Advances in the Management of Viral Hepatitis C Infection in HIV-Coinfected Pati

[Guest guest]

http://www.medscape.com/viewarticle/554156?src=mp

14th Conference on Retroviruses and Opportunistic Infections

Selection from: CROI 2007 - Key Challenges in HIV: Metabolic Complications

and Adverse Effects; HIV/Hepatitis Coinfection; and Clinical Pharmacology

Advances in the Management of Viral Hepatitis B and Hepatitis C Infection in

HIV-Coinfected Patients - CROI 2007 CME

V. Soriano, MD, PhD

Disclosures

Introduction

This year's Conference on Retroviruses and Opportunistic Infections (CROI)

convened in Los Angeles, California, and drew nearly 4000 attendees, 45% of

whom were from abroad. The opening ceremony coincided with the Academy

Awards ceremony in Hollywood. In light of the number of abstracts on viral

hepatitis infection in people with HIV coinfection -- 75 out of 1100

abstracts in total -- there is no doubt that HIV-viral hepatitis coinfection

should have merited at least 1 at CROI.

Hepatitis C Virus

Factors Contributing to the Spread of HCV Among Those With HIV Infection

Hepatitis C virus (HCV) has not been thought to be efficiently transmitted

through sexual contact. However, recent reports of outbreaks of acute

hepatitis C among men who have sex with men (MSM) have changed this view.

British researchers examined 7223 MSM who attended a single clinic in

Brighton, United Kingdom, since 2000.[7] The study investigators reported

that highly risky sexual practices along with multiple sex partners

explained the increase in episodes of acute HCV infection in this

population. Other sexually transmitted diseases, such as syphilis and

gonorrhea, were also common among those with acute HCV infection. This

phenomenon was not restricted to HIV-infected MSM, although compared with

HIV-uninfected MSM, those with HIV infection seemed to be particularly prone

to spreading and acquiring HCV infection, most likely due to high levels of

HCV viremia and impaired immune responses, respectively. In view of these

findings, MSM who engage in risky sexual behaviors should be screened

periodically for HCV as well as for HIV antibodies, and preventive measures

and counseling must be reinforced in this population.

In a totally different scenario, a study performed in St. sburg,

Russia, examined the rates of HCV and HIV infections among intravenous drug

users.[8] HCV genotype 3 and HIV subtype A were the predominant variants

rapidly spreading in this community. Most new infections seemed to derive

from people who were themselves recently infected, most likely as a

consequence of high levels of HCV and/or HIV viremia and the fact that most

individuals who transmitted viruses were unaware of their HCV and/or HIV

infection status.

The Use of Liver Biopsy in HCV/HIV-Coinfected Patients

The use of liver biopsy in HCV/HIV-coinfected patients was elegantly

discussed by , MD, s Hopkins, Baltimore, land.[9] He

began his presentation by acknowledging that the extent of hepatic fibrosis

is the best prognostic factor of liver disease progression in patients with

chronic HCV infection. Therefore, it is worth considering the degree of

hepatic fibrosis before initiating HCV therapy. Liver biopsy has for many

years been the only tool for assessing hepatic fibrosis. This method has the

advantage of providing additional information on other relevant histologic

findings, such as necroinflammation and steatosis. However, several

limitations of the procedure, including: (1) its invasive nature with

occasional serious and even life-threatening complications; (2) the

possibility of sampling error due to a relatively small biopsy size, the

fragmentation of examined tissue, and/or the inherent heterogeneity of

hepatic fibrosis[10,11]; (3) low acceptance by most patients; and (4) its

relatively elevated cost; have prompted the development of noninvasive tools

for staging hepatic fibrosis.

Noninvasive procedures for assessing liver fibrosis are currently split into

2 major categories: imaging techniques, such as elastometry (FibroScan),[12]

and serum biochemical marker tests (eg, Fibrotest, APRI, SHASTA, FIB-4,

Forns, serum hyaluronic acid).[12] These tools are generally accurate in

discriminating between a lack of fibrosis and advanced fibrosis, but they

are less precise at distinguishing between intermediate fibrosis stages. The

predictive value of these tests is particularly good for advanced hepatic

fibrosis and cirrhosis. Liver fibrosis staging using elastometry seems to be

particularly reliable. Elastometric measurements can be made in 10 minutes,

can be repeated periodically, are inexpensive, and have a positive

predictive value greater than 90% for advanced fibrosis.[12]

Dr. concluded that when the diagnosis of hepatic disease is clear by

other means, such as the detection of serum HCV RNA indicative of chronic

HCV infection, the need for a liver biopsy to stage hepatic fibrosis and

guide the treatment decision is no longer justified in most instances.[9]

The relatively high response to pegylated interferon plus ribavirin, the

faster progression of HCV-related liver disease in the HIV-coinfected

population, and the opportunity for assessing the HCV response at earlier

time points to identify who will and will not respond to therapy all favor

initiating anti-HCV therapy without the need for a liver biopsy in most

cases.

