Impact of HIV status on prognosis of malignancies among people living with HIV in Japan.

BACKGROUND: Antiretroviral therapy has reduced the incidence and mortality of AIDS-defining malignancies (ADM); however, non-AIDS-defining malignancies (NADM) are a major cause of death among people living with HIV (PLWH) today. Though current guidelines suggest that PLWH should receive the same treatment as the general population, there are limited studies focused on how HIV status affects the prognosis of cancers. The present study aimed to investigate the characteristics and prognosis of malignant diseases among PLWH in Japan. METHODS: Patients with HIV diagnosed with malignant diseases at our institution between 2011 and 2021 were retrospectively reviewed. RESULTS: There were 205 patients who were diagnosed with malignancies. Of these, 87 (42.4%) were diagnosed with ADM and 118 (57.6%) were diagnosed with NADM. Among 69 patients who received chemotherapy for ADM, 24 (34.8%) developed AIDS-defining opportunistic infections during treatment. In contrast, only one (1.8%) of the 56 patients administered chemotherapy for NADM developed AIDS-defining opportunistic infections. Complications of opportunistic infections at diagnosis of malignancies, low CD4+ T-cell count, positive HIV RNA, and nonadministration of antiretroviral therapy were associated with 5-year overall survival among patients with malignant lymphomas. However, the variables associated with HIV did not affect NADM prognosis. CONCLUSIONS: In this analysis, HIV status had a small impact on the prognosis of malignant diseases in PLWH. Few patients with NADM developed AIDS-defining opportunistic infections after receiving chemotherapy.

Surgical management of appendicitis in patients with human immunodeficiency virus (HIV) positivity: a propensity score-matched analysis in a base hospital for HIV treatment in Japan.

PURPOSE: To investigate the impact of human immunodeficiency virus (HIV) infection on surgical outcomes after appendectomy. METHODS: Data on patients who underwent appendectomy for acute appendicitis between 2010 and 2020 at our hospital were investigated retrospectively. The patients were classified into HIV-positive and HIV-negative groups using propensity score-matching (PSM) analysis, adjusting for the five reported risk factors for postoperative complications: age, sex, Blumberg's sign, C-reactive protein level, and white blood cell count. We compared the postoperative outcomes of the two groups. HIV infection parameters, including the number and proportion of CD4 + lymphocytes and the HIV-RNA levels were also compared before and after appendectomy in the HIV-positive patients. RESULTS: Among 636 patients enrolled, 42 were HIV-positive and 594 were HIV-negative. Postoperative complications occurred in five HIV-positive patients and eight HIV-negative patients, with no significant difference in the incidence (p = 0.405) or severity of any complication (p = 0.655) between the groups. HIV infection was well-controlled preoperatively using antiretroviral therapy (83.3%). There was no deterioration in parameters and no changes in the postoperative treatment in any of the HIV-positive patients. CONCLUSION: Advances in antiviral drugs have made appendectomy a safe and feasible procedure for HIV-positive patients, with similar postoperative complication risks to HIV-negative patients.

Impact of sustained viral response for hepatitis C virus on the outcomes of liver transplantation in hemophilic patients with human immunodeficiency virus/hepatitis C virus co-infection: A nationwide survey in Japan.

