Switch from efavirenz delivers benefits in HIV+ fatty liver disease

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Switching to raltegravir from efavirenz is associated with significant improvements in liver steatosis for HIV-positive people with non-alcoholic fatty liver disease, Spanish investigators report.

The benefits of changing therapy were observed in people with and without active hepatitis C virus (HCV) co-infection. “It is highly likely that the results reported…can be generalized to HIV-infected patients without HCV co-infection,” comment the Spanish AIDS Research Network-HEP09 Study Group, led by researchers at the Hospital Universitario de Valme, Seville.

Non-alcoholic fatty liver disease (NAFLD) is common among people with HIV. The condition can increase the risk of liver fibrosis progression. Causes of NAFLD include metabolic disorders and therapy with antiretrovirals that cause mitochondrial toxicity. Efavirenz has been associated with this side-effect and the progression of liver steatosis (accumulation of fat in the liver). In contrast, raltegravir does not cause mitochondrial toxicity. However, the effect of therapy with this drug on fatty liver disease in unclear.
Liver disease is now a leading cause of serious illness and death among people with HIV, especially if they have co-infection with HCV. Identification of antiretrovirals that do not cause liver-related side-effects is therefore a priority.

With this in mind, investigators in Spain designed an open-label, multicentre, randomised study to assess the impact on liver steatosis over 48 weeks of switching from efavirenz to raltegravir while maintaining a stable nucleoside reverse transcriptase inhibitor (NRTI) backbone (emtricitabine/tenofovir or lamivudine/abacavir).

The study population consisted of 39 individuals with hepatic steatosis, all with a suppressed viral load and evidence of significant liver steatosis. A total of 19 were randomised to switch to raltegravir, the other 20 remaining on efavirenz. Approximately three-quarters of the participants taking raltegravir and two-thirds of those treated with efavirenz had detectable HCV viral load. People with active drug/alcohol abuse were excluded from participation.

Changes in liver steatosis were assessed by transient elastography (Fibroscan), which measures liver stiffness and fat accumulation in the liver. Liver fat is calculated by measuring the controlled attenuation parameter (CAP). At baseline, all the participants had hepatic steatosis defined as CAP values above 238 dB/m.

At the start of the study, the median CAP values were 273 dB/m for people taking raltegravir and 263 dB/m for those remaining on efavirenz, a non-significant difference. After 48 weeks of therapy, median CAP values had fallen to 250 dB/m in the raltegravir group but increased to 286 dB/m for individuals on efavirenz (p = 0.035). The median difference in CAP values between baseline and week 48 was a fall of 20 dB/m for people on raltegravir compared to an increase of 30 dB/m for those on efavirenz (p = 0.011).
At the end of follow-up, CAP measurements below 238 dB/m – indicative of the absence of significant liver steatosis – were observed in 47% of individuals on raltegravir but just 15% of the efavirenz group (p = 0.029).

Results remained unchanged when the investigators restricted their analysis to individuals on the emtricitabine/tenofovir NRTI backbone.

Analysis of the 26 people with active HCV disease at baseline showed median baseline CAP values 277 dB/m and 262 dB/m for the raltegravir and efavirenz groups, respectively.

At week 48, median CAP values had fallen to 266 dB/m for the people taking raltegravir but increased to 285 db/m for those remaining on efavirenz. The median difference in CAP measurements between baseline and week 48 was a fall of 7 dB/m for people on raltegravir and an increase of 30 dB/m for those on efavirenz (p = 0.019). At the end of follow-up, 36% of people on raltegravir had CAP values indicating no significant liver steatosis compared to 8% of people on efavirenz.

“After 48 weeks, HIV-infected individuals with NAFLD switched from an EFV [efavirenz]- to a RAL [raltegravir]-based combination showed a decrease in the degree of hepatic steatosis, as measured by CAP, compared to patients with an EFV-based regimen,” write the authors. “In addition, the proportion of patients showing regression in significant hepatic steatosis after 48 weeks was greater in those who switched from EFV to RAL.”

The researchers suggest that the improvements seen in the raltegravir group may be related to the discontinuation of a drug associated with mitochondrial toxicity. “Replacement of EFV by RAL among patients with significant hepatic steatosis led to reductions in the grade of hepatic steatosis, even reversal of fatty liver in some cases,” they conclude. “These results need confirmation in a larger study.”

Abstract
Background: Antiretroviral drugs with a lower potential to induce hepatic steatosis in human immunodeficiency virus (HIV) infection need to be identified. We compared the effect of switching efavirenz (EFV) to raltegravir (RAL) on hepatic steatosis among HIV-infected patients with nonalcoholic fatty liver disease (NAFLD) receiving EFV plus 2 nucleoside analogues.
Methods: HIV-infected patients on EFV plus tenofovir/emtricitabine or abacavir/lamivudine with NAFLD were randomized 1:1 to switch from EFV to RAL (400 mg twice daily), maintaining nucleoside analogues unchanged, or to continue with EFV plus 2 nucleoside analogues. At baseline, eligible patients should show controlled attenuation parameter (CAP) values ≥238 dB/m. Changes in hepatic steatosis at 48 weeks of follow-up over baseline levels were measured by CAP.
Results: Overall, 39 patients were included, and 19 of them were randomized to switch to RAL. At week 48, median CAP for the RAL group was 250 (Q1–Q3, 221–277) dB/m and 286 (Q1–Q3, 269–314) dB/m for the EFV group (P = .035). The median decrease in CAP values was –20 (Q1–Q3, –67 to 15) dB/m for the RAL arm and 30 (Q1–Q3, –17 to 49) dB/m for the EFV group (P = .011). CAP values <238 dB/m at week 48 were observed in 9 (47%) patients on RAL and 3 (15%) individuals on EFV (P = .029).
Conclusions: After 48 weeks, HIV-infected individuals switching EFV to RAL showed decreases in the degree of hepatic steatosis, as measured by CAP, compared with those continuing with EFV. In addition, the proportion of patients without significant hepatic steatosis after 48 weeks was greater for those who switched to RAL.

Authors
Juan Macías, María Mancebo, Dolores Merino, Francisco Téllez, M Luisa Montes-Ramírez, Federico Pulido, Antonio Rivero-Juárez, Miguel Raffo, Montserrat Pérez-Pérez, Nicolás Merchante, Manuel Cotarelo, Juan A Pineda

Aidsmap material
Clinical Infectious Diseases abstract


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