TFV-3TC selected K65R (with reduced susceptibility to all three inhibitors) and then Y115F. TFV-containing regimens might increase K65R selection, which confers multiple nucleoside reverse transcriptase inhibitor resistance.

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Safety and Pharmacokinetics of Quick-Dissolving Polymeric Vaginal Films Delivering the Antiretroviral IQP-0528 for Preexposure Prophylaxis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00082-16 ◽

2016 ◽

Vol 60 (7) ◽

pp. 4140-4150 ◽

Cited By ~ 15

Author(s):

Priya Srinivasan ◽

Jining Zhang ◽

Amy Martin ◽

Kristin Kelley ◽

Janet M. McNicholl ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Transcriptase Inhibitor ◽

Vaginal Fluid ◽

Vaginal Tissue ◽

Human Dose ◽

Preexposure Prophylaxis ◽

Compact Size ◽

Immunodeficiency Virus ◽

Plga Nanoparticle

ABSTRACTFor human immunodeficiency virus (HIV) prevention, microbicides or drugs delivered as quick-dissolving films may be more acceptable to women than gels because of their compact size, minimal waste, lack of an applicator, and easier storage and transport. This has the potential to improve adherence to promising products for preexposure prophylaxis. Vaginal films containing IQP-0528, a nonnucleoside reverse transcriptase inhibitor, were evaluated for their pharmacokinetics in pigtailed macaques. Polymeric films (22 by 44 by 0.1 mm; providing 75% of a human dose) containing IQP-0528 (1.5%, wt/wt) with and without poly(lactic-co-glycolic acid) (PLGA) nanoparticle encapsulation were inserted vaginally into pigtailed macaques in a crossover study design (n= 6). With unencapsulated drug, the median (range) vaginal fluid concentrations of IQP-0528 were 160.97 (2.73 to 2,104), 181.79 (1.86 to 15,800), and 484.50 (8.26 to 4,045) μg/ml at 1, 4, and 24 h after film application, respectively. Median vaginal tissue IQP-0528 concentrations at 24 h were 3.10 (0.03 to 222.58) μg/g. The values were similar at locations proximal, medial, and distal to the cervix. The IQP-0528 nanoparticle-formulated films delivered IQP-0528 in vaginal tissue and secretions at levels similar to those obtained with the unencapsulated formulation. A single application of either formulation did not disturb the vaginal microflora or the pH (7.24 ± 0.84 [mean ± standard deviation]). The high mucosal IQP-0528 levels delivered by both vaginal film formulations were between 1 and 5 log higher than thein vitro90% inhibitory concentration (IC90) of 0.146 μg/ml. The excellent coverage and high mucosal levels of IQP-0528, well above the IC90, suggest that the films may be protective and warrant further evaluation in a vaginal repeated low dose simian-human immunodeficiency virus (SHIV) transmission study in macaques and clinically in women.

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

Clinical Infectious Diseases ◽

10.1093/cid/ciy881 ◽

2018 ◽

Vol 69 (2) ◽

pp. 207-214 ◽

Cited By ~ 23

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.

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Activity against Human Immunodeficiency Virus Type 1, Intracellular Metabolism, and Effects on Human DNA Polymerases of 4′-Ethynyl-2-Fluoro-2′-Deoxyadenosine

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00277-07 ◽

2007 ◽

Vol 51 (8) ◽

pp. 2701-2708 ◽

Cited By ~ 72

Author(s):

Hirotomo Nakata ◽

Masayuki Amano ◽

Yasuhiro Koh ◽

Eiichi Kodama ◽

Guangwei Yang ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Transcriptase Inhibitor ◽

