Takeshi Nishijima

Objectives: To determine the mortality and causes of death in people living with HIV (PLHIV) in Japan. Design: A prospective cohort study at AIDS Clinical Center, Tokyo, which treats approximately 10% of PLHIV in care in Japan. Methods: Either PLHIV who visited our center for the first time between January 2005 and December 2014 or PLHIV who started their regular visit before January 2005 and visited us between January and March 2005 were included and followed by the end of 2016. Causes of death were defined according to the CoDe protocol. Results: Two thousand, seven hundred and ninety-seven PLHIV were analysed with total of 18 858 person-years of follow-up, which constitutes 14% of the estimated number of PLHIV in care in Japan. One hundred and sixty-five (5.9%) PLHIV died with all-cause mortality rate of 8.75 per 1000 person-years. All-cause mortality rate for PLHIV in care in Japan was estimated to be 8.75 per 1000 person-years (95% CI 5.53–12.0). Among causes of death, AIDS-defining illnesses accounted for 39% and malignancy contributed to 47%. Standardized mortality ratio (SMR) for all-cause mortality, malignancy-related mortality, and suicide were 5.96 (95% CI 5.05–6.87), 7.76 (95% CI 6.02–9.51), and 3.24 (95% CI 1.54–4.94), respectively. Even among the patients who were diagnosed early or without history of AIDS, SMR was four times higher than the general population. Conclusion: Mortality of PLHIV, even among those with early diagnosis, is substantially higher than that of the general population in Japan, highlighting the importance of further efforts towards prevention, early diagnosis and prompt treatment initiation.

Tenofovir disoproxil fumarate (TDF), prodrug of tenofovir (TFV), is one of the most widely used nucleotide reverse transcriptase inhibitors (NRTIs) for the treatment of HIV infection in resource-rich and resourcelimited settings with proven efficacy and safety, and also for the treatment of hepatitis B infections. However, TDF can cause renal proximal tubular dysfunction and also reduces estimated glomerular filtration rate (eGFR) more than other NRTIs. To date, TDF-associated renal dysfunction is generally regarded as mild and tolerable. However, it is notable that low body weight is one of the risk factors for TFV nephrotoxicity and that Asians are generally of smaller body stature and can be susceptible to such nephrotoxicity, as shown in several cohort studies. Until tenofovir alafenamide (TAF), another prodrug of TFV with minimal renal toxicity, becomes widely accessible for people living with HIV and replaces TDF, it is warranted that physicians who prescribe TDF have a good understanding of TFV nephrotoxicity. This paper reviews recent literature on TFV nephrotoxicity among people living with HIV especially focusing on Asians who might be susceptible to TFV nephrotoxicity due to their lower body weight and discusses implications for clinical care and future directions.

Data on the long-term risks of non-AIDS defining cancers (NADCs) are limited, especially in Asians. The incidence of NADCs may correlate with the epidemiological trend of cancers or oncogenic infection in each country, and thus the target cancers would be different between Western and Asian countries. We aimed to elucidate the incidence of NADCs and its predictive factors in Asian HIV-infected patients. Subjects were HIV-infected patients (n = 1001) periodically followed-up for 9 years on average. NADCs were diagnosed by histopathology and/ or imaging findings. Standardized incidence ratios (SIR) were calculated as the ratio of the observed to expected number of NADCs for comparison with an age-and sex-matched general population. Cox’s proportional hazards model was used to estimate hazard ratios (HR). During the median follow-up of 9 years, the 10-year cumulative incidence of NADCs was 6.4%.At NADC diagnosis, half of patients presented at age 40–59 years and with advanced tumor stage. Compared with the age-and sex-matched general population, HIV-infected patients are at increased risk for liver cancer (SIR, 4.7), colon cancer (SIR, 2.1), and stomach cancer (SIR, 1.8). In multivariate analysis, a predictive model for NADCs was developed that included age group (40–49, 50–59, 60–69, and ≥ 70 years), smoker, HIV infection through blood transmission, and injection drug use (IDU), and HBV co-infection. The c-statistic for the NADCs predictive model was 0.8 (95%CI, 0.8–0.9, P < 0.001). The higher 10-year incidence rate of NADCs was associated with increasing prediction score. Liver and colon cancer risk was elevated in Asian HIV-infected individuals, similar to in Western populations, whereas stomach cancer risk was characteristically elevated in Asian populations. Half of Asian NADC patients were aged 40–59 years and had advanced-stage disease at diagnosis. Periodic cancer screening may be warranted for high-risk subpopulations with smoking habit, HIV infection through blood transmission or IDU, and HBV co-infection, and screening should be started over 40 years of age.

