Highlights from the Second International Workshop on HIV and HCV Co-infection

[Guest guest]

Highlights from the Second International Workshop on HIV and Hepatitis Co-infectionAmsterdam, The Netherlands. January 12-14, 2006 By Marina Núñez, MD, PhD

IntroductionThis is the second of a series of annual workshops focused on HIV and hepatitis coinfection, a growing and rapidly evolving field that is increasingly attracting the attention of HIV health care providers. The workshop brought together a group of experts who focused on the most important aspects of these infections, including the results of new research studies.

In addition to the pros-and-cons presentations, the expert roundtables, and the “clinical case scenarios” discussions, this year’s program also included a session of poster discussion.

This annual workshop is becoming an important forum for scientists and clinicians responsible for the care of HIV- and hepatitis-coinfected patients. The present summary reviews the most important research data presented as well as the most significant issues discussed at the workshop.

The Natural History of Hepatitis C in HIV-coinfection

Several studies have demonstrated that liver disease secondary to hepatitis C virus (HCV) infection progresses faster in the setting of HIV-coinfection. The aims of a study by Dr. Antonieta Cargnel´s group were to assess fibrosis progression and to explore its risk factors in HIV-HCV-coinfected subjects by comparing paired liver biopsies [1].

This retrospective study examined biopsies from 36 patients performed between 1985 and 2002. The biopsy was recommended as part of the evaluation for IFN therapy. Fibrosis progression was defined as an increase of at least one stage from the first to the second biopsy.

Median time between biopsies was 54 months (IQR 50-86). Half of patients (18/36) showed fibrosis progression, and the mean staging score at the second biopsy was significantly higher than at the first one (2.1 vs. 1.2; p=0.04). Only 2 of the 33 patients who received treatment achieved a sustained virologic response (SVR), and they did not show fibrosis progression.

The median fibrosis progression rate, defined as the difference between the scores at the consecutive biopsies divided by the years elapsing between the two procedures was 0.23. The calculated median expected time to cirrhosis was 21 years. Regarding factors associated with progression of fibrosis, a decrease in the CD4% of at least 10% was the only one identified (OR 6.85; 0.002) in multivariate regression analysis.

It is unclear if the decrease in CD4 counts reflects the immune deficiency that might favor fibrosis progression, or on the contrary, whether it is the result of lymphopenia caused by hypersplenism secondary to a cirrhotic liver. The analysis did not include an adjustment for the duration of chronic infection.

In a French study, investigators evaluated liver fibrosis progression in HIV-HCV-coinfected patients [2]. As in the Italian study, the assessment was based on two successive liver biopsies, but patients did not receive treatment for HCV in- between. From a population of 261 HIV-HCV-coinfected patients, those who had 2 biopsies but no treatment were identified (N=32). At first biopsy their mean age was 43 years and 79% were receiving antiretroviral therapy (ART). Three patients were staged F2 (8%) and the remainder F0-F1 (92%).

The median interval between biopsies was 46 months. At the second biopsy, the proportion of patients with score F0-F1 had decreased to 40%, while 33% had F2 score, 18% F3, and 9% F4. The mean rate of fibrosis progression was 0.25 points per year, and 9 patients (28%) were considered as rapid fibrosis progressors (more than two points increase). Based on these results, the authors suggested frequent monitoring of liver disease in HCV-HIV-coinfected subjects, probably using non-invasive techniques to measure fibrosis (serum markers, transient elastography).

The problem with this type of study, which is based on consecutive biopsies, is the bias introduced in the selection of the study population, leading to errors of both under- and overestimation of liver damage. Results will completely differ with the different indications for biopsy (evaluation for HCV treatment within a study in which it is a requirement, assessment of HCV infection with low transaminases, etc.), the different populations (more or less reluctant to undergo liver biopsy or to receive treatment, naive or failing anti-HCV therapy), etc.

Nevertheless, these two studies continue to support the concept of a more rapid progression of liver damage in HCV-HIV-coinfected patients and the need to offer anti-HCV treatment for eradication of the HCV infection.

The natural history and predictors of liver decompensation and survival in cirrhotic HIV-HCV-coinfected patients were investigated in another Italian study [3]. A cohort of 115 cirrhotic patients referred to a tertiary center from 2002 to 2005 was followed for a median time of 707 days (IQR 281-1,106). At study entry 17% had end stage liver disease (ESLD). Ten patients were lost from follow up. The cumulative risk of death was 32% at three years. Baseline Child Turcotte Pugh (CTP) stage was the only variable independently related to risk of death (HR 3.28, 95%CI 1.37-7.28 for class B; and HR 9.28, 95%CI 3.06-28.09 for class C.