AIM: Human immunodeficiency virus (HIV)/hepatitis C virus (HCV) co-infection from blood products for hemophilia has been a social problem in Japan, and liver transplantation (LT) for these patients has been a challenging procedure. However, with the advent of the direct-acting antiviral agent for HCV and change in the policy for prioritization of deceased donor LT, the results of LT for patients co-infected with HCV/HIV may have improved. METHODS: This study was conducted to provide updated results of our nationwide survey of LT for patients co-infected with HCV/HIV, from January 1997 to December 2019. We collected data on 17 patients with HIV/HCV co-infection who underwent either deceased donor LT (n = 5) or living donor LT (n = 12). RESULTS: All the patients were men with hemophilia, and the median age was 41 (range, 23-61) years. The median CD4 count before LT was 258 (range, 63-751). Most patients had poor liver function before surgery with Child-Pugh grade C and a Model for End-stage Liver Disease score of 20 (range, 11-48). The right lobe was used for most grafts for living donor liver transplantation (n = 10). Overall survival was significantly better with a sustained viral response (SVR) than without an SVR, and a univariate analysis indicated that SVR after direct-acting antiviral or interferon/ribavirin showed the highest hazard ratio for patient survival after LT. A multivariate analysis was not possible because of the limited number of cases. CONCLUSION: SVR for HCV showed the highest impact on the outcome of LT for patients with hemophilia co-infected with HIV/HCV. SVR for HCV should be achieved before or after LT for patients with hemophilia co-infected with HIV/HCV for a better outcome.

Unmasking latent extrapulmonary tuberculosis with newly diagnosed HIV-1 infection in a COVID-19 patient with prolonged fever.

Prolonged fever is a common symptom of COVID-19 infection. However, other febrile diseases continue during the pandemic. Herein, we report a COVID-19-infected patient with prolonged fever despite the lack of oxygen requirement, who was finally diagnosed with tuberculotic lymphadenitis and HIV-1 infection. All symptoms improved rapidly after the initiation of antituberculosis medications. Tuberculosis is an important differential diagnosis for patients with prolonged fever during the COVID-19 pandemic. It is possible that COVID-19 infection could serve to unmask latent infections via a cytokine storm.

Characteristics of 2-drug regimen users living with HIV-1 in a real-world setting: A large-scale medical claim database analysis in Japan.

BACKGROUND: Regimen simplification to 2-drug antiretroviral therapy (2-ART) may address potential tolerability issues, increase adherence, and reduce toxicity and potential drug-drug-interactions among people living with HIV-1 (PLWH). However, real-world treatment patterns and characteristics of 2-ART users are unclear. METHODS: This retrospective observational cohort study employed a large-scale medical claim database of Japanese hospitals to extract data on 4,293 PLWH aged ≥18 years with diagnosis of HIV and treated with any ART regimens between April 2008 and April 2019. A 2-ART cohort was compared with a 3-drug antiretroviral therapy (3-ART) cohort in terms of population characteristics, comorbid conditions, and treatment patterns. Treatment switching rates were calculated for each cohort followed by sensitivity analysis to confirm the robustness of the findings. RESULTS: There were 94 individuals identified in the 2-ART cohort. Compared to the standard 3-ART cohort (n = 3,993), the 2-ART cohort was older (median age 53 [IQR 44-64] vs 42 years [IQR 35-50]), with a lower proportion of males (87.2% vs 93.8%), higher Charlson Comorbidity Index (CCI) (median score 6 [IQR 5-8] vs 5 [IQR 4-6]), more co-medications (median 6 [IQR 4-11] vs 3 [IQR 2-7]), and a higher percentage of AIDS-defining conditions (66.0% vs 42.8%). The most common 2-ART were protease inhibitor (PI) + integrase strand transfer inhibitor (INSTI) and non-nucleoside reverse transcriptase inhibitor (NNRTI) + INSTI (33.0% and 31.9%, respectively). Overall, most of the regimens were nucleoside reverse transcriptase inhibitor (NRTI)-sparing (71.3%), with a decreasing trend over time (76.2% to 70.2%). ART regimen switch occurred more often in the 2-ART cohort than in the 3-ART cohort (33.0% vs 21.2%). CONCLUSION: The profiles of individuals on 2-ART in Japan were demonstrated to be complex. Most were treated with NRTI-sparing regimens which may reflect an effort to reduce treatment-related toxicities.

Genetic and cytometric analyses of subcutaneous adipose tissue in patients with hemophilia and HIV-associated lipodystrophy.

