Danielle Mroz

The presence of thrombocytopenia is associated with an increased risk of all-cause mortality and cardiovascular-related mortalities in patients with severe hepatic steatosis, according to the results of a new study.

Previous studies have shown that the presence of thrombocytopenia leads to an increased risk of mortality; however, no studies, to date, have looked at the combined risk of mortality for patients with thrombocytopenia and severe hepatic steatosis. As such, a team of investigators led by Mohamed Elsaid, MPH, Rutgers, the State University of New Jersey, and Robert Wood Johnson Medical School, in New Brunswick, New Jersey, looked at thrombocytopenia as a risk modifier of the link between severe hepatic steatosis and “mortality related to all-cause and cardiovascular disease,” wrote the study authors.

The team of investigators linked national mortality records with data pulled from the Third National Health and Nutrition Examination Survey (NHANES III), on 12,798 adults between the ages of 20 and 74 years. More than 3000 of the study participants (3227) died during the follow-up period (up to 23 years after recruitment); 911 of these deaths were linked with cardiovascular disease.

Prevalence of severe hepatic steatosis (identified and classified via ultrasound) was found to be 6.56% (95% CI; 5.24, 7.67), and the prevalence of thrombocytopenia (platelet count of <150,000 platelets / μl) was found to be significantly higher in those patients (4.56%), versus patients without severe hepatic steatosis (1.43%; 

According to the study authors, “severe hepatic steatosis alone was not a significant predictor of mortality,” with the results indicating an adjusted hazard ratio (aHR) of 1.16 (95% CI; 0.99, 1.36) for all-cause mortality and 0.97 (95% CI; 0.65, 1.43) for cardiovascular-related mortality.

In those patients in the study who had thrombocytopenia and severe hepatic steatosis, the risk of all-cause and cardiovascular-related mortalities was aHR 3.14 (95% CI; 1.19, 8.27) versus 4.55 (95% CI; 1.02, 20.30) for those without severe hepatic steatosis.

As a result of the significant interactions between severe hepatic steatosis and thrombocytopenia observed in the adjusted models, the team concluded that the presence of thrombocytopenia was “associated with increased risks of all-cause and cardiovascular-related mortalities due to severe hepatic steatosis.”

The Impact of Thrombocytopenia on the Risk of Mortality Amongst Adult Patients with Severe Hepatic Steatosis: A Population Based Study United States Adults

,” was presented at the 2018 American Association for the Study of Liver Diseases (

) Liver Meeting, November 9-13, 2018, in San Francisco, California.

Articles

No studies to-date have looked at the combined risk of mortality for patients with thrombocytopenia and severe hepatic steatosis.

Severe Hepatic Steatosis and Thrombocytopenia Increase Risk of All-Cause, Cardiovascular-Related Mortality

People who inject drugs who are infected with hepatitis C virus can achieve sustained viral response, despite imperfect adherence, according to the results of a new trial.

Although they are at high risk of hepatitis C virus infection and transmission, people who inject drugs tend to be excluded from treatment and coverage of treatment by health insurance because of concerns over adherence to therapy. As this population is most urgently in need of treatment, a team of investigators, led by Elana Rosenthal, MD, assistant professor of medicine in the Division of Clinical Care and Research, at the Institute of Human Virology, of the University of Maryland School of Medicine, in Baltimore, Maryland, set out to evaluate adherence in this population and determine if people who inject drugs are able to achieve cure of hepatitis C virus infection.

For the open-label, nonrandomized observational study—the ANCHOR study (

)—Rosenthal and her team evaluated a model of care for the treatment of hepatitis C virus infection in people who inject drugs with chronic hepatitis C virus infection. All patients in the trial are treated with direct-acting antivirals (sofosbuvir/velpatasvir [SOF/VEL] for 12 weeks, dispensed monthly in 28-pill bottles) and are also offered pre-exposure prophylaxis for HIV prevention, as well as buprenorphine for treatment of opioid use disorder when clinically indicated, according to the study design.

® to discuss the study further (see video).

A total of 160 patients were screened for the trial and 100 were enrolled. The majority of the patients were male (n = 76, 76%), with a median age of 57 years (interquartile range 53-62 years), black (n = 93, 93%) and about half (n = 51, 51%) were unstably housed. More than half (n = 58, 58%) reported daily injection drug use.

