Study protocol for an efficacy trial of the "PrEP for Health" intervention to increase HIV PrEP use among people who inject drugs.

BACKGROUND: HIV incidence has recently increased among people who inject drugs (PWID) across the United States, with outbreaks occurring in states with long-standing syringe service programs (SSPs) including Massachusetts (MA). Antiretroviral pre-exposure prophylaxis (PrEP) is an evidence-based HIV prevention strategy recommended for PWID, but uptake in this marginalized population is extraordinarily low. METHODS: We describe the design and procedures for a National Institute on Drug Abuse (NIDA)-funded (R01) randomized controlled trial (RCT) testing the efficacy of "PrEP for Health," a multicomponent behavioral intervention to increase PrEP uptake, adherence, and persistence among HIV-negative PWID attending SSPs in two areas of the U.S. Northeast that are heavily affected by injection-related HIV transmission. Participants are equally randomized to receive the "PrEP for Health" intervention (involving individually tailored HIV and PrEP education, motivational interviewing, problem-solving skills and planning, and ongoing navigation support) or an enhanced standard of care (eSOC) control condition involving a brief educational video on the utility of PrEP for HIV prevention. Co-primary outcomes are PrEP uptake (using medical/pharmacy records) and adherence (using tenofovir quantification in hair samples); a secondary outcome is PrEP persistence (using medical/pharmacy records) over 12 months. Major assessments occur at baseline, 1-, 3-, 6-, and 12-month follow-up visits. Planned analyses will examine intervention efficacy, specific hypothesized conceptual mediators of the intervention effect (e.g., self-perceived HIV risk; PrEP knowledge, interest in use, motivation, and behavioral skills) and epidemiologically linked moderators (e.g., age; gender; condomless vaginal or anal sex). DISCUSSION: Findings from our extensive preliminary research with the study population revealed that a multicomponent, theory-based intervention targeting PrEP knowledge, motivation, self-efficacy, behavioral skills, and structural barriers to PrEP access is urgently needed for PWID who are at risk of HIV acquisition. We also learned that SSPs represent a highly acceptable service setting for delivering such interventions. In this study, we are evaluating the efficacy of the "PrEP for Health" intervention. If efficacious, findings from our implementation evaluation could help guide its dissemination to diverse SSPs and possibly other community-based settings accessed by this population. TRIAL REGISTRATION: ClinicalTrials.gov number NCT04430257, registered June 12, 2020.

Liver Disease: Evaluation of Patients With Abnormal Liver Test Results.

The prevalence of abnormal liver test results in the general population is estimated to be between 10% and 20%. The terms liver tests or liver chemistries are recommended to describe more accurately the tests used to assess liver health, instead of the term liver function tests. Defining normal ranges for liver transaminase levels can be challenging. Levels are affected by factors such as body mass index and sex. Elevated transaminase levels are associated with increased risks of liver-related and all-cause mortality. Patient with signs or symptoms of liver disease or abnormal liver test results should be evaluated to determine the etiology. For patients with abnormal liver test results, the initial evaluation should include a review of previous laboratory test results, medical and family histories, substance use, and drugs, including over-the-counter drugs and herbal supplements. Physical examination results often are normal but findings may be consistent with acute disease. Tests should include a complete blood cell count; alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total bilirubin, and albumin levels; prothrombin time; hepatitis B surface antigen; hepatitis B core antibody; hepatitis C antibody; ferritin and iron levels and transferrin saturation; and right upper quadrant abdominal ultrasonography. Additional tests and imaging should be based on patient-specific risk factors and the pattern of abnormal liver test results.

Liver Disease: Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) describes a spectrum of fatty infiltration, inflammation, and fibrosis of the liver caused by metabolic factors. It is projected to become the leading cause of cirrhosis and need for liver transplantation in the United States. Guidelines from the American Association for the Study of Liver Diseases (AASLD) do not recommend routine screening of patients at high risk of NAFLD. European guidelines recommend testing for certain high-risk patients. Hepatic steatosis and nonalcoholic steatohepatitis (NASH) are difficult to diagnose and often go unrecognized until patients have advanced fibrosis or cirrhosis. Noninvasive methods are used to assess fibrosis, such as fibrosis scores and vibration-controlled transient elastography. Liver biopsy remains the reference standard for NASH diagnosis and fibrosis staging. The mainstays of treatment for NAFLD, NASH, and fibrosis are weight loss and a healthy diet. Currently, no drugs have been approved by the Food and Drug Administration (FDA) for management of these conditions. Drugs for diabetes management (eg, glucagon-like peptide 1 receptor agonists, pioglitazone) can be useful in patients with diabetes and NASH. Among patients with NAFLD, cardiovascular disease is a common cause of mortality. Thus, the AASLD guidelines recommend consideration of omega-3 fatty acids for hypertriglyceridemia management in patients with NAFLD, and statins for hyperlipidemia management in most patients with NAFLD and NASH.

