Advanced Liver Disease in People with HIV

As HIV positive people live longer due to effective antiretroviral therapy, liver disease has become an increasingly important cause of illness and death in this population.

In some cases, advanced liver disease in people with HIV is related to coinfection with hepatitis B or C virus (HBV or HCV), certain antiretroviral drugs are known to cause liver toxicity, and in other cases the cause of liver disease is unclear. Three presentations at the recent 9th International Congress on Drug Therapy in HIV Infection (HIV9) in Glasgow discussed end-stage liver disease (ESLD), advanced liver fibrosis, and severe portal hypertension in HIV-infected individuals.

End-stage Liver Disease

R. Teira and colleagues examined risk factors for ESLD among HIV-HCV coinfected patients in the Spanish VACH cohort, in particular the association between exposure to protease inhibitors (PIs) or non-nucleoside reverse transcriptase inhibitors (NNRTIs) and HCV-related chronic liver disease.

There is increasing evidence that HAART has a beneficial effect on the evolution and outcome of chronic liver disease due to hepatitis C, the researchers noted as background, but the relative merit of different antiretroviral drugs or drug classes is not fully understood.

The investigators identified HIV-HCV coinfected participants in the VACH cohort who had started HAART and had at least 1 follow-up visit. The main exposure variable was total duration of PI or NNRTI use. The outcome of interest was occurrence of ESLD, defined ascites, esophageal varices, hepatic encephalopathy, hepatorenal syndrome, portal hypertension, hepatocellular carcinoma, or a related diagnosis such as upper gastrointestinal bleeding or spontaneous bacterial peritonitis.


• The researchers identified 2669 evaluable HIV-HCV coinfected patients (44%) out of the total 15,183 participants in the VACH database.

• 128 patients (4%) developed ESLD.

• In a univariate analysis, the following factors were associated with ESLD:

• Being hepatitis B surface antigen (HBsAg) positive, indicating HIV-HCV-HBV triple infection;

• Low nadir CD4 cell count;

• Older age;

• Prior AIDS diagnosis.

• However, exposure to either PIs or NNRTIs was not a predictor of ESLD.

• In a multivariate regression model, only HBsAg positivity, age, and nadir CD4 count remained associated with ESLD.

• In an analysis of time from initiation of HAART to ESLD, looking only at individuals who had exclusively taken one or the other drug class, there were no differences between those on PIs and those on NNRTIs.

In conclusion, the researchers stated, "we found no evidence to support the hypothesis of a different effect of PIs and [NNRTIs] on the occurrence of ESLD among HIV and HCV coinfected individuals."

However, "[h]epatitis B coinfection, more profound immunosuppression, and older age were associated with this outcome."

Advanced Liver Fibrosis

In the second study, researchers from Hospital Carlos III in Madrid, Spain, performed a cross-sectional analysis of all HIV positive outpatients who underwent examination using transient elastometry (FibroScan) at a single HIV clinic since 2005.

Most patients (78%) were men, the mean age was 43 years, 64% were injection drug users, 77% were on antiretroviral therapy, 72% had HIV viral load < 50 copies/mL, and the mean CD4 count was 524 cells/mm3. Nearly two-thirds (60%) were HIV-HCV coinfected (HCV RNA positive) and 9% were HIV-HBV coinfected (HBsAg positive). One-third had a history of excessive alcohol use, and 10% were current alcohol abusers.

A total of 681 patients had a valid Fibroscan evaluation. Advanced liver fibrosis was defined as liver stiffness > 9.5 kiloPascals (kP), which has been shown to correspond to Metavir stages F3-F4 on liver biopsy.


• In a univariate analysis, several factors differed significantly between patients with and those without advanced liver fibrosis:

• Mean age: 44 vs 42 years, respectively;
• HIV transmission risk factors:

• Injection drug use: 81% vs 54%;
• Men who have sex with men (MSM): 11% vs 33%;
• Heterosexual: 6% vs 12%)

• Past alcohol abuse: 50% vs 26%;
• Mean CD4 count: 469 vs 550 cells/mm3;
• HCV RNA positivity: 77% vs 52%;
• Elevated ALT (> 50 IU/L): 29% vs 9%;
• Mean plasma glucose: 127 vs 116 mg/dL;
• Triglyceride level: 223 vs 172 mg/dL;
• Total cholesterol level: 177 vs 188 mg/dL;
• Insulin resistance: HOMA-IR index 4.5 vs 3.2;
• Past exposure to didanosine (ddI; Videx) with or without stavudine (d4T, Zerit): 51% vs 40%;
• Mean duration of antiretroviral drug use:
• Any antiretroviral therapy: 85 vs 78 months;
Nevirapine(Viramune): 11 vs 16 months;
Lopinavir/ritonavir (Kaletra): 13 vs 8 months;
Atazanavir(Reyataz): 7 vs 5 months;
Tenofovir(Viread, also in the Truvada and Atripla combination pills): 21 vs 18 months.

