Higher colorectal tissue HIV infectivity in cisgender women compared with MSM before and during oral preexposure prophylaxis

Abstract

Objective: The objective of this study was to compare HIV-negative cisgender women (CGW) with MSM for mucosal tissue differences in pharmacokinetics, HIV infectivity and cell phenotype.

Design: A substudy of HPTN 069/ACTG A5305, 48-week study of three oral candidate preexposure prophylaxis regimens: maraviroc, maraviroc/emtricitabine and maraviroc/tenofovir disoproxil fumarate (TDF) compared with a TDF/emtricitabine control group.

Methods: Plasma, peripheral blood mononuclear cells and cervical and colorectal tissue biopsies were collected at Baseline (no drug), Week 24 and 48 (on drug), and Week 49 (1-week postdrug). Drug concentrations were assessed in all matrices. HIV infectivity was assessed using tissue biopsy 'explants' challenged with HIV ex vivo followed by HIV p24 measurement. Flow cytometry evaluated colorectal cell phenotype.

Results: Thirty-seven CGW and 54 MSM participated. CGW's colorectal explant p24 was higher than MSM before (0.31 log10, P = 0.046), during (1.01-1.19 log10, P = 0.016) and one week after (0.61 log10, P = 0.011) study drug dosing. Pooling regimens, cervical explant p24 did not differ among visits. CGW had higher plasma maraviroc and colorectal tissue tenofovir diphosphate and lower colorectal tissue emtricitabine (all P < 0.005) compared with MSM. Each study drug's cervical tissue concentrations were more than 10-fold below paired colorectal concentrations (P < 0.001). Cell phenotype sex differences included 4% higher CD38+/CD8+ cells at baseline and 3-7% higher CD69+/CD8+ cells throughout Weeks 24-49 in CGW compared with MSM (P < 0.05).

Conclusion: Colorectal explants in CGW demonstrated greater HIV infectivity than MSM with and without study drugs. Small differences in adherence, drug concentration and colorectal tissue flow cytometry cannot fully explain this difference.

Figure 1.

Study enrollment and outcome availability summary for the parent HPTN 069/ACTG A5305 study and the mucosal tissue substudy that enrolled 91 participants from within the larger parent study. Pharmacokinetic samples were contributed by all substudy participants. Cervical biopsies were contributed for PK and PD (explant) analysis by all of the CGW, but only some provided rectal tissue biopsies. Flow cytometry was performed only on rectal tissue. Abbreviations: MSM, men who have sex with men; TGW, transgender women; CGW, cisgender women; MVC, maraviroc; FTC, emtricitabine; TDF, tenofovir disoproxil fumarate. MSM may be truncated to MSM for space.

Figure 2.

Explant p24 antigen concentration (cumulative biopsy weight-adjusted) change from baseline by tissue type, gender group, and antiviral drug regimen (median and interquartile range). Values are difference between active (on drug or post-drug) phase (week 24, 48, or 49) log₁₀ p24 minus baseline (pre-drug) log₁₀ p24 (equivalent to log₁₀ of active phase divided by baseline p24). Zero value reference line indicates no change compared to baseline. Key: black diamond, all genders and all regimens; brown diamond, CGW all regimens; blue (open) diamond, MSM all regimens. Regimen specific groups (CGW for cervical tissue and all genders for rectal tissue) are blue circle MVC only, green up triangle MVC + FTC (M/F), cyan down triangle MVC + TDF (M/T), and red diamond TDF + FTC (T/F). Triplets in each coded grouping are (left to right) week 24, week 48, and week 49 relative to baseline. Asterisks indicate p value < 0.05 for Wilcoxon signed rank test comparing baseline to each of three active periods (week 24, 48, and 49).

Figure 3.

Antiretroviral concentration vs. p24 antigen response plots of 120 cervical tissue (left) and 243 rectal tissue (right) homogenates. Y-axis is log₁₀ cumulative p24 antigen with biopsy weight-adjustment. X-axis is sum of molar tissue concentration (pmol/mg) for the one or two antiretroviral drugs in the assigned regimen. Closed symbols represent cisgender women participants and open symbols are men who have sex with men and transgender women participants. Colors and symbol indicate the four drug regimens (blue circle, MVC only; green up triangle, MVC/FTC; green down triangle, MVC/TDF; red diamond, TDF/FTC). Drug concentrations below the limit of assay quantitation (BLQ) and at baseline (BL) are imputed as LLOQ/2 and LLOQ/10, respectively, of the median drug LLOQ; these are offset to avoid overlap. Gender group median log₁₀ p24 concentrations associated with BLQ and BL are indicated with horizontal bars (dark yellow CGW, blue MSM). Pharmacodynamic I_max model fit predicted values are shown (black line).

Figure 4.

Colorectal tissue flow cytometry changes over time relative to a reference visit (baseline or post-drug) expressed as a ratio on the y-axis are displayed by several layers of groupings along the x-axis, starting with surface marker subset, study arm, study week (numerator of ratio), and gender (MSM beside CGW). The four flow cytometry markers displayed all had visit-to-visit temporal changes among regimens (Friedman test p<0.05). Within each marker subsets, each study arm is indicated as M (MVC only), M/F (MVC and FTC), M/T (MVC and TDF), and T/F (TDF and FTC). Within each regimen grouping, temporal changes are indicated by the ratio of marker expression percent at a given visit divided by a temporal reference value, either Baseline or Week 49 depending on which ratio was statistically significant. For CD3+ FCI, CCR5+/CD8+ FCS, and CCR5+/CXCR4+/CD8+ FCS, the ratios (left to right) are Week 24, Week 48, and Week 49 divided by pre-drug baseline. For CD69/CD4 FCS, the ratios (left to right) are Baseline, Week 24, and Week 48 divided by Week 49. Symbols are medians and error bars are either interquartile range for the larger MSM cohort (blue diamond and error bars) or range for the smaller 2–3 person CGW within a regimen (dark red diamond). Asterisks along the x-axis indicate paired Wilcoxon rank sum test p<0.05 for each of 3 observation times compared to the reference visit for pooled CGW, MSM, and TGW genders; dashes indicate p>0.05.