[show abstract][hide abstract] ABSTRACT: Objective: The 2010 WHO antiretroviral therapy (ART) guidelines have resulted in increased tenofovir use. Little is known about tenofovir-induced chronic kidney disease (CKD) in HIV-infected Vietnamese with mean body weight of 55 kg. We evaluated the prevalence and risk factors of CKD in this country. Design: Cross-sectional study was performed. Methods: Clinical data on HIV-infected Vietnamese cohort were collected twice a year. To evaluate the prevalence of CKD, serum creatinine was measured in 771 patients in October 2011 and April 2012. CKD was defined as creatinine clearance less than 60 ml/min at both time points. Multivariate logistic regression was used to determine the factors associated with CKD Results: Tenofovir use increased in Vietnam from 11.9% in April 2011 to 40.3% in April 2012. CKD was diagnosed in 7.3%, of which 7% was considered moderate and 0.3% was severe. Multivariate analysis of October-2011 data identified age per year-increase (OR: 1.229, 95%CI, 1.170-1.291), body weight per 1 kg-decrement (1.286, 1.193-1.386), and tenofovir use (2.715, 1.028-7.168) as risk factors for CKD. Conclusions: Older age, low body weight and tenofovir use were independent risk factors for CKD in Vietnam. Further longitudinal study is required to evaluate the impact of TDF on renal function in Vietnam and other countries with small-body weight patients.
[show abstract][hide abstract] ABSTRACT: The epidemiology of hepatitis C virus (HCV) infection among HIV-infected men who have sex with men (MSM) who do not inject drugs in Asia remains unknown.
The incidence and risk factors for incident HCV infection among HIV-infected MSM at a large HIV clinic in Tokyo were elucidated. Poisson regression compared the incidence of HCV seroconversion at different observation periods.
Of 753 HIV-1 infected MSM patients negative for HCV antibody (HCVAb) at baseline and available follow-up HCVAb test, 21 patients (2.8%) seroconverted to HCVAb-positive over 2,246 person-years (PY), for an incidence of 9.35/1,000 PY. The incidence increased over time from 0/1,000 PY in 2005 to 2006, 3.0/1,000 PY in 2007 to 2008, 7.7/1,000 PY in 2009 to 2010, and 24.9/1,000 PY in 2011 to 2012 (p=0.012). Of 21 incident cases, only 4 (21%) were injection drug users, and sensitivity analysis that excluded injection drug users yielded similar findings. Multivariate analysis identified illicit drug use to be an independent risk for HCV infection (HR=3.006; 95%CI, 1.092-8.275; p=0.033).
Incident HCV infection is increasing among HIV-1-infected MSM non-injection drug users at resource-rich setting in Asia. Illicit drug use is an independent risk factor for incident HCV infection in this population.
[show abstract][hide abstract] ABSTRACT: Background: Although ritonavir-boosted atazanavir (ATV/r) is known to be associated with nephrolithiasis, little is known about the incidence of nephrolithiasis in patients treated with ritonavir-boosted Darunavir (DRV/r), the other preferred protease inhibitor.
[show abstract][hide abstract] ABSTRACT: Identification of cross-clade T cell epitopes is one of key factors for the development of a widely applicable AIDS vaccine. We here investigated cross-clade CD8(+) T cell responses between clade B and A/E viruses in chronically HIV-1 clade A/E-infected Japanese individuals. CD8(+) T cell responses to 11-mer overlapping peptides derived from Nef, Gag, and Pol clade B consensus sequences were at a similar level to those to the same peptides found in clade B-infected individuals. Fifteen cross-clade CTL epitopes were identified from 13 regions where the frequency of responders was high in the clade A/E infected-individuals. The sequences of 6 epitopes were conserved between the clade B and clade A/E viruses whereas 9 epitopes had different amino acid sequences between the 2 viruses. CD8(+) T cells specific for the 6 conserved epitopes recognized cells infected with the clade A/E virus, whereas those for 8 diverse epitopes recognized both the clade A/E virus-infected and clade B-infected cells. All of the cross-clade CD8(+) T cells specific for conserved and diverse epitopes were detected in chronically HIV-1 clade A/E-infected individuals. These results show that in addition to conserved regions polymorphic ones across the clades can be targets for cross-clade CTLs.
