Caryn G. Morse

The Incidence and Natural History of Osteonecrosis in HIV-Infected Adults

BACKGROUND Osteonecrosis is increasingly recognized as a debilitating complication of human immunodeficiency virus (HIV) infection, but the natural history has not been well described. We previously documented a high prevalence (4.4%) of magnetic resonance imaging (MRI)-documented osteonecrosis of the hip in a cohort of 339 asymptomatic HIV-infected patients. The present study was designed to determine the incidence of newly diagnosed osteonecrosis in this cohort and to describe the natural history of osteonecrosis in HIV-infected patients. METHODS Asymptomatic HIV-infected patients with a previous hip MRI negative for osteonecrosis underwent follow-up MRI. Patients with asymptomatic or symptomatic osteonecrosis were enrolled in a natural history study, which included serial MRIs and a physiotherapy follow-up. RESULTS Two hundred thirty-nine patients underwent a second MRI a median of 23 months after the initial MRI. Osteonecrosis of the femoral head was diagnosed in 3 patients (incidence, 0.65 cases per 100 person-years). During the period of January 1999 through April 2006, symptomatic hip osteonecrosis developed in 13 clinic patients (incidence, 0.26 cases per 100 person-years). Among 22 patients enrolled with symptomatic hip osteonecrosis, 18 had bilateral involvement of the femoral heads, and 7 had osteonecrosis involving other bones. Two (11%) of 18 asymptomatic patients and 13 (59%) of 22 symptomatic patients underwent total hip replacement. The percentage of involvement of the weight-bearing surface of the femoral head and the rate of progression to total hip replacement was significantly greater (P<.001) in symptomatic patients than in asymptomatic patients. CONCLUSIONS HIV-infected patients are at approximately 100-fold greater risk of developing osteonecrosis than the general population. Disease progression is slower in asymptomatic patients than in symptomatic patients. Given the high frequency of total hip replacement in symptomatic patients, studies to assess preventive and treatment strategies are essential.

Nonalcoholic Steatohepatitis and Hepatic Fibrosis in HIV-1–Monoinfected Adults With Elevated Aminotransferase Levels on Antiretroviral Therapy

BACKGROUND Persistent aminotransferase elevations are common in human immunodeficiency virus (HIV)-infected patients on antiretroviral therapy (ART), including those without hepatitis B or C coinfection, but their clinical significance is unknown. METHODS HIV-infected adults with aminotransferase levels elevated above the upper limit of normal for ≥6 months while receiving ART, and without chronic viral hepatitis or other known causes of chronic liver disease, underwent a detailed metabolic assessment and liver biopsy. RESULTS Sixty-two HIV-infected subjects completed the study. Forty (65%) had clinically significant liver pathology, including 34 (55%) with nonalcoholic steatohepatitis (NASH) and 11 (18%) with bridging fibrosis, 10 of whom also had NASH. Nonspecific abnormalities alone were seen in 22 (35%) subjects, including mild steatosis, mild to moderate inflammation, and evidence of drug adaptation. Insulin resistance, obesity, and the presence of either of 2 minor alleles in the PNPLA3 gene were significantly associated with increased risk of NASH and fibrosis. NASH and/or fibrosis were not associated with duration of HIV infection or ART, specific antiretroviral drugs, history of opportunistic infection, immune status, or duration of aminotransferase elevation. CONCLUSIONS HIV-infected adults with chronic aminotransferase elevations while receiving ART have a high rate of liver disease. Noninvasive testing can help identify liver disease in such patients, but liver biopsy is necessary to definitively identify those at risk for liver disease progression and complications. Longitudinal follow-up of this cohort will better characterize the natural history of aminotransferase elevations in this population and identify noninvasive biomarkers of liver disease progression.

Simtuzumab treatment of advanced liver fibrosis in HIV and HCV-infected adults: results of a 6-month open-label safety trial

Chronic liver injury can result in fibrosis that may progress over years to end‐stage liver disease. The most effective anti‐fibrotic therapy is treatment of the underlying disease, however when not possible, interventions to reverse or slow fibrosis progression are needed.

