Impact and Management of hepatitis B and hepatitis C virus co-infection in HIV patients

With the introduction of highly active antiretroviral therapy (HAART) in 1996, and associated improvement in survival, HBV and HCV have emerged as significant viral pathogens associated with morbidity and mortality in coinfected individuals.[1,2,3] Because of the common mode of transmission, the expected, prevalence of these infections is higher in HIV positive individuals, than in the general population. Other infectious agent alter the course of each of these infections. Coinfection poses a special diagnostic and management problem for the clinician.

Magnitude of the problem

Worldwide, HBV infection accounts for an estimated 370 million chronic infections, HCV infection for an estimated 130 million, and HIV infection for an estimated 40 million. Among the estimated 40 million persons infected with HIV worldwide, an estimated 2–4 million are chronically infected with HBV and an estimated 4–5 million are chronically infected with HCV.[4,5]

Epidemiology of HBV and HIV coinfection

In regions with low endemicity for HBV, most HBV infections occur in adolescents and young adults, and sexual and percutaneous transmission is the most common mode of transmission.[6] Within these areas HBV infection occur among the high-risk adult population that includes intravenous (IV) drug users, persons with multiple heterosexual partners, men who have sex with men (MSM), and health care workers. Since most HIV and HBV transmission occurs sexually or percutaneously in low HBV endemic areas, chronic hepatitis B prevalence is higher in HIV-infected populations. HIV positive patients infected through male homosexual contact tend to show the highest rates for chronic HBV infection, approaching 10%; prevalence is slightly lower among intravenous drug users (IDU) and individuals infected through heterosexual contact.[1,7,8,9,10,11,12] By contrast, in regions of high HBV endemicity, most HBV infections occur within the first 5 years of life through vertical or horizontal transmission. Perinatal transmission predominates in East and Southeast Asia,[13] whereas in Africa most infections are believed to occur in children, through the horizontal mode of transmission (child to child).[14] HBV infection acquired at young age is more likely to progress to chronic infection, resulting in high prevalence of chronic HBV infection among the general population of adolescents and adults who are at risk to acquire HIV through sexual transmission. The maximum number of HIV and HBV coinfected individuals live in sub-Saharan Africa and the Far East, but the prevalence of HBV amongst HIV positive individuals is not different from that of the general population.[13,15,16,17,18,19] HIV infection is acquired in adults, but adult HBV transmission even among individuals with high risk sexual behavior is minimal. Even in high-risk populations such as sex workers, adult transmission contributes to less than 10% of HBV infections in areas of high endemicity,[15,20,21,22] possibly because most adults have already been exposed to HBV and have developed either chronic hepatitis B or immunity. Three-quarters of the HIV infected population in much of Asia and Africa have been exposed to hepatitis B, and is at risk of acquiring reactivated HBV even after the development of antihepatitis B surface antibodies.[23] Therefore in low HBV endemic countries, HIV and HBV coinfection usually occur in adults predominantly either through the sexual route or through IV drug abuse, whereas in hyper endemic HBV areas, where childhood HBV infection leads to chronic HBV disease, HIV superinfection is usually an event subsequent to sexual exposure in adult age.

Epidemiology of HCV and HIV coinfection

The estimated worldwide prevalence of HCV infection is 2.2%.[5] The highest prevalence of HCV infection (>3%) has been reported from Northern Africa (particularly Egypt), moderate prevalence (2-2.9%) from Eastern Europe and most of Asia, low prevalence (1-1.9%) from Western Europe, North and South America, and Australia, and very low prevalence (<1%) from Northern Europe.[24] In high prevalence and many moderate prevalence countries, unsafe therapeutic injections, and blood transfusion from unscreened donors appear to be the predominant mode of HCV transmission and may account for up to 40% of all HCV infections worldwide.[24,25] In most low prevalence areas, illegal IV drug use is the predominant mode of transmission for HCV infection.[24] HCV is not efficiently transmitted by perinatal or sexual exposures, which are important modes of transmission for HBV and HIV. Becauseof the similar mode of transmission, HCV infected individuals are also at high risk for HIV, prevalence of confection varies depending upon the route of HCV infection. Thus, in subpopulations of HIV-positive persons with history of injection drug use, 72–95% have been seen as coinfected with HCV.[26,27,28,29] In HIV-positive persons who acquired their infection from sexual exposure, the prevalence of HCV coinfection was 8–35-fold lower, ranging from 1 to 12% among MSM[26,27,28,29]and 9–27% among heterosexuals.[27,28] Therefore HIV infected individuals acquire HCV through IV drug abuse and HCV infected individuals get HIV through sexual route or unsafe transfusion.

HIV impact on HBV infection

Amongst 400 million patients infected with HBV worldwide, 2- 4 million are coinfected with HIV. HBV is not a cytopathic virus, and the severity of liver disease is related to the intensity of host immunologic response to the virus. Whereas both humoral and cellular immune responses are needed for effective virus clearance, the cellular immune response appears to be the arm principally involved in disease pathogenesis. The outcome of HBV infection depends on the immune response mounted by the host.[30] In persistently infected patients who fail to downregulate or clear HBV, the continued expression of inflammatory cytokines and recruitment of activated lymphomononuclear cells to the liver ultimately results in fibrosis, cirrhosis and hepatocellular carcinoma.[30] HIV infection is known to extensively damage the immune system through virus-related and indirect pathogenic mechanisms.[31] HIV infected individuals show a quantitative depletion of CD4+ T cells, dysregulation of the cytokine network, decrease of the functional capability of CD8+ CTL and, at late stages, a significant reduction in their number, and an aberrant activation of cells of the immune system. HIV coinfection is associated with higher chances of chronicity after acute hepatitis, higher HBV DNA load, lower rate of spontaneous loss of HBeAg and/or HBsAg and seroconversion to anti-HBe and anti-HBs with a high rate of seroreversion after CD4+ cell depletion in those with spontaneous or interferon induced anti-HBe seroconversion.[32,33,34,35,36,37,38,39,40,41,42,43] Cohort studies from northern Europe and USA of homosexual men showed a significantly less severe necro-inflammatory activity in HIV coinfected patients.[35,38,44,45] In contrast, some studies performed in Californian and French cohorts amongst injection drug users showed increased necro-inflammatory activity in HIV seropositive subject.[46,47] Further the process of progression towards cirrhosis is unclear. Earlier studies from northern Europe and USA did not reveal an unfavorable impact of HIV coinfection on hepatitis B evolution[34,35,37,38,48] while three French studies[39,43,47] identified a more rapid progression towards cirrhosis in HIV co-infected individuals. Risk of decompensation is higher in coinfected individuals with cirrhosis.[39,43,49] Although there is a more severe presentation of hepatocellular carcinoma and a lower survival in HBsAg carriers with HIV infection,[50] there are no data supporting an accelerated progression towards hepatic cancer in HIV/HBV co-infected people. Immune reconstitution during HAART may lead to flare of HBV infection, IP-10 (an activated T-cell and natural killer cell chemokine) and soluble CD30 (a T-cell activation marker) may play an important role in thepathogenesis of such flare.[51]

HIV impact on HCV infection

While HBV infection prior to 5 years of age results in chronicity, HBV infection in adults rarely does the same. Unlike HBV, 50- 80% of individuals acutely infected with HCV in adult develop chronicity.[52 ,53] HIV infection exacerbates the natural history of HCV infection.[29,54 ,55 ,56 ,57 ,58 ,59] HIV-infected patients are less likely to clear hepatitis C viremia following acute infection (particularly in the setting of low CD4 count), have higher HCV RNA load, and experience more rapid progression to HCVrelated liver disease than those without HIV infection.[60 ,61] Spontaneous clearance occurs in only 5% to 15% of HIVpositive individuals compared to 20% of HIV-negative patients.[29] The host immune system, involving CD4 and CD8 T cells, endogenous interferon and other antiviral cytokines clears the HCV. By impairing the immune response to HCVinfected cells, HIV permits increased HCV replication.[62 Coinfection appears to accelerate the development and progression of HCV induced fibrosis. In a metaanalysis, HCV and HIV coinfected patients developed cirrhosis more frequently, and much faster than in patients with HCV monoinfection, [63] the overall RR of decompensated liver disease or histological cirrhosis was 2.92 (95% CI, 1.70–5.01). Eyster and colleagues reported that HCV RNA levels were higher in people with hemophilia who became HIV infected than in those with HCV who remained HIV negative, and liver failure occurred exclusively in coinfected patients.[54] In hemophiliac patients, infected with HCV, Goedert et al estimated the 16-year cumulative incidence of end-stage liver disease (ESLD) among men with and without HIV as 14.0% and 2.6%, respectively.[64] Among those men with coinfection, the ESLD risk increased 2.1-fold with CD4 cell counts below 200 cells/ mm3. Although opportunistic infection remains the dominant cause of mortality in untreated patients with HIV infection, hepatitis C and advanced liver disease play a greater role in determining mortality among those receiving HAART. A recent analysis of more than 12,000 patients receiving HAART in the Veterans’ Administration health care system, USA, demonstrated a 30% to 80% increased risk of death among HCV and HIV coinfected patients compared with HIV monoinfected patients.[65] HCV was associated with a decreased immunologic (CD4 cell recovery) but similar virologic response to HAART and the negative effect of HCV on survival was independent of the CD4 cell response and HIV viral load suppression