Microbes and Infection 08/2013; · 2.92 Impact Factor
[show abstract][hide abstract] ABSTRACT: The third variable region (V3) of HIV-1 envelope glycoprotein gp120 plays a key role in determination of viral coreceptor usage (tropism). However, which combinations of mutations in V3 confer a tropism shift is still unclear. A unique pattern of mutations in antiretroviral therapy-naive HIV-1 patient was observed associated with the HIV-1 tropism shift CCR5 to CXCR4. The insertion of arginine at position 11 and the loss of the N-linked glycosylation site were indispensable for acquiring pure CXCR4-tropism, which were confirmed by cell-cell fusion assay and phenotype analysis of recombinant HIV-1 variants. The same pattern of mutations in V3 and the associated tropism shift were identified in two of 53 other patients (3.8%) with CD4(+) cell count <200/mm(3). The combination of arginine insertion and loss of N-linked glycosylation site usually confers CXCR4-tropism. Awareness of this rule will help to confirm the tropism prediction from V3 sequences by conventional rules.
[show abstract][hide abstract] ABSTRACT: Background
Whether tenofovir nephrotoxicity is reversible after its withdrawal is unknown. Furthermore, there are no data on the viral efficacy of raltegravir (RAL) plus ritonavir-boosted Darunavir (DRV/r) in patients with suppressed viral load.
This multicenter, randomized trial compared renal function and viral efficacy in patients with suppressed viral load treated with RAL+DRV/r and ritonavir-boosted lopinavir (LPV/r) plus tenofovir/emtricitabine (TVD), who had been previously on LPV/r+TVD. The primary endpoint was the proportion of patients with >10% improvement in estimated glomerular filtration rate (eGFR) at 48 weeks calculated with Cockcroft-Gault equation.
58 randomized and treatment-exposed patients were analyzed (28 on RAL+DRV/r and 30 on LPV/r+TVD). Greater than 10% improvement in eGFR was noted in 6 (25%) out of 24 with RAL+DRV/r and 3 (11%) of 28 with LPV/r+TVD, and the difference was not statistically significant (p=0.272, 95% CI -0.067 to 0.354). Sensitivity analyses using three other equations for eGFR showed the same results. Urinary β2 microglobulin, a sensitive marker of tenofovir tubulopathy, significantly improved with RAL+DRV/r than with LPV/r+TVD (-271 versus -64 µg/gCr, p=0.026). Per protocol analysis showed that the HIV-RNA was <50 copies/mL at week 48 in all patients of both arms (24 in RAL+DRV and 29 in LPV/r+TVD).
Switching LPV/r+TVD to RAL+DRV/r did not significantly increase the proportion of patients who showed >10% improvement in renal function among those with relatively preserved eGFR. However, the switch improved urinary β2 microglobulin, suggesting that discontinuation of TDF might be beneficial in the long-term. RAL+DRV/r showed favorable viral efficacy in patients with suppressed viral load.
[show abstract][hide abstract] ABSTRACT: Background: Loss to follow up (LTFU) is an important prognostic factor in patients with HIV-1 infection. The impact of illicit drug use on LTFU of patients with HIV-1 infection is unknown in Japan.
[show abstract][hide abstract] ABSTRACT: Viral protein R (Vpr), a protein of human immunodeficiency virus type-1 (HIV-1) with various biological functions, was shown to be present in the blood of HIV-1-positive patients. However, it remained unclear whether circulating Vpr in patients' blood is biologically active. Here, we examined the activity of blood Vpr using an assay system by which retrotransposition of long interspersed element-1 (L1-RTP) was detected. We also investigated the in vivo effects of recombinant Vpr (rVpr) by administrating it to transgenic mice harboring human L1 as a transgene (hL1-Tg mice). Based on our data, we discuss the involvement of blood Vpr in the clinical symptoms of acquired immunodeficiency syndrome (AIDS).
We first discovered that rVpr was active in induction of L1-RTP. Biochemical analyses revealed that rVpr-induced L1-RTP depended on the aryl hydrocarbon receptor, mitogen-activated protein kinases, and CCAAT/enhancer-binding protein beta. By using a sensitive L1-RTP assay system, we showed that 6 of the 15 blood samples from HIV-1 patients examined were positive for induction of L1-RTP. Of note, the L1-RTP-inducing activity was blocked by a monoclonal antibody specific for Vpr. Moreover, L1-RTP was reproducibly induced in various organs, including the kidney, when rVpr was administered to hL1-Tg mice.
