Treatment breaks lead to fibrosis in HIV/HCV-co-infected patients

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Interrupting HIV therapy is associated with the progression of liver damage in patients co-infected with HIV and hepatitis C, Canadian investigators report in the online edition of AIDS.

Taking a break from antiretroviral therapy more than doubled the risk of fibrosis.

“We found a significant, harmful effect of interruption on the development of fibrosis after accounting for clinical factors,” comment the investigators, who call for further research into the reasons co-infected patients take breaks from their HIV treatment.

Glossary

fibrosis

Thickening and scarring of connective tissue. Often refers to fibrosis of the liver. See also ‘cirrhosis’, which is more severe scarring.

cirrhosis

Severe fibrosis, or scarring of organs. The structure of the organs is altered, and their function diminished. The term cirrhosis is often used in relation to the liver. 

prospective study

A type of longitudinal study in which people join the study and information is then collected on them for several weeks, months or years. 

treatment interruption

Taking a planned break from HIV treatment, sometimes known as a ‘drugs holiday’. As this has been shown to lead to worse outcomes, treatment interruptions are not recommended. 

not significant

Usually means ‘not statistically significant’, meaning that the observed difference between two or more figures could have arisen by chance. 

Liver disease is now a major cause of illness and death in patients co-infected with HIV and hepatitis C.  However, some research suggests that treatment with antiretroviral drugs protects co-infected patients from the development of liver disease.

Results of the SMART study showed that interrupting antiretroviral therapy increased the risk of illness and death from HIV and non-HIV-related causes, including liver disease.

Although treatment interruptions are not recommended, they still occur. Canadian investigators hypothesised that breaks from HIV therapy contributed to the development of liver fibrosis in co-infected patients.

To test this theory they designed a prospective study involving 514 patients who were enrolled in the Canadian HIV-HCV Co-infection Cohort (CCC). All the patients were recruited between 2003 and 2009, and none had fibrosis at baseline.

Liver fibrosis was assessed using a blood test that measured aspartate aminotransferase (AST)-to-platelet-ratio (APRI). This is a validated surrogate marker of fibrosis. An APRI score of 1.5 used to diagnose significant fibrosis and cirrhosis was diagnosed if an individual had an APRI score of 2.0 or above

Patients were assessed at baseline and then at six-monthly intervals. Blood samples were taken and patients reported if they had interrupted HIV therapy.

The median duration of follow-up was 1.02 years. During 760 person-years of follow-up, 10% of patients achieved an APRI score of at least 1.5 and 10% interrupted their antiretroviral therapy.

The total number of treatment interruptions was 55, with two patients interrupting their therapy twice. The median duration of each interruption was 180 days. Interruptions peaked in 2004 when 15% of individuals took a break from their HIV treatment.

Overall, only 38% of patients resumed therapy during follow-up.

Platelet count fell by a median of 2x109/l when treatment was interrupted and AST increased by 21 u/l.

Statistical analysis that controlled for potentially confounding factors (including changes in CD4 cell count and viral load) showed that interrupting HIV therapy more than doubled the risk of liver fibrosis (hazard ration [HR] = 2.52; 95% CI, 1.20-5.28). A baseline APRI score of between 0.5-1.49 was also strongly correlated with the progression of liver disease.

Their analysis also showed a treatment interruptions were associated with a non-significant increase in the risk of serious clinical liver disease or cirrhosis (HR = 2.12; 95% CI, 0.87-5.16). The investigators believe that it was only lack of statistical power that prevented this relationship from achieving significance.

“Interruption of antiretroviral therapy has been shown to lead to a greater risk of nonopportunistic disease-related death in randomized trials, particularly among HIV-HCV co-infected participants,” comment the investigators.

They believe that the results of their study have for the first time shown that interrupting HIV treatment “was associated with the development of significant liver fibrosis among participants co-infected with HIV and HCV.”

A possible reason for the association is the increased inflammation that occurs when treatment is interrupted.

However, the investigators acknowledge that their study has some limitations. Although the APRI score is a validated measure of fibrosis in co-infected patients, it is known that stopping HIV therapy can lead to changes in platelet counts. Nevertheless the investigators had confidence in their findings. Closer analysis of platelet counts and AST scores before and during treatment breaks lead them to conclude that fibrosis did progress when therapy was interrupted.

“Studies to determine factors associated with antiretroviral treatment interruption in co-infected patients would be beneficial to assist clinicians in reducing treatment discontinuations as would studies aimed at understanding the underlying mechanisms driving fibrosis in this setting,” conclude the authors.

Thorpe J et al. Antiretroviral treatment interruption leads to progression of liver fibrosis in HIV-hepatitis C virus co-infection. AIDS, 25 (online edition), doi: 10. 1097/QAD.0b013e3283455e4b, 2011 (click here for the free abstract).