High rate of liver fibrosis progression in HIV-positive patients, but signs that earlier initiation of antiretrovirals protective

HIV-positive patients have a “significant” risk of experiencing progression of liver fibrosis even without hepatitis co-infection, Italian investigators report in the May 1^st edition of Clinical Infectious Diseases.

All the patients in the prospective, observational study were taking antiretroviral therapy, and none were co-infected with hepatitis B or C.

Depending on the method of assessment, rates of progression ranged between 8% and 31%.

A higher CD4 cell count was protective against fibrosis, as was control of viral load, and the investigators believe that this has implications for the debate about the best time to start antiretroviral therapy. “The positive impact of the control of HIV infection suggests that early initiation of HAART [highly active antiretroviral therapy] may provide an opportunity to prevent liver fibrosis progression.”

Liver disease is now a major cause of illness and death in patients with HIV. Co-infection with hepatitis B or C is responsible for much of this disease, but there is little information about the incidence and risk factors for liver fibrosis in HIV-positive patients who do not have these co-infections.

Therefore investigators in northern Italy monitored liver health in 1112 HIV-mono-infected patients who started antiretroviral therapy between 1996 and 2006.

Two validated methods were used to assess liver fibrosis. These were the FIB-4 score, which is calculated using ALT (alaine aminotranserase), and AST (aspartate aminotransferse) levels (both assessments of liver function), platelet count and age; and the AST-to-platelet ration index (APRI). The investigators calculated the concordance between these methods of assessment.

Almost two-thirds (65%) of patients were men, median baseline age was 38 years, and 50% had a CD4 cell count below 200 cells/mm³ when they started HIV therapy. A quarter of patients took a combination of drugs that included a “d” drug (ddC, ddI, d4T), which have been associated with an increased risk of liver toxicity.

For both FIB-4 and APRI, the patients were placed into one of three groups. At baseline, 81% of patients belong to FIB-4 and APRI groups 1 and 2, indicating either no or mild fibrosis. Concordance between the assessment methods was moderate (kappa value, 0.573; 95% CI, 0.524-0.623).

Patients were followed for a median of 2249 days.  The investigators were especially interested to see if patients experienced a worsening of fibrosis during this period that resulted to their transition to a higher grouping.

When the FIB-4 method of assessment was used, 24% of patients were found to have some worsening in fibrosis. This provided an incidence of 0.064 per 100 person years of follow-up. Transition to a higher group was observed in 8% of patients, an incidence rate of 0.018 per 100 person years.

Using APRI scores, the investigators found liver fibrosis progression in 31% of patients, an incidence of 0.099 per 100 person years of follow-up. Analysis also showed that 12% of patients had transition to a higher group, an incidence rate of 0.028 per 100 person years.

However, worsening of fibrosis was often transitory, and 45% of patients reverted to a lower FIB-4 class, with 52% of individuals reverting to a lower APRI class.

Progression to a class 3 FIB-4 score occurred in 6% of patients (incidence 0.013 per 100 person years), and 8% of patients progressed to APRI class 3 (incidence 0.018 per 100 person years).

Baseline factors associated with progression to higher classes were assessed for both FIB-4 and APRI.

For both FIB-4 and APRI they included more advanced fibrosis on entry to the study (p = 0.004 and p = 0.007 respectively).

Older age (< 0.01) and injecting drug use (p = 0.031) were both associated with a worsening of FIB-4 class, and male sex (p = 0.018) and gamma-GT score (p = 0.015).

Progression to class 3 as associated with baseline fibrosis values for both methods of assessment (both p < 0.01), as well as older age for FIB-4 (p = 0.023).

Starting HIV therapy with a higher CD4 cell count was protective against the progression of fibrosis, as was control of viral load. Sensitivity analysis showed that therapy that included a “d” drug was associated with transition to a higher fibrosis class (FIB-4, p < 0.001; APRI, p = 0.015).

“This study demonstrated that HIV-mono-infected patients display a significant risk of liver fibrosis progression,” comment the investigators.

They recommend, “FIB-4 and APRI should be used to identify patients who are most at risk and who need further clinical work…and more proactive counselling to modify dangerous behaviours (such as alcohol abuse).”

The authors conclude, “our results suggest the benefit of earlier HAART initiation for liver fibrosis in HIV-monoinfected patients, provided that the most dangerous [“d”] drugs are avoided.”