Hydrogen-1 MR Spectroscopy for Measurement and Diagnosis of Hepatic Steatosis

OBJECTIVE Hydrogen-1 MR spectroscopy ((1)H-MRS) is gaining acceptance as a noninvasive technique for assessment of hepatic steatosis, and the findings have been found to correlate closely with histopathologic grade. The aims of this study were to validate (1)H-MRS performed with a 3-T MRI system for quantifying hepatic steatosis and to determine threshold values of (1)H-MRS proton density fat fraction corresponding to standard histopathologic grade in patients undergoing diagnostic liver biopsy. SUBJECTS AND METHODS We conducted a prospective cross-sectional liver MRS study with 52 subjects undergoing diagnostic liver biopsy. The diagnostic accuracy of (1)H-MRS was evaluated with receiver operating characteristic curves. RESULTS The diagnostic accuracy of (1)H-MRS for hepatic steatosis was high with an area under the receiver operating characteristic curve of 0.94 (95% CI, 0.88-1.0). Results were similar for three (1)H-MRS measurements obtained at different locations in the liver, for two independent pathologists, and whether fibrosis was present or absent. One third of participants had elevated transaminase concentrations of unknown cause, and (1)H-MRS estimates of steatosis had perfect agreement with histopathologic grade in this group. Calculated (1)H-MRS proton density fat fraction thresholds for histologic grades were less than 17% for grade 0 or trace steatosis, 17-38.6% for grade 1, and greater than 38.6% for grade 2 or higher. CONCLUSION Hydrogen-1 MR spectroscopy is an effective, noninvasive technique that can be used to diagnose and quantify hepatic steatosis. Hydrogen-1 MR spectroscopy thresholds corresponded with histopathologic grades and may be useful in the workup of patients with elevated transaminase concentrations.

HIV Infection and Antiretroviral Therapy Have Divergent Effects on Mitochondria in Adipose Tissue

BACKGROUND Although human immunodeficiency virus (HIV) infection and antiretroviral therapy (ART) affect mitochondrial DNA (mtDNA) content and function, comprehensive evaluations of their effects on mitochondria in muscle, adipose tissue, and blood cells are limited. METHODS Mitochondrial DNA quantification, mitochondrial genome sequencing, and gene expression analysis were performed on muscle, adipose tissue, and peripheral blood mononuclear cell (PBMC) samples from untreated HIV-positive patients, HIV-positive patients receiving nucleoside reverse transcriptase inhibitor (NRTI)-based ART, and HIV-negative controls. RESULTS The adipose tissue mtDNA/nuclear DNA (nDNA) ratio was increased in untreated HIV-infected patients (ratio, 353) and decreased in those receiving ART (ratio, 162) compared with controls (ratio, 255; P < .05 for both comparisons); the difference between the 2 HIV-infected groups was also significant (P = .002). In HIV-infected participants, mtDNA/nDNA in adipose tissue correlated with the level of activation (CD38+ /HLA-DR+) for CD4+ and CD8+ lymphocytes. No significant differences in mtDNA content were noted in muscle or PMBCs among groups. Exploratory DNA microarray analysis identified differential gene expression between patient groups, including a subset of adipose tissue genes. CONCLUSIONS HIV infection and ART have opposing effects on mtDNA content in adipose tissue; immune activation may mediate the effects of HIV, whereas NRTIs likely mediate the effects of ART.

Enfuvirtide antiviral activity despite rebound viremia and resistance mutations: fitness tampering or a case of persistent braking on entering?

