Virological and Immunological Responses to Raltegravir and Dolutegravir in the Gut-Associated Lymphoid Tissue of HIV-Infected Men and Women

Abstract

Background

Raltegravir (RTG) and dolutegravir (DTG) have different pharmacokinetic patterns in the gastrointestinal tract. To determine if this results in pharmacodynamic differences, we compared HIV RNA, HIV DNA and immunological markers in gut-associated lymphoid tissue (GALT) of HIV-infected participants receiving RTG or DTG with tenofovir+emtricitabine (TDF/FTC).

Methods

GALT specimens from the terminal ileum, splenic flexure and rectum were obtained by colonoscopy at a single time point in 20 adults treated with RTG (n=10) or DTG (n=10) with HIV RNA <50 copies/ml. Flow cytometry, drug concentrations, and HIV RNA and DNA were analysed in tissue. CD4/8⁺ T-cells were tested for γδ TCR, and markers of T-cell activation and exhaustion. Data are reported as median (Q1–Q3).

Results

A total of 15 men and 5 women were enrolled. There was no difference in time since HIV diagnosis for those on RTG (9.5 [4–22] years) and DTG (17 [1–24] years; P=0.6), although time on RTG (5.4 [2.3–6.7] years) was greater than DTG (1.0 [0.1–1.5] years; P<0.001). Concentrations of RTG and DTG in rectal tissue were similar to previous reports: median tissue:plasma ratio was 11.25 for RTG and 0.44 for DTG. RNA:DNA ratios were 1.14 (0.18–5.10) for the RTG group and 0.90 (0.30–18.87) for the DTG group (P=0.95). No differences (P≥0.1) between CD4⁺ and CD8⁺ T-cell markers were found.

Conclusions

RTG produced higher tissue exposures than DTG, but no significant differences in GALT HIV RNA, DNA or most immunological markers were observed. ClinicalTrials.gov NCT02218320.

References

Cihlar

, Fordyce

Current status and prospects of HIV treatment.

Curr Opin Virol 2016; 18: 50–56.

Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. (Updated 28 January 2016. Accessed 12 May 2016.) Available from http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf.

Chun

T-W

, Nickle

D.C.

, Justement

J.S.

Persistence of HIV in gut-associated lymphoid tissue despite long-term antiretroviral therapy.

J Infect Dis 2008; 197: 714–720.

George

M.D.

, Asmuth

D.M.

Mucosal immunity in HIV infection: what can be done to restore gastrointestinal-associated lymphoid tissue function?

Curr Opin Infect Dis 2014; 27: 275–281.

Deeks

S.G.

, Kitchen

C.M.R.

, Liu

Immune activation set point during early HIV infection predicts subsequent CD4+ T-cell changes independent of viral load.

Blood 2004; 104: 942–947.

Patterson

K.B.

, Prince

H.A.

, Stevens

Differential penetration of raltegravir throughout gastrointestinal tissue: implications for eradication and cure.

AIDS 2013; 27: 1413–1419.

Greener

B.N.

, Patterson

K.B.

, Prince

H.M.A.

Dolutegravir pharmacokinetics in the genital tract and colorectum of HIV-negative men after single and multiple dosing.

J Acquir Immune Defic Syndr 2013; 64: 39–44.

Robichaud

, Barry

J.A.

, Garrard

K.P.

, Muddiman

D.C.

Infrared matrix-assisted laser desorption electrospray ionization (IR-MALDESI) imaginf source coupled to a FT-ICR mass spectrometer.

J Am Soc Mass Spectrom 2013; 24: 92–100.

Barry

J.A.

, Robichaud

, Bokhart

M.T.

Mapping antiretroviral drugs in tissue by IR-MALDESI MSI coupled to the Q Exactive and comparison with LC-MS/MS SRM Assay.

J Am Soc Mass Spectrom 2014; 25: 2038–2047.

10.

Bokhart

M.T.

, Rosen

, Thompson

, Sykes

, Kashuba

A.D.M.

, Muddiman

D.C.

Quantitative mass spectrometry imaging of emtricitabine in cervical tissue model using infrared matrix-assisted laser desorption electrospray ionization.

Anal Bioanal Chem 2015; 407: 2073–2084.

11.

Nelson

K.A.

, Daniels

G.J.

, Fournie

J.W.

, Hemmer

M.J.

Optimization of whole-body zebrafish sectioning methods for mass spectrometry imaging.

J Biomol Tech 2013; 24: 119–127.

12.

Otsu

A threshold selection method from gray-level histograms.

IEEE Trans Syst Man Cybern 1979; 9: 62.

13.

ThermoFisher Scientific. Simultaneous Extraction of RNA and DNA. (Accessed 12 May 2016.) Available from http://www.thermofisher.com/us/en/home/references/ambion-tech-support/rna-isolation/tech-notes/simultaneous-extraction-of-rna-and-dna.html.

14.

Palmer

, Wiegand

A.P.

, Maldarelli

New real-time reverse transcriptase-initiated PCR assay with single-copy sensitivity for human immunodeficiency virus type 1 RNA in plasma.

J Clin Microbiol 2003; 41: 4531–4536.

15.

Jensen

, Nabi

, Van Rompay

K.K.A.