HBV impact on HIV infection

HBV has been shown to have minimal impact on HIV pathogenesis. In vitro, the HBV X protein has been implicated in increasing HIV-1 replication and transcription.66 But studies on the influence of hepatitis on progression of HIV have delivered conflicting results. There is no major difference in HIV-related mortality between hepatitis B coinfected individuals and patients infected with HIV alone, particularly if antiretroviral treatment is given, however, there is increased risk of liver disease related morbidity and mortality as well as more hepatoxicity after antiretroviral treatment regimens.[19,67 ,68 ,69 ,70] In a Multicenter AIDS Cohort Study on 4498 homosexual men, HBV positivity was not related to initial low or rapid subsequent decline in T-helper lymphocyte counts, or an increasedincidence of AIDS during 2.5 years of follow-up.[67] In a Thai cohort (HIV NAT cohort),[19] HIV-RNA suppression, CD4 cell count recovery, and HIV disease progression were examined. Prevalence of HBV, HCV and HBV/HCV-coinfection was 8.7, 7.2 and 0.4% of patients, respectively. The median HIV-RNA reduction after HAART was similar in HBV+ve and HBV-ve groups. The mean increase in CD4 cell count was significantly lower among HIV–HBV subgroups at week 4; however, by week 48 rise in CD4 count was similar. EuroSIDA[68] and HIV-NAT[19] cohort, and a recent Danish study[70] found no difference in response to HAART, in terms of CD-4 counts and viral suppression, while Sheng et al[69] reported higher chances of virological failure in coinfected patients due to treatment interruption because of hepatotoxicity, while CD4 response and incidence of opportunistic infections was not affected by HBV status. Studies have reported excess liver-related mortality in HIV-HBV coinfected patients as compared to HIV monoinfected patients, which can be due to the worsened natural course of HBV infection or due to HAART related hepatotoxicity, or immune reconstitution against HBV infection. Higher liver related mortality in coinfected patients has been reported even in the pre-HAART era suggesting altered natural history of HBV in coinfected patients.[68,69] Most studies report higher liver related mortality after introduction of HAART when compared to the pre-HAART era suggesting more hepatotoxicity and possibly the role of immune reconstitution.[69,71 ,72 ,7]

HCV impact on HIV infection

The effect of HCV infection on HIV disease progression is less clear.[9,49,74 ,75 ,76 ,77 ,78] In the Swiss Cohort, the presence of HCV was independently associated with an increased risk of progression to AIDS and death.[75] The increased risk was mainly attributed to lower recovery of the CD4-cell count 1 year after the initiation of HAART in HIV/ HCV-coinfected than in HCV-negative individuals. Similarly in HIV-NAT (Netherlands Australia Thailand) cohort, there was delayed CD4 count recovery in coinfected patients after starting ART as compared to that in HIV monoinfection, and the cytopathic effect of HCV on CD4 cells may be responsible for this.[12,74] Similar resultswere also reported from some other smaller cohorts.[74,76] Subsequent studies from other cohorts, however, did not find any difference in survival when multivariate analysis was applied.[12,49,77,78] The EuroSIDA cohort found no difference between HCV-positive and HCV-negative HIV-infected patients responding to newly initiated HAART with regard to virological control or the time for CD4- cell countrecovery.[12] Interestingly, analysis of recent 4-year follow-up data from the Swiss HIV Cohort Study did not find any significant difference with regard to the recovery of CD4 cell count between HCV-positive and HCV-negative patients.[79] Coinfected patients are more prone to the hepatotoxic effects of ART, which is related to the stage of hepatic fibrosis, but the overall effect may not be significant as only 10% of coinfected patients develop hepatotoxicity.[80 ,81] Effective treatment of HCV infection prior to starting ART may reduce the risk of epatotoxicity.[82] Liver disease itself may also have important effects on CD4 cell count with advancing portal hypertension and hypersplenism.

Diagnosis of HCV in HIV infected patients

All HIV-infected patients should be tested for evidence ofchronic HCV infection.82,83 Initial testing for HCV should be performed using sensitive immunoassays (3rd generation EIA) licensed for detection of anti-HCV. False negative anti- HCV EIA results may occur in HIV-infected persons with advanced immunosupression (CD4 < 100/mm3) and true negative EIA are common in the setting of acute HCV infection (<12 weeks following acquisition) prior to seroconversion.[84] In one study, 5.5% of coinfected patients with negative secondgeneration ELISA results had circulating serum HCV RNA.[85] In patients in the United States Adult AIDS clinical trial group, the second-generation ELISA correctly identified HCV infection in 97.2% of those with HCV RNA. In a prospective study of more than 500 HIV-infected and uninfected intravenous drug users, the sensitivity of the third-generation ELISA was more than 99%.[86] If the clinical suspicion for HCV is high and the anti-HCV antibody test is negative, testing for HCV RNA should be performed, particularly in patients with low CD4 counts. Ultrasonography and CT or MRI scans are used to evaluate hepatic parenchymal changes, but are abnormal only in advanced disease. Ultrasonography may be used as the initial test for the evaluation of cirrhosis, or for preliminary detection of hepatic mass lesions where there is suspicion of hepatocellular carcinoma. Due to the high cost, the use of CT with contrast or MRI scanning should generally be limited to evaluation of hepatic mass lesions among patients with cirrhosis. Liver biopsy remains the preferred test for evaluation of HCV-related disease (fibrosis stage) and is useful to assess prognosis and guide HCV treatment decisions.

Diagnosis of HBV in HIV infected patients

The diagnostic approach for HBV infection in coinfected patients is similar to that used in HBV monoinfection. HBV infection is diagnosed when HBsAg and HBV DNA is detected in the blood. All persons with detectable HBsAg should be assessed for the evidence of active HBV replication by HBV DNA assays independent of the HBeAg status. During the course of an infection, the loss of HBeAg and development of anti-HBe are usually associated with a decrease in serum HBV viral load, and are associated with a favorable prognosis. However, the loss of HBeAg may also reflect the emergence of HBeAg-negative HBV with precore and core promoter mutations that alter the normal HBeAg synthesis. All patients with detectable HbsAg should undergo screening for hepatocellular carcinoma with serum AFP and liver ultrasound at regular intervals (6–12 months).[87] Antibodies to the HBV core may be detected in HIV patients without HBsAg, HBeAg, or antibodies to these antigens and it is reasonable to attribute this to past infection, rather than consider the test result as false positive. The incidence of occult infection (HBV DNA positivity) in these patients varies from 0-10%.[88 ,89 ,90] Based on current evidence, routine surveillance for HBV DNA in this group of patients is not indicated.

The Indian scenario

India has the second highest number of people living with HIV[91] . Moreover, among the HIV infected patients, 2-4 million are estimated to have chronic HBV coinfection while 4-5 million are coinfected with HCV.[92] HBV and HCV co-infection among HIV infected patients have been reported from different regions.[93 ,94 ,95 ,96 ,97 ,98] In a South Indian cohort, comprised of patients attending an AIDS clinic, Saravanan et al reportedhigh prevalence of HBV (9%) and HCV (2.2%), which is fairly higher than the HBV and HCV prevalence reported in the Indian general population.[93,99 ,100] and it was seen that coinfection was more common in men. Similarly Gupta et al showed that a high prevalence of HBV (5.3%) and HCV (2.43%) in HIV positive patients,[94] While reported HCV prevalence is low in these study groups, which can be attributed to heterosexual mode of HIV transmission. Saha et al101 reported an HCV coinfection rate of 92% in intravenous drug-users from Northeast India, whilst in the report by Kumarasamy et al[95] HCV coinfection was 4.8%, and in those patients 50% were injection drug users (IVDU).

Management

1. Hepatitis B/HIV coinfection

The treatment of chronic hepatitis B in HIV co-infection is complex. Many issues are still controversial and need to be resolved.

Goals of treatment

The important goal is to achieve long-term sustained viral (HBV) suppression below the level of detection by the most sensitive assay available, and thereby prevent the progression of liver disease, cirrhosis and hepatocellular carcinoma. Another goal of treatment is to minimise hepatotoxicity associated with ART.