BACKGROUND: The authors recently performed plastic surgeries for a small number of patients with hemophilia, HIV infection, and morphologic evidence of lipodystrophy. Because the pathophysiological mechanism of HIV-associated lipodystrophy remains to be elucidated, we analyzed subcutaneous adipose tissues from the patients. METHODS: All six patients had previously been treated with older nucleoside analogue reverse-transcriptase inhibitors (NRTIs; stavudine, didanosine or zidovudine). Abdominal and inguinal subcutaneous fat samples were obtained from the HIV+ patients with hemophilia and HIV- healthy volunteers (n = 6 per group), and analyzed via DNA microarray, real-time PCR, flow cytometry and immunohistochemistry. RESULTS: The time from initial NRTI treatment to collecting samples were 21.7 years in average. Cytometric analysis revealed infiltration of inflammatory M1 macrophages into HIV-infected adipose tissue and depletion of adipose-derived stem cells, possibly due to exhaustion following sustained adipocyte death. Genetic analysis revealed that adipose tissue from HIV+ group had increased immune activation, mitochondrial toxicity, chronic inflammation, progressive fibrosis and adipocyte dysfunction (e.g. insulin resistance, inhibited adipocyte differentiation and accelerated apoptosis). Of note, both triglyceride synthesis and lipolysis were inhibited in adipose tissue from patients with HIV. CONCLUSIONS: Our findings provide important insights into the pathogenesis of HIV-associated lipodystrophy, suggesting that fat redistribution may critically depend on adipocytes' sensitivity to drug-induced mitochondrial toxicity, which may lead either to atrophy or metabolic complications.

Outcomes following cholecystectomy in human immunodeficiency virus-positive patients treated with antiretroviral therapy: A retrospective cohort study.

The number of the human immunodeficiency virus (HIV)-positive patients are increasing worldwide, and more HIV-positive patients are undergoing urgent or elective cholecystectomy. There is still insufficient evidence on the relationship between surgical complications of cholecystectomy and antiviral status in HIV-positive patients. The purpose of the present study is to evaluate surgical outcomes after cholecystectomy in HIV-positive patients. Records of consecutive HIV-positive patients who underwent cholecystectomy between January 2010 and December 2020 were reviewed retrospectively. Patients were divided into urgent and elective surgery groups. Urgent surgery was defined as surgery within 48 hours of admission. Postoperative complications were evaluated according to the Clavien-Dindo classification. A total of 30 HIV-positive patients underwent urgent (n = 7) or elective (n = 23) cholecystectomy. Four complications (13.3%) occurred, and the rate was significantly higher in the urgent group than in the elective group (p = 0.008). However, all complications were minor (3 cases of grade I and one case of grade II), and there were no severe postoperative complications. There was no significant difference in CD4+ lymphocyte status in all patients and between the 2 groups before and after surgery (p = 0.133). No cases of postoperative deterioration in the control of HIV infection were observed. In conclusion, cholecystectomy in HIV-positive patients with controlled HIV under recent antiretroviral therapy may be performed safely even in an emergency situation.

Progressive Cytopenia Developing during Treatment of Cryptococcosis in a Patient with HIV Infection and Bone Marrow Cryptococcal Infection.

Cytopenia is a common complication in patients with human immunodeficiency virus (HIV) infection. Identifying the cause is demanding because of the wide range of possible diagnoses. We herein report an HIV-infected patient with disseminated cryptococcosis involving multiple organs including the blood, brain, lungs, and bone marrow, who developed progressive pancytopenia after initiation of anti-fungal treatment with liposomal amphotericin-B (L-AMB) and flucytosine (5FC). The pancytopenia persisted despite early 5FC discontinuation. A bone marrow biopsy revealed cryptococcal infiltration and the blood examination findings recovered quickly after resuming L-AMB. Thus, this HIV-infected patient's pathological findings and clinical course suggested that the primary cause of the pancytopenia was bone marrow cryptococcosis.

Anal human papillomavirus infection and its relationship with abnormal anal cytology among MSM with or without HIV infection in Japan.