Vaccine-elicited mucosal and systemic antibody responses are associated with reduced simian immunodeficiency viremia in infant macaques.

J Virol 2016; 90: 7285–7302.

16.

Rahangdale

, De Paris

, Kashuba

A.D.M.

Immunologic, virologic, and pharmacologic characterization of the female upper genital tract in HIV-infected women.

J Acquir Immune Defic Syndr 2015; 68: 420–424.

17.

Pauza

C.D.

, Poonia

, Li

γδ T cells in HIV disease: past, present, and future.

Front Immunol 2015; 5: 687.

18.

Soriano-Sarabia

, Archin

N.M.

, Bateson

Peripheral Vγ9Vδ2 T cells are a novel reservoir of latent HIV infection.

PLoS Pathog 2015; 11: e1005201.

19.

Cristy

, Eckerman

K.F.

Specific absorbed fractions of energy at various ages from internal photon sources. I Methods. Oak Ridge National Laboratory Report ORNL/ NUREG/TM-367. Oak Ridge, TN: Oak Ridge National Laboratory; 1987.

20.

Rockstroh

J.K.

, DeJesus

, Lennox

J.L.

Durable efficacy and safety of raltegravir versus efavirenz when combined with tenofovir/emtricitabine in treatment-naive HIV-1-infected patients: final 5-year results from STARTMRK.

J Acquir Immune Defic Syndr 2013; 63: 77–85.

21.

Raff

, Rachlis

, Stellbrink

H-J

. Once-daily dolutegravir versus raltegravir in antiretroviral-naive adults with HIV-1 infection: 48 week results from the randomised, double-blind, non-inferiority SPRING-2 study. Lancet 2013; 381: 735–743.

22.

Song

, Chen

, Piscitelli

Meta-analysis of pharmacokinetic-pharmacodynamic relationship of integrase inhibitors. 11th International Workshop on Clinical Pharmacology of HIV Therapy. 7–9 April 2010, Sorrento, Italy.

23.

Cottrell

M.L.

, Hadzic

, Kashuba

A.D.M.

Clinical pharmacokinetic, pharmacodynamic and drug-interaction profile of the integrase inhibitor dolutegravir.

Clin Pharmacokinet 2013; 52: 981–994.

24.

Thompson

C.G.

, Gay

C.L.

, Kashuba

A.D.M.

HIV persistence in gut-associated lymphoid tissues: pharmacological challenges and opportunities.

AIDS Res Hum Retroviruses 2017; 33: 513–523.

25.

Bourry

, Mannioui

, Sellier

Effect of a short-term HAART on SIV load in macaque tissues is dependent on time of initiation and antiviral diffusion.

Retrovirology 2010; 7: 78.

26.

Klatt

N.R.

, Chomont

, Douek

D.C.

, Deeks

S.G.

Immune activation and HIV persistence: implications for curative approaches to HIV infection.

Immunol Rev 2013; 254: 326–342.

27.

Boulware

D.R.

, Hullsiek

K.H.

, Puronen

C.E.

Higher levels of CRP, D-dimer, IL-6, and hyaluronic acid before initiation of antiretroviral therapy (ART) are associated with increased risk of AIDS or death.

J Infect Dis 2011; 203: 1637–1646.

28.

Hunt

P.W.

, Cao

H.L.

, Muzoora

Impact of CD8+ T cell activation on CD4+ T cell recovery and mortality in HIV-infected Ugandans initiating antiretroviral therapy.

AIDS 2011; 25: 2123–2131.

29.

Ledwaba

, Tavel

J.A.

, Khabo

Pre-ART levels of inflammation and coagulation markers are strong predictors of death in a South African cohort with advanced HIV disease.

PLoS One 2012; 7: e24243.

30.

Yukl

S.A.

, Shergill

, McQuaid

Effect of raltegravir-containing intensification on HIV burden and T cell activation in multiple gut sites of HIV+ adults on suppressive antiretroviral therapy.

AIDS 2010; 24: 2451–2460.

31.

Hatano

, Hayes

T.L.

, Dahl

A randomized, controlled trial of raltegravir intensification in antiretroviral-treated, HIV-infected patients with a suboptimal CD4+ T cell response.

J Infect Dis 2011; 203: 960–968.

32.

Villanueva-Millán

M.J.

, Pérez-Matute

, Recio-Fernández

Differential effects of antiretrovirals on microbial translocation and gut microbiota composition of HIV-infected patients.

J Int AIDS Soc 2017; 20: 21526.

33.

Kelesidis

, Moser

, Stein

J.H.

Changes in markers of T-cell senescence and exhaustion with atazanavir-, raltegravir-, and darunavir-based initial antiviral therapy: ACTG 5260s.

J Infect Dis 2016; 214: 748–752.

34.

Ananworanich

, Chomont

, Fletcher

J.L.

Markers of HIV reservoir size and immune activation after treatment in acute HIV infection with and without raltegravir and maraviroc intensification.

J Virus Erad 2015; 1: 116–122.

35.

Fukada

, Sobao

, Tomiyama

, Oka

, Takiguchi

Functional expression of the chemokine receptor CCR5 on virus epitope-specific memory and effector CD8+ T cells.

J Immunol 2002; 168: 2225–2232.