Selection of treatment candidates

Selection of treatment candidates is largely empiric owing to insufficient data and lack of evidence-based guidelines. Several variables determine the selection of treatment candidates. These are

1. Aminotransferase (ALT) levels: Hepatic necro-inflammation is less severe in HIV-HCV coinfection compared to HCV monoinfected patients.[39] Therefore, ALT may be only mildly elevated. A normal ALT level should be viewed with caution as significant fibrosis is still possible.

2. HBV viral load: Level of viremia is a critical determinant of disease progression in HBV monoinfection.[102] A threshold of HBV DNA=5 log in HBeAg+ve or =4 log in HBeAg–ve cases has been used as treatment indication in HBV monoinfection.[103] Although the DNA threshold for treatment in HBV/HIV coinfection is not known, it should be less than that in HBV monoinfected patients because such patients are at greater risk of rapid progression of liver disease.

3. Liver Histology: The role of liver biopsy in coinfected patients is not well defined. However, it greatly helps to assess the degree of hepatic fibrosis and identify patients at risk of decompensation with immune reconstitution using ART. Significant fibrosis (Metavir score =A2 or F2) is an important indication for HBV treatment. Therefore, liver biopsy should be considered prior to deciding HBV therapy even if the ALT levels are normal.

In conclusion, anti HBV therapy should be considered in coinfected patients with elevated HBV DNA (arbitrarily =4 log copies/ml) or significant hepatic fibrosis (Metavir score =A2 or F2). HBV infection should probably be treated irrespective of viral load and degree of fibrosis, if co infected patients arereceiving ART, since immune reconstitution under antiretroviral therapy poses risk for immune mediated hepatitis.[104]

Approved drugs for HBV treatment in co infected patients

The Food and Drug Administration (FDA) has approved 5 drugs for the treatment of chronic hepatitis B which include interferon, lamivudine, adefovir dipivoxil, entecavir, and more recently, peginterferon _-2a.

Interferon _ and pegylated IFN-_

IFN- _ and pegylated IFN-_ can be used in coinfected HBV/HIV patients who require treatment of HBV but not HIV.[103,105] An advantage of IFN-_ is the lack of potential for drug resistance. However, several small, retrospective and non randomized studies suggest a lower response rate in patients coinfected with HIV.[106 ,107] Several factors have been implicated for poor response to IFN e.g. reduced T cell function, down-regulation of IFN-_ receptor, presence of anti IFN antibodies.[108 ,109] The optimum dose and duration of pegylated interferon has not yet been defined. Further, pegylated IFN-_, itself, may cause a fall in CD4 cell and platelets counts, thereby limiting its application in HIV coinfected patients.

Nucleoside analogues

Lamivudine has antiviral activity against both HBV and HIV. However, efficient anti-HIV activity is seen at higher doses (300mg/day). Several studies have evaluated the effectiveness of lamivudine in the HBV/HIV-coinfected population.[110 ,111 ,112] Hoff and colleagues evaluating 66 HBV/HIV-coinfected patients who were treated with lamivudine along with other antiretrovirals found that 86.4% of patients did respond to therapy.111 The occurrence of lamivudine resistance is more common in HBV/HIV-coinfected patients than in those patients with HBV alone[103,105] and resistance rates of 50% after 2 years and 90% after 4 years have been reported in coinfected patients.[113]

Emtricitabine is another nucleoside analogue that has activity against both HIV and HBV.[105,114] Lamivudine and emtricitabine share similar mechanisms of action, side effects and resistance patterns. If a patient is resistant to lamivudine, emtricitabine should not be given. Rather, agents with different resistance patterns e.g. adefovir and tenofovir should be considered.[105]

Entecavir is a purine-derived nucleoside analogue with good anti-HBV activity. Although, it was initially believed to have no anti-HIV activity, it has been seen recently that the use of entecavir is associated with partial suppression of HIV.[115] Therefore its use as monotherapy can lead to the development of HIV resistance. ETV has shown an almost 7log10 copies/ml reduction in HBV DNA in HBV monoinfected patients. In a randomised controlled 24-week trial of ETV vs. placebo in HIV/LAM resistant coinfected patients, the mean reduction in HBV DNA from the baseline was -3.66 log₁₀copies/ml in the entecavir arm.[116]

Nucleotide analogues

Adefovir dipivoxil is a nucleotide reverse transcriptase inhibitor that has activity against both HBV and HIV. It is effective in thetreatment of wild-type HBV and lamivudine-resistant HBV.[117 ,118] At the approved 10 mg dose of adefovir, there was no reported significant antiviral effect against HIV. In 35 HIV/HBV-LAM resistant coinfected patients, ADV 10 mg once daily produced a median reduction in serum HBV DNA of 4.7log₁₀copies/ml, 5.5log₁₀ copies/ml and 6.0 log₁₀ copies/ml at weeks 48, 96 and 192, respectively.[119 ,120] An advantage of adefovir therapy is the limited resistance observed against it.120

Tenofovir is another nucleotide analogue that has activity against both HIV and HBV, but is only FDA approved for the treatment of HIV.[103] One study evaluating tenofovir in 10 HBV/ HIV co infected patients found a reduction of 4.9log₁₀ copies/ ml of HBV DNA at 24 weeks of therapy.[121] In a randomisedcontrolled trial to assess the non-inferiority of tenofovir compared with adefovir, the mean log₁₀ decline from the baseline to week 48 was -4.44 and -3.21 log10 copies/ml respectively.[122] It is interesting to note that no HBV resistance to TDF has been reported yet in HIV/HBV coinfected patients. Tenofovir causes a greater decline in HBV DNA than adefovir. Tenofovir can sometimes cause renal impairement and hypophosphatemia.[123]

Treatment strategies

General consideration before commencing treatment
It is important to know whether the chosen antiviral drugs have effect only on HBV (adefovir, telbivudine and pegylated interferon) or on both HBV and HIV (lamivudine, mtricitabine, entecavir and tenofovir). This is because drugs with dual antiviral effect can cause early HIV resistance when used in coinfected patients requiring only HBV treatment. Also, the chances of HBV drug resistance are more in coinfected patients, therefore, a drug with a favourable resistance profile or combination therapy should ideally be used to avoid or delay the development of resistance. Furthermore, hepatotoxicity of all antiviral agents increases in coinfected patients. Therefore, careful monitoring of liver function is required during therapy. HBV genotype has important influence on treatment response, genotype A infection has better prognosis than non genotype A infection.[124]

Selection of drug(s)

Coinfected patients requiring only Hepatitis B therapy

This is the case of patients with CD4 count >350 cells/mm³ and HIV viral load of <100,000 copies/ml. Under these circumstances drugs with dual antiviral activity should not be used in order to avoid early HIV resistance. Here it is reasonable to propose the following regimen in HBeAg positive patients: pegylated interferon alpha 2a, adefoviror or newer drugs i.e. telbivudine, clevudine. Entecavir should ideally be avoided as per recent findings of its dual antiviral activity.[115] In HBeAg negative patients there are currently not enough data to propose pegylated interferon.

Coinfected patients requiring both HBV and HIV therapy

When both HIV and HBV meet the criteria for treatment, agents with dual activity (tenofovir, lamivudine embricitabine) should be included in the anti-retroviral regimen. A combination of nucleoside and nucleotide analogue is the preferred regimen in order to prevent long-term resistance. If monotherapy is chosen nucleotides should be used because of a more favourable resistance profile.

Coinfected patients requiring HIV but no HBV therapy These patients should be monitored for ALT and serum HBV DNA every 3 to 4 months. In patients with high serum HBV DNA (>4–5 log10 copies/ml) and little or no liver disease, drugs with dual antiviral activity should be used in order to prevent hepatitis of immune reconstitution.

Patients with cirrhosis

The rationale of using antiviral drugs in these patients is to prevent or delay liver decompensation and hepatocellular carcinoma. The HBV DNA threshold taken as the cut-off for initiation of HBV treatment is lower than in patients with cirrhosis (~2-3 log10 copies/mL). In order to minimise hepatotoxicity, the dose of ART metabolised by the liver should be adjusted accordingly. Didanosine and stavudine are better avoided in view of the increased risk of mitochondrial toxicity.

Monitoring treatment

Treatment should be monitored by periodically testing for ALT and HBV DNA levels and assessing the clinical response. The aim is sustained HBV DNA suppression below the level of detection by the most sensitive available assays. In view of the very high risk, screening for HCC should be done every six months by carrying out ultrasonography of the liver and measuring theserum alpha-feto protein level The duration of HBV treatment in coinfected patients is not known and as per some guidelines should be lifelong.[125,126]

2. Management of Hepatitis C/HIV co-infection

Which infection should be treated first?

This decision should be made on a case-to-case basis. If the individual has advanced liver disease, then HCV should be treated first. In patients with CD4 counts <200 cells/ìl and/or plasma HIV RNA more than 100,000 copies/ml and/or presence of opportunistic infections, it may be better to consider anti HIV treatment before beginning HCV therapy.127 Simultaneous treatment for both conditions should not be initiated because if side effects develop it will be difficult to determine which drug was responsible. But if HIV infection is well controlled with HAART, then egylated IFN with ribavirin may be initiated over and above HIV medications.