Anal high-risk human papillomavirus (hr-HPV) infection is widely considered a cause of anal cancer. However, epidemiological data are quite limited in Japan. This study investigated anal HPV infections and cytological abnormalities among MSM with or without HIV infection. Anal swabs were obtained, and cytological results were examined. Hybrid capture-based methodology was used for hr-HPV genotyping. The exclusion criterion was a history of vaccination against HPV. 644 subjects participated, and the overall prevalence of hr-HPV was 59.7% (95% CI 54.7-62.3), HIV-infected had higher prevalence than HIV-uninfected (68.9% vs 40.6%) p < .001. Among hr-HPV-infected participants, 82.8% (312/377) were infected with at least one of 9 valent vaccine-covered hr-HPV genotypes. From regression analysis, detection of abnormal cytology correlated positively with HIV infection (OR 2.17 [95% CI 1.51-3.13]), number of hr-HPV genotypes infected (OR 1.83 [1.59-2.10]), history of STI (OR 1.58 [1.14-2.22]) and No. of lifetime sexual partners (OR 1.56 [1.10-2.21]), albeit multivariate analysis identified the number of detected hr-HPV genotypes (adjusted OR 1.78 [1.54-2.06]) as the independent risk factor for abnormal cytology. High rates of anal hr-HPV infection, especially 9-valent HPV vaccine-preventable hr-HPV were detected among our MSM participants in Japan. HPV vaccination should also be encouraged for MSM in Japan.

Indications and waiting list priority for deceased donor liver transplantation in HIV/HCV co-infected hemophilic patients in Japan through contaminated blood product.

HIV/HCV co-infection from blood products for hemophilia has been a social problem in Japan. Liver transplantation (LT) is an important treatment option for hepatic failure and cirrhosis of the liver in co-infected patients, and appropriate indications for LT, especially organ form deceased donors, are required by society. The aim is to propose priority status for the waiting list for deceased donor (DD) LT in HIV/HCV co-infected patients in Japan based on medical and scientific considerations. Since 2009, we have been working on the subject in research projects under grants-in-aid for health and labour sciences research on AIDS measures provided by the Ministry of Health, Labour and Welfare (the Kanematsu project and Eguchi project). Our research showed that hepatic fibrosis is advanced in HIV/HCV co-infected Japanese patients, especially those with hemophilia who became infected from blood products at a faster rate than HCV mono-infected patients. In addition, those patients who developed portal hypertension had a poor prognosis at a young age. The results of our research contributed to increasing the priority score of those patients on the deceased donor liver transplantation (DDLT) waiting list in 2013 and to establishing a scoring system for DDLT corresponding to the Model for End-stage Liver disease (MELD) score in 2019. This paper introduces changes in priority and the current state of priority of the DDLT waiting list for HIV/HCV co-infected patients in Japan.

The treatment choices and outcome of hepatocellular carcinoma in hemophilic patients with human immunodeficiency virus/hepatitis C virus (HIV/HCV) coinfection due to contaminated blood products in Japan.

BACKGROUND: Human immunodeficiency virus (HIV) and hepatitis C virus (HCV) coinfection through unheated blood product for hemophilia caused in early 1980s has been significantly serious problem in Japan. After the development of HIV treatment in 1990s, HCV-related hepatocellular carcinoma (HCC) has been one of the most significant problem in these population. Treatment choices for HCC might be limited in hemophilia patients because of their bleeding tendency. The aim of this study was to elucidate the treatment choices and outcome of HCC in hemophilic patients coinfected with HIV/HCV due to contaminated blood products. METHODS: We asked 444 Japanese centers that specialize in treating HIV patients for participation, whether they have HIV/HCV coinfected cases with HCC, and the patient characteristics, treatments for HCC and survival after treatments were retrospectively reviewed according to each institutional medical records. RESULTS: Of 444 centers, 139 centers (31%) responded to the first query, and 8 centers (1.8%) ultimately provided 26 cases of HCC in coinfected hemophilic patients, diagnosed between December 1999 and December 2017. All 26 were male hemophilic patients, with a median age at HCC diagnosis of 49 (range, 34-73) years. Thirteen cases (50%) were HCV-RNA positive, and 14 cases (54%) had a solitary tumor. Even in the cases of Child-Pugh grade A, only 1 case underwent resection, and 18 cases (69%) did not receive the standard treatment recommended by the Japanese Society of Hepatology. CONCLUSIONS: Hemophilic HCC patients with HIV/HCV coinfection may not routinely receive standard treatment due to their bleeding tendency and several complications related to HIV/HCV coinfection.

