Early antiretroviral therapy (ART) reduces the risk of liver fibrosis progression in people living with HIV, including in people who do not have co-infection with viral hepatitis, according to the results of the SMART study.
People with a high CD4 cell count (500 cells/mm3) who started immediate ART were about a third less likely to experience fibrosis progression compared to people who started ART when their CD4 cell count fell to 350 cells/mm3. Baseline fibrosis was also more likely to resolve in people who initiated ART at the higher CD4 threshold.
“In this largest study of its kind in predominantly HIV-monoinfected individuals, we show firstly that significant fibrosis was rare and both fibrosis and other liver related events continued to be uncommon over 14,379 person year of follow-up,” comment the authors led by Nila Dharan at the Kirby Institute, University of New South Wales, Sydney. “We also found a potential benefit of reducing markers of liver fibrosis among persons immediately treated with ART and confirmed lack of hepatotoxicity of the ART regimens used in this study.”
Liver disease is a leading cause of serious illness and death among people with HIV. The risk is increased by co-infection with hepatitis B or hepatitis C, as well as by alcohol or drug dependence. The risk of non-alcoholic fatty liver disease (NAFLD) is increased in individuals who are overweight or obese, have high cholesterol and triglyceride levels, have high blood pressure and insulin resistance or have type 2 diabetes.
The role of ART in reducing or causing liver fibrosis progression is unclear. The START (Strategic Timing of Antiretroviral Treatment) study provided an opportunity to address this gap in research.
The randomised controlled trial involved ART-naïve HIV-positive people with a CD4 cell count above 500 cells/mm3. Participants were randomised to start immediate ART or to defer treatment until their CD4 cell count fell to 350 cells/mm3. The study was designed to inform decisions about when to initiate ART, its results showing the benefits of early treatment especially in relation to avoiding cancers and other serious illnesses.
Individuals were enrolled between 2009 and 2013 at 222 treatment centres in 35 countries. The investigators analysed the prevalence and risk factors of significant fibrosis at enrolment and during follow-up, and the effect of early ART compared to delayed therapy on progression of liver fibrosis over time.
Liver function was assessed using two validated non-invasive scoring systems (APRI and FIB-4). The first takes into account aspartate aminotransferase (AST) and platelet counts, with the second also considering age and alanine aminotransferase (ALT).
A total of 4,580 people were included in the analysis, with 2,273 randomised to immediate ART and 2,307 to deferred ART. The median age was 36 years, 27% were female and 30% were black. Almost half the participants (45%) currently smoked or had quit, 3% had diagnosed alcohol or substance dependence, 4% had co-infection with hepatitis C and 3% with hepatitis B. The prevalence of chronic liver disease (0.3%), hepatic steatosis (0.2%) and diabetes (3%) was low. Approximately 2% were taking statins and just over 1% were on tuberculosis therapy.
The median CD4 cell count was 651 cells/mm3 and 5% had a viral load below 200 copies/ml before starting ART. Abnormal laboratory values were present in 26% for ALT, 6% for AST, 2% for platelets, 0.6% for albumin and 7% for bilirubin.
At baseline, rates of liver fibrosis were low. Overall, 84% of people had no significant fibrosis at baseline by either APRI or FIB-4 and 94% had no significant fibrosis by both APRI and FIB-4. A low proportion of people had intermediate significant fibrosis scores by either APRI or FIB-4 (15%) or both (5%). Confirmed significant fibrosis was present in just 1% by either APRI and FIB-4 and in 0.3% using both measures.
For people without fibrosis at baseline, immediate ART was associated with a significant reduction in the risk of developing fibrosis (HR = 0.66; 95% CI, 0.57-0.78, p < 0.001). Factors associated with an increased fibrosis score during follow-up using both APRI and FIB-4 included deferred ART, male gender and hepatitis co-infection. Additionally, a history of alcoholism or substance abuse and higher ALT were risk factors by APRI only, whereas lower albumin, higher total cholesterol and higher triglycerides were associated with increased risk by FIB-4 only.
The risk of developing fibrosis during follow-up did not differ according to baseline viral load (above vs below 100,000 copies/ml). Changes in fibrosis score did not differ according to type of ART (non-nucleoside reverse transcriptase inhibitor vs protease inhibitor).
Incidence of hepatic flare was low in both the immediate and deferred treatment groups. However, people taking immediate ART were significantly more likely to experience normalisation of elevated baseline fibrosis scores than those in the deferred ART group (HR = 1.6; 95% CI, 1.13-1.9, p < 0.001). There was a very low incidence of viral hepatitis infection in both study groups. Very few liver events were reported during follow-up and there were no liver-related deaths. “Our results support current guidance to initiate ART in all patients with HIV regardless of CD4 count, particularly considering that modern ART regimens have lower rates of hepatotoxicity than older regimens,” conclude the authors. “Patients with hepatitis B and C co-infection, as well as those with NAFLD and existing steatosis, should be particularly prioritized for treatment to possibly reduce progression of liver fibrosis in such patients with elevated risk and to preserve overall liver health.”
Abstract Background: The role of antiretroviral therapy (ART) in reducing or contributing to liver fibrosis in persons with HIV is unclear. We evaluated participants in the Strategic Timing of AntiRetroviral Treatment trial (START) for liver fibrosis using the AST to platelet ratio index (APRI) and Fibrosis‐4 Index (FIB‐4), and assessed for a benefit of early versus delayed antiretroviral therapy (ART) on liver fibrosis progression. Design and Intervention: ART‐naïve persons with high CD4 counts (>500 cells/μL) from 222 clinical sites in 35 countries were randomized to receive ART either at study enrolment (immediate treatment arm) or when their CD4 count fell below 350 cells/μL (deferred treatment arm). The following outcomes were evaluated: fibrosis (APRI>0.5 or FIB‐4>1.45), significant fibrosis (APRI>1.5 or FIB‐4>3.25), hepatic flare, and resolution of elevated APRI and FIB‐4 scores.
Results: Of the 4684 enrolled into the START study, 104 did not have APRI or FIB‐4 results and were excluded. Among 4580 participants (2273 immediate treatment; 2307 deferred treatment), the median age was 36 years, 26.9% were female, and 30.4% were black. Three percent had an alcoholism or substance abuse history, 6.4% had hepatitis, and 1.1% had significant fibrosis at baseline. The median CD4 count was 651 and 5.3% had HIV RNA≤200. Immediate arm participants were at lower risk of developing increased fibrosis scores than deferred arm participants (hazard ratio [HR]=0.66; 95% confidence interval [CI]=0.57—0.78; p<0.001), and more likely to have resolution of elevated baseline scores (HR 1.6; 95% CI 1.3—1.9; p<0.001).
Conclusions: Significant liver fibrosis was rare among ART‐naïve HIV‐positive persons with high CD4 counts. Our findings suggest a benefit of early ART in preventing the development of liver fibrosis.
Nila J Dharan, Jacqueline Neuhaus, Juergen K Rockstroh, Lars Peters, Fred Gordin, Alejandro Arenas‐Pinto, Carol Emerson, Kristen Marks, Jose Hidalgo, Rui Sarmento‐Castro, Christoph Stephan, Nagalingeswaran Kumarasamy, Sean Emery, Gail V Matthews