Three of the participants were infected with HIV and all 3 were not on treatment for HIV when they started treatment for their hepatitis C virus coinfection. According to Rosenthal, those patients were linked with care for their HIV infection. Two of the patients initiated treatment for HIV, and although 1 did not, his CD4 count was >500c/mL.

“People who have HIV and hepatitis C virus coinfection and in HIV care had already been preferentially treated early on [for their hepatitis C virus coinfection],” Rosenthal explained. “The coinfected people that we saw were not in HIV care. Some of our patients had very low CD4 counts and so we prioritized HIV treatment in those patients.”

After 24 weeks of treatment, Rosenthal and her team found that even with imperfect adherence to treatment, the majority of the participants in the study were able to achieve cure, and the majority had completed all 3 bottles of the treatment (n = 87, 87%). Twenty-one patients had completed the treatment on time (at week 12) and 46 patients completed treatment after week 12.

The team found that having a suppressed viral load (<200 IU/mL) at week 4, was significantly associated with achieving sustained viral response, and about 84 patients achieved this goal. Interestingly, an interruption in treatment did not impact their sustained viral response. Furthermore, although completing the full course of treatment (3 bottles) was associated with sustained viral response (n = 87), so was completing 2 or more bottles (n = 7). Those participants who completed less than 2 bottles did not achieve sustained viral response (n = 6).

Thirteen participants had an interruption in treatment at varying time points in the study period, and these ranged from 3 days to 70 days.

“The most surprising result we had was the number of patients who cured, despite significant nonadherence,” Rosenthal said. “I had 1 patient who completed his medication 5 weeks after week 12, and he still cured. I had a patient who disappeared for 8 weeks and then came back to treatment. He cured. I had a patient with a 70-day interruption. He cured.”

“Our per-protocol sustained viral response was 89%, and I think that is probably more reflective of the sustained in reality because when I look at the patients who are lost-to-follow-up, 7 had undetectable viral load at week 4, 2 had unknown viral load at week 4, and 1 had a detectable viral load at week 4. This leads me to believe that the majority of people who were lost to follow-up were also cured,” Rosenthal continued. She elaborated on these results in her interview (see video).

® asked Rosenthal if the participants’ age had an impact on the results.

“I don’t think patients’ ages impacted the results because we did not really find different outcomes between the men and the women in the study,” she explained. “We were treating patients in Washington, DC, and so [in this region] there are different subgroups of the opioid epidemic. The opioid epidemic that we are seeing now in more rural and suburban areas tends to be a white, younger population. A lot of the patients we are treating [in DC] tend to be from the ‘original’ opioid epidemic that started in the 1970s and 1980s and that tends to be made up of individuals from more urban areas who are ethnic minorities. The people we are seeing are people who have been using heroin for 20, 30, and 40 years already.”

According to Rosenthal, the biggest takeaway from this study is that people who inject drugs should not be excluded from treatment for their hepatitis C virus infection because of concerns regarding treatment adherence. She explained that their findings indicate that there is not a clear factor at the beginning of treatment that should result in a patient being excluded from access to hepatitis C virus infection treatment purely because they are a person who injects drugs.

“The individuals that we were treating in this study were facing so many challenging socioeconomic and demographic factors that, if they can be cured, anyone can be cured,” Rosenthal said. “I think the biggest distinction [among this population] is going to be, interest. If patients are not interested in getting treated, it is unlikely that they are going to take the treatment. However, in anyone who is coming to you and wants to get treated for hepatitis C virus infection, I don’t think having opioid use disorder or ongoing injection drug use should preclude them from being treated and achieving cure. If patients are interested in taking treatment, they can take treatment.”

Data on any reinfections in the population treated are forthcoming; however, Rosenthal explained that if the team ends up seeing reinfections in this population, that indicates they are treating the right population.

“Our goal was to find the people who are actively transmitting [hepatitis C virus]. When you see reinfection, it means you are treating a patient population who continues to transmit the virus,” Rosenthal explained. “That was critical for us: We were not just treating people with hepatitis C virus infection, but we were curing their infection to interrupt transmission to others, and helping to eliminate the epidemic.”