Combination antiretroviral therapy has revolutionized the care of HIV1-infected individuals, producing profound improvements in morbidity and mortality. Therapy does not, however, cure HIV infection, and the goal of combination therapy remains the suppression of HIV-1I replication below the limit of detection. Despite a growing array of antiretroviral therapy options, virologic suppression is difficult for many patients to achieve, and treatment of drug-resistant virus is a critical challenge confronting HIV therapeutics. Resistance emerges as a result of both virologic and clinical factors. HIV-1 replication is rapid and error prone, yielding a large, genetically diverse virus population. As a consequence, many single amino-acid changes conferring drug resistance may preexist as low frequency polymorphisms before the initiation of antiviral therapy [1, 2]. Individuals who received their diagnosis of HIV infection before the widespread use of combination antiretroviral regimens often received serial therapy with 1 or 2 agents, resulting in the accumulation of additional drugresistance mutations to each new approved agent. Poor adherence to therapy has been associated with higher rates of virologic failure and the emergence of drug resistance, and sequential regimens for drug-resistant virus fail in patients [36] more often than initial regimens in drug-naive individuals [7-9]. Current therapeutic regimens to treat highly drug-resistant HIV-1 remain inadequate. The recommendation that regimens to treat drug-resistant HIV1 should include at least 2 new drugs to which patients have not been exposed [10] is often impossible to fulfill if patients have extensive prior therapy experience. Recently, several studies have suggested the presence of residual virologic activity for some antivirals even in the presence of mutations [11-14]. In this issue of the Journal of Infectious Diseases, Deeks et al. [15] report the presence of virologic benefit of enfuvirtide (T-20) in the presence of rebound viremia and enfuvirtide resistance mutations. Enfuvirtide is the first of a new class of

Transient elastography for the detection of hepatic fibrosis in HIV-monoinfected adults with elevated aminotransferases on antiretroviral therapy.

Objective:Vibration-controlled transient elastography (VCTE) is increasingly used to assess liver fibrosis in viral hepatitis and fatty liver disease populations. Because the accuracy of VCTE in HIV-monoinfected populations has not been established, we evaluated its performance in assessing liver fibrosis in a cohort of HIV-monoinfected adults undergoing liver biopsy as part of a recently published clinical trial. Methods:HIV-infected adults with elevated aminotransferase levels for at least 6 months while receiving antiretroviral therapy, and without chronic viral hepatitis or other known causes of liver disease, were prospectively evaluated by VCTE, other noninvasive markers of fibrosis, and percutaneous liver biopsy as part of a cross-sectional study examining liver pathology. Results:Sixty-six patients were evaluated by VCTE and liver biopsy. The cohort was in the majority male (92%), with a median age of 50 years (range 17–68). Biopsy identified bridging fibrosis in 14 (21%) and nonalcoholic steatohepatitis in 38 (58%) participants. VCTE was unsuccessful or unreliable in seven participants (11%). In the 59 participants with reliable results, median liver stiffness measurement (LSM) was 5.9 kPa (range 3.3–29.2 kPa); 25 participants (42%) had a LSM above 7.1 kPa, a value consistent with increased liver stiffness in other populations. VCTE had good sensitivity and specificity with an area under the receiver-operating characteristic curve (AUROC) of 93% for detection of moderate fibrosis (Ishak F ≥ 2; 95% confidence interval 86–99%). Conclusions:In HIV-monoinfected adults with biopsy-proven liver disease, LSM by VCTE was the best noninvasive predictor of fibrosis. Our findings support the continued use of VCTE for fibrosis screening in HIV-monoinfected patients with elevated aminotransferases.

Impaired maraviroc and raltegravir clearance in a human immunodeficiency virus-infected patient with end-stage liver disease and renal impairment: a management dilemma.

