Sustained Response to Interferon Reduces both Liver-related and AIDS-related Disease and Death in HIV/HCV Coinfected Patients

		SUMMARY: Sustained virological response (SVR) to interferon-based therapy for chronic hepatitis C led not only to a reduction in liver-related complications and deaths in HIV/HCV coinfected individuals, but also to decreased HIV disease progression and deaths due to AIDS and other causes, according to a Spanish study presented last week at the 17th Conference on Retroviruses and Opportunistic Infections (CROI 2010) in San Francisco.

By Liz Highleyman

Over years or decades, chronic hepatitis C virus (HCV) infection can progress to advanced liver disease, including cirrhosis, hepatocellular carcinoma (HCC), liver decompensation or failure requiring transplantation, and liver-related death. HIV positive people coinfected with HCV tend to experience more rapid liver disease progression than individuals with hepatitis C alone.

Prior studies in both HIV negative and HIV/HCV coinfected populations have shown that interferon-based therapy reduces the likelihood of liver disease progression and liver-related death. This is seen most often in people who achieve sustained response, but some studies have found that even people who are not "cured" can still benefit from treatment.

While the detrimental effect of HIV infection and immune suppression on hepatitis C progression is well recognized, the effect of HCV on HIV disease is more controversial, as research has produced conflicting data.

Juan Berenguer from Hospital Universitario Gregorio Maranon in Madrid and colleagues designed a study to assess whether sustained response to treatment would affect HIV disease progression and mortality not related to liver disease.

The analysis included 1428 HIV/HCV coinfected participants enrolled in the multicenter Spanish GESIDA 3603 Study Cohort who started treatment with interferon-based therapy between January 2000 and July 2007.

As is typical of coinfected patients in Spain, about 75% were men, the median age was 42 years, and 81% had a history of injection drug use. More than 80% were on combination antiretroviral therapy (ART) and 62% had suppressed HIV viral load. The median current CD4 cell count was 528 cells/mm3, but the median CD4 nadir (lowest-ever level) was 216 cells/mm3 and 22% had a prior AIDS diagnosis.

With regard to hepatitis C status, 60% had hard-to-treat HCV genotypes 1 or 4, a majority (65%) had high HCV viral load (>500,000 IU/mL), and 30% had advanced liver fibrosis (stage F3 or greater) -- all factors that predict poor treatment response -- but very few (5%) were very heavy drinkers (> 50 g/day).

Most patients received the current standard-of-care therapy consisting of pegylated interferon alfa-2a (Pegasys) (48%) or pegylated interferon alfa-2b (PegIntron) (38%) plus ribavirin; however, 14% used the older conventional form of interferon.

SVR was defined as continued undetectable HCV viral load 24 weeks after completion of treatment. The non-SVR group included patients who never responded, those who responded only partially, and those who had undetectable HCV RNA at the end of treatment but then relapsed.

Results

	36% of participants overall achieved SVR, with the expected variation according to HCV genotype (58% for genotypes 2 or 3; 24% for genotypes 1 or 4).
	After a median follow-up period of about 4 years, participants who achieved SVR had better outcomes than non-SVR patients.
	A total of 69 deaths occurred during follow-up:
	38 due to liver disease; 31 due to non-liver-related causes; 3 (of the 31) due to AIDS-related causes; 28 (of the 31) due to other causes.
	Among surviving participants, there were:
	39 new AIDS-defining conditions; 86 cases of liver decompensation; 16 cases of hepatocellular carcinoma; 16 liver transplants.
	The overall mortality rate was significantly lower among participants who achieved SVR compared with non-SVR patients: 0.31 vs 1.71 per 100 person-years (PY).
	As expected, participants who achieved SVR had significantly lower rates of all liver disease complications compared with non-SVR patients:
	Decompensation: 0.10 vs 2.37 per 100 PY; Hepatocellular carcinoma: 0 vs 0.44 per 100 PY; Liver transplantation: 0 vs 0.44 per 100 PY; Liver-related death: 0.10 vs 0.98 per 100 PY;
	Sustained responders were also significantly less likely than non-SVR patients to experience AIDS-related complications:
	New AIDS-defining conditions: 0.26 vs 0.94 per 100 PY. AIDS-related death: 0 vs 0.08 per 100 PY.
	Finally, sustained responders also had a lower rate of mortality attributed to other (non-liver and non-AIDS) causes compared with non-SVR patients: 0.21 vs 0.65 per 100 PY.
	Looking at a combined outcome of progression to a new AIDS-defining condition or non-liver-related death, people who achieved SVR reduced their risk by approximately two-thirds compared with non-SVR patients: 0.47 vs 1.54 per 100 PY.
	In a multivariate analysis controlling for potentially confounding factors including extent of liver fibrosis, stage of HIV disease, and nadir CD4 count, non-SVR patients had a significantly higher risk of:
	Developing a new AIDS-defining event: adjusted hazard ratio (HR) 3.24; Dying from a non-liver-related cause: adjusted HR 2.60; Both outcomes combined: adjusted HR 2.86.

The researchers concluded that these results suggest that "achievement of an SVR after interferon-ribavirin therapy in HIV/HCV [coinfected] patients reduces not only liver-related complications and mortality, but also HIV progression and mortality not related to liver disease."

"These findings may be associated with a poorer immune response (that does not seem to depend on control of HIV) and/or complications of HCV viremia in patients that did not achieve an SVR," they suggested.

During his presentation, Berenguer briefly showed data from another study indicating that HIV/HCV coinfected people have elevated levels of biomarkers of endothelial dysfunction, but these improved among patients who achieved SVR.

At a press conference following his session, Berenguer was asked whether hepatitis C treatment that does not result in SVR might still have beneficial effects. He said this does appear to be the case, compared with remaining untreated. While these data are not yet fully analyzed, there were "some hints" that coinfected individuals who achieved an end-of-treatment response but relapsed also had improved clinical outcomes.

Hosp Univ Gregorio Marañon, Madrid, Spain; Hosp Univ Bellvitge, Spain; Hosp Clin Valencia, Spain; Hosp Clin San Carlos, Spain; Hosp de Mostoles, Spain; Hosp Santa Creu y Sant Pau, Spain; Hosp 12 de Octubre, Madrid, Spain; Fndn SEIMC-GESIDA, Spain; Hosp Univ La Paz, Madrid, Spain.

2/23/10

Reference
J Berenguer, M Crespo, M Galindo, and others. Sustained Virological Response to Interferon plus Ribavirin Reduces HIV Progression and Non-liver-related Mortality in Patients Co-infected with HIV and HCV. 17th Conference on Retroviruses & Opportunistic Infections (CROI 2010). San Francisco. February 16-19, 2010. Abstract 167.