Liver Disease: Hepatitis C.

Approximately 4.1 million individuals in the United States have a history of hepatitis C virus (HCV) exposure, including 2.5 million with chronic infection. Screening guidelines recommend one-time, routine, opt out HCV screening for all individuals 18 years or older. Risk-based testing is recommended for specific individuals. Although many patients with chronic hepatitis C may progress to cirrhosis, end-stage liver disease, and hepatocellular carcinoma, early treatment can prevent development of these sequelae. Management of hepatitis C has simplified significantly, and primary care physicians now can monitor and provide treatment for most patients. Adults with chronic hepatitis C who do not have cirrhosis and have not received hepatitis C treatment previously are eligible for primary care-based treatment. These patients should undergo a comprehensive pretreatment evaluation to guide treatment planning. Patients typically are treated with one of two pangenotypic regimens: glecaprevir-pibrentasvir for 8 weeks or sofosbuvir-velpatasvir for 12 weeks. Virologic cure, defined as sustained virologic response (SVR) at 12 weeks after treatment completion, should be confirmed by an undetectable quantitative HCV RNA via polymerase chain reaction test performed 12 weeks or later after treatment completion. Management results in rates of virologic cure of greater than 95% across genotypes. Patients who do not achieve SVR at 12 weeks should be referred to a subspecialist experienced in management of treatment failure.

Liver Disease: Cirrhosis.

Cirrhosis is pathologic scarring of liver tissue that leads to impaired liver function. It can result from any etiology of chronic liver inflammation and causes significant disease burden. Cirrhosis potentially is reversible through management of the cause, such as nonalcoholic fatty liver disease, viral hepatitis, or alcohol use. As liver disease progresses, compensated (ie, asymptomatic) cirrhosis may decompensate, causing ascites, hepatic encephalopathy, or variceal bleeding. Cirrhosis typically is diagnosed with a history, physical examination, and noninvasive testing, which includes laboratory tests, combination scoring indices, and imaging (eg, ultrasonography, transient elastography). Liver biopsy remains the reference standard for diagnosis. It should be used when results of noninvasive evaluation are indeterminate, when the etiology of liver disease remains unknown, or when the result may alter management. Clinicians should counsel patients about alcohol use, obesity management, and prevention of infection. Drugs with potential for hepatotoxicity should be avoided. Clinical assessment with laboratory tests and calculation of the Child-Pugh and Model for End-stage Liver Disease (MELD) scores should occur every 6 months. Clinicians should evaluate for and manage cirrhosis-related complications, including hepatocellular carcinoma, ascites, spontaneous bacterial peritonitis, hepatic encephalopathy, esophageal varices, and other complications. Evaluation for liver transplantation is indicated for patients with a MELD score of 15 or greater, complications of cirrhosis, or hepatocellular carcinoma.

Cirrhosis: Diagnosis and Management.

Cirrhosis is the 12th leading cause of death in the United States. Newer research has established that liver fibrosis is a dynamic process and that early cirrhosis may be reversible. Only one in three people with cirrhosis knows they have it. Most patients with cirrhosis remain asymptomatic until the onset of decompensation. When clinical signs, symptoms, or abnormal liver function tests are discovered, further evaluation should be pursued promptly. The most common causes of cirrhosis are viral hepatitis, alcoholic liver disease, and nonalcoholic steatohepatitis. Initial workup includes viral hepatitis serologies, ferritin, transferrin saturation, and abdominal ultrasonography as well as complete blood count, liver function tests, and prothrombin time/international normalized ratio, if not already ordered. Additional testing is based on demographics and risk factors. Common serum and ultrasound-based screening tests to assess fibrosis include the aspartate transaminase to platelet ratio index score, Fibrosis 4 score, FibroTest/FibroSure, nonalcoholic fatty liver fibrosis score, standard ultrasonography, and transient elastography. Generally, noninvasive tests are most useful in identifying patients with no to minimal fibrosis or advanced fibrosis. Chronic liver disease management includes directed counseling, laboratory testing, and ultrasound monitoring. Treatment goals are preventing cirrhosis, decompensation, and death. Varices are monitored with endoscopy and often require prophylaxis with nonselective beta blockers. Ascites treatment includes diuresis, salt restriction, and antibiotic prophylaxis for spontaneous bacterial peritonitis, when indicated. Hepatic encephalopathy is managed with lifestyle and nutritional modifications and, as needed, with lactulose and rifaximin. Hepatocellular carcinoma screening includes ultrasound screening every six months for patients with cirrhosis.