The cumulative risk of liver decompensation was 42% at three years. CD4 count < 200 cells/mm3 at entry was a factor independently associated with liver decompensation (HR adjusted by CTP score 2.44, 95%CI 1.06-5.63; p=0.04). Six patients developed ex-novo hepatocellular carcinoma with a cumulative risk of 15% at three years.

Grade 4 liver enzyme elevation after initiating a new ART was observed in 12 of 85 subjects treated with HAART. Based on this, and on the fact that low CD4 counts predicted liver decompensation, the authors advocate the use of ART in HIV-HCV-coinfected with compensated cirrhosis.

The Effects of HAART in Patients with Chronic Hepatitis Coinfection

Dr. Massimo Puoti presented data from an Italian study assessing the factors associated with liver-related death in a cohort of HIV-infected patients followed up for a median of 6.2 years starting in 1997-1998 [4]. Among 812 patients (status was missing in 2%), 129 deaths occurred. The most frequent causes of these deaths were AIDS-related conditions (37.2%), followed by liver-related causes (35.6%) (Figure 1).

Figure 1. Causes of death in HIV-infected patients in an Italian cohort (BRHILCO).

Supporting the conclusions of another published study that evaluated patients in the HAART era [5], Dr. Puoti’s group also found that life-threatening hepatotoxicity was an independent risk factor for liver-related death (HR:5.8, 95% CI 2.6-13.4; p<0.0001).

Other factors identified to be associated with liver-related death in HIV-positive individuals were HCV and HBV coinfections, and alcohol abuse. Figure 2 shows the impact of the presence of 1, 2, or 3 of these independent risk factors. On the other hand, use of HAART per se appeared to be independently protective, with a decreased risk in liver-related deaths (HR: 0.31, 95% CI 0.15-0.61; p=0.0001).

Figure 2. Cumulative hazard of liver related death according to exposure to risk factors for liver injury: HCV infection, HBV infection, alcohol abuse and life threatening hepatotoxicity.

Another Italian study (ICoNA cohort) evaluated the impact of HAART, as well as of other factors, on cirrhosis decompensation [6].

Thirty six cases of decompensated cirrhosis occurred in 5,138 patients evaluated, with a crude incidence of 1.85 per 1,000 person-years. Intravenous drug use (IVDU) as HIV acquisition route was identified as factor associated with liver decompensation (RR: 17.3, 95% CI 3.5-86.5; p=0.0005).

Antiretroviral therapy (ART) status (naive versus current ART), type of ART (HAART versus dual therapy) or different classes of antiretrovirals used (protease inhibitors versus non-nucleoside analogues) were not found to be predictor factors of liver decompensation. However, HIV suppression was not evaluated as a variable that might impact on the occurrence of decompensated cirrhosis.

It is unclear whether alcohol use, or lack of adherence to ART (among other factors often present among IVDU) might be the true factors explaining the association between this HIV acquisition route and liver decompensation.

Dr. Jürgen Rockstroh (pros) and Dr. Marina Núñez (cons) reviewed the positive and negative effects of HAART use in patients with chronic hepatitis (Table 1).

Table 1. HAART in patients coinfected with chronic hepatitis: beneficial or deleterious?

PROS

CONS

- HIV accelerates fibrosis progression in the natural course of hepatitis C in HIV coinfection

- HAART may slow down fibrosis progression and lead to a reduction in liver disease related morbidity and mortality

- Therefore, coinfected patients should be treated according to the existing ART guidelines

- PI-based regimens appear particularly beneficial in the coinfected patient

- Alcohol use should be strongly discouraged

• ncreased risk of fulminant hepatic failure with HAART in hepatitis & HIV coinfected patients.

• Uncertain consequences of long-term mild-to-moderate elevated liver transaminases.

– Increased fibrosis with NVP-containing HAART?

– Unexplained advanced liver disease in patients with long exposure to ddI?• Liver steatosis promoted by antiretrovirals might aggravate liver damage in patients with chronic viral hepatitis.

Dr. Giuseppe Lapadula and colleagues assesses the role of HCV genotypes in relation to HAART hepatotoxicity [7]. In a multicenter cohort of 492 HIV-HCV-coinfected subjects, severe liver toxicity (grades 3 and 4) occurred more often in those with HCV genotype 3 (HR: 1.96, 95% CI 1.31-2.93; p=0.001) (Figure 3), which reflects similar findings from other reported studies [8,9].

