Impact of Small Body Weight on Tenofovir-Associated Renal Dysfunction in HIV-Infected Patients: A Retrospective Cohort Study of Japanese Patients

BACKGROUND: Treatment with tenofovir is sometimes associated with renal dysfunction. Limited information is available on this side effect in patients with small body weight, although the use of tenofovir will spread rapidly in Asia and Africa, where patients are likely to be of smaller body weight. METHODS: In a single-center cohort, Japanese patients with HIV infection who started tenofovir-containing antiretroviral therapy were retrospectively analyzed. The incidence of tenofovir-associated renal dysfunction, defined as more than 25% decrement of estimated glomerular filtration rate (eGFR) from the baseline, was determined. The effects of small body weight and body mass index (BMI) on tenofovir-associated renal dysfunction, respectively, were estimated in univariate and multivariate Cox hazards models as the primary exposure. Other possible risk factors were evaluated by univariate analysis and those found significant were entered into the multivariate analysis. RESULTS: The median weight of 495 patients was 63 kg. Tenofovir-related renal dysfunction occurred in 97 (19.6%) patients (incidence: 10.5 per 100 person-years). Univariate analysis showed that the incidence of tenofovir-related renal dysfunction was significantly associated with smaller body weight and BMI, respectively (per 5 kg decrement, HR = 1.23; 95% CI, 1.10-1.37; p<0.001)(per 1 kg/m(2) decrement, HR = 1.14; 95% CI, 1.05-1.23; p = 0.001). Old age, high baseline eGFR, low serum creatinine, low CD4 count, high HIV viral load, concurrent nephrotoxic drugs, hepatitis C infection, and current smoking were also associated with tenofovir-related renal dysfunction. Multivariate analysis identified small body weight as a significant risk (adjusted HR = 1.13; 95% CI, 1.01-1.27; p = 0.039), while small BMI had marginal significance (adjusted HR = 1.07; 95% CI 1.00-1.16; p = 0.058). CONCLUSION: The incidence of tenofovir-associated renal dysfunction in Japanese patients was high. Small body weight was identified as an independent risk factor for tenofovir-associated renal dysfunction. Close monitoring of renal function is advocated for patients with small body weight treated with tenofovir

Acute hepatitis C in HIV-1 infected Japanese Cohort: single center retrospective cohort study.

OBJECTIVES: HCV co-infection is a poor prognostic factor in HIV-1-infected patients. Although the number of newly reported patients who show seroconversion is increasing, the clinical features are still unclear, especially in Asian countries. DESIGN: A single-center retrospective cohort study of patients diagnosed between 2001-2012. METHODS: Acute hepatitis C (AHC) was diagnosed upon detection of high serum ALT (>100 IU) followed by anti-HCV seroconversion. Clinical characteristics, HIV-1-related immunological status and IL-28B genotypes (rs12979860, rs8099917) were collected. We compared these variables between patients with and without spontaneous clearance of HCV and between responders and non-responders to treatment with pegylated interferon (PEG-IFN) plus ribavirin. RESULTS: Thirty-five patients were diagnosed with AHC during the study period. The majority (96.9%) were MSM. Three were lost to follow-up. Seventy-five percent of patients with AHC (24/32) were asymptomatic and found incidentally to have high serum ALT. Compared to those who did not show spontaneous clearance, patients with spontaneous HCV viral clearance showed more symptoms and more severe abnormalities related to acute hepatitis. Spontaneous clearance was seen in 4 out of 28 patients with CC+TT genotype, but not in 6 patients with IL-28B CT+TG genotype. PEG-IFN plus ribavirin treatment was initiated in 12 out of 28 cases without spontaneous clearance. The sustained virological response rate was high (81.8%, 9/11), even in cases with CT+TG genotype infected with HCV genotype 1b (SVR 2/2). CONCLUSIONS: Careful attention to AHC is needed in HIV-1-infected MSM. Early diagnosis and PEG-IFN plus ribavirin treatment should be considered for AHC cases