• In a multivariate model, the factors independently associated with advanced liver disease were:

• Older age: odds ratio (OR) 1.08;
• Past alcohol abuse: OR 2.62;
• Exposure to didanosine and/or stavudine: OR 1.94;
• Higher HOMA index: OR 1.25;
• Elevated ALT: OR 1.05.

• In contrast, chronic hepatitis B or C were no longer associated with advanced fibrosis after controlling for other factors.

Based on these findings, the researchers concluded, "Former alcohol abuse and non-alcoholic steatohepatitis as a result of insulin resistance and/or exposure to dideoxynucleosides represent an emerging cause of advanced liver fibrosis in HIV patients."

Portal Hypertension

Finally, I. Maida and colleagues reported on several cases of severe portal hypertension in people with HIV.

Portal hypertension, or high blood pressure in the portal vein due to backed up blood, is a symptom of liver cirrhosis. It can lead to complications including ascites and potentially life-threatening esophageal and gastrointestinal bleeding.

Severe portal hypertension is typically not seen in non-cirrhotic individuals, but some cases have been reported in HIV negative people associated with exposure to adenosine analog drugs (e.g., azathioprine), bacterial infections, exposure to various trace metals and chemicals, genetic coagulation disorders, or autoimmune diseases.

The investigators described clinical and histological findings for all consecutive cases of severe portal hypertension of unknown cause seen in HIV positive patients at 3 outpatient clinics in Spain and Italy.


• A total of 13 out of 41 patients (31.7%) with liver disease of unknown cause were diagnosed with severe portal hypertension.

• All had elevated ALT for longer than 12 months and were followed for at least 4 years.

• The majority were men (85%) and gay/bisexual (77%), with a median age of 50 years.

• The median time since HIV diagnosis was more than 7.5 years.

• All but 1 were on antiretroviral therapy and had undetectable plasma HIV viral load.

• None had a current CD4 count < 200 cells/mm3, although 4 had a nadir (lowest-ever) CD4 count below this level in the past.

• Median time of exposure to antiretroviral drugs was 51 months for didanosine, 21 months for stavudine, and 18 months for nevirapine.

• During follow-up, 8 patients (61%) experienced complications of severe portal hypertension, including 6 episodes of upper gastrointestinal (GI) bleeding from esophageal varices and 5 episodes of portal thrombosis.

• All patients underwent liver biopsy, and none showed advanced liver fibrosis.

• The main biopsy findings were nodular regenerative hyperplasia (31%), perisinusoidal fibrosis (8%), drug-induced hepatitis (8%), non-alcoholic steatohepatitis (31%), and unspecific lesions (22%).

"A small subset of HIV patients may develop severe portal hypertension in the absence of known predisposing conditions and advanced hepatic fibrosis," the investigators concluded. "These patients may eventually experience potentially fatal GI bleeding."

"Exposure to didanosine seems to be involved in most cases," they continued. "A primary injury of the portal vessels by this adenosine analog may play a central pathogenic role in this condition."



R Teira, P Geijo, J Cosín, and others. Risk factors for end-stage liver disease among HIV and hepatitis C virus co-infected patients in the Spanish VACH Cohort. 9th International Congress on Drug Therapy in HIV Infection. Glasgow, Scotland. November 9-13, 2008. Journal of the International AIDS Society 11(Suppl 1): P134. November 10, 2008.

F Blanco, P Barreiro, P Ryan, and others. Risk factors for advanced liver fibrosis in HIV-infected individuals: role of the metabolic syndrome. 9th International Congress on Drug Therapy in HIV Infection. Glasgow, Scotland. November 9-13, 2008. Journal of the International AIDS Society 11(Suppl 1): P137. November 10, 2008.

I Maida, E Vispo, G Sotgiu, and others. Unexplained severe portal hypertension in HIV-infected patients: a new clinical entity? 9th International Congress on Drug Therapy in HIV Infection. Glasgow, Scotland. November 9-13, 2008. Journal of the International AIDS Society 11(Suppl 1): P138. November 10, 2008.