Chung, MD, from the Massachusetts General Hospital in Boston,

provided an excellent overview of the current treatment of chronic hepatitis

C in HIV-infected individuals.[13] After reviewing the data from the pivotal

prospective, randomized clinical trials of HCV treatment in the setting of

HIV coinfection -- APRICOT, RIBAVIC, and ACTG 5071[14-16] -- he addressed

which strategies improved the response rates in the coinfected populations.

Dr. Chung mentioned that the results from the PRESCO trial[17] suggest that

the use of high ribavirin doses (1000-1200 mg/day) -- much higher than doses

used in prior studies (800 mg/day) -- may provide a significant benefit

(Table 1). Moreover, the appropriate selection of candidates for anti-HCV

therapy (eg, excluding individuals concomitantly using zidovudine and

didanosine or patients with low CD4+ cell counts) may allow for improved

sustained virologic response rates in the coinfected population, as was

discussed in another presentation.[18] According to these criteria, the rate

of premature treatment discontinuations due to side effects in PRESCO was

only 8.2% -- a rate quite similar to that seen in HCV-monoinfected

individuals.[17]

Table 1. Comparison of Large Trials Using Pegylated Interferon and Ribavirin

in HCV/HIV-Coinfected Patients

Baseline, Treatment, and Outcomes APRICOT[14]

(n = 289) RIBAVIC[15]

(n = 205) ACTG 5071[16]

(n = 66) PRESCO[17]

(n = 389)

Type of pegIFN Alfa-2a Alfa-2b Alfa-2a Alfa-2a

RBV dose 800 mg/d 800 mg/d Escalating 600¨ 1000 mg/d 1000-1200 mg/d

(if weight is

< or > 75 kg)

IDU (% of patients) 62% 81% 80% 89.5%

Liver cirrhosis (% of patients) 15% 18% 11% 8.7%

HCV genotypes 1 or 4 (% of patients) 67% 69% 77% 61%

Median CD4+ cell count (cells/mcL) 520 525 492 546

On ART 84% 82% 85% 74%

Premature treatment discontinuation (% of patients) 25% 36% 12% 27.8%

ETR (ITT) (% of patients) 49% 36% 41% 67.3%

SVR (ITT) (% of patients) 40% 27% 27% 49.6%

ART = antiretroviral therapy; ETR = end-of-treatment response; HCV =

hepatitis C virus; IDU = injection drug use; ITT = intention to treat;

pegIFN = pegylated interferon; RBV = ribavirin; SVR = sustained virologic

response.

A number of studies presented at this meeting provided new and interesting

information that may help to optimize the treatment of chronic hepatitis C

in HIV-infected individuals. A substudy of the RIBAVIC trial acknowledged

that the concomitant use of abacavir and ribavirin could be deleterious,

given that response rates were lower in this subset of patients compared

with the rest of the study participants.[19] The basis for this negative

interaction may have to do with the fact that both nucleoside analogues are

guanosine derivatives and may compete in the same phosphorylation pathways

within cells.

Another intriguing observation came from a substudy of the PRESCO trial,

which showed that virologic relapse following undetectable HCV RNA at the

end of pegylated interferon plus ribavirin therapy did not diminish with

extended treatment.[20] The rates of virologic failure were comparable

whether individuals with HCV genotypes 2 or 3 received 24 or 48 weeks of

treatment or whether individuals with HCV genotype 1 or 4 received 8 or 72

weeks of treatment (Figure 4).