Pathogenesis, clinical course, and recent issues in HIV-1-infected Japanese hemophiliacs: a three-decade follow-up.

Nearly 30% of Japanese hemophiliacs were infected with HIV-1 in the early 1980s. They have unique characteristics compared to HIV-1-infected individuals through other routes, including date of infection of 1986 or earlier, mean age of nearly 50 years, and common co-infection with hepatitis C, but rarely with other sexually transmitted diseases. Antiretroviral therapy (ART) was introduced in Japan in 1997. The clinical courses before and after 1997 were quite different. Careful analysis of the pre-1997 clinical data allowed expansion of our knowledge about the natural course and pathogenesis of the disease. Switching to the second receptor agents proved critical in subsequent disease progression. HIV-1 continued to escape immune pressure, pushing disease progression faster. In contrast, ART was effective enough to overcome the natural course. Prognosis improved dramatically and cause of death changed from AIDS-related opportunistic infections and malignancies before 1997, to hepatitis C virus-related cirrhosis and hepatocellular carcinoma (HCC) around 2010, and again to non-AIDS defining malignancies recently. In most cases, hepatitis C was cured with direct acting antiviral therapy. However, HCV progressed to cirrhosis in some cases and risk of HCC is still high among these patients. Together with improvement in anticoagulants and aging of the patients, risk of myocardial infarction has increased recently. In addition, the numbers of patients with life-style related co-morbidities, such as diabetes mellitus, hypertension, and chronic kidney disease have been also increasing. Finally, stigma is still an important barrier to a better life in HIV-1-positive individuals.

Mortality and causes of death in people living with HIV in the era of combination antiretroviral therapy compared with the general population in Japan.

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.

Nucleos(t)ide reverse transcriptase inhibitor-sparing regimens in the era of standard 3-drug combination therapies for HIV-1 infection.

Nucleos(t)ide reverse transcriptase inhibitor (NRTI)-sparing regimens have often been selected as antiretroviral therapy (ART) for HIV-1 infection recently, but data for characteristics have been lacking. This study aimed to document the current status of NRTI-sparing regimens in the era of standard 3-drug combination therapies. We cross-sectionally compared characteristics of patients treated with NRTI-sparing regimens (NRTI-sparing group) with dolutegravir plus tenofovir alafenamide fumarate/emtricitabine as a standard ART group in 2018. The NRTI-sparing and the standard ART groups included 61 and 469 patients, respectively. The mean (± standard deviation) age and serum creatinine of the NRTI-sparing group were significantly higher than those of the standard ART group (57.6 ± 12.8 years vs 42.8 ± 10.4 years (p < 0.05) and 2.09 ± 3.10 mg/dL vs. 0.93 ± 0.19 mg/dL (p < 0.05), respectively. The percentage of patients with NRTI-sparing regimens increased with age; with less than 5% in their 50s or younger, 8.4% in their 60s, and 14.1% aged ≥ 70 years. The primary reason for switching to the NRTI-sparing regimen was due to reduced renal function. According to the limited data, viral suppression was achieved at week 48 in all patients in the NRTI-sparing group. No patient had treatment failure nor developed drug resistance. The use of NRTI-sparing regimens increased with age. They were more frequently used in patients aged ≥ 60 years and those with decreased renal function.