Selection of HCV treatment candidates

Every HIV-HCV coinfected person with compensated chronic HCV infection should be considered for HCV antiviral therapy.[128] Patients with decompensated cirrhosis should not be treated and should be evaluated for liver transplantation. The only contraindication to HCV therapy specific to HIV coinfected persons is an active opportunistic infection.

Favourable genotype and advanced stage of fibrosis influence the selection of treatment candidates. Therefore, treatment should be strongly considered in patients with high likelihood of achieving SVR as follows:[129]

· Genotype 2 or 3 regardless of HCV viral load or histology

· Genotype 1, viral load <800 000 IU/ml regardless of histology

· Genotype 1 or 4, viral load >800 000 IU/ml and moderate or severe fibrosis.

Role of liver biopsy

Liver biopsy, though not mandatory, helps to assess the grade and stage of disease and rule out other diagnoses. The role of non-invasive markers of liver fibrosis is under research. Treatment should not be deferred in coinfected patients with minimal liver disease on biopsy as disease may progress rapidly over a short period of time.[130]

Recommended HCV Therapy in coinfected patients

Quantitative serum HCV-RNA measurement and HCV genotyping should be performed before considering any therapeutic intervention against HCV. Published guidelines for anti-HCV therapy[83,131,132] indicate that the standard of care in coinfected patients is pegylated interferon alfa-2a (Pegasys) or -2b (Peg-Intron) plus ribavirin. Several studies were published in recent years showing the effectiveness of peginterferon and ribavirin for chronic hepatitis C in HIV infected persons.[133 ,134 ,135 ,136] The biggest study has been APRICOT which demonstrated an overall sustained viral response of 40%.[133]

The lower response rates to HCV therapy in HIV-HCV coinfected patients is due to several reasons, including themore advanced fibrosis stages seen, immunodeficiency, higher rate of insulin resistance and liver steatosis, and side effects of treatment leading to frequent discontinuation and use of lower doses of ribavirin in most trials.

Doses of PEG IFN and ribavirin

In coinfected patients, pegylated interferon is administered at either 180 micrograms (pegylated interferon _-2a) or 1.5 microgram/kg (pegylated interferon _-2b) weekly. The optimum dose and duration of treatment for ribavirin have not yet been established. Most large studies have used lower doses (e.g. 800 mg daily) of ribavirin rather than the weightbased higher doses used in the HCV-monoinfection trials due to concerns about possible side effects, especially anaemia (following drop in red blood cell count). Recently-published results of the WIN-R trial137 suggest that weight-based dosage of ribavirin is superior to the standard fixed dose in combination with pegylated interferon for treatment of genotype 1 hepatitis C. In the recent PRESCO (Pegasys Plus Ribavirin for HCV Treatment in HIV/HCV Coinfection) trial, the impact of higher ribavirin doses and longer duration of therapy with pegylated interferon and ribavirin was evaluated in a multi-centre, prospective study across 25 HIV clinics in Spain. nvestigators found that the use of higher doses of ribavirin (800 mg/day for those who weighed less than 65 kg; 1000 mg/day for those who weighed between 65-85 kg; and 1200 mg/day for those who weighed over 85 kg) as against extended duration of lower dose therapy seemed to account for the higher SVR.[138]

Duration of treatment

Preliminary studies suggest that all coinfected patients should be treated for 48 weeks irrespective of genotype. However, for HCV genotypes 2 or 3 in HIV coinfected infected patients, treatment for 24 weeks is associated with an overall SVR of 53% which may be adequate.139 The pegylated interferon plus ribavirin regimen for 24 weeks was as effective as 48 week treatment in HCV genotype 1 patients who achieved an undetectable HCV RNA level after 4 weeks of treatment.[140 ,141] Conversely, the relapse rate was greater than 50% among HCV genotype 1 patients who achieved an undetectable HCV RNA after 24 weeks of therapy, indicating longer treatment may be required.[142]

Predictors of response

1. Genotype non-1 is associated with better response. Overall SVR rates for genotype non-1 varied from 44% to 29%. But for Genotype 1, SVR rates were 14%, 17% and 29% in ACTG 5071, RIBAVIC and APRICOT trials respectively.

2. Low pretreatment HCV RNA levels were also associated with higher SVR rates. In the APRICOT study SVR rates were more than 60% in persons with genotype 1 and HCV RNA level =800,000 IU/ml. In contrast, SVR was only 18% for those with genotype 1 and HCV RNA level =800,000 IU/ ml.

3. Absence of prior history of injection use, age <40 years, ALT > 3 folds, absence of crrhosis and no use of protease inhibitors for HIV treatment were found to be predictors of SVR in some studies.[134,135]

4. Baseline CD4 count was probably not associated with the SVR. However, patients with CD4 <200/mm3 were excluded in all studies except the APRICOT study where this population represented only 6% of the randomized subjects.

Monitoring treatment

Early virological response (EVR) assessed after 12 weeks of anti-HCV therapy is an important indicator of treatment failure. The failure to achieve an undetectable HCV RNA level or reduction in HCV RNA of at least 2 log₁₀ by 12 weeks has a negative predictive value of 98-100% for treatment failure.[143] Therefore, HCV treatment should be discontinued if an adequate EVR is not achieved at 12 weeks. Patients should be made aware of the importance of strict dherence to dose and schedule during the first 3 months of combination therapy, to thereby increase the probability of chieving an EVR.

In those with HCV RNA reduction >2log10 after 12 weeks of therapy; treatment should be continued and repeat HCV RNA tested at 24 weeks. Treatment should be continued for 48 weeks if HCV RNA is negative at this stage. If HCV RNA is still positive at 24 weeks, therapy may be discontinued unless liver fibrosis is significant where maitainance treatment may be considered in a hope to retard liver disease progression.

Drugs interactions

Ribavirin should be used with caution in patients taking zidovudine in view of worsening of anaemia due to bone marrow suppression by the latter drug. Furthermore, in vitro, ribavirin inhibits the anti HIV effect of zidovudine and stavudine through inhibition of their intracellular phosphorylation.[144] Ribavirin increases the mitochondrial toxicity of didanosine and therefore didanosine should be replaced with other antiretroviral drugs before administering HCV therapy.[145 ,146] Severe weight loss mimicking rapid progression of lipoatrophy has been sporadically reported in patients receiving stavudine along with RBV.[147]

Patients with end stage liver disease

The management of coinfected persons with advanced liver cirrhosis is complex. Antiretroviral therapy may significantly improve short- and mid-term outcome in HIV positive patients with hepatic decompensation and, therefore, HAART should not be discouraged. Anti HCV therapy should not be given at least at standared doses and these patients should be evaluated for the liver transplantation. Multiple small studies in the era of HAART suggest that patient and graft survival rates are similar to those in HIV negativerecipients.[148 ,149 ,150] The major issue in this HIV-HCV coinfected subpopulation is reinfection of the liver graft - an outcome that may lead to rapid development of cirrhosis in the new liver. The use of interferon plus ribavirin combination therapy for the first 3 months after transplantation may improve the outcome.

Management of patients not responding to standared therapy. Unfortunately, no data or guidelines are available to advise management of such patients. Those who previously received suboptimal therapy (e.g., conventional interferon, interferon monotherapy, low ribavirin doses) may be retreated with the best current standard therapy. Maintenance treatment with low dose 0.5 mcg/kg weekly peginterferon can be given in coinfected patients as it may provide histologic benefit despite failure to achieve sustained virological response.(135) Multiple strategies are under evaluation including high dose peginterferon, combination with serine protease inhibitor, IL- 2 therapy to boost anti HCV immune responses and alternative formulation of interferon – albuferon-alfa which is a fusion of interferon and albumin that prolongs the half life of interferon.

References

1. Puoti M, Airoldi M, Bruno R, Zanini B, Spinetti A, Pezzoli C, et al. Hepatitis B virus co-infection in HIV-infected subjects. AIDS Rev. 2002;4:27–35.

2. Thio C. Hepatitis B in the HIV-infected patient: Epidemiology, natural history and treatment. Semin Liver Dis. 2003;23:125–136.

3. Rockstroh J, Mocroft A, Soriano V, Tural C, Losso M, Horban A, et al. Inf luence of hepatitis C on HIV disease progression and response to ant iret roviral therapy. J Infect Dis. 2005;192:992–1002.

4. WHO. Hepatitis B fact sheet. http://www.who.int/mediacentre/ factsheets/fs204/en/ Accessed June 2008.

5. Perz JF, Farrington LA, Pecoraro C, Hutin YJF, Armstrong GL. Estimated global prevalence of hepatitis C virus infection [abstract]. In: Abstracts of the Infectious Diseases Society of America 42^nd annual meeting, Boston, MA, September 2004.