Figure 4. Relapse rates in the PRESCO trial according to HCV genotype and

length of therapy. Subjects with HCV genotypes 2 or 3 received 24 (short

arm) or 48 weeks (extended arm) of treatment; subjects with HCV genotypes 1

or 4 received 48 (short arm) or 72 weeks (extended arm) of treatment. G1 =

genotype 1; G2/3 = genotypes 2 or 3; G4 = genotype 4. Adapted from Nunez et

al.[20]

Another interesting report examined the potential of transcription-mediated

amplification (TMA), a very sensitive tool that has a lower limit of HCV RNA

detection of 5 IU/mL, for detecting serum HCV RNA at the end of a course of

anti-HCV therapy and predicting subsequent relapse.[21] The positive and

negative predictive values of relapse were above 80% using this assay.

Finally, one study compared the proportion of patients with advanced liver

fibrosis (Metavir scores of F3 or F4) in HCV/HIV-coinfected patients with

repeated normal liver enzyme levels vs a matched control group of patients

with elevated liver enzymes.[22] The study investigators used elastometry

(FibroScan) to measure liver fibrosis. The main results are summarized in

Table 2. Nearly 15% of coinfected patients with persistently normal alanine

aminotransferase (PNALT) levels showed advanced liver fibrosis (Metavir

estimates F3 to F4), and this finding was more frequent in women and in

individuals infected with HCV genotype 4. Thus, coinfected patients with

normal liver enzyme levels should not be excluded from anti-HCV therapy, as

liver disease progression may occur in a significant proportion of these

patients in a silent manner.

Table 2. Liver Fibrosis Staging in HCV/HIV-Coinfected Patients With Elevated

and Persistently Normal ALT (PNALT)

ALT Liver Fibrosis

Mild

Metavir F0 to F2;

FibroScan < 9.5 kPa Moderate

Metavir F3;

FibroScan 9.5-13.9 kPa Severe

Metavir F4;

FibroScan > 14 kPa

Elevated ALT

(n = 133) 65 (49%) 22 (16%) 46 (35%)

PNALT

(n = 87) 76 (86%) 9 (10%) 3 (4%)

Adapted from -Carbonero et al.[22]

ALT=alanine amino transferase; kPa = kilopascals; PNALT = persistently

normal ALT.

Supported by an independent educational grant from Bristol-Myers Squibb

_________________________________________________________________

Mortgage refinance is Hot. *Terms. Get a 5.375%* fix rate. Check savings

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tgage_text_links_88_h2bbb & disc=y & vers=925 & s=4056 & p=5117

[Guest guest]

http://www.medscape.com/viewarticle/554156?src=mp

14th Conference on Retroviruses and Opportunistic Infections

Selection from: CROI 2007 - Key Challenges in HIV: Metabolic Complications

and Adverse Effects; HIV/Hepatitis Coinfection; and Clinical Pharmacology

Advances in the Management of Viral Hepatitis B and Hepatitis C Infection in

HIV-Coinfected Patients - CROI 2007 CME

V. Soriano, MD, PhD

Disclosures

Introduction

This year's Conference on Retroviruses and Opportunistic Infections (CROI)

convened in Los Angeles, California, and drew nearly 4000 attendees, 45% of

whom were from abroad. The opening ceremony coincided with the Academy

Awards ceremony in Hollywood. In light of the number of abstracts on viral

hepatitis infection in people with HIV coinfection -- 75 out of 1100

abstracts in total -- there is no doubt that HIV-viral hepatitis coinfection

should have merited at least 1 at CROI.

Hepatitis C Virus

Factors Contributing to the Spread of HCV Among Those With HIV Infection

Hepatitis C virus (HCV) has not been thought to be efficiently transmitted

through sexual contact. However, recent reports of outbreaks of acute

hepatitis C among men who have sex with men (MSM) have changed this view.

British researchers examined 7223 MSM who attended a single clinic in

Brighton, United Kingdom, since 2000.[7] The study investigators reported

that highly risky sexual practices along with multiple sex partners

explained the increase in episodes of acute HCV infection in this

population. Other sexually transmitted diseases, such as syphilis and

gonorrhea, were also common among those with acute HCV infection. This

phenomenon was not restricted to HIV-infected MSM, although compared with

HIV-uninfected MSM, those with HIV infection seemed to be particularly prone

to spreading and acquiring HCV infection, most likely due to high levels of

HCV viremia and impaired immune responses, respectively. In view of these

findings, MSM who engage in risky sexual behaviors should be screened

periodically for HCV as well as for HIV antibodies, and preventive measures

and counseling must be reinforced in this population.

