Dipeptidyl peptidase IV inhibition does not adversely affect immune or virological status in HIV infected men and women: a pilot safety study

Abstract

Context: People infected with HIV have a higher risk for developing insulin resistance, diabetes, and cardiovascular disease than the general population. Dipeptidyl peptidase IV (DPP4) inhibitors are glucose-lowering medications with pleiotropic actions that may particularly benefit people with HIV, but the immune and virological safety of DPP4 inhibition in HIV is unknown.

Objective: DPP4 inhibition will not reduce CD4+ T lymphocyte number or increase HIV viremia in HIV-positive adults.

Design: This was a randomized, placebo-controlled, double-blind safety trial of sitagliptin in HIV-positive adults.

Setting: The study was conducted at an academic medical center.

Participants: Twenty nondiabetic HIV-positive men and women (9.8 ± 5.5 years of known HIV) taking antiretroviral therapy and with stable immune (625 ± 134 CD4+ T cells per microliter) and virological (<48 copies HIV RNA per milliliter) status.

Intervention: The intervention included sitagliptin (100 mg/d) vs matching placebo for up to 24 weeks.

Main outcome measures: CD4+ T cell number and plasma HIV RNA were measured every 4 weeks; fasting serum regulated upon activation normal T-cell expressed and secreted (RANTES), stromal derived factor (SDF)-1α, Soluble TNF receptor II, and oral glucose tolerance were measured at baseline, week 8, and the end of study. ANOVA was used for between-group comparisons; P < .05 was considered significant.

Results: Compared with placebo, sitagliptin did not reduce CD4+ T cell count, plasma HIV RNA remained less than 48 copies/mL, RANTES and soluble TNF receptor II concentrations did not increase. SDF1α concentrations declined (P < .0002) in the sitagliptin group. The oral glucose tolerance levels improved in the sitagliptin group at week 8.

Conclusions: Despite lowering SDF1α levels, sitagliptin did not adversely affect immune or virological status, or increase immune activation, but did improve glycemia in healthy, nondiabetic HIV-positive adults. These safety data allow future efficacy studies of sitagliptin in HIV-positive people with cardiometabolic complications.

Figures

Figure 1.

Immunological and virological status. CD4+ T lymphocyte number (A) absolute count, and (B) percentage of PBMCs were not different between the groups at baseline (P = .55 and P = .39, respectively) and not different at any time point during sitagliptin or placebo exposure (P = .58 and P = .82, respectively). Additionally, plasma HIV RNA copy number remained undetectable (<48 copies HIV RNA/mL) at all time points in both groups throughout the study period. The data points at week 24 represent n = 4 placebo and n = 3 sitagliptin.

Figure 2.

Chemokines and markers of immune activation. A, Baseline serum SDF-1α concentrations were not different between the groups (P = .80), but at week 8 and the end of study, SDF-1α levels were lower in the sitagliptin group than in the placebo group. *, P < .0001. B, Serum RANTES levels were not different between the groups at baseline (P = .27) and were not different at any time point during placebo or sitagliptin exposure (P > .25). C, Serum sTNFRII levels were not different between the groups at baseline (P = .60) and were not different at any time point during placebo or sitagliptin exposure (P > .28).

Figure 3.

Oral glucose tolerance. A, Baseline glucose values and area under the OGTT curve were not different between the groups (P > .50). B, After 8 weeks of sitagliptin exposure, fasting glucose, glucose at 60 min, and AUC were lower for sitagliptin than placebo. *, P < .04. C, At the end of the study, only fasting glucose levels remained lower in sitagliptin than placebo. *, P = .0004.