The usefulness of an automated latex turbidimetric rapid plasma reagin (RPR) assay, compared to the conventional manual card test (serial 2-fold dilution method), for the diagnosis of syphilis and evaluation of treatment response remains unknown. We conducted (i) a cross-sectional study and (ii) a prospective cohort study to elucidate the correlation between automated and manual tests and whether a 4-fold decrement is a feasible criterion for successful treatment with the automated test, respectively, in HIV-infected patients, from October 2015 to November 2017.

The extent and duration of long-term recovery of CD4 count, CD4 percentage (CD4%), and CD4/CD8 ratio after initiation of combination antiretroviral therapy (cART) in patients with a suppressed viral load (VL) are largely unknown. Patients infected with human immunodeficiency virus type 1 who started cART between January 2004 and January 2012 and showed persistent viral suppression (VL, 10 years. Change point analysis showed that CD4 count, CD4%, and CD4/CD8 ratio continued to increase until 78.6, 62.2, and 64.3 months, respectively, with adjusted means of 590/µL (95% confidence interval, 29.5%, and 0.89, respectively, at the change point. Although CD4 counts ≥500/μL were achieved in 73.8% of the study patients, they were not achieved in 48.2% of those with a baseline CD4 count <100/μL. Neither the CD4% nor the CD4/CD8 ratio were normalized in a majority of patients. The results showed lack of normalization of CD4 count, CD4%, and CD4/CD8 ratio to the levels seen in healthy individuals even after long-term successful cART in patients with a suppressed VL.

Objective: Tenofovir disoproxil fumarate (TDF) increases the risk of kidney tubular dysfunction (KTD). This study was conducted to elucidate whether KTD persists after discontinuation of TDF. Design: A prospective cross-sectional study which enrolled 941 HIV-1-infected patients. Methods: KTD was predefined as the presence of at least two abnormalities among the five tubular markers (fractional excretion of phosphate, fractional excretion of uric acid, β2 microglobulinuria, N-acetyl-β-D-glucosaminidase, nondiabetic glycosuria). Logistic regression model was used to examine the association between KTD and cumulative TDF use, as well as current status of TDF use. Results: In total, 94% of study patients were men (median age 45, estimated glomerular filtration rate 75 ml/min per 1.73 m², CD4⁺ 575 cells/μl. About 98% were on antiretroviral therapy. In total, 64% of the patients ever used TDF and 39% currently used TDF. Twenty-nine percent used TDF for more than 5 years. KTD was diagnosed in 116 (12%) patients. In multivariate model, more than 5 years of TDF exposure and current TDF use [odds ratio (OR) 4.2, 95% confidence interval (CI) 2.37–7.56], more than 5 years and past TDF use (OR 2.4, 95% CI 1.09–5.33), less than 5 years and current TDF (OR 2.4, 95% CI 1.24–4.85), and less than 5 years and past TDF (OR 2.4, 95% CI 1.22–4.64) were all significantly associated with KTD, with never TDF use as reference. The results were the same using 4 and 3 years of exposure as the cutoff. However, with 2 years exposure, both less than 2 years and current TDF (OR 2.3, 95% CI 0.84–6.20) and less than 2 years and past TDF (OR 1.9, 95% CI 0.73–4.93) were not associated with KTD, whereas both more than 2 years and current TDF and more than 2 years and past TDF were associated. Conclusion: The association between cumulative TDF use and KTD was strong and robust. The results of the study suggested that TDF-related KTD might persist after discontinuation of TDF if patients used TDF for more than 2 years.