Non-AIDS-defining malignancies in Japanese hemophiliacs with HIV-1 infection.

Along improvement of prognosis of HIV-1-infected patients due to successful anti-retroviral therapy, main causes of death in the patients have been changing from AIDS to non-AIDS defining malignancies (NADM) recently. However, little is known about the prevalence and incidence of NADM in patients, and especially in HIV-1-infected hemophiliacs. We prospectively conducted NADM screening with FDG-PET, chest CT, upper gastrointestinal endoscopy, tumor markers, and stool occult blood in hemophiliacs with a mean age of 48.9 years. Screening was done twice from December 2016 through March 2019; the first screening was used to calculate prevalence in 69 patients and the second was used to calculate incidence in 56 patients. The first screening revealed 4 cases of malignancies; three were cases of thyroid cancer and one was a case of a neuroendocrine tumor in the pancreas; prevalence was 5.8% (95% CI: 0.2-11.4%). During a mean follow-up of 1.2 years with 68.2 person-years (PYs), cancer was diagnosed in 2 cases (pancreatic and liver cancer) during the second screening. Incidence was 2.99/100 PY. It can be speculated that there might be around 40 cases of undiagnosed NADM currently and 20 cases of new NADM annually in this population, because 718 HIV-1-infected hemophiliacs are surviving in Japan according to the 2018 Nationwide Survey on Coagulation Disorders. Screening for NADM in HIV-1-infected hemophiliacs at other hospitals is strongly recommended.

Prevalence and factors associated with chronic kidney disease and end-stage renal disease in HIV-1-infected Asian patients in Tokyo.

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 <60 ml/min/1.73 m2 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.

Interferon-free therapy with direct acting antivirals for HCV/HIV-1 co-infected Japanese patients with inherited bleeding disorders.

INTRODUCTION: Almost 30 years ago, about 30% of Japanese hemophiliacs became infected with HIV-1 and hepatitis C virus (HCV) after receiving contaminated blood products. While several studies have reported the high efficacy and safety of direct acting antivirals (DAA) in HIV-1 co-infected patients, such data are limited in hemophiliacs. METHODS: We conducted a single-center, open-label study involving 27 Japanese patients (median age; 45 years) with inherited bleeding disorders who were co-infected with HCV/HIV-1. Patients with HCV genotype 1 (GT1) and GT4 received ledipasvir (90 mg) plus sofosbuvir (400 mg), those with HCV GT2 received sofosbuvir plus weight-based ribavirin, and those with HCV GT3 received daclatasvir (60 mg) plus sofosbuvir. Treatment was continued for 12 weeks in all patients. The primary endpoints were rate of sustained virologic response at 12 weeks after end of therapy (SVR12) and occurrence of adverse events during DAA therapy. RESULTS: Eighteen (67%) patients had had received interferon-based therapy, and 11 (41%) had compensated cirrhosis. HCV genotypes were GT1a 4 (15%), GT1b 16 (59%), GT1 undetermined 2 (7%), GT2a 1 (4%), GT3a 3 (11%) and GT4a 1 (4%). All patients were on combination antiretroviral therapy (cART) and had undetectable HIV-1 viral load (<20 copies/µL) at baseline. All patients achieved SVR12. Serious adverse events were observed in 3 patients: arteritis of the leg, which resolved after completion of DAA therapy, asymptomatic QT prolongation and gastrointestinal hemorrhage. cART failure was noted in one patient due to emergence of raltegravir resistance during ledipasvir/sofosbuvir treatment. Although α-fetoprotein, Mac-2 binding protein glycosylation isomer (M2BPGi), and Fibro Scan (FS) scores decreased in most patients during DAA therapy, M2BPGi (>2.0 cutoff index) and FS scores (>15.0 kPa) were still high in 6 patients at week 36. CONCLUSIONS: DAA therapy is effective in all patients. However, adverse events and efficacy of cART should be monitored closely.

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.