Protease inhibitor-associated bone mineral density loss is related to hypothyroidism and related bone turnover acceleration.

BACKGROUND: Clinical and experiments evidence indicate that protease inhibitors (PI) can cause bone mineral density (BMD) loss. However, the mechanism of such loss remains obscure. METHODS: This single-center, cross-sectional study included 184 HIV-infected patients treated with PI who underwent dual-energy X-ray absorptiometry scan. Serum phosphorus, percentage of tubular reabsorption of phosphate (%TRP), thyroid and parathyroid function (iPTH), vitamin D, osteocalcin (OC), urinary deoxypyridinoline (DPD), and urinary cross-linked N-telopeptide of type I collagen (u-NTx) were measured. RESULTS: The rate of hypothyroidism in PI-users [32/117 (27%)] was double that in non-PI users [8/67 (12%), p = 0.016] and was significantly associated with PI use in multivariate analysis [odds ratio (OR) 11.37, 95% confidence interval (CI) 1.358-95.17, p = 0.025]. Spine BMD was significantly lower in hypothyroid patients than euthyroid, for both total population (-1.37 vs. -1.00, p = 0.041) and PI users (-1.56 vs. -1.13, p = 0.029). Multivariate regression analysis identified inverse correlation between hypothyroidism and spine BMD [estimate -0.437, 95% CI -0.858 to -0.024, p = 0.042]. OC, DPD and u-NTx were significantly higher in PI users than in non-PI users (p = 0.01, 0.05, and 0.01, respectively). CONCLUSIONS: PI use is associated with hypothyroidism as well as bone turnover acceleration, which worsens PI-associated BMD loss. In PI-treated patients, thyroid function tests are warranted to prevent further progression of PI-associated BMD loss.

Simultaneous vaccination in Japanese travelers.

BACKGROUND: Simultaneous vaccination is not common in Japan because there is little information available on its effects. Some people are quite concerned about the possibility of adverse reactions due to simultaneous vaccination. The objective of this study was to evaluate whether the frequency and severity of adverse effects are increased by simultaneous vaccination in comparison to single vaccination. METHOD: A retrospective observational study was conducted in 399 asymptomatic travelers who visited the travel clinic during the period January-July 2005. One hundred forty-two participants were given a single vaccination, 257 participants were given simultaneous vaccination. Travel-specific vaccinations were for hepatitis A, hepatitis B, tetanus, rabies and Japanese encephalitis, and routine vaccines were for diphtheria+tetanus, measles, mumps and oral polio vaccine. To evaluate adverse effects, travelers were asked to complete a prepared questionnaire after vaccination. RESULTS: Adverse effects were reported by 26.3% of travelers, with 21.8% reporting local reactions and 4.5% reporting systemic reactions. The simultaneous vaccination group reported significantly more frequent adverse effects than those reported by the single vaccination group. Particularly, tetanus vaccination was shown to significantly raise the risk of adverse effects (P<0.001). However, no serious adverse effects were reported. CONCLUSIONS: Simultaneous vaccination was feasible for Japanese travelers because most problems were generally minor and related to local reactions at the sites of injections. Provision of a simultaneous vaccination schedule should motivate more Japanese travelers to obtain immunizations and thereby reduce the risk of vaccine-preventable diseases.

Urinary beta2-microglobulin as a possible sensitive marker for renal injury caused by tenofovir disoproxil fumarate.

Tenofovir disoproxil fumarate (TDF) is renally excreted by a combination of glomerular filtration and active tubular secretion, and its renal safety profiles have been reported based on a limited increase of serum creatinine (sCr) levels. However, renal tubular function has not previously been well monitored. We measured sCr and urinary beta2-microglobulin (U-beta2MG) levels cross-sectionally in 70 patients treated with TDF [TDF+] and 90 patients on other antiretroviral therapy who had never been exposed to TDF [TDF-]. The mean U-beta2MG was significantly higher in TDF+ patients than that in TDF- patients (p < 0.0001), though no statistical difference was detected in their creatinine clearance estimated by using the Cockcroft-Gault equation. Multivariate analysis showed that coadministration of boosted lopinavir (LPV) and patients' body weight were associated with U-beta 2MG levels in TDF+ patients. U-beta2MG levels were significantly higher in those who also received boosted LPV [TDF+LPV+] (p = 0.0007), and abnormally high levels were noted in 67.7% of them. Furthermore, in the TDF+LPV+ group, U-beta2MG levels showed significant negative correlation with patients' body weight (p = 0.0029) and abnormal U-beta2MG was observed in all six patients with body weight less than 55 kg. In four patients, a rapid fall in U-beta2MG occurred after cessation of TDF. Relative to sCr, U-beta2MG could be a more sensitive marker of renal tubular injury caused by TDF. Boosted LPV co-administration and low body weight may be risk factors for TDF-induced renal tubular dysfunction, probably because these factors are associated with an increase in TDF concentration.