In contrast, HCV-4 genotype seemed to confer “protection” against HAART-related severe hepatotoxicity. Of note, transaminase levels at baseline were also significantly higher in HCV-3-infected patients compared to those with other HCV genotypes.

The reasons underlying the different behaviors of HCV genotypes in relation to HAART hepatotoxicity are unclear.

Figure 3. Severe transaminase elevation in HIV-HCV-coinfected patients according to HCV genotype.

Dr. Soriano’s team in Madrid, Spain evaluated the impact of HCV replication and antiretroviral treatment on mitochondrial DNA (mtDNA) [10].

HCV/HIV-coinfected patients (N= 29: 21 on HAART and 8 without HAART) treated for HCV were examined. At baseline, there was a moderate inverse correlation between HCV RNA and mtDNA levels in peripheral blood mononuclear cells (PBMC) (r=-0.48; p=0.04).

Multivariate analysis with adjustment by HCV genotype and HAART use revealed a trend among patients with HCV RNA levels > 106 IU/mL to have lower mtDNA levels than those with HCV RNA levels < 106 IU/mL (p=0.06).

Interestingly, HCV treatment resulted in an increase in mtDNA levels in PBMC only in patients not receiving HAART. Subjects with concomitant HAART even experienced a significant decrease in mtDNA levels after being treated for HCV, with no differences by type of HAART used (Figure 4).

Figure 4. mtDNA levels in PBMC in patients undergoing anti-HCV therapy according to use of HAART.

These results suggest that HCV replication itself may damage the mitochondria, and that the benefit obtained by HCV clearance is blunted by the mitochondrial toxicity linked to the use of HAART, and that there is a deleterious synergistic effect on mtDNA when RBV is taken along with nucleoside analogues.

Further studies are warranted to better understand the complex interactions between HIV and HCV infections and antiretroviral drugs in the depletion of mitochondrial DNA.

Treatment of Hepatitis C: More about Ribavirin and Treatment Duration

Acute HCV infection

A prospective, multicenter German study currently under way is assessing the efficacy of pegylated interferon (pegIFN) in the treatment of acute HCV infection [11].

Monotherapy was initially started immediately after diagnosis and continued for 24 weeks. Ribavirin (RBV) is being given with pegIFN to patients with HCV genotypes 1 and 4, and a 12 week observational period is required for symptomatic infections prior to treatment decision (no treatment if HCV-RNA levels declined >2log10). In the analysis of data, these two factors were examined: time from diagnosis to treatment and mono- versus combined therapy.

Dr. Vogel presented 24 week results on 41 patients at this meeting. Thirty of these patients received treatment: pegIFN, 12 (8 with HCV-1/4 and 4 with HCV-2/3); pegIFN+RBV, 18 (16 with HCV 1/4 and 2 with HCV-2/3).

In an intent-to-treat analysis, the overall end-of-treatment response was 61%, with no significant differences between genotypes (54% for HCV-1/4 and 67% for HCV-2/3), and no statistically significant differences according to treatment modality.

Treatment response was associated with negativity of HCV-RNA at weeks 4-8 (p=0.02) and 12 (p=0.002). There was also a trend among patients with higher ALT levels to experience a better response was seen. However, unlike other studies, the presence of symptoms was not found to be a factor predicting response.

Other factors analyzed, including time from diagnosis to treatment, were not associated with treatment outcome. Members of the audience brought up the problem of an overestimation of the treatment response in those patients who initiated immediate treatment.

It will be interesting to see if RBV has an impact on sustained virological response (SVR).

Early virological response

Spanish investigators analyzed the role of RBV doses in the achievement of early virological response in HCV-HIV-coinfected patients receiving anti-HCV therapy [12].

Dr. Belen Ramos presented data from the PRESCO study (1,000-1,200 mg/day RBV) compared to another HIV-HCV study (800 mg/day RBV) and to a HCV-monoinfection study (1,000-1,200 mg/day RBV) [13,14].

Among patients with genotype 1, a ³2-log10 decline at week 12 was observed in 80% of subjects in the HCV-monoinfection trial, and in 78% in the PRESCO study, compared to 63% in APRICOT.

Among patients with genotype 4, a ³2-log10 decline at week 12 was observed in 93% in the HCV-monoinfection trial, and in 72% in the PRESCO study, compared to 56% in APRICOT. Differences were less marked in patients with genotypes 2 and 3.

Although the characteristics of the studies and the populations differ, these data suggest that the highest doses of RBV tolerated are needed for maximizing response to combined pegIFN and RBV therapy in HIV-coinfected individuals.