Preemptive Therapy Prevents Cytomegalovirus End-Organ Disease in Treatment-Naïve Patients with Advanced HIV-1 Infection in the HAART Era

<div><p>Background</p><p>The efficacy of preemptive therapy against cytomegalovirus (CMV) infection remains unknown in treatment-naïve patients with advanced HIV-1 infection in the HAART era.</p><p>Methods</p><p>The subjects of this single-center observation study were126 treatment-naïve HIV-1 infected patients with positive CMV viremia between January 1, 2000 and December 31, 2006. Inclusion criteria were age more than 17 years, CD4 count less than 100/μl, plasma CMV DNA positive, never having received antiretroviral therapy (ART) and no CMV end-organ disease (EOD) at first visit. The incidence of CMV-EOD was compared in patients with and without preemptive therapy against CMV-EOD. The effects of the CMV preemptive therapy were estimated in uni- and multivariate Cox hazards models.</p><p>Results</p><p>CMV-EOD was diagnosed in 30 of the 96 patients of the non-preemptive therapy group (31%, 230.3 per 1000 person-years), compared with 3 of the 30 patients of the preemptive therapy group (10%, 60.9 per 1000 person-years). Univariate (HR = 0.286; 95%CI, 0.087–0.939; p = 0.039) and multivariate (adjusted HR = 0.170; 95%CI, 0.049–0.602; p = 0.005) analyses confirmed that CMV-EOD is significantly prevented by CMV preemptive therapy. Multivariate analysis showed that plasma CMV DNA level correlated significantly with CMV-EOD (per log10/ml, adjusted HR = 1.941; 95%CI, 1.266–2.975; p = 0.002). Among the 30 patients on preemptive therapy, 7 (23.3%) developed grade 3–4 leukopenia. The mortality rate was not significantly different between the two groups (p = 0.193, Log-rank test).</p><p>Conclusions</p><p>The results indicate that preemptive therapy lowers the incidence of CMV-EOD by almost 25%. Preemptive therapy for treatment-naïve patients with CMV viremia is effective, although monitoring of potential treatment-related side effects is required.</p></div

Renal function declines more in tenofovir- than abacavir-based antiretroviral therapy in low-body weight treatment-naïve patients with HIV infection.

OBJECTIVE: To compare the rate of decline of renal function in tenofovir- and abacavir-based antiretroviral therapy (ART) in low-body weight treatment-naïve patients with HIV infection. DESIGN: We conducted a single-center retrospective cohort study of 503 Japanese patients who commenced on either tenofovir- or abacavir-based initial ART. METHODS: The incidence of renal dysfunction, defined as more than 25% fall in estimated glomerular filtration rate (eGFR) from the baseline, was determined in each group. The effect of tenofovir on renal dysfunction was estimated by univariate and multivariate Cox hazards models as the primary exposure. Changes in eGFR until 96 weeks were estimated in both groups with a repeated measures mixed model. RESULTS: The median body weight of the cohort was 64 kg. The estimated incidence of renal dysfunction in the tenofovir and the abacavir arm was 9.84 per 100 and 4.55 per 100 person-years, respectively. Tenofovir was significantly associated with renal dysfunction by univariate and multivariate analysis (HR = 1.747; 95% CI, 1.152-2.648; p = 0.009) (adjusted HR = 2.080; 95% CI, 1.339-3.232; p<0.001). In subgroup analysis of the patients stratified by intertertile baseline body weight, the effect of tenofovir on renal dysfunction was more evident in patients with lower baseline body weight by multivariate analysis (≤60 kg: adjusted HR = 2.771; 95%CI, 1.494-5.139; p = 0.001) (61-68 kg: adjusted HR = 1.908; 95%CI, 0.764-4.768; p = 0.167) (>68 kg: adjusted HR = 0.997; 95%CI, 0.318-3.121; p = 0.995). The fall in eGFR was significantly greater in the tenofovir arm than the abacavir arm after starting ART (p = 0.003). CONCLUSION: The incidence of renal dysfunction in low body weight patients treated with tenofovir was twice as high as those treated with abacavir. Close monitoring of renal function is recommended for patients with small body weight especially those with baseline body weight <60 kg treated with tenofovir