[A case of severe falciparum malaria successfully treated with intravenous artesunate and continuous hemodiafiltration].

We report a 54-year-old Japanese man who contracted severe falciparum malaria after visiting West African countries. The patient presented with Plasmodium falciparum parasitemia of 10% on admission and was successfully treated with intravenous artesunate combined with continuous hemodiafiltration. We found that intravenous artesunate had excellent antimalarial activity with rapid parasite clearance and that few adverse effects were observed compared to those reported for intravenous quinine treatment. Supportive therapy was indispensable for saving the life of the patient. Few cases of intravenous artesunate treatment are reported in Japan because the drug has not been legally registered. We wish to emphasize the efficacy of intravenous artesunate with general supportive therapy in the treatment of possible imported severe malaria patients in Japanese medical settings.

Incidence and Risk Factors for Incident Syphilis among HIV-1-Infected Men Who Have Sex with Men in a Large Urban HIV Clinic in Tokyo, 2008-2015.

BACKGROUND: The epidemiology of incident syphilis infection among HIV-1-infected men who have sex with men (MSM) largely remains unknown. METHODS: The incidence and risk factors for incident syphilis (positive TPHA and RPR> = 1:8) among HIV-1-infected MSM who visited a large HIV clinic in Tokyo for the first time between 2008 and 2013 were determined, using clinical data and stored blood samples taken every three months for screening and determination of the date of incident syphilis. Poisson regression compared the incidence of syphilis at different observation periods. RESULTS: Of 885 HIV-1-infected MSM with baseline data, 34% either presented with active syphilis at baseline (21%) or became infected with syphilis during follow-up (13%). After excluding 214 patients (MSM with syphilis at baseline (n = 190) and no follow-up syphilis test (n = 24)), of 671 men, 112 (17%) developed incident syphilis with an incidence of 43.7/1,000 person-years [95% CI, 36.5-52.3]. The incidence decreased slightly during observation period although the trend was not significant (2008-2009: 48.2/1,000 person-years, 2010-2011: 51.1/1,000 person-years, 2012-2013: 42.6/1,000 person-years, 2014 to 2015: 37.9/1,000 person-years, p = 0.315). Multivariable analysis identified young age (<33 years versus >40, HR 4.0, 95%CI 2.22-7.18, p<0.001), history of syphilis at baseline (HR 3.0, 95%CI 2.03-4.47, p<0.001), positive anti-amoeba antibody (HR 1.8, 95%CI 1.17-2.68, p = 0.006), and high baseline CD4 count (CD4 ≥350 /µL versus CD4 <200, HR 1.6, 95%CI 1.00-2.53, p = 0.050) as risk factors for incident syphilis. Incidence of syphilis was particularly high among young patients (age <33 years: 60.1/1,000 person-years). Interestingly, 37% of patients with incident syphilis were asymptomatic. CONCLUSIONS: Although incidence of syphilis did not increase during the observation period, it was high among HIV-1-infected MSM, especially among young HIV-1-infected MSM and those with history of syphilis, in Tokyo. Regular screening for syphilis needs to be strictly applied to this population.

Serious bradyarrhythmia that was possibly induced by lopinavir-ritonavir in 2 patients with acquired immunodeficiency syndrome.

We describe 2 patients with acquired immunodeficiency syndrome who had potentially fatal bradyarrhythmia that occurred shortly after commencement of antiretroviral therapy. Lopinavir-ritonavir was the only drug that both patients were using.

Primary nelfinavir (NFV)-associated resistance mutations during a follow-up period of 108 weeks in protease inhibitor naïve patients treated with NFV-containing regimens in an HIV clinic cohort.

BACKGROUND: Nelfinavir (NFV) is a widely prescribed HIV-1 specific protease inhibitor (PI). However, there are only a few reports that have described the long-term effects of NFV-containing regimens, especially with regard to the emergence of drug resistance in inner-city clinics. OBJECTIVES: The aim of this study was to investigate the clinical and virologic responses to treatment with NFV-containing regimens for up to 108 weeks and determine the timing and rate of emergence of primary NFV-resistance associated mutations in daily clinical practice. STUDY DESIGN: A cohort study in an inner-city clinic. Our study included 51 consecutive patients who were PI-nai;ve and commenced therapy in February 1997 through April 1999. RESULTS AND CONCLUSIONS: The proportions of patients who continued the same therapeutic regimen and showed virologic success (viral load <400 copies/ml) up to 108 weeks were 78 and 63%, respectively, based on intent-to-treat analysis. Among patients with a viral load persistently >400 copies/ml at week 12 (n=30), 11 developed primary NFV-resistance associated mutations by 108 weeks (stratified log-rank test; P<0.05). The Cox proportional hazard model showed that prior use of reverse transcriptase inhibitors (n=22) (relative hazard (RH); 2.10, 95% CI; 0.67-6.62), prior AIDS diagnosis (n=6) (RH; 1.70, 95% CI; 0.37-7.77), CD4 < 200/microl at baseline (n=19) (RH; 2.48, 95% CI; 0.78-7.81) and viral load >30,000 copies/ml at baseline (n=21) (RH; 2.10, 95% CI; 0.67-6.62) were not independent predictors of the NFV-resistance, although some tendency was noted. In total, 77% of the patients continued NFV-containing treatment without the NFV-resistance for 108 weeks. The viral load at week 12 could be used as a predictor of treatment success in our cohort study.