Rosenthal and her colleagues explained that an important component of treating hepatitis C virus infection in people who use drugs and have opioid use disorder is understanding why they have hepatitis C virus infection, and that is their opioid use disorder. Therefore, it is important to address this underlying cause of infection during treatment for their hepatitis C virus infection to improve their overall outcomes (see video).  

High SVR in PWID with HCV Despite Imperfect Medication Adherence: Data from the Anchor Study

People who inject drugs who are infected with hepatitis C virus can achieve sustained viral response at the completion of treatment, despite imperfect adherence.

PWID Infected With Hepatitis C Virus Can Achieve SVR Despite Imperfect Adherence to Treatment

Although acute kidney injury is common in patients with cirrhosis, those who are admitted to the hospital are at increased risk, especially if they are of older age, Child-Pugh Class C, or have ascites or sepsis, according to the results of a new study.

Research indicates that the prevalence of acute kidney injury in people with cirrhosis can range between 14% and 50%. Mortality is also high in these patients, particularly among those who are admitted to the hospital and with the highest stage of acute kidney injury, but firmer estimates of prevalence are not known. As such, investigators led by Raseen Tariq, MD, resident in internal medicine at Rochester General Hospital in Rochester, New York, performed a meta-analysis to determine the prevalence and mortality outcomes in patients with cirrhosis who subsequently developed acute kidney injury and further evaluation of the predictors of acute kidney injury in these patients.

“As a medical resident, I see a lot of patients with acute kidney injury who have cirrhosis,” Tariq said in an interview with 

®. “Whenever these patients are admitted to the hospital, we don’t know what else we can do for them to prevent liver disease progression, and what the long-term outcomes are going to be for these patients. The questions that we were hoping to answer with this study were, ‘Why did they develop acute kidney injury?’ and ‘What are their long-term outcomes going to be?”

Studies to address this have been completed in the past, but most are retrospective studies and there are no clinical trials. Furthermore, the data are scant in terms of pooled analyses, particularly regarding trends in acute kidney injury in this population.

Tariq and her team performed a literature search up to March 2018 and identified 30 studies that assessed the prevalence or mortality of acute kidney injury in patients with cirrhosis. The Newcastle-Ottawa scale was used to assess the quality of each study and meta-analyses were performed using random effects models, according to the study abstract. 

 values of <.05 were deemed as significant when assessing heterogeneity and publication bias.

Tariq explained why the team did not find more studies to include in the analysis.

“We excluded a lot of studies because we wanted to include only those studies that actually assessed the prevalence of acute kidney injury,” Tariq said. “We wanted to ensure that every study had specific criteria to diagnose these patients. Most of the studies determined it by serum creatinine at least more than 1.5 times baseline. Our strict inclusion criteria might be the reason why we only found 30 studies to include in the analysis, which is actually more than we were expecting.”

A total of 18,645 patients were included in the studies, of which, 5,744 developed acute kidney injury (pooled prevalence 37.4%, 95% CI, 30.7%-44%). Data from 8 studies revealed that among patients with cirrhosis and acute kidney injury, in-hospital mortality was 6 times in those with acute kidney injury than those without (odds ratio [OR] 6.72, 95% CI 3.47-13, 

 ,70%). Furthermore, 7 studies reported higher 30-day mortality in those with acute kidney injury than those without (OR 3.37, 95% CI 2.35-4.84). Mortality at 90 days to a year after the development of acute kidney injury was also high at (OR 4.43, 95% CI 2.93-6.70) and (OR 5.37, 95% CI 2.45-11.79) respectively. For those patients with acute kidney injury who were admitted to the intensive care unit (ICU), mortality was 6 times higher than those without acute kidney injury (OR 5.90, 95% CI 3.21-10.85).

The long-term follow-up data from those studies in terms of mortality was surprising, according to Tariq. “In those patients who developed acute kidney injury, even when they are discharged from the hospital, and the renal dysfunction had resolved, the mortality remained high. The clinicians had treated their renal dysfunction and their underlying etiology (because of infection or ATN, or something else); however, the patients still had increased mortality, even at 1 year follow up.”

