Benefit of Early versus Deferred Antiretroviral Therapy on Progression of Liver Fibrosis among People with HIV in the START Randomized Trial

Abstract

The role of antiretroviral therapy (ART) in reducing or contributing to liver fibrosis in persons with human immunodeficiency virus (HIV) is unclear. We evaluated participants in the Strategic Timing of AntiRetroviral Treatment (START) trial 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 ART on liver fibrosis progression. 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 enrollment (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. Of the 4,684 enrolled into the START study, 104 did not have APRI or FIB‐4 results and were excluded. Among 4,580 participants (2,273 immediate treatment; 2,307 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 B and/or C, 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.

Liver cirrhosis in HIV/HCV‐coinfected individuals is related to NK cell dysfunction and exhaustion, but not to an impaired NK cell modulation by CD4+ T‐cells

“…Second, we observed that the response to activation stimuli of CD4 + T‐cells in coinfected subjects as well as their ability to modulate the function of NK cells did not differ between individuals with minimal and maximal degree of fibrosis. It has been reported that HIV/HCV‐coinfected subjects with higher chances to develop liver fibrosis are those with lower CD4 + T‐cell recovery after HIV treatment . In view of our results, CD4 + T‐cell count might contribute more significantly to fibrosis progression than a deficient CD4 + T‐cell modulation capacity.…”

Epidemiological risk factors associated with primary infection by Epstein–Barr virus in HIV-1-positive subjects in the Brazilian Amazon region

“…With the late initiation of HAART, there was a clear progression in coinfection symptoms, evidenced by the increase in cases of oligosymptomatic and polysymptomatic patients with HAART initiation greater than 12 months after the primary diagnosis. Although our results indicate that most patients sought specific medical care at the onset of the disease, we show how neglect of the condition can affect the pathological status of HIV infection, given that antiretroviral therapy initiated as soon as possible delays the progression of the disease and viral transmission 124 and has secondary benefits 125 , 126 .…”

Liver Fibrosis during Antiretroviral Treatment in HIV-Infected Individuals. Truth or Tale?

“…Apart from those already mentioned, other factors associated with significant LF appear to be chronically elevated serum alanine aminotransferase (ALT) and gamma glutamyl-aminotransferase (γGT) levels, while findings concerning body-mass index and the presence of hypertriglyceridemia or diabetes mellitus (common predisposing factors for NAFLD) are inconsistent [ 26 , 28 , 30 , 32 , 33 , 41 , 42 , 43 , 44 , 45 , 46 , 47 ].…”

“…As already mentioned, HIV leads to LF via multiple pathways; the effective control of HIV infection seems to be beneficial for liver histopathology. Proof of this comes from the START trial which involved more than 4500 patients, and showed that LF is rather rare in HIV infected individuals with early ART initiation, implying a protective role for early therapeutic intervention on LF progression [ 30 ]. In another study by Ding et al including 3900 patients, ART was correlated with an improvement of LF as evaluated by the fibrosis-4 (FIB-4) score [ 31 ], while Thorpe et al found that ART interruption in 541 HIV/HCV co-infected patients led to a higher probability of liver fibrosis [ 68 ].…”

“…Several studies have explored the possible causes of liver fibrosis in HIV-infected patients, with most of them pointing out viral hepatitis co-infections, age, and alcohol abuse as the major risk factors [ 16 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 ]. On the other hand, the long-term hepatotoxicity of ART has been debated, with various studies remaining inconclusive.…”