Blood Vpr is biologically active, suggesting that its monitoring is worthwhile for clarification of the roles of Vpr in the pathogenesis of AIDS. This is the first report to demonstrate a soluble factor in patients' blood active for L1-RTP activity, and implies the involvement of L1-RTP in the development of human diseases.
[show abstract][hide abstract] ABSTRACT: Abstract We conducted a single-center prospective study to evaluate the utility of cytomegalovirus (CMV) antigenemia assay for the diagnosis of CMV-gastrointestinal disease (GID). The study subjects were HIV-infected patients with CD4 count ≤200 μL/cells who had undergone endoscopy. A definite diagnosis of CMV-GID was made by histological examination of endoscopic biopsied specimen. CMV antigenemia assay (C10/C11 monoclonal antibodies), CD4 count, HIV viral load, history of HAART, and gastrointestinal symptoms as measured by 7-point Likert scale, were assessed on the same day of endoscopy. One hundred cases were selected for analysis, which were derived from 110 cases assessed as at high-risk for CMV-GID after endoscopy screening of 423 patients. Twelve patients were diagnosed with CMV-GID. Among the gastrointestinal symptoms, mean bloody stool score was significantly higher in patients with CMV-GID than in those without (2.5 vs. 1.7, p=0.02). The area under the receiver-operating characteristic curve of antigenemia was 0.80 (95%CI 0.64-0.96). The sensitivity, specificity, positive likelihood ratio (LR), and negative LR of antigenemia were 75.0%, 79.5%, 3.7, and 0.31, respectively, when the cutoff value for antigenemia was ≥1 positive cell per 300,000 granulocytes, and 50%, 92.0%, 5.5, and 0.55, respectively, for ≥5 positive cells per 300,000 granulocytes. In conclusion, CMV antigenemia seems a useful diagnostic test for CMV-GID in patients with HIV infection. The use of ≥5 positive cells per 300,000 granulocytes as a cutoff value was associated with high specificity and high positive LR. Thus, a positive antigenemia assay with positive endoscopic findings should allow the diagnosis of CMV-GID without biopsy.
AIDS patient care and STDs 06/2013; · 2.68 Impact Factor
[show abstract][hide abstract] ABSTRACT: Background. Rilpivirine is listed as an alternative key-drug in the current antiretroviral therapy (ART) guidelines. E138G/A/K in HIV-1 reverse transcriptase (RT) are rilpivirine resistance-associated mutations and can be identified in a few ART-naïve patients though at low frequency. The 138th position in HIV-1 RT is located in one of the putative epitopes of human leukocyte antigen (HLA)-B*18-restricted cytotoxic T lymphocytes (CTL). CTL-mediated immune pressure selects escape mutations within the CTL epitope. Here we tested whether E138G/A/K could be selected by HLA-B*18-restricted CTL. Methods. The amino acid variation at the 138th position was compared between ART-naïve HIV-1-infected patients with and without HLA-B*18. The optimal epitope containing the 138th position was determined and the impact of E138G/A/K on CTL response was analyzed by epitope-specific CTL. The effect of E138G/A/K on drug susceptibility was determined by constructing recombinant HIV-1 variants. Results. The prevalence of E138G/A/K was 21% and 0.37% in 19 and 1,088 patients with and without HLA-B*18, respectively (odds ratio 72.3; p=4.9x10(-25)). The CTL response was completely abolished by the substitution of E138G/A/K in the epitope peptide. E138G/A/K conferred 5.1-, 7.1-, and 2.7-fold resistance to rilpivirine, respectively. Conclusions. E138G/A/K can be selected by HLA-B*18-restricted CTL and confer significant rilpivirine resistance. We recommend drug-resistance testing before the introduction of rilpivirine-based ART in HLA-B*18-positive patients.
[show abstract][hide abstract] ABSTRACT: We present a case of HIV-related thrombocytopenic purpura (HIV-ITP) successfully treated with high-dose dexamethasone and antiretroviral therapy (ART). Although high-dose dexamethasone is regarded as the first-line therapy in adult patients with non-HIV ITP, there is limited information on treatment of HIV-ITP and long-term prednisone therapy is considered the standard therapy. High-dose dexamethasone is preferable to conventional long-term prednisone therapy, because of fewer side effects mainly due to shorter steroid use. The ART helps achieve long-term remission for HIV-ITP, although this therapy lacks an immediate effect. In our patient, administration of high-dose dexamethasone resulted in rapid rise in platelet count and ART maintained long-term remission of HIV-ITP. The combination therapy is potentially suitable strategy for the treatment of patients with HIV-ITP and severe thrombocytopenia or bleeding.
