Tissue Pharmacologic and Virologic Determinants of Duodenal and Rectal Gastrointestinal-Associated Lymphoid Tissue Immune Reconstitution in HIV-Infected Patients Initiating Antiretroviral Therapy

Abstract

Plasma, duodenal, and rectal tissue antiretroviral therapy (ART) drug concentrations, human immunodeficiency virus (HIV) RNA and HIV DNA copy numbers, and recovery of mucosal immunity were measured before and 9 months after initiation of 3 different ART regimens in 26 subjects. Plasma and tissue HIV RNA correlated at baseline and when 9-month declines were compared, suggesting that these compartments are tightly associated. Antiretroviral tissue:blood penetration ratios were above the 50% inhibitory concentration values in almost 100% of cases. There were no correlations between drug concentrations and HIV DNA/RNA. Importantly, no evidence was found for residual viral replication or deficient tissue drug penetration to account for delayed gastrointestinal-associated lymphoid tissue immune recovery.

Trial registration: ClinicalTrials.gov NCT00870363.

Keywords: ART tissue penetration; HIV persistence; antiretroviral concentration; gastrointestinal-associated lymphoid tissue; immune reconstitution.

© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

Figures

Figure 1.

Antiretroviral tissue penetration ratios (TPRs) into small and large intestinal tissue. TPRs represent the extent of drug exposure in a given tissue relative to plasma and are calculated by dividing the tissue concentration (converted to ng/g) by a paired plasma concentration (ng/mL) using an assumed tissue density of 1.06 g/mL. A, Tenofovir (TFV) and emtricitabine TPRs were not significantly different across dosing cohorts in either the duodenum or rectum (P > .05); therefore, the TPRs for these 2 drugs were pooled when making further comparisons. Maraviroc (MVC) TPRs between the MVC and MVC + raltegravir (RAL) cohort were not significantly different and these values were also pooled. Significantly higher TFV penetration was observed in the duodenum compared to the colon, and MVC penetration was higher in the rectum vs the duodenum (*P = .001 for both). B, Tissue concentrations as reported in Table 2 were individually compared to the highest 50% inhibitory concentration (IC50) reported in the literature (IC90 for efavirenz) after converting reported nM IC values to ng/mg. Tissue drug concentrations were above the IC50 nearly 100% of the time. These TPRs are consistent with what has been observed in previous studies of gut tissue, except for RAL, which was lower than what has been previously reported [11]. C and D, All drug penetration vs human immunodeficiency virus (HIV) decreases from baseline: No correlation was observed between tissue levels of viral decay assayed from biopsy specimens collected after 9 months of combination antiretroviral therapy. C, HIV DNA was measured in single-cell suspensions of rectal and duodenal tissue biopsies. D, HIV RNA was measured from rectal and duodenal tissue homogenates. Tissue penetration ratios are shown in (A). Abbreviations: FTC, emtricitabine; MVC, maraviroc; NNRTI, nonnucleoside reverse transcriptase inhibitor; RAL, raltegravir; TFV, tenofovir.