6. Edmunds W, Medley G, Nokes D, O’Callaghan C, Whittle H, Hall A. Epidemiological patterns of hepatitis B virus in highly endemic areas. Epidemiol Infect. 1996;117:313–25.

7. Brook MG, Gilson R, Wilkins E, on behalf of the British HIV Association. BHIVA Guidelines: coinfection with HIV and chronic hepatitis B. HIV Med. 2003;4 Suppl 1:42–51.

8. Kellerman S, Hanson D, McNaghten A, Fleming P. Prevalence of chronic hepatitis B and incidence of acute hepatitis B infection in HIV-infected subjects. J Infect Dis. 2003;188:571–7.

9. Lincoln D, Petoumenos K, Dore GJ. HIV/HBV and HIV/HCV coinfection, and outcomes following highly active antiretroviral therapy. HIV Med. 2003;4:241–9.

10. Saillour F, Dabis F, Dupon M, Lacoste D, Trimoulet P, Rispal P, et al. Prevalence and determinants of antibodies to HCV and markers of HBV infection in patients with HIV infection in Aquitaine. BMJ. 1996;313:461–4.

11. Lavanchy D. Hepatitis B virus epidemiology, disease burden, treatment, and current and emerging prevention and control measures: a review. J Viral Hepatol. 2004;11:97–107.

12. Rockstroh J, Konopnicki D, Soriano V, Kirk O, Antunes F, Knysz B, et al. Hepatitis B hepatitis C in the EuroSIDA Cohort: prevalence and effect on mortality, AIDS progression and response to HAART. In: 11th Conference on Retroviruses and Opportunistic Infections. San Francisco, February 2004 [Abstract 799].

13. Merican I, Guan R, Amarapuka D, Alexander MJ, Chutaputti A, Chien RN, et al. Chronic hepatitis B virus infection in Asian countries. J Gastroenterol Hepatol. 2000;15:1356–61.

14. Vardas E, Mathai M, Blaauw D, McAnerney J, Coppin A, Sim J. Preimmunization epidemiology of hepatitis B virus infection inSouth African children. J Med Virol. 1999;58:111–5.

15. Menendez C, Sanchez-Tapias JM, Kahigwa E, Mshinda H, Costa J, Vidal J, et al. Prevalence and mother-to-infant transmission of hepatitis viruses B, C, and E in southern Tanzania. J Med Virol. 1999;58:215–20.

16. Rouet F, Chaix ML, Inwoley A, Msellati P, Viho I, Combe P, et al. HBV and HCV prevalence and viraemia in HIV-positive and HIV-negative pregnant women in Abijan, Cote d’Ivoire: the ANRS 1236 Study. J Med Virol. 2004;74:34–40.

17. Sutcliffe S, Taha TE, Kumwenda NI, Taylor E, Liomba GN. HIV-1 prevalence and herpes simplex virus 2, hepatitis C virus, and hepatitis B virus infections among male workers at a sugar estate in Malawi. J Acquir Immune Defic Syndr. 2002;31:90–7.

18. Matee MI, Magesa PM, Lyamuya EF. Seroprevalence of human immunodeficiency virus, hepatitis B and C viruses and syphilis infections among blood donors at the Muhimbili National Hospital in Dar es Salaam, Tanzania. BMC Public Health. 2006;6:21.

19. Law WP, Duncombe CJ, Mahanontharit A, Boyd MA, Ruxrungtham K, Lange JM, et al. Impact of viral hepatitis co-infection on response to antiretroviral therapy and HIV disease progression in the HIVNAT cohort. AIDS. 2004;18:1169–77.

20. Oshitani H, Kasolo FC, Mpabalwani M, Mizuta K, Luo NP, Suzuki H,et al. Prevalence ofhepatitis B antigens in human immunode. ciency virus type 1seropositive and seronegative pregnant women in Zambia. Trans R Soc Trop Med Hyg. 1996;90:235–36.

21. Ghebrekidan H, Cox S, Wahren B, Grandien M. Prevalence of infection with HIV, hepatitis B and C viruses, in four high risk groups in Eritrea. Clin Diagn Virol. 1998;9:29–35.

22. Nakwagala FN, Kagimu MM. Hepatitis B virus and HIV infections among patients in Mulago hospital. East Afr Med J. 2002;79:68–72.

23. Biggar RJ, Goedert JJ, Hoofnagle J. Accelerated loss of antibody to hepatitis B surface antigen among immunodeficient homosexual men infected with HIV. N Engl J Med. 1987;316:630–1.

24. Wasley A, Alter M. Epidemiology of hepatitis C: geographic differences and temporal trends. Semin Liver Dis. 2000;20:1–16.

25. Hauri AM, Armstrong GL, Hutin YJ. The global burden of disease attributable to contaminated injections given in health care settings. Int J STD AIDS. 2004;15:7–16.

26. Denis F, Adjide CC, Rogez S, Delpeyroux C, Rogez JP, Weinbreck P. Seroprevalence of HBV, HCV and HDV hepatitis markers in 500 patients infected with the human immunodeficiency virus. Pathol Biol (Paris).1997;45:701–708.

27. Roca B, Suarez I, Gonzalez J, Garrido M, de la Fuente B, Teira R, et al. Hepatitis C virus and human immuno def iciency virus coinfection in Spain. J Infect. 2003;47:117–124.

28. Sherman KE, Rouster SD, Chung RT, Rajicic N. Hepatitis C virus prevalence among patients infected with human immunodeficiency virus: a cross-sectional analysis of the US Adult AIDS Clinical Trials Group. Clin Infect Dis. 2002;34:831–7.

29. Sulkowski MS, Thomas DL. Hepatitis C in the HIV-infected person. Ann Intern Med. 2003;138:197–207.

30. Rehermann B. Immune responses in hepatitis B virus infection. Semin Liver Dis. 2003;23:21–38.

31. Fauci AS, Lane HC. Human immunodeficiency virus (HIV) diseases: AIDS and related disorders. In: Braunwald E, Fauci AS, Kasper DL, Hauser SL, Longo DL, Jameson JL, editors. Harrison’s principles of internal medicine. 15th ed. New York: McGraw-Hill; 2001. p. 1852–1912.

32. Eskil A, Magnus P, Petersen G, Sohlberg C, Jensen F, Kittelsen P, et al. Hepatitis B antibodies in HIV-infected homosexual men are associated with more rapid progression to AIDS. AIDS. 1992;6: 571–4.

33. Weller IV, Brown A, Morgan B, Hawkins A, Briggs M, Waite J, et al. Spontaneous loss of HBeAg and the prevalence of HTLV-III/ LAV infection in a cohort of homosexual hepatitis B virus carriers and the implication for antiviral therapy. J Hepatol. 1986;3:S9–S16.

34. Krogsgaard K, Lindhart BO, Nielsen JO, Andersson P, Kryger P, Aldershvile J, et al. The influence of HTLV III infection on the natural history of hepatitis B virus infection in male homosexual HbsAg carriers. Hepatology 1987;7:37–41

35. Bodswor th N, Donovan B, Nightingale BN. The ef fects of concurrent human immunodeficiency virus infection on chronic hepatitis B: a study of 150 homosexual men. J Infect Dis. 1989;160:577–582.

36. Koblin BA, Taylor PE, Rubinstein P, Stevens CE. Effect of duration of hepatitis B virus infection on the association between human immunodeficiency virus type-1 and hepatitis B viral replication. Hepatology. 1992;15:590–2.

37. Goldin RD, Fish DE, Hay A, Waters JA, McGarvey MJ, Main J, et al. Histological and immunohistochemical study of hepatitis B virus in human immunodef iciency virus infect ion. J Clin Pathol. 1990;43:203–205.

38. Perillo RP, Regenstein FG, Roodman ST. Chronic hepatitis Bin asymptomatic homosexual men with antibody to the human immunodeficiency virus. Ann Intern Med. 1986;105:382–383.

39. Colin JF, Cazals-Hatem D, Loriot MA, Martinot-Peignoux M, Pham BN, Auperin A, et al. Influence of human immunodeficiency virus infection on chronic hepatitis B in homosexual men. Hepatology. 1999;29:1306–1310.

40. McDonald JA, Harris S, Waters JA, Thomas HC. Effect of human immunodeficiency virus (HIV) infection on chronic hepatitis B hepatic viral antigen display. J Hepatol. 1987;4:337–42.

41. Hadler S, Judson F, O’Malley P. Outcome of hepatitis B virus infection in homosexual men and its relation to prior HIV infection. J Infect Dis. 1991;163:454–9.

42. Thio C, Netski D, Myung J, Seaberg E, Thomas D. Changes in hepatitis B DNA levels with acute HIV infection. Clin Infect Dis. 2004;38:1024–9.