Multidrug Resistant ◽

Wild Type ◽

Immunodeficiency Virus ◽

Reverse Transcriptase Inhibitor ◽

Hiv 1

ABSTRACT We examined the intracytoplasmic anabolism and kinetics of antiviral activity against human immunodeficiency virus type 1 (HIV-1) of a nucleoside reverse transcriptase inhibitor, 4′-ethynyl-2-fluoro-2′-deoxyadenosine (EFdA), which has potent activity against wild-type and multidrug-resistant HIV-1 strains. When CEM cells were exposed to 0.1 μM [3H]EFdA or [3H]3′-azido-2′,3′-dideoxythymidine (AZT) for 6 h, the intracellular EFdA-triphosphate (TP) level was 91.6 pmol/109 cells, while that of AZT was 396.5 pmol/109 cells. When CEM cells were exposed to 10 μM [3H]EFdA, the amount of EFdA-TP increased by 22-fold (2,090 pmol/109 cells), while the amount of [3H]AZT-TP increased only moderately by 2.4-fold (970 pmol/109 cells). The intracellular half-life values of EFdA-TP and AZT-TP were ∼17 and ∼3 h, respectively. When MT-4 cells were cultured with 0.01 μM EFdA for 24 h, thoroughly washed to remove EFdA, further cultured without EFdA for various periods of time, exposed to HIV-1NL4-3, and cultured for an additional 5 days, the protection values were 75 and 47%, respectively, after 24 and 48 h with no drug incubation, while those with 1 μM AZT were 55 and 9.2%, respectively. The 50% inhibitory concentration values of EFdA-TP against human polymerases α, β, and γ were >100 μM, >100 μM, and 10 μM, respectively, while those of ddA-TP were >100 μM, 0.2 μM, and 0.2 μM, respectively. These data warrant further development of EFdA as a potential therapeutic agent for those patients who harbor wild-type HIV-1 and/or multidrug-resistant variants.

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Clinical Impact of Pretreatment Human Immunodeficiency Virus Drug Resistance in People Initiating Nonnucleoside Reverse Transcriptase Inhibitor–Containing Antiretroviral Therapy: A Systematic Review and Meta-analysis

The Journal of Infectious Diseases ◽

10.1093/infdis/jiaa683 ◽

2020 ◽

Author(s):

Silvia Bertagnolio ◽

Lucas Hermans ◽

Michael R Jordan ◽

Santiago Avila-Rios ◽

Collins Iwuji ◽

...

Keyword(s):

Systematic Review ◽

Human Immunodeficiency Virus ◽

Drug Resistance ◽

Reverse Transcriptase ◽

Treatment Outcomes ◽

Meta Analysis ◽

Transcriptase Inhibitor ◽

Nonnucleoside Reverse Transcriptase Inhibitor ◽

Immunodeficiency Virus ◽

Reverse Transcriptase Inhibitor

Abstract Background Increased access to antiretroviral therapy (ART) has resulted in rising levels of pretreatment human immunodeficiency virus drug resistance (PDR). This is the first systematic review and meta-analysis to assess the impact of PDR on treatment outcomes among people initiating nonnucleoside reverse transcriptase inhibitor (NNRTI)–based ART, including the combination of efavirenz (EFV), tenofovir (TDF), and lamivudine or emtricitabine (XTC). Methods We systematically reviewed studies and conference proceedings comparing treatment outcomes in populations initiating NNRTI-based ART with and without PDR. We conducted subgroup analyses by regimen: (1) NNRTIs + 2 nucleoside reverse transcriptase inhibitors (NRTIs), (2) EFV + 2 NRTIs, or (3) EFV/TDF/XTC; by population (children vs adults); and by definition of resistance (PDR vs NNRTI PDR). Results Among 6197 studies screened, 32 were analyzed (31 441 patients). We found that individuals with PDR initiating NNRTIs across all the subgroups had increased risk of virological failure compared to those without PDR. Risk of acquisition of new resistance mutations and ART switch was also higher in people with PDR. Conclusions This review shows poorer treatment outcomes in the presence of PDR, supporting the World Health Organization’s recommendation to avoid using NNRTIs in countries where levels of PDR are high.

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A case of M184V mutant human immunodeficiency virus in a patient using daily pre-exposure prophylaxis

International Journal of STD & AIDS ◽

10.1177/0956462419879620 ◽

2019 ◽

Vol 31 (1) ◽

pp. 85-87 ◽

Cited By ~ 1

Author(s):

Sally Jewsbury ◽

Chris Ward

Keyword(s):