Pharmacokinetics of Rifabutin in Japanese HIV-Infected Patients with or without Antiretroviral Therapy

<div><p>Objective</p><p>Based on drug-drug interaction, dose reduction of rifabutin is recommended when co-administered with HIV protease inhibitors for human immunodeficiency virus (HIV)-associated mycobacterial infection. The aim of this study was to compare the pharmacokinetics of rifabutin administered at 300 mg/day alone to that at 150 mg every other day combined with lopinavir-ritonavir in Japanese patients with HIV/mycobacterium co-infection.</p><p>Methods</p><p>Plasma concentrations of rifabutin and its biologically active metabolite, 25-<i>O</i>-desacetyl rifabutin were measured in 16 cases with HIV-mycobacterial coinfection. Nine were treated with 300 mg/day rifabutin and 7 with 150 mg rifabutin every other day combined with lopinavir-ritonavir antiretroviral therapy (ART). Samples were collected at a median of 15 days (range, 5–63) of rifabutin use.</p><p>Results</p><p>The mean C_max and AUC_0–24 of rifabutin in patients on rifabutin 150 mg every other day were 36% and 26% lower than on 300 mg/day rifabutin, while the mean C_max and AUC_0–24 of 25–<i>O</i>-desacetyl rifabutin were 186% and 152% higher, respectively. The plasma concentrations of rifabutin plus its metabolite were similar between the groups within the first 24 hours, but it remained low during subsequent 24 to 48 hours under rifabutin 150 mg alternate day dosing.</p><p>Conclusion</p><p>Rifabutin dose of 150 mg every other day combined with lopinavir-ritonavir seems to be associated with lower exposure to rifabutin and its metabolite compared with rifabutin 300 mg/day alone in Japanese patients. Further studies are needed to establish the optimal rifabutin dose during ART. The results highlight the importance of monitoring rifabutin plasma concentration during ART.</p><p>Trial registration</p><p>UMIN-CTR (<a href="https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=search&action=input&language=E" target="_blank">https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=search&action=input&language=E</a>) UMIN000001102</p></div

Flow diagram of patient selection.

<p>ART, antiretroviral therapy; ATV, atazanavir; DRV/r, ritonavir-boosted darunavir; ATV/r, ritonavir-boosted atazanavir.</p

Clinical presentation of AHC patients (n = 32).

<p>Data are number (%) of patients or median [range] values.</p><p>*Time between AHC diagnosis and HCV clearance (weeks).</p>¶<p>Data of 6 patients not available for analysis.</p>†<p>Data of 5 patients not available for analysis.</p>‡<p>Data of 1 patient not available for analysis.</p

Comparison of patients of the SVR and non-SVR groups.

<p>Data are number (%) of patients or median [range] values.</p><p>*Time between AHC diagnosis and initiation of therapy (months).</p>¶<p>Time between initiation of therapy and HCV clearance (weeks).</p><p>ART, antiretroviral therapy; UD, undetectable; PEG-IFN+RBV, pegylated interferon plus ribavirin; SVR, sustained viral response; EVR, early viral response; RVR, rapid viral response.</p

Histological findings in needle liver biopsy specimen from the patient who showed null-response (Table 3).

<p>The pre-treatment biopsy specimen obtained at 13 weeks after AHC diagnosis showed stage 2 fibrosis (F2) according to the classification of chronic hepatitis C (New Inuyama Classification). (A and B) Formation of bridging fibrosis by fibrous and cellular expansion in the portal tract. (C) Magnified view showing centrilobular piece-meal necrosis (green arrow), acid folic body (yellow arrow) and spotty necrosis (red arrow). (A) Hematoxylin-eosin stain, x100, (B) Silver impregnation stain, x100, (C) Hematoxylin-eosin stain, x400. PEG-IFN: pegylated interferon, RBV: ribavirin, AHC: acute C hepatitis.</p