43. Di Martino V, Thevenot T, Colin J. Influence of HIV infection on the response to interferon therapy and the long-term outcome of chronic hepatitis B. Gastroenterology. 2002;123:1812–22.

44. Mills CT, Lee E, Perrillo R. Relationship between histology, aminotransferase levels and viral replication in chronic hepatitis B. Gastroenterology. 1990;99:519–24.

45. Rector W, Govindarajan S, Horsburgh C, Penley K, Cohn D, Judson F. Hepatic inflammation, hepatitis B replication, and cellular immune function in homosexual males with chronic hepatitis B andantibody to HIV. Am J Gastroenterol. 1988;83:262–6.

46. Bonacini M, Govindarajan S, Redeker AG. Human immunodeficiency virus infection does not alter serum transaminases and hepatitis B virus (HBV) DNA in homosexual patients with chronic HBV infection. Am J Gastroenterol.1991;86:570–3.

47. Housset C, Pol S, Carnot F, Dubois F, Nalpas B, Housset B, et al. Interactions between human immunodeficiency virus-1, hepatitis delta and hepatitis B virus infection in 260 chronic carriers of hepatitis B virus. Hepatology. 1992;15:578–83.

48. Gilson R, Hawkins AE, Beecham MR, Ross E, Waite J, Briggs M, et al. Interaction between HIV and hepatitis B virus in homosexual men: effects on the natural history of infect ion. AIDS. 1997;11:597–606.

49. Bonacini M, Louie S, Bzowej N, Wohl AR. Survival in patients with HIV infection and viral hepatitis B or C: a cohort study. AIDS. 2004;18:2039–45.

50. Puoti M, Bruno R, Soriano V, Donato F, Gaeta GB, Quinzan GP, et al. Hepatocellular carcinoma in HIV-infected patients: epidemiological features, clinical presentation and outcome. AIDS. 2004;18:2285–93.

51. M Crane, B Oliver, G Matthews, et al. Immunopathogenesis of Hepatic Flares after Initiation of ART in HIV/HBV-co-infected Individuals. 15th Conference on Retroviruses and Opportunistic Infections (CROI 2008). Boston, MA. February 3-6, 2008. Abstract 1033.

52. Orland JR, Wright TL, Cooper S. Acute Hepatitis C. Hepatology. 2001;33:321–7.

53. Villano SA, Vlahov D, Nelson KE, Cohn S, Thomas DL. Persistence of viremia and the importance of long-term follow-up after acute hepatitis C infection. Hepatology. 1999;29:908–14.

54. Eyster ME, Diamondstone LS, Lien JM, Ehmann WC, Quan S, Goedert JJ. Natural history of hepatitis C virus infection in multitransfused hemophiliacs: effect of coinfection with human immunodeficiency virus. The Multicenter Hemophilia Cohort Study. J Acquir Immune Defic Syndr. 1993;6:602–610.

55. Goedert JJ, Hatzakis A, Maloney EM, Eyster ME. Increased liver decompensation risk with atypical hepatitis C virus antibody levels. J Infect Dis. 2000;182:590–4.

56. Darby SC, Ewart DW, Giangrande PL, Spooner RJ, Rizza CR, Dusheiko GM, et al. Mortality from liver cancer and liver disease in haemophilic men and boys in UK given blood products contaminated with hepatitis C. Lancet. 1997;350:1425–31.

57. Pol S, Lamorthe B, Thi NT, Thiers V, Carnot F, Zylberberg H, et al. Retrospective analysis of the impact of HIV infection and alcohol use on chronic hepatitis C in a large cohort of drug users. J Hepatol. 1998;28:945–50.

58. Zylberberg H, Pol S. Reciprocal interactions between human immunodeficiency virus and hepatitis C virus infections. Clin Infect Dis. 1996;23:1117–25.

59. Soriano V, Rodriguez-Rosado R, Garcia-Samaniego J. Management of chronic hepatitis C in HIV-infected patients. AIDS. 1999;13:539–46.

60. Thomas DL, Astemborski J, Rai RM, Anania FA, Schaeffer M, Galai N, et al. The natural history of hepatitis C virus infection: host, viral, and environmental factors. JAMA. 2000;284:450–6.

61. Sherman K, O’Brien J, Gutierrez A, Harrison S, Urdea M, Neuwald P, et al. Quantitative evaluation of hepatitis C virus RNA in patients with concurrent human immunodeficiency virus infections. J Clin Microbiol. 1993;31:2679–82.

62. Fauci A, Schnit tman S, Poli G, Koenig S, Pantaleo G.Immunopathogenic mechanisms in human immunodeficiency virus HIV infection. Ann Intern Med. 1991;114:678–93.

63. Graham C, Baden L, Yu E, Mrus JM, Carnie J, Heeren T, et al. Influence of human immunodeficiency virus infection on the course of hepatitis C virus infection: a meta-analysis. Clin Infect Dis. 2001;33:562–9.

64. Goedert JJ, Eyster ME, Lederman MM, Mandalaki T, De Moerloose P, White GC, et al. End-stage liver disease in persons with hemophilia and transfusion-associated infections. Blood. 2002;100:1584–9.

65. Backus L, Phillips B, Boothroyd D, Mole LA, Burgess J, Rigsby MO, et al. Effects of hepatitis C virus coinfection on survival in veterans with hiv treated with highly active antiretroviral therapy. J Acquir Immune Defic Syndr. 2005;39:613–9.

66. Gomez-Gonzalo M, Carretero M, Rullas J, Lara-Pezzi E, Aramburu J, Berkhout B, et al. The hepatitis B virus X protein induces HIV-1 replication and transcription in synergy with T-cell activationsignals: functional roles of NF-kappaB/NF-AT and SP1-binding sites in the HIV-1 long terminal repeat promoter. J Biol Chem. 2001;276:35435–43.

67. Thio CL, Seaberg EC, Skolasky R Jr, Phair J, Visscher B, Muñoz A, et al. HIV-1, hepatitis B virus, and risk of liver-related mortality in the Multicenter Cohort Study (MACS). Lancet. 2002;360:1921–6.

68. Konopnicki D, Mocroft A, de Wit S, Antunes F, Ledergerber B, Katlama C, et al. For the EuroSIDA group. Hepatitis B in HIV: prevalence, AIDS progression, response to highly active antiretroviral therapy and increased mortality in the EuroSIDA cohort. AIDS. 2005;19:593–601.

69. Sheng WH, Chen MY, Hsieh SM, Hsiao CF, Wang JT, Hung CC, et al. Impact of chronic hepatitis B virus (HBV) infection on outcomes of patients infected with HIV in an area where HBV infection is hyperendemic. Clin Infect Dis. 2004;38:1471–7.

70. Omland LH, Weis N, Skinhoj P, Laursen AL, Christensen PB, Nielsen HI, et al. Impact of hepatitis B virus co-infection on response to highly active antiretroviral treatment and outcome in HIV-infected individuals: a nationwide cohor t study. HIV Medicine. 2008;9:300–6.

71. Puoti M, Spinetti A, Ghezzi A, Donato F, Zaltron S, Putzolu V, et al. Mortality for liver disease in patients with HIV infection: a cohort study. J Acquir Immune Defic Syndr. 2000;24:211–7.

72. Sulkowski MS, Thomas DL, Chaisson RE, Moore RD. Hepatotoxicity associated with antiretroviral therapy in adults infected with human immunodeficiency virus and the role of hepatitis C or B virus infection. JAMA. 2000;283:74–80.

73. Sulkowski MS, Thomas DL, Mehta SH, Chaisson RE, Moore RD. Hepatotoxicity associated with nevirapine or efavirenzcontaining antiretroviral therapy: role of hepat itis C and B infections. Hepatology. 2002;35:182–189.

74. De Luca A, Bugarini R, Lepri AC, Puoti M, Girardi E, Antinori A, et al. Coinfection with hepatitis viruses and outcome of initial antiretroviral regimens in previously naý¨ve HIV-infected subjects. Arch Intern Med. 2002;162:2125–32.

75. Greub G, Ledergerber B, Battegay M,Grob P, Perrin L, Furrer H,et al. Clinical progression, survival, and immune recovery during antiretroviral therapy in patients with HIV-1 and hepatitis C virus coinfection: the Swiss HIV Cohort Study. Lancet. 2000;356:1800–5.

76. Piroth L, Grappin M, Cuzin L, Mouton Y, Bouchard O, Raffi F, et al. Hepatitis C virus co-infection is a negative prognostic factor for clinical evolution in human immunodeficiency virus-positive patients. J Viral Hepat. 2000;7:302–8.

77. Sulkowski MS, Moore RD, Mehta SH, Chaisson RE, Thomas DL. Hepatit is C and progression of HIV-disease. JAMA. 2002;288:199–206.