Human Immunodeficiency Virus ◽

Transcriptase Inhibitor ◽

Wild Type Virus ◽

Development Of Resistance ◽

Health Clinics ◽

Immunodeficiency Virus ◽

Sexual Health Clinics ◽

Exposure Prophylaxis ◽

Reverse Transcriptase Inhibitor ◽

Optimal Adherence

This study presents a case report of a 31-year-old gay man who acquired human immunodeficiency virus while using daily emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF) pre-exposure prophylaxis (PrEP). He had an M184V nucleoside reverse-transcriptase inhibitor mutation at diagnosis. Either he acquired a pre-existing M184V mutation or he acquired a wild-type virus but then suboptimal use of FTC/TDF led to the development of resistance. For PrEP to be safely managed and seroconvertors to be identified quickly, PrEP should be commissioned by the NHS and managed within sexual health clinics. Notwithstanding the current provision of PrEP, those accessing it must be reminded about the importance of regular testing and optimal adherence.

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Safety, tolerance, and efficacy of atevirdine in asymptomatic human immunodeficiency virus-infected individuals.

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.40.11.2664 ◽

1996 ◽

Vol 40 (11) ◽

pp. 2664-2668 ◽

Cited By ~ 2

Author(s):

A M Been-Tiktak ◽

I Williams ◽

H M Vrehen ◽

J Richens ◽

D Aldam ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Transcriptase Inhibitor ◽

Viral Loads ◽

Nonnucleoside Reverse Transcriptase Inhibitor ◽

Cell Counts ◽

Cd4 Cell Counts ◽

Immunodeficiency Virus ◽

Reverse Transcriptase Inhibitor ◽

Cd4 Cell ◽

Hiv 1

Atevirdine is a nonnucleoside reverse transcriptase inhibitor of human immunodeficiency virus type 1 (HIV-1). In this study we investigated the effect of atevirdine in asymptomatic antiretroviral naive HIV-infected patients with CD4+ cell counts of between 200 and 750 cells per mm3. Patients were randomized to receive 600 mg of atevirdine (n = 15) or a placebo (n = 15) three times a day for 12 weeks. There was no statistically significant effect of atevirdine on viral loads (HIV p24 antigen and HIV-1 RNA levels by PCR) or CD4+ cell counts. The data do not support the use of atevirdine as a monotherapy in the treatment of HIV-infected patients.

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CD4-Negative Cells Bind Human Immunodeficiency Virus Type 1 and Efficiently Transfer Virus to T Cells

Journal of Virology ◽

10.1128/jvi.74.18.8550-8557.2000 ◽

2000 ◽

Vol 74 (18) ◽

pp. 8550-8557 ◽

Cited By ~ 32

Author(s):

Gene G. Olinger ◽

Mohammed Saifuddin ◽

Gregory T. Spear

Keyword(s):

Human Immunodeficiency Virus ◽

T Cells ◽

Mononuclear Cells ◽

Cell Types ◽

Virus Binding ◽

Peripheral Blood Mononuclear ◽

Human Immunodeficiency Virus Strain ◽

Immunodeficiency Virus

ABSTRACT The ability of human immunodeficiency virus strain MN (HIVMN), a T-cell line-adapted strain of HIV, and X4 and R5 primary isolates to bind to various cell types was investigated. In general, HIVMN bound to cells at higher levels than did the primary isolates. Virus bound to both CD4-positive (CD4+) and CD4-negative (CD4−) cells, including neutrophils, Raji cells, tonsil mononuclear cells, erythrocytes, platelets, and peripheral blood mononuclear cells (PBMC), although virus bound at significantly higher levels to PBMC. However, there was no difference in the amount of HIV that bound to CD4-enriched or CD4-depleted PBMC. Virus bound to CD4− cells was up to 17 times more infectious for T cells in cocultures than was the same amount of cell-free virus. Virus bound to nucleated cells was significantly more infectious than virus bound to erythrocytes or platelets. The enhanced infection of T cells by virus bound to CD4− cells was not due to stimulatory signals provided by CD4− cells or infection of CD4− cells. However, anti-CD18 antibody substantially reduced the enhanced virus replication in T cells, suggesting that virus that bound to the surface of CD4−cells is efficiently passed to CD4+ T cells during cell-cell adhesion. These studies show that HIV binds at relatively high levels to CD4− cells and, once bound, is highly infectious for T cells. This suggests that virus binding to the surface of CD4− cells is an important route for infection of T cells in vivo.

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