In a totally different scenario, a study performed in St. sburg,

Russia, examined the rates of HCV and HIV infections among intravenous drug

users.[8] HCV genotype 3 and HIV subtype A were the predominant variants

rapidly spreading in this community. Most new infections seemed to derive

from people who were themselves recently infected, most likely as a

consequence of high levels of HCV and/or HIV viremia and the fact that most

individuals who transmitted viruses were unaware of their HCV and/or HIV

infection status.

The Use of Liver Biopsy in HCV/HIV-Coinfected Patients

The use of liver biopsy in HCV/HIV-coinfected patients was elegantly

discussed by , MD, s Hopkins, Baltimore, land.[9] He

began his presentation by acknowledging that the extent of hepatic fibrosis

is the best prognostic factor of liver disease progression in patients with

chronic HCV infection. Therefore, it is worth considering the degree of

hepatic fibrosis before initiating HCV therapy. Liver biopsy has for many

years been the only tool for assessing hepatic fibrosis. This method has the

advantage of providing additional information on other relevant histologic

findings, such as necroinflammation and steatosis. However, several

limitations of the procedure, including: (1) its invasive nature with

occasional serious and even life-threatening complications; (2) the

possibility of sampling error due to a relatively small biopsy size, the

fragmentation of examined tissue, and/or the inherent heterogeneity of

hepatic fibrosis[10,11]; (3) low acceptance by most patients; and (4) its

relatively elevated cost; have prompted the development of noninvasive tools

for staging hepatic fibrosis.

Noninvasive procedures for assessing liver fibrosis are currently split into

2 major categories: imaging techniques, such as elastometry (FibroScan),[12]

and serum biochemical marker tests (eg, Fibrotest, APRI, SHASTA, FIB-4,

Forns, serum hyaluronic acid).[12] These tools are generally accurate in

discriminating between a lack of fibrosis and advanced fibrosis, but they

are less precise at distinguishing between intermediate fibrosis stages. The

predictive value of these tests is particularly good for advanced hepatic

fibrosis and cirrhosis. Liver fibrosis staging using elastometry seems to be

particularly reliable. Elastometric measurements can be made in 10 minutes,

can be repeated periodically, are inexpensive, and have a positive

predictive value greater than 90% for advanced fibrosis.[12]

Dr. concluded that when the diagnosis of hepatic disease is clear by

other means, such as the detection of serum HCV RNA indicative of chronic

HCV infection, the need for a liver biopsy to stage hepatic fibrosis and

guide the treatment decision is no longer justified in most instances.[9]

The relatively high response to pegylated interferon plus ribavirin, the

faster progression of HCV-related liver disease in the HIV-coinfected

population, and the opportunity for assessing the HCV response at earlier

time points to identify who will and will not respond to therapy all favor

initiating anti-HCV therapy without the need for a liver biopsy in most

cases.

Chung, MD, from the Massachusetts General Hospital in Boston,

provided an excellent overview of the current treatment of chronic hepatitis

C in HIV-infected individuals.[13] After reviewing the data from the pivotal

prospective, randomized clinical trials of HCV treatment in the setting of

HIV coinfection -- APRICOT, RIBAVIC, and ACTG 5071[14-16] -- he addressed

which strategies improved the response rates in the coinfected populations.

Dr. Chung mentioned that the results from the PRESCO trial[17] suggest that

the use of high ribavirin doses (1000-1200 mg/day) -- much higher than doses

used in prior studies (800 mg/day) -- may provide a significant benefit

(Table 1). Moreover, the appropriate selection of candidates for anti-HCV

therapy (eg, excluding individuals concomitantly using zidovudine and

didanosine or patients with low CD4+ cell counts) may allow for improved

sustained virologic response rates in the coinfected population, as was

discussed in another presentation.[18] According to these criteria, the rate

of premature treatment discontinuations due to side effects in PRESCO was

only 8.2% -- a rate quite similar to that seen in HCV-monoinfected

individuals.[17]

Table 1. Comparison of Large Trials Using Pegylated Interferon and Ribavirin

in HCV/HIV-Coinfected Patients

Baseline, Treatment, and Outcomes APRICOT[14]

(n = 289) RIBAVIC[15]

(n = 205) ACTG 5071[16]

(n = 66) PRESCO[17]

(n = 389)

Type of pegIFN Alfa-2a Alfa-2b Alfa-2a Alfa-2a

RBV dose 800 mg/d 800 mg/d Escalating 600¨ 1000 mg/d 1000-1200 mg/d

(if weight is

< or > 75 kg)