This single-center cross-sectional study determined the prevalence and factors associated with chronic kidney disease (CKD) and end-stage renal disease (ESRD) in HIV-1-infected Asian patients at the largest HIV clinic in Japan. HIV-1-infected patients who visited the clinic between September and December 2016 were analyzed. CKD was defined as estimated glomerular filtration rate of 2 or proteinuria ≥1+, observed at least over three months. A logistic regression model was used to estimate the effects of various variables on CKD. The study included 1,990 patients; with 97% Asians, 34% aged of ≥50 years, and 94% had HIV-1 load <50 copies/ml. The median time from HIV-1 diagnosis to study enrollment and duration of ART were 9.1 years (IQR4.8–14.2) and 7.35 years (IQR3.28–12), respectively. CKD and ESRD were diagnosed in 256 (13%) and 9 (0.5%) patients, respectively. The prevalence of CKD was 18.6% for age 50–59, 28.5% for 60–69, and 47% for over 70. Older age, heavier body weight, diabetes mellitus, hypertension, and longer duration of ART, but not duration of TDF exposure, were associated with CKD. The traditional risk factors, rather than HIV-1-related variables, were associated with CKD, suggesting the importance of management of such comorbidities in maintenance of renal function.

Little information exists on the frequency, severity, and timing of first-line anti-tuberculosis drug-related adverse events (TB-AEs) in HIV-tuberculosis coinfected (HIV-TB) patients in the antiretroviral therapy (ART) era. This matched-cohort study included HIV-TB patients as cases and HIV-uninfected tuberculosis (non-HIV-TB) patients as controls. Tuberculosis was culture-confirmed in both groups. Cases were matched to controls in a 1:4 ratio on age, sex, and year of diagnosis. TB-AEs were defined as Grade 2 or higher requiring drug discontinuation/regimen change. From 2003 to 2015, 94 cases and 376 controls were analyzed (95% men, 98% Asians). Standard four-drug combination therapy was initiated in 91% of cases and 89% of controls (p = 0.45). Cases had a higher frequency of TB-AE [51% (48/94) vs. 10% (39/376), p < 0.001]. Their major TB-AEs were fever (19%), rash (11%), and neutropenia (11%). TB-AEs were more severe in cases [Grade 3 or higher: cases (71%, 34/48) vs. controls (49%, 19/39), p < 0.001]. The time from treatment initiation to TB-AE was shorter in cases [median 18 (interquartile range 12–28) vs. 27 (15–57) days, p = 0.027], and 73% of TB-AEs in cases occurred within 4 weeks of starting anti-tuberculosis treatment. HIV infection was an independent risk factor for TB-AEs in the multivariate Cox analysis [adjusted HR (aHR): 6.96; 95% confidence interval: 3.93–12.3]. TB-AEs occurred more frequently in HIV-TB than in non-HIV-TB patients, and were more severe. The majority of TB-AEs occurred within 4 weeks of initiating anti-tuberculosis treatment. Because TB-AEs may delay ART initiation, careful monitoring during this period is warranted in coinfected patients.

Little evidence is available for the incidence of chronic kidney disease (CKD) and rate of estimated glomerular filtration rate (eGFR) decrement among Asians with low body weight who are susceptible to tenofovir disoproxil fumarate (TDF) nephrotoxicity. In this 12-year observational cohort in Tokyo, we examined 1383 treatment-naïve HIV-1-infected Asians [720 started TDF-containing (TDF group) and 663 started non-TDF-containing (control) combination antiretroviral therapy (cART)]. The CKD incidence was calculated, and the effect of TDF use on CKD development was estimated using logistic regression. The eGFR slopes, before and after cART initiation, were estimated using mixed-effects linear spline models. Most patients were males (median weight, 62.6 kg; 83% started ritonavir-boosted protease inhibitors; median observation duration, 5.08 years). CKD developed in 150 patients (10.8%), with an incidence of 20.6 per 1000 person-years [confidence interval (95% CI), 17.6–24.2]. None developed end-stage renal disease. TDF use was associated with CKD [odds ratio (OR), 1.8; 95% CI, 1.00–3.13; p = 0.052]. The cumulative mean loss in the TDF group, relative to the control, increased over time after 1, 4, and 8 years of TDF exposure (−3.8, −5.5, and −9.0 mL/min/1.73 m², respectively; p < 0.0001). The eGFR rapidly declined during the first 3 months of cART, particularly in the TDF group (−26.4 vs. −7.4 mL/min/1.73 m²/year in the control). In the TDF group, cART introduction was significantly associated with a faster rate of eGFR decline (from −0.44 to −2.11 mL/min/1.73 m²/year; p = 0.010), whereas in the control, the difference was not significant. For HIV-1-infected Asian patients with low body weight, TDF-containing cART is associated with CKD and faster eGFR declines.