78. Amin J, Kaye M, Skidmore S, Pillay D, Cooper DA, Dore GJ. HIV and hepatitis C co-infection within the CAESAR study. HIV Med. 2004;5:174–9.

79. Kaufmann GR, Perrin L, Panteleo G, Opravil M, Furrer H, Telenti A, et al. For the swiss HIV cohort study group. CD4-T-lymphocyte recovery in individuals with advanced HIV-1 infection receiving potent antiretroviral therapy for four years. Arch Intern Med. 2003;163:2187–95.

80. Wit FW, Weverling GJ, Weel J, Jurriaans S, Lange JM. Incidence of and risk factors for severe hepatotoxicity associated with antiretroviral combination therapy. J Infect Dis. 2002;186:23–31.

81. Aranzabal L, Casado JL, Moya J, Quereda C, Diz S, Moreno A, et al. Influence of liver fibrosis on highly active antiretroviral therapyassociated hepatotoxicity in patients with HIV and hepatitis C virus coinfection. Clin Infect Dis. 2005;40:588–93.

82. Soriano V, Puoti M, Sulkowski M, Cargnel A, Benhamou Y, Peters M, et al. Care of patients coinfected with HIV and hepatitis C virus: 2007 updated recommendations from the HCV–HIV International Panel. AIDS. 2007;21:1073–89.

83. Strader DB, Wright T, Thomas DL, Seeff LB. Diagnosis, management, and treatment of hepatitis C. Hepatology. 2004;39:1147–71.

84. Lefrère JJ, Guiramand S, Lefrère F, Mariotti M, Aumont P, Lerable J, et al. Full or partial seroreversion in patients infected by hepatitisC virus. J Infect Dis. 1997;175:316–22.

85. Bonacini M, Lin H, Hollinger F. Effect of coexisting HIV-1 infection on the diagnosis and evaluation of hepatitis C virus. J Acquir Immune Defic Syndr. 2001;26:340–4.

86. Thio C, Nolt K, Astemborski J, Vlahov D, Nelson KE, Thomas DL. Screening for hepatitis C virus in human immunodeficiency virusinfected individuals. J Clin Microbiol. 2000;38:575–7.

87. Wilson LE, Torbenson M, Astemborski J, Faruki H, Spoler C, Rai R, et al. Progression of liver fibrosis among injection drug users with chronic hepatitis C. Hepatology. 2006;43:788–95.

88. Shire NJ, Rouster SD, Rajicic N, Sherman KE. Occult hepatitis B in HIV infected patients. J Acquir Immune Def ic Syndr. 2004;36:869–75.

89. Tsui JI, French AL, Seaberg EC, Augenbraun M, Nowicki M, Peters M, et al. Prevalence and long-term effects of occult hepatitis B virus infection in HIV-infected women. Clin Infect Dis. 2007;45:736–40

90. Rodriguez-Torres M, Gonzalez-Garcia J, Brau N, Sola R, Moreno S, Rockstroh J, et al. Occult hepatitis B virus infection in the setting of hepatitis C virus (HCV) and human immunodeficiency virus (HIV) co-infection: clinically relevant or a diagnostic problem? J Med Virol. 2007;79:694–700.

91. National AIDS Cont rol Organization (NACO) . HIV/AIDS epidemiological Surveillance & Estimation report for the year 2005. Available from: http://www.nacoonline.org/NACO Accessed on June 2008.

92. Alter MJ. Epidemiology of viral hepatitis and HIV coinfection. J Hepatol. 2006;44:S6–9

93. Saravanan S, Velu V, Kumarasamy N, Nandakumar S, Murugavel KG, Balakrishnan P, et al. Co infection of hepatitis B and hepatitis C virus in HIV-infected patients in south India. World J Gastroenterol. 2007;13:5015–20.

94. Gupta S, Singh S. Hepatitis B and C virus co-infections in human immunodeficiency virus positive North Indian patients. World J Gastroenterol. 2006;12:6879–83.

95. Kumarasamy N, Solomon S, Flanigan TP, Hemalatha R, Thyagarajan SP, Mayer KH. Natural history of human immunodefi ciency virus disease in southern India. Clin Infect Dis. 2003;36:79–85.

96. Bhattacharya S, Badrinath S, Hamide A, Sujatha S. Coinfection with hepatitis C virus and human immunodefi ciency virus among patients with sexually transmitted diseases in Pondicherry, South India. Indian J Pathol Microbiol. 2003;46:495–7.

97. Hussain T, Kulshreshtha KK, Sinha S, Yadav VS, Katoch VM. HIV, HBV, HCV, and syphilis co-infections among patients attending the STD clinics of district hospitals in Northern India. Int J Infect Dis. 2006;10:358–63.

98. Padmapriyadarsini C, Chandrabose J, Victor L, Hanna LE, Arunkumar N, Swaminathan S. Hepatitis B or hepatitis C co-infection in individuals infected with human immunodefi ciency virus and effect of anti-tuberculosis drugs on liver function. J Postgrad Med. 2006;52:92–6.

99. Tandon BN, Acharya SK, Tandon A. Epidemiology of hepatitis B virus infection in India. Gut. 1996;38:S56–9.

100.Chandra M, Khaja MN, Farees N, Poduri CD, Hussain MM, Aejaz Habeeb M, et al. Prevalence, risk factors and genotype distribution of HCV and HBV infection in the tribal population: a community based study in south India. Trop Gastroenterol. 2003;24:193–5.

101.Saha MK, Chakrabarti S, Panda S, Naik TN, Manna B, Chatterjee A, et al. Prevalence of HCV & HBV infection amongst HIV seropositive intravenous drug users & their non-injecting wives in Manipur, India. Indian J Med Res. 2000;11:37–9.

102.Iloeje U, Yang H, Su J, Jen CL, You SL, Chen CJ. Predicting cirrhosis risk based on the level of circulating hepatitis B viral load. Gastroenterology. 2006;130:678–86.

103.Soriano V, Puoti M, Bonacini M, Brook G, Cargnel A, Rockstroh J,, et al. Care of patients wit chronic hepatitis B and HIV co-infection: recommendation from an HIV-HBV International Panel. AIDS. 2005;19:221–40.

104.Proia L, Ngui S, Kaur S, Kessler H, Trenholme G. Reactivation of hepatitis B in patients with human immunodeficiency virus infection treated with combination antiret roviral therapy. Am J Med. 2000;108:249–51.

105.Núñez M, Soriano V.. Management of patients co-infected wit hepatitis B virus and HIV. Lancet Infect Dis. 2005;5:374–382.

106.Brook MG, Karayiannis P, Thomas HC. Which patients with chronic hepatitis B virus infection will respond to alpha-interferon therapy? A statistical analysis of predictive factors. Hepatology. 1989;10:761–3.

107.Zylberberg H, Jiang J, Pialoux G, Driss F, Carnot F, Dubois F, et al. Alpha- interferon for chronic active hepatitis B in human immunodeficiency virus-infected patients. Gastroenterol Clin Biol. 1996;20:968–71.

108.Lau A, Read S, Williams B. Downregulation of interferon alpha but not gamma receptor expression in vivo in AIDS. J.Clin Invest. 1988;82:1415–21.

109.Joller-Jemelka HI, Joller PW. Antibodies to endogenous interferon alpha in control and HIV infected person in differenr disease states. Vth International Conference on AIDS, Montreal, 1989.

110.Dore GJ, Cooper DA, Barrett C, Goh LE, Thakrar B, Atkins M. Dual efficacy of lamivudine treatment in human immunodeficiency virus/ hepatitis B virus-coinfected persons in a randomized, controlled study (CAESAR). J Infect Dis. 1999;180:607–13.

111.Hoff J, Bani-Sadr F, Gassin M, Raffi F. Evaluation of chronic hepatitis B virus (HBV) infection in coinfected patients receiving lamivudine as a component of anti-human immunodeficiency virus regimens. Clin Infect Dis. 2001;32:963–9.

112.Benhamou Y, Bochet M, Thibault V, Bochet M, Katlama C, Bricaire F, et al. Long-term incidence of hepatitis B virus resistance to lamivudine in human immunodeficiency virus-infected patients. Hepatology. 1999;30:1302–6.

113.Matthews G, Bartholomeusz A, Locarnini S, Ayres A, Sasaduesz J, Seaberg E, et al. Characteristics Of drug resistant HBV in an international collaborative study of HIV-HBV-infected individuals on extended lamivudine therapy. AIDS. 2006;20:863–70.

114.Frampton JE, Perry CM. Emtricitabine: a review of its use in the management of HIV infection. Drugs. 2005;65:1427–48.

115.McMahon M, Jilek B, Brennan T, Shen L, Zhou Y, Wind-Rotolo M, et al. The HBV drug entecavir – effects on HIV-1 replication and resistance. N Engl J Med. 2007;356:2614–21.