<.001), Child Pugh Class C (OR 2.51, 95% CI 1.83-3.44), the presence of ascites (OR 2.06, 95% CI 1.25-3.41) and the presence of severe sepsis/septic shock (OR 2.72, 95% CI 1.05-7.06) were all associated with the risk of acute kidney injury. These are not surprising, but Tariq explained that it was important that we now had the data to support it.

“We know these are the risk factors, but it was good to have the data on it,” Tariq explained. “If patients come into the hospital with these risk factors, we now have the data to support that they should be monitored very closely. Not only in terms of bloodwork, but also in terms of urine output.

Variables not associated with a risk of acute kidney injury included model for end-stage liver disease (MELD) score, diabetes, being male, hepatic encephalopathy or bacterial infection on admission, or etiology of cirrhosis (alcoholic vs viral).

Furthermore, investigators found a trend of decreased risk of acute kidney injury in patients with a history of, or current variceal bleed (OR 0.69, 95% CI 0.48-0.99).

Overall, about 37% of the patients with cirrhosis who were admitted to the hospital developed acute kidney injury. Furthermore, among admitted patients who in ICU or non-ICU floor, the risk of in-hospital mortality was 6 times greater in patients with acute kidney injury than those without.

Some of the limitations of this study include that all studies included in the analysis were retrospective studies. Furthermore, in all studies monitored serum creatinine levels as an indicator of acute kidney injury; but, according to Tariq, monitoring urine output is just as important.

“Creatinine is a marker that is read from the muscle and sometimes in patients with cirrhosis, they are so malnourished that their muscle mass is reduced and so their serum creatinine may be falsely low,” Tariq said. “They might have a higher creatinine level than we are seeing. In those cases, urine output may tell us they have much more renal dysfunction or renal injury than we are seeing from the serum creatinine levels.”

According to Tariq, additional prospective studies are warranted to aid in the development of strategies to improve long-term outcomes for patients with cirrhosis who develop acute kidney injury to lower the risk of in-hospital mortality.

“For future studies—and we are planning to do one&mdash;our goal would be to include both the serum creatinine levels and urine output as a marker of renal dysfunction just to ensure that we are not characterizing something that might not be of much significance, or might be of more significance. The other thing we want to consider from this study is, ‘Is there anything that we can do prophylactically to prevent this from happening?’ Our study can be a base for a prospective study to see if patients can receive and albumin infusion or Transjugular Intrahepatic Portosystemic Shunt (TIPS) procedure that reduces the hypo to hypertension to see if we can prevent the development of acute kidney injury and underlying mortality.”

Prevalence, Outcomes and Predictors of Acute Kidney Injury in Patients with Cirrhosis: A Systematic Review and Meta-Analysis

Although acute kidney injury is common in patients with cirrhosis, those who are admitted to the hospital are at increased risk, especially if they are of older age, Child-Pugh Class C, or have ascites or sepsis.

Additional Risk Factors for Acute Kidney Injury Defined in Patients with Cirrhosis

A fixed-dose combination therapy of sofosbuvir, velpatasvir, and voxilaprevir (SOF/VEL/VOX, Vosevi, Gilead) was highly effective after 12 weeks in retreating direct-acting antiviral-experienced patients with hepatitis C virus infection, with and without HIV co-infection, including those with prior noncompletion of treatment or poor adherence, according to results of a new study.

Hepatitis C virus infection can be successfully treated with the use of direct-acting antiviral agents. In rare cases, patients can relapse; however, they can still be retreated successfully. SOF/VEL/VOX is one such treatment for hepatitis C virus infection that has shown 

success in patients who are treatment-experienced

; however, many studies have not assessed the success of retreatment in patients with HIV or hepatitis B virus co-infection.

“I think many people expect that the drugs will work the same in HIV-positive patients as in HIV negative patients because of the early data in ledipasvir/sofosbuvir (Harvoni, Gilead) especially showing similar efficacy like in the 

,” study lead investigator Eleanor MP Wilson, MD, MHS, assistant professor of medicine at the University of Maryland School of Medicine in Baltimore, Maryland, explained in an email with 

®. “[However,] some recent data has shown that in real-world studies, patients with HIV may be less likely to succeed, because of drug interactions, immunologic effects, or other factors. [Therefore,] the newer retreatment regimens need to be tested in people with HIV infection, to show that there are no drug interactions and that patients with HIV and hepatitis C virus [or hepatitis B virus] co-infection will have retreatment options.”