Journal of Infection and Chemotherapy 03/2013; · 1.55 Impact Factor
[show abstract][hide abstract] ABSTRACT: The efficacy and safety of fixed-dose abacavir/lamivudine against tenofovir/emtricitabine, both with once-daily darunavir/ritonavir, was examined in 80 treatment-naïve patients with a baseline HIV-1 viral load of more than 100 000 copies/ml. The time to virologic failure by 48 weeks was not different between the two groups. The percentage of patients with viral suppression was not significantly different with per protocol population. Tenofovir/emtricitabine showed better tolerability; more patients on abacavir/lamivudine changed regimen than those on tenofovir/emtricitabine. A randomized trial to elucidate the efficacy and safety of these two regimens is warranted.
AIDS (London, England) 03/2013; 27(5):839-842. · 4.91 Impact Factor
[show abstract][hide abstract] ABSTRACT: Background. Hepatitis B virus (HBV) infection is common in HIV-infected individuals, especially in men who have sex with men (MSM). Almost all currently used regimens of antiretroviral therapy (ART) contain lamivudine (LAM) or tenofovir disoproxil fumarate (TDF), both of which have significant anti-HBV activity. However, the prophylactic effect of ART on HBV infection has not been assessed previously. Methods. HBV-non-vaccinated HIV-infected MSM were serologically evaluated for HBV infection using stocked serum samples. Cases negative for HBV surface antigen (HBsAg), antibody to HBsAg (anti-HBs), and antibody to HBV core antigen (anti-HBc) in first serum samples were serologically followed until last available stocked samples. HBV genotype and LAM-resistant mutation (rtM204V/I) were analyzed in cases that became HBsAg-positive. Results. The first stocked samples were negative for all analyzed HBV serological markers in 354 of 1,434 evaluated patients. The analysis of their last samples indicated HBV incident infection in 43 of them during the follow-up period. The rate of incident infections was lower during LAM- or TDF-containing ART (0.669 incident infections in 100 person-years) than during no ART period (6.726 incident infections in 100 person-years) and other ART (5.263 incident infections in 100 person-years) (P<0.001). Genotype A was most prevalent in them (76.5%) and LAM-resistant HBV was more frequent in incident infections during LAM-containing ART (50.0%) than in those during no ART and other ART (7.1%) (P=0.029). Conclusions. LAM- and TDF-containing ART seem to provide prophylaxis against HBV infection, though drug-resistant strains seem to evade these effects.
[show abstract][hide abstract] ABSTRACT: Kidney tubulopathy is a well-known adverse event of antiretroviral agent tenofovir. A cross-sectional study was conducted to compare the diagnostic accuracy of five tubular markers, with a collection of abnormalities in these markers as the reference standard. The study subjects were patients with HIV-1 infection on ritonavir-boosted darunavir plus tenofovir/emtricitabine with suppressed viral load. Kidney tubular dysfunction (KTD) was predefined as the presence of at least three abnormalities in the following five parameters: β2-microglobulinuria (β2M), α1-microglobulinuria (α1M), high urinary N-acetyl-β-D-glucosaminidase (NAG), fractional excretion of phosphate (FEIP), and fractional excretion of uric acid (FEUA). Receiver operating characteristic curves and areas under the curves (AUC) were estimated, and the differences between the largest AUC and each of the other AUCs were tested using a nonparametric method. The cutoff value of each tubular marker was determined using raw data of 100 % sensitivity with maximal specificity. KTD was diagnosed in 19 of the 190 (10 %) patients. The AUCs (95 % CIs) of each tubular marker were β2M, 0.970 (0.947-0.992); α1M, 0.968 (0.944-0.992); NAG, 0.901 (0.828-0.974); FEIP, 0.757 (0.607-0.907), and FEUA, 0.762 (0.653-0.872). The AUCs of β2M and α1M were not significantly different, whereas those of the other three markers were smaller. The optimal cutoff values with 100 % sensitivity were 1,123 μg/gCr (β2M, specificity 89 %), 15.4 mg/gCr (α1M, specificity 87 %), 3.58 U/gCr (NAG, specificity 46 %), 1.02 % (FEIP, specificity 0 %), and 3.92 % (FEUA, specificity 12 %). Urinary β2M and α1M are potentially suitable screening tools for tenofovir-induced KTD. Monitoring either urinary β2M or α1M should be useful in early detection of tenofovir nephrotoxicity.