RBV plasma levels

French investigators presented a study focused on therapeutic drug monitoring of RBV early in the course of combined anti-HCV treatment [15]. RBV plasma and erythrocyte concentrations (Cmin) were measured at weeks 4 and 12 of treatment and correlated with tolerance and virological response to treatment. Twelve patients were included (5 HCV-1, 5 HCV-3,and 2 HCV-4).

As in previous reports, a wide inter-individual variation in RBV concentrations was observed [16]. There was a strong correlation between RBV concentrations in plasma and in erythrocytes (p=0.001). An association between plasma and erythrocyte levels of RBV and decreases in hemoglobin levels was found, supporting previous reports of studies evaluating RBV plasma levels (p<0.001) [16]. However, early virological response at week 12 (drop of >2 log10 ) was associated only with RBV erythrocyte concentrations. According to published data, RBV plasma levels predict early response only in HCV genotypes 1/4 [16]. The small sample of the present study prevented from stratifying by HCV genotype.

The good correlation between plasma and erythrocyte concentrations of RBV obtained in this study is relevant information. Further research is needed to establish the role of RBV therapeutic drug monitoring in the care of the HCV-HIV-coinfected patient under treatment.

Treatment duration for HCV genotypes 2/3

There are data suggesting that the optimal duration of combined treatment of chronic hepatitis C should be longer in HIV-HCV-coinfected than in HCV-monoinfected patients (i.e., 48 weeks). Italian researchers have performed a randomized study assessing the efficacy of 24 and 48 weeks for the treatment of genotypes 2 and 3 [17].

Eighty four HCV treatment-naïve patients received pegIFN-a-2a and RBV (800-1,200 mg/day) for 24 weeks, and 74 were negative at that time, when the randomization (to stop treatment or to continue for 24 more weeks) was performed. Of 36 patients in the 48 weeks arm, 16 prematurely stopped treatment. In an on-treatment analysis, relapses occurred significantly less often in the 48 weeks arm (2/20, 10%) than in the 24 weeks arm (15/38, 39%) (p=0.04).

These results advocate for an extension of therapy to 48 weeks in HIV-HCV-coinfected patients with genotypes 2/3. However, the high proportion of drop-outs (30%) in this study prevents drawing a definitive conclusion on this issue.01/27/06