Current product labels for maraviroc and raltegravir provide no dosing guidance for patients with end‐stage liver disease and worsening renal function. We describe a 41‐year‐old man with human immunodeficiency virus (HIV) infection and rapidly progressive liver failure and vanishing bile duct syndrome at presentation. Despite discontinuation of all potential offending drugs, the patients liver function continued to deteriorate. To achieve and maintain HIV suppression while awaiting liver transplantation, a regimen consisting of maraviroc, raltegravir, and enfuvirtide was started. These agents were chosen because the patient was not exposed to them before the onset of liver failure. While receiving product label–recommended twice‐daily dosing of these drugs, he achieved and maintained HIV suppression. During a complicated and prolonged hospitalization, the patient also developed renal dysfunction. As hepatic metabolism is the primary route of clearance of maraviroc and raltegravir, we predicted that using approved doses of these drugs could result in significant drug accumulation. Since the safety profiles of supratherapeutic concentrations of these agents are not well defined, we chose to use therapeutic drug monitoring to guide further dosing. The reported concentrations showed severely impaired metabolic clearance of both drugs, with markedly prolonged elimination half‐lives of 189 hours for maraviroc and 61 hours for raltegravir. Previously reported half‐lives for maraviroc and raltegravir in HIV‐infected patients with normal hepatic and renal function are 14–18 hours and 9–12 hours, respectively. Based on these results, the dosing intervals were extended from twice/day to twice/week for maraviroc and every 48 hours for raltegravir. Unfortunately, the patients clinical condition continued to deteriorate, and he eventually died of complications related to end‐stage liver disease. This case illustrates the difficulties in managing antiretroviral therapy in an HIV‐infected patient with combined severe liver and renal failure. Prolonged excessively high exposure to maraviroc and raltegravir is likely to result in some level of concentration‐dependent toxicity. Until more data are available, therapeutic drug monitoring remains the only evidence‐based approach to optimize dosage selection of these drugs in this patient population.

Magnetic Resonance Elastography Shear Wave Velocity Correlates with Liver Fibrosis and Hepatic Venous Pressure Gradient in Adults with Advanced Liver Disease

Background. Portal hypertension, an elevation in the hepatic venous pressure gradient (HVPG), can be used to monitor disease progression and response to therapy in cirrhosis. Since obtaining HVPG measurements is invasive, reliable noninvasive methods of assessing portal hypertension are needed. Methods. Noninvasive markers of fibrosis, including magnetic resonance elastography (MRE) shear wave velocity, were correlated with histologic fibrosis and HVPG measurements in hepatitis C (HCV) and/or HIV-infected patients with advanced liver disease enrolled in a clinical trial of treatment with simtuzumab, an anti-LOXL2 antibody. Results. This exploratory analysis includes 23 subjects: 9 with HCV monoinfection, 9 with HIV and HCV, and 5 with HIV and nonalcoholic steatohepatitis. Median Ishak fibrosis score was 4 (range 1–6); 11 subjects (48%) had cirrhosis. Median HVPG was 6 mmHg (range 3–16). Liver stiffness measured by MRE correlated with HVPG (r = 0.64, p = 0.01), histologic fibrosis score (r = 0.71, p = 0.004), noninvasive fibrosis indices, including APRI (r = 0.81, p < 0.001), and soluble LOXL2 (r = 0.82, p = 0.001). On stepwise multivariate regression analysis, MRE was the only variable independently associated with HVPG (R2 = 0.377, p = 0.02). Conclusions. MRE of the liver correlated independently with HVPG. MRE is a valid noninvasive measure of liver disease severity and may prove to be a useful tool for noninvasive portal hypertension assessment. Trial Registration Number. This trial is registered with NCT01707472.

Vanishing bile duct syndrome in human immunodeficiency virus infected adults: A report of two cases

Vanishing bile duct syndrome (VBDS) is a group of rare disorders characterized by ductopenia, the progressive destruction and disappearance of intrahepatic bile ducts leading to cholestasis. Described in association with medications, autoimmune disorders, cancer, transplantation, and infections, the specific mechanisms of disease are not known. To date, only 4 cases of VBDS have been reported in human immunodeficiency virus (HIV) infected patients. We report 2 additional cases of HIV-associated VBDS and review the features common to the HIV-associated cases. Presentation includes hyperbilirubinemia, normal liver imaging, and negative viral and autoimmune hepatitis studies. In HIV-infected subjects, VBDS occurred at a range of CD4+ T-cell counts, in some cases following initiation or change in antiretroviral therapy. Lymphoma was associated with two cases; nevirapine, antibiotics, and viral co-infection were suggested as etiologies in the other cases. In HIV-positive patients with progressive cholestasis, early identification of VBDS and referral for transplantation may improve outcomes.