[Comparison of pharmacokinetics of saquinavir soft-gel capsule (SQV-SGC) combined with ritonavir (RTV), SQV hard-gel capsule with RTV, and SQV-SGC alone].

Saquinavir (SQV) is a human immunodeficiency virus (HIV) specific protease inhibitor. When combined with ritonavir (RTV), plasma concentration of SQV is increased. In this study, we examined pharmacokinetics of SQV soft-gel capsule (SQV-SGC) 400 mg twice daily (BID) combined with RTV in HIV-1-infected patients (n = 4) and compared with those of SQV hard-gel capsule (SQV-HGC) 400 mg BID combined with RTV (n = 12). Pharmacokinetics of SQV-SGC 1,200 mg single dose in healthy subjects (n = 10) were also studied. Peak SQV concentration in plasma (Cmax) and area under the plasma concentration-time curve from 0 to 8 hour (AUC0-8 h) of SQV-SGC 400 mg BID combined with RTV group were higher than those of SQV-HGC 400 mg BID combined with RTV group; increase of 14.7% and 25.5%, respectively. Cmax and AUC0-8 h of SQV-SGC were higher than SQV-SGC 1,200 mg single dose group; increase of 3.9 fold and 8.5 fold, respectively. These results indicated that SQV-SGC combined with RTV therapy is the most potent antiviral effect among SQV-SGC with RTV, SQV-HGC with RTV, and SQV-SGC alone.

Long-term use of protease inhibitors is associated with bone mineral density loss.

HIV-infected patients are at high risk for bone mineral density (BMD) loss. The present study was designed to provide information on characteristics of BMD abnormalities in Japanese HIV-1-infected patients and risk factors involved in worsening of BMD. A total of 184 Japanese HIV-1-infected men were studied with a dual-energy X-ray absorptiometry scan (DXA) at the lumbar spine and femoral neck. Multivariate logistic regression models were used for comparison of the impact of risk factors on BMD loss. Osteopenia and osteoporosis were diagnosed in 46% and 10% of the patients at lumbar spine, and 54% and 12% at femoral neck, respectively. In logistic analysis, factors associated with low BMD at both lumbar spine and femoral neck were long-term treatment with a protease inhibitor (PI) [odds ratio (OR) 1.100 and 1.187 per 1 year increase of PI use; 95% confidence interval (CI) 1.003-1.207 and 1.043-1.351; p=0.042 and 0.009, respectively] and a low body mass index [OR: 0.938 and 0.852, CI 0.892-0.992 and 0.783-0.927; p=0.024 and <0.001, respectively]. Patients who discontinued PI had a significantly higher BMD than those who currently use PI at lumbar spine (t score -0.8 vs. -1.3, p=0.04) but not at femoral neck (-1.3 vs. -1.5, p=0.38). In HIV-infected Japanese patients, the duration of treatment with PI correlated significantly with BMD loss. Discontinuation of PI is a promising option in the treatment of BMD loss since it allows recovery of BMD, especially in the lumbar spine.

Effectiveness of subcutaneous growth hormone in HIV-1 patients with moderate to severe facial lipoatrophy.

OBJECTIVE: To evaluate effect of recombinant human growth hormone (rhGH) among HIV-infected adults with moderate to severe facial lipoatrophy as a side effect of long-term antiretroviral treatment. DESIGN: A prospective open-label study METHODS: Twenty-five HIV-1 patients with moderate to severe facial lipoatrophy who had been on antiretroviral treatment for more than 18 months were enrolled. rhGH (5 mg) was given every other day for 6 months. After treatment was completed, the participants were followed up for 6 months. Facial lipoatrophy was evaluated by computed tomography at months 0, 3, 6 and 12. RESULTS: Nearly all participants (24 of 25) completed the study. The sum of bilateral soft tissue thickness at the level of zygomatics at months 0, 3, 6, 12 were 7.23, 8.59, 8.35, 8.60 mm, respectively. There was significant improvement from baseline in month 3 (p=0.009) and month 12 (p=0.021). In the 6 months of follow-up, the soft tissue showed no significant decrease. Several side effects including diarrhea, arthralgia, myalgia, mastalgia and hand numbness were seen, which were self-limited and transient. CONCLUSION: rhGH is effective and relatively safe for moderate to severe facial lipoatrophy. Its effect was sustained at least for 6 months after the cessation of rhGH.