IDU (% of patients) 62% 81% 80% 89.5%

Liver cirrhosis (% of patients) 15% 18% 11% 8.7%

HCV genotypes 1 or 4 (% of patients) 67% 69% 77% 61%

Median CD4+ cell count (cells/mcL) 520 525 492 546

On ART 84% 82% 85% 74%

Premature treatment discontinuation (% of patients) 25% 36% 12% 27.8%

ETR (ITT) (% of patients) 49% 36% 41% 67.3%

SVR (ITT) (% of patients) 40% 27% 27% 49.6%

ART = antiretroviral therapy; ETR = end-of-treatment response; HCV =

hepatitis C virus; IDU = injection drug use; ITT = intention to treat;

pegIFN = pegylated interferon; RBV = ribavirin; SVR = sustained virologic

response.

A number of studies presented at this meeting provided new and interesting

information that may help to optimize the treatment of chronic hepatitis C

in HIV-infected individuals. A substudy of the RIBAVIC trial acknowledged

that the concomitant use of abacavir and ribavirin could be deleterious,

given that response rates were lower in this subset of patients compared

with the rest of the study participants.[19] The basis for this negative

interaction may have to do with the fact that both nucleoside analogues are

guanosine derivatives and may compete in the same phosphorylation pathways

within cells.

Another intriguing observation came from a substudy of the PRESCO trial,

which showed that virologic relapse following undetectable HCV RNA at the

end of pegylated interferon plus ribavirin therapy did not diminish with

extended treatment.[20] The rates of virologic failure were comparable

whether individuals with HCV genotypes 2 or 3 received 24 or 48 weeks of

treatment or whether individuals with HCV genotype 1 or 4 received 8 or 72

weeks of treatment (Figure 4).

Figure 4. Relapse rates in the PRESCO trial according to HCV genotype and

length of therapy. Subjects with HCV genotypes 2 or 3 received 24 (short

arm) or 48 weeks (extended arm) of treatment; subjects with HCV genotypes 1

or 4 received 48 (short arm) or 72 weeks (extended arm) of treatment. G1 =

genotype 1; G2/3 = genotypes 2 or 3; G4 = genotype 4. Adapted from Nunez et

al.[20]

Another interesting report examined the potential of transcription-mediated

amplification (TMA), a very sensitive tool that has a lower limit of HCV RNA

detection of 5 IU/mL, for detecting serum HCV RNA at the end of a course of

anti-HCV therapy and predicting subsequent relapse.[21] The positive and

negative predictive values of relapse were above 80% using this assay.

Finally, one study compared the proportion of patients with advanced liver

fibrosis (Metavir scores of F3 or F4) in HCV/HIV-coinfected patients with

repeated normal liver enzyme levels vs a matched control group of patients

with elevated liver enzymes.[22] The study investigators used elastometry

(FibroScan) to measure liver fibrosis. The main results are summarized in

Table 2. Nearly 15% of coinfected patients with persistently normal alanine

aminotransferase (PNALT) levels showed advanced liver fibrosis (Metavir

estimates F3 to F4), and this finding was more frequent in women and in

individuals infected with HCV genotype 4. Thus, coinfected patients with

normal liver enzyme levels should not be excluded from anti-HCV therapy, as

liver disease progression may occur in a significant proportion of these

patients in a silent manner.

Table 2. Liver Fibrosis Staging in HCV/HIV-Coinfected Patients With Elevated

and Persistently Normal ALT (PNALT)

ALT Liver Fibrosis

Mild

Metavir F0 to F2;

FibroScan < 9.5 kPa Moderate

Metavir F3;

FibroScan 9.5-13.9 kPa Severe

Metavir F4;

FibroScan > 14 kPa

Elevated ALT

(n = 133) 65 (49%) 22 (16%) 46 (35%)

PNALT

(n = 87) 76 (86%) 9 (10%) 3 (4%)

Adapted from -Carbonero et al.[22]

ALT=alanine amino transferase; kPa = kilopascals; PNALT = persistently

normal ALT.

Supported by an independent educational grant from Bristol-Myers Squibb

_________________________________________________________________

Mortgage refinance is Hot. *Terms. Get a 5.375%* fix rate. Check savings

https://www2.nextag.com/goto.jsp?product=100000035 & url=%2fst.jsp & tm=y & search=mor\

tgage_text_links_88_h2bbb & disc=y & vers=925 & s=4056 & p=5117