116.Pessoa W, Gazzard B, Huang A, Brandao-Mello C, Cassetti L, Correa M, et al. Entecavir in HIV/HBV-co-infected Patients: Safety and Eff icacy in a Phase II Study (ETV-038). Conference on retroviruses and opportunistic infections, Boston, MA; 2005

117.Hepsera (adefovir dipivoxil) [package insert]. Foster City, Calif: Gilead Sciences; 2004

118.Lok AS, McMahon BJ; AASLD (American Association for the Study of Liver Diseases). Chronic hepatitis B: update of recommendations. Hepatology. 2004;39:857–61

119.Benhamou Y, Bochet M, Thibault V, Calvez V, Fievet MH, Vig P, et al. Safety and efficacy of adefovir dipivoxil in patients co-infected with HIV-1 and lamivudine-resistant hepatitis B virus. Lancet. 2001;358:718–23.

120.Benhamou Y, Thibault V, Vig P, Valantin MA, Guyon P, Katlama C, et al. Significant and sustained efficacy of adefovir dipivoxil after 4 Years of treatment in chronic hepatitis B patients with lamivudine resistant HBV and HIV co-infection virus. New Orleans, LA: Digestive Disease Week; 2004.

121.Dore G, Cooper D, Pozniak A, DeJesus E, Zhong L, Miller MD, Lu B, et al. Efficacy of tenofovir disoproxil fumarate in antiretroviral therapy-naive and –experienced patients coinfected with HIV-1 and hepatitis B virus. J Infect Dis. 2004;189:1185–92.

122.Peters M, Anderson J, Lynch P, Jacobson J, Sherman K, Smith BA, et al. Tenofovir disoproxil fumarate is not inferior to adefovir dipivoxil for the treatment of hepatitis B virus in subjects who are coinfected with HIV: results of ACTG A5127. Conference on retorviruses and opportunistic infections, Boston, MA; 2005. p. 127

123.Buchacz K, Brooks J, Tong T, Moorman AC, Baker RK, Holmberg SD, et al. Evaluation of hypophosphataemia in tenofovir disoproxil fumarate (TDF)- exposed and TDF-unexposed HIV-infected outpatients receiving highly active antiretroviral therapy. HIV Med. 2006;7:451–6.

124.Sanchez-Tapias JM, Costa J, Mas A, Bruguera M, Rodes J. Influence of hepatitis B virus genotype on the long-term outcome of chronic hepatit is B in western patients. Gastroenterology 2002;123:1848–56.

125.Benhamou Y. Hepatitis B in the HIV-coinfected patient. J Acquir Immune Defic Syndr. 2007;45:S57–65.

126.Alberti A, Clumeck N, Collins S, Gerlich W, Lundgren J, Palù G, et al. Short statement of the first European Consensus Conference on the treatment of chronic hepatitis B and C in HIV co-infected patients. J. Hepatol. 2005;42:615–24.

127.Brau N. Treatment of chronic hepatitis C in HIV/hepatitis C viruscoinfected patients in the era of pegylated interferon and ribavirin. Semin Liver Dis. 2005;25:33–51.

128.Hadziyannis SJ, Sette H Jr, Morgan TR, Balan V, Diago M, Marcellin P, et al. Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med 2004;140:346–55.

129.Management of Hepatitis C and HIV Coinfection. Clinical protocol for WHO Europian region. 2006. www.euro.who.int/document/ SHA/e90840 Chapter 6

130.Soriano V, Martín-Carbonero L, García-Samaniego J. Treatment of chronic hepatitis C virus infection: we must target the virus or liver fibrosis? AIDS. 2003;17:751–3.

131.Soriano V, Sulkowski M, Bergin C, Hatzakis A, Cacoub P, Katlama C, Care of patients with chronic hepatitis C and HIV co-infection: recommendations from the HIV-HCV International Panel. AIDS. 2002;16:813–28.

132.Benson CA, Kaplan JE, Masur H, Pau A, Holmes KK; CDC; National Institutes of Health; Infectious Diseases Society of America. Treating opportunistic infections among HIV-exposed and infected children: recommendations from CDC, the National Institutes of Health, and the Infectious Diseases Society of America. MMWR Recomm Rep. 2004;53:1–112.

133.Torriani FJ, Rodriguez-Torres M, Rockstroh JK, Lissen E, Gonzalez- García J, Lazzarin A, et al. Peginterferon Alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV-infected patients. N Engl J Med. 2004;351:438–50.

134.Carrat F, Bani-Sadr F, Pol S, Rosenthal E, Lunel-Fabiani F, Benzekri A, et al. Pegylated interferon alpha-2b vs standard interferon alpha- 2b, plus ribavirin, for chronic hepatitis C in HIV-infected patients: a randomized controlled trial. JAMA. 2004;292:2839–48.

135.Chung RT, Andersen J, Volberding P, Robbins GK, Liu T, Sherman KE, et al. Peginterferon Alfa-2a plus ribavirin versus interferon alfa-2a plus ribavirin for chronic hepatitis C in HIV coinfected persons. N Engl J Med. 2004;351:451–9.

136.Laguno M, Murillas J, Blanco JL, Martinez E, Miquel R, Sanchez- Tapias JM, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for treatment of HIV/HCV coinfected patients. AIDS. 2004;18:F27–36.

137.Jacobson I, Brown Jr. R, Freilich B, et al. Weight based ribavirin dosing (WBD) increases sustained viral response (SVR) in patients with chronic hepatitis C (CHC): final results of the WIN-R study, a U.S. community-based trial. Hepatology. 2005;42(suppl 1):749A.

138.Nunez M, Maida I, Berden MA, et al. Efficacy and safety of pegylated interferon alfa2a plus ribavirin for the treatment of hepatitis C in the HIV-infected patient: the PRESCO trial. Presented at the 44^th Interscience Conference on Antimicrobial Agents and Chemotherapy 2004; Washington, D.C.

139.Hopkins S, Lambourne J, Farrell G, McCullagh L, Hennessy M, Clarke S, et al. Role of individualization of hepatitis C virus (HCV) therapy duration in HIV/HCV-coinfected individuals. HIV Med. 2006;7:248–54.

140.Zeuzem S, Buti M, Ferenci P, Sperl J, Horsmans Y, Cianciara J, et al. Efficacy of 24 weeks treatment with peginterferon alfa-2b plus ribavirin in patients with chronic hepatitis C infected with genotype 1 and low pretreatment viremia. J Hepatol. 2006;44:97–103.

141.Mangia A, Santoro R, Minerva N, Ricci GL, Carretta V, Persico M, et al. Peginterferon alfa-2b and ribavirin for 12 vs. 24 weeks in HCV genotype 2 or 3. N Engl J Med. 2005;352:2609–17.

142.Ferenci P, Fried MW, Shiffman ML, Smith CI, Marinos G, Gonçales FL Jr, et al. Predicting sustained virological responses in chronic hepatitis C patients treated with peginterferon alfa-2a (40 KD)/ ribavirin. J Hepatol. 2005;43:425–33.

143.Soriano V, Núñez M, Camino N, Maida I, Barreiro P, Romero M, et al. Hepatitis C virus-RNA clearance in HIV-coinfected patients with chronic hepatitis C treated with pegylated interferon plus ribavirin. Antiviral Therapy. 2004;9:505–9.

144.Vogt MW, Hartshorn KL, Furman PA, Chou TC, Fyfe JA, Coleman LA et al. Ribavirin antagonisesthe effect of azidothymidine on HIV replication. Science. 1987;235:1376–9.

145.Lafeuillade A, Hittinger G, Chadapaud S. Increased mitochondrial toxicity with ribavirin in HIV/HCV co-infection. Lancet 2001;357:280–1.

146.Moreno A, Quereda C, Moreno L, Perez-Elias MJ, Muriel A, Casado JL, et al. High rate of didanosine-related mitochondrial toxicity in HIV/HCV-co-infected patients receiving ribavirin. Antiviral Ther. 2004;9:133–8.

147.Garcia-Benayas T, Blanco F, Soriano V. Weight loss in HIV-infected patients. N Engl J Med. 2002;347:1287–8.

148.Ragni M, Belle S, Im K, Neff G, Roland M, Stock P, et al. Survival in HIV-infected liver transplant recipients. Tenth Conference on Retroviruses and Opportunistic Infections. Boston 2003 [abstract 155].

149.Teicher EVD, Duclos-Valles J, Azulay D, Castaing D, Bismuth H, Roque-Afonso A, et al. Liver transplantation in HIV-HCV co-infected patients. Presented at 11th Conference on Retroviruses and Opportunistic Infections, San Francisco, CA, 2004.

150.Samuel D, Duclos Vallee JC, Teicher E, Vittecoq D. Liver transplantation in patients with HIV infection. J Hepatol. 2003;39:3–6.

sertraline 50 mg