A team of investigators led by Wilson, pulled data from the RESOLVE trial (

), an open-label phase 2b study on the safety and efficacy of 12 weeks of a fixed dose of SOF/VEL/VOX (sofosbuvir 400mg/velpatasvir 100mg/voxilaprevir 100mg) in hepatitis C virus-infected patients with early and advanced liver disease, including those with HIV or hepatitis B virus infection, who failed previous combination direct-acting antiviral therapy. The primary endpoint was the proportion of patients who achieve sustained viral response at 12 weeks, as well as the incidence of grade 3 or grade 4 adverse events during treatment or within 30 days of treatment completion.

A total of 77 subjects were enrolled in the study at 3 sites in Baltimore and Washington, DC. The subjects were predominantly male (n = 64, 83%) and black (n = 66, 86%), with a mean age of 60 years (SD 8 years). Three-quarters of the patients (n = 58, 75%) were infected with hepatitis C virus genotype 1a, 17 patients (22%) were HIV-positive, and 2 (3%) were co-infected with HIV and hepatitis B virus.

A little over half of the participants (n = 39, 51%) had previously used intravenous drugs. About 40% (n = 31) had compensated cirrhosis at baseline and 35% (n = 27) had F2 or lower liver fibrosis.

Direct-acting antiviral experience included ledipasvir/sofosbuvir (n = 69, 89%); paritaprevir/ritonavir/ombitasvir plus dasabuvir (n = 3, 4%); elbasvir/grazoprevir (n = 2, 3%); simeprevir/sofosbuvir (n = 2, 3%); sofosbuvir/daclatasvir (n = 1, 1%), while 9 patients (12%) had received other regimens (not listed in the study abstract). A total of 19 patients (25%) had received more than 1 treatment for hepatitis C virus infection, which included 13 patients (17%) who had prior interferon experience and 11 patients (14%) who had experience with more than 1 direct-acting antiviral regimen.

A total of 22 patients (29%) did not complete their previous direct-acting antiviral treatment for reasons that included poor adherence (n = 14, 64%), interruption (n = 4, 18%), lost or stolen medication (n = 2, 9%), or adverse event (n = 1, 5%), according to the study.

Sustained viral response at 12 weeks was achieved by 70 of the 77 patients (90.9%). Of the 22 patients who did not complete their previous treatment with direct-acting antivirals, 18 achieved sustained viral response at 12 weeks. Two patients were awaiting sustained viral response determination and 2 had discontinued treatment early because of intercurrent illness, according to the study authors.

A total of 3 participants (4%) discontinued treatment early for non-SOF/VEL/VOX-related adverse events. These were traumatic subdural hematoma, hypertensive urgency, and colitis. Two patients (3%) were lost to follow up, and 1 patient died because of an unrelated newly diagnosed hepatocellular carcinoma. Furthermore, 1 patient had virologic relapse.

Adverse events that were related to SOF/VEL/VOX were reported by 

5% of the participants and included fatigue, headache, diarrhea, abdominal pain, and constipation. Three grade 4 adverse events were reported, but they were determined to be unrelated to the study drug. These included subdural hematoma and new carcinoma diagnoses (squamous cell and hepatocellular).

“Our study shows that SOF/VEL/VOX is a good option, in terms of both safety and efficacy, for retreatment of hepatitis C virus infection in patients with HIV, those with hepatitis B virus infection on treatment, and in those patients who had previously not completed their initial direct-acting antiviral regimen (with either poor adherence or treatment interruption),” Wilson said. “We were able to show high retreatment responses for these traditionally difficult to treat groups, at rates similar to those reported in the registrational studies. It’s important that these traditionally understudied groups have validation that they have options for retreatment, including options that minimize drug interactions and very safe toxicity profiles.”

Looking to the future and next steps, Wilson stated that “we need to continue to show the real-world effectiveness of retreatment [for hepatitis C virus infection] to help further ongoing public health eradication efforts [of the disease].”

Retreatment with SOF/VEL/VOX in Treatment-Experienced Patients with and without HIV: The Resolve Study

Treatment was also successful in patients with prior noncompletion or poor adherence to direct-acting antiviral therapy.