End of Part I. Part 2 will be posted on Tuesday 01-27-06

References (Includes references for Parts I and Part 2

M Schiavini and others. Fibrosis progression in HIV/HCV coinfected patients with paired liver biopsies: evaluation of risk factors. Second International Workshop on HIV and Hepatitis Co-infection. Amsterdam, January 12th-14th, 2006 [Abstract 9] P Bonnard and others. Assessment of fibrosis progression in patients dually infected by HIV and HCV. Second International Workshop on HIV and Hepatitis Co-infection. Amsterdam, January 12th-14th, 2006. [Abstract 49]. M Puoti and others. Natural history of cirrhosis in HIV-HCV coinfected patients. Second International Workshop on HIV and Hepatitis Co-infection. Amsterdam, January 12th-14th, 2006 [Abstract 51]. K Prestini and others. Liver related mortality in the HAART era in a cohort of HIV infected patients: incidence, risk factors and impact of highly active antiretroviral therapy. Second International Workshop on HIV and Hepatitis Co-infection. Amsterdam, January 12th-14th, 2006 [Abstract 3]. J Kramer and others. Hepatitis C coinfection increases the risk of fulminant hepatic failure in patients with HIV in the HAART era. J Hepatol 2005; 42:309-14 P Cicconi and others. Risk factors for decompensated cirrhosis and associated morbidity and mortality in I.Co.N.A. Second International Workshop on HIV and Hepatitis Co-infection. Amsterdam, January 12th-14th, 2006 [Abstract 48]. C. Torti and others. The influence of genotype 3 hepatitis C coinfection on liver enzyme elevation in human immunodeficiency virus type 1 positive patients after commencement of a new highly active antiretroviral regimen: results from the Epoka-master cohort. Second International Workshop on HIV and Hepatitis Co-infection. Amsterdam, January 12th-14th, 2006 [Abstract 15]. M Núñez and others. Role of hepatitis C virus genotype in the development of severe transaminase elevation after the introduction of antiretroviral therapy. J Acquir Immune Defic Syndr 2002; 30:65-68. I Maida and others. Liver enzyme elevation in hepatitis C virus (HCV)-HIV-coinfected patients prior to and after initiating HAART: role of HCV genotypes. AIDS Research and Human Retroviruses 2006; 22. C de Mendoza and others. Relationship between hepatitis C virus (HCV) replication and mitochondrial DNA depletion in HCV/HIV-coinfected patients. Second International Workshop on HIV and Hepatitis Co-infection. Amsterdam, January 12th-14th, 2006. [Abstract 43] M Vogel and others. Pegylated interferon in the treatment of acute HCV infection in HIV-positive individuals _ Interim analysis of a large German multicenter study. Second International Workshop on HIV and Hepatitis Co-infection. Amsterdam, January 12th-14th, 2006 [Abstract 25]. B Ramos and others. High ribavirin doses and early virological response in HCV/HIV-coinfected patients. Second International Workshop on HIV and Hepatitis Co-infection. Amsterdam, January 12th-14th, 2006 [Abstract 36]. M Fried and others. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002; 347:975-82. F Torriani and others. Peginterferon Alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV-infected patients. N Engl J Med 2004; 351:438-50. B Cassard and others. Early predictive TDM of ribavirin in HIV-HCv-coinfected patients. Second International Workshop on HIV and Hepatitis Co-infection. Amsterdam, January 12th-14th, 2006 [Abstract 26]. A Rendón and others. Early monitoring of ribavirin plasma concentrations may predict anemia and early virologic response in HIV/hepatitis C virus-coinfected patients. J Acquir Immune Defic Syndr 2005:39:401-05 B Zanini and others. The optimal duration of treatment for HIV infected patients with chronic hepatitis C (CHC) and genotype 2 or 3 is 48 weeks: results of a randomized controlled trial. Second International Workshop on HIV and Hepatitis Co-infection. Amsterdam, January 12th-14th, 2006 [Abstract 27]. Afdhal and others. Epoetin alfa maintains ribavirin dose in HCV-infected patients: a prospective, double-blind, randomized controlled study. Gastroenterology 2004; 126:1302-11 P Yachimski and others. Editorial comment: erythropoietin for treatment-related anemia in persons with hepatitis C--questions remain. AIDS Read 2004; 14:568-69. Dieterich D. Treatment of hepatitis C and anemia in HIV-infected patients. J Infect Dis 2002; 185 (suppl 2): 128-37. M Shiffman and others. Treatment of chronic hepatitis C viris (HCV) genotype 1 with peginterferon alfa-2b (PEGIFN), high weight based dose ribavirin (RVN) and epoetin alfa (EPO) enhances sustained virologic response (SVR). Abstract 55. 56th annual meeting of the American Association for the Study of Liver Diseases (56th AASLD). November 11-15, 2005. San Francisco, CA. A Orani and others. Elegibility for pegIFN plus RBV treatment in HIV-HCV-coinfected patients: role of counseling intervention. Second International Workshop on HIV and Hepatitis Co-infection. Amsterdam, January 12th-14th, 2006 [Abstract 37]. K and others. High prevalence of fatigue and depression in HIV/Hepatitis C coinfected patients treated with interferon and RBV. Second International Workshop on HIV and Hepatitis Co-infection. Amsterdam, January 12th-14th, 2006 [Abstract 38].

N Ndembi and others. HIV-1 and hepatitis B and C multiple infection are common in Cameroon. Second International Workshop on HIV and Hepatitis Co-infection. Amsterdam, January 12th-14th, 2006. [Abstract 7] C Valente and others. HCV genotype 4 in Portuguese patients. Second International Workshop on HIV and Hepatitis Co-infection. Amsterdam, January 12th-14th, 2006. [Abstract 4] C Valente and others. HCV genotype 4 in monoinfected and coinfected (HIV) patients. Second International Workshop on HIV and Hepatitis Co-infection. Amsterdam, January 12th-14th, 2006. [Abstract 12].

27. Schildgen and others. Primary resistance of a novel hepatitis B virus variant to adefovir. Second International Workshop on HIV and Hepatitis Co-infection. Amsterdam, January 12th-14th, 2006 [Abstract 41]

S Mauss and others. First line combination therapy of chronic hepatitis B with tenofovir plus lamivudine versus sequential therapy with tenofovir monotherapy after lamivudine failure. Second International Workshop on HIV and Hepatitis Co-infection. Amsterdam, January 12th-14th, 2006 [Abstract 42]. I Maida and others. Liver fibrosis in HIV-infected patients with chronic hepatitis B receiving prolonged anti-HBV active antiretroviral therapy. Second International Workshop on HIV and Hepatitis Co-infection. Amsterdam, January 12th-14th, 2006 [Abstract 2]

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