Journal of Infection and Chemotherapy 03/2013; · 1.55 Impact Factor
[show abstract][hide abstract] ABSTRACT: We herein report the case of an HIV-positive man who was diagnosed with idiopathic esophageal and oropharyngeal ulceration. The esophageal and oropharyngeal ulcers were considered to be idiopathic and related to HIV infection after excluding the possibility of infection with known pathogens. Both the esophageal and oropharyngeal ulcers showed significant improvements following antiretroviral therapy alone. Idiopathic esophageal ulcers are a well-known complication of late-stage HIV infection. However, involvement of both the esophagus and pharynx is rare. Furthermore, antiretroviral therapy without concomitant steroids is effective against idiopathic esophageal and oropharyngeal ulcers related to HIV infection.
Internal Medicine 01/2013; 52(3):393-395. · 0.97 Impact Factor
[show abstract][hide abstract] ABSTRACT: Antigen cross-reactivity is an inbuilt feature of the T cell compartment. However, little is known about the flexibility of T cell recognition in the context of genetically variable pathogens such as HIV-1. In this study, we used a combinatorial library containing 24 billion octamer peptides to characterize the cross-reactivity profiles of CD8(+) T cells specific for the immunodominant HIV-1 subtype B Nef epitope VY8 (VPLRPMTY) presented by HLA-B(*)35∶01. In conjunction, we examined naturally occurring antigenic variations within the VY8 epitope. Sequence analysis of plasma viral RNA isolated from 336 HIV-1-infected individuals revealed variability at position (P) 3 and P8 of VY8; Phe at P8, but not Val at P3, was identified as an HLA-B(*)35∶01-associated polymorphism. VY8-specific T cells generated from several different HIV-1-infected patients showed unique and clonotype-dependent cross-reactivity footprints. Nonetheless, all T cells recognized both the index Leu and mutant Val at P3 equally well. In contrast, competitive titration assays revealed that the Tyr to Phe substitution at P8 reduced T cell recognition by 50-130 fold despite intact peptide binding to HLA-B(*)35∶01. These findings explain the preferential selection of Phe at the C-terminus of VY8 in HLA-B(*)35∶01(+) individuals and demonstrate that HIV-1 can exploit the limitations of T cell recognition in vivo.
PLoS ONE 01/2013; 8(6):e66152. · 3.73 Impact Factor
[show abstract][hide abstract] ABSTRACT: The efficacy of preemptive therapy against cytomegalovirus (CMV) infection remains unknown in treatment-naïve patients with advanced HIV-1 infection in the HAART era.
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.
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).
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.
PLoS ONE 01/2013; 8(5):e65348. · 3.73 Impact Factor
[show abstract][hide abstract] ABSTRACT: Loss to follow up (LTFU) is an important prognostic factor in patients with HIV-1 infection. The impact of illicit drug use on LTFU of patients with HIV-1 infection is unknown in Japan.
A single center observational study was conducted to elucidate the impact of illicit drug use on LTFU at a large HIV clinic in Tokyo. LTFU was defined as those who discontinued their visits to the clinic for at least 12 months and were not known to be under the care of other facilities or have died within 12 months of their last visit. Patients who first visited the clinic between January 2005 and August 2010 were enrolled. Information on illicit drug use was collected in a structured interview and medical charts. Comparison of the effects of illicit drug use and no use on LTFU was conducted by uni- and multi-variate Cox hazards models as the primary exposure.
The study subjects were 1,208 patients, mostly Japanese men, of relatively young age, and infected through homosexual contact. A total of 111 patients (9.2%) were LTFU (incidence: 24.9 per 1,000 person-years). Among illicit drug users and non users, 55 (13.3%) and 56 (7.1%) patients, respectively, were LTFU, with incidence of 35.7 and 19.2 per 1,000 person-years, respectively. Uni- and multi-variate analyses showed that illicit drug use was a significant risk for LTFU (HR=1.860; 95% CI, 1.282-2.699; p=0.001) (adjusted HR=1.544; 95% CI, 1.028-2.318; p=0.036). Multivariate analysis also identified young age, high CD4 count, no antiretroviral therapy, and no health insurance as risk factors for LTFU.
The incidence of LTFU among illicit drug users was almost twice higher than that among non users. Effective intervention for illicit drug use in this population is warranted to ensure proper treatment and prevent the spread of HIV.
PLoS ONE 01/2013; 8(8):e72310. · 3.73 Impact Factor