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2007
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2006
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Jan-Christian Wasmuth and Jurgen Rockstroh

Epidemiology and transmission

Coinfection with HIV and HCV occurs frequently, due to the fact that both are transmitted via the same pathways (parenteral, sexual, vertical). 240,000 people (30 % of HIV-infected individuals) are estimated to be infected with both viruses in the USA.

Several European countries have even higher rates of coinfection. In Spain, at least 50 % of the 130,000 HIV-infected patients are also HCV-positive as a result of the high incidence of i.v. drug users. More than 90 % of coinfected individuals are positive for HCV RNA, i.e. have chronic hepatitis C.

As HCV is ten times more infectious than HIV on blood-to-blood contact, intravenous drug users and recipients of blood products are particularly susceptible to coinfection. The probability of transmission from needlestick injuries after exposure to HCV-contaminated blood is 2-8 %, compared to only 0.3 % after exposure to HIV-contaminated blood.

In contrast, sexual transmission of HCV occurs significantly less frequently than HBV or HIV. As a result, HCV is rare in homosexual men and coinfection is more seldom in this group. However, there have been reported clusters of cases of acute hepatitis C among homosexual HIV-positive men, clearly indicating that HCV can be sexually transmitted. The risk of transmission probably depends on the number of sexual partners and the performance of sexual practices that are prone to injuries (Vogel 2005). In total, about 4-8 % of all HIV-infected homosexuals are also infected with HCV.

Perinatal transmission of hepatitis C is rare in immunocompetent individuals (<1 %). The transmission rate rises with increasing immunosuppression in HIV-positive mothers, and is estimated to be as high as 20 %. On the other hand, HIV-positive mothers treated effectively with HAART do not appear to have an increased risk for materno-fetal transmission of the hepatitis C virus (< 3 % in combination with cesarean section; Pembreya 2005).

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Clinical course and pathogenesis Course of hepatitis C in HIV/HCV-coinfected patients The clinical course of hepatitis C coinfection is determined by the HIV-associated immunosuppression. Progression of immunosuppression accelerates the course of hepatitis C. The latent period until liver failure or hepatocellular carcinoma is extimated to be 10-20 years, whereas it is 30-40 years in HCV-monoinfection. The improved treatment options for HIV infection have increased the likelihood of patients actually living to experience the development of liver failure. The associated decrease in mortality with HIV infection has resulted in a relative increase in hepatitis-associated mortality. In many centers, liver failure is now the most frequent cause of death in HIV-infected patients. Conversely there is no significant influence of hepatitis C on the course of HIV-infection, whose progression is not altered (Rockstroh 2005). The unfavorable course of hepatitis C in HIV infection can be improved by treatment of HIV infection with HAART. In addition, the development of liver failure can be delayed by the improved immune function under HAART. This is particularly true for patients who achieve a good immune recovery. On the other hand, hepatitis C infection can aggravate the potential hepatotoxicity of several HAART regimens. Up to 10 % of patients have to discontinue HAART due to severe hepatotoxicity. This risk is associated especially with the so-called "d-nucleosides" (ddI, ddC, d4T). These substances should be avoided in coinfected patients. Nevirapine and tipranavir should be used with caution. In some coinfected patients, a temporary increase in transaminases is observed after initiation of HAART. This most likely corresponds to an increased inflammatory activity of hepatitis C as a result of the improved immune status. Nevertheless, long-term follow-up has shown that HAART improves the course of hepatitis C. Indications for HAART, according to current treatment guidelines, should be carefully checked in all coinfected patients. Diagnosis The diagnostic tests used in coinfected patients are the same used in patients with HCV monoinfection (table 1). Detection of HCV antibodies (anti-HCV) proves exposure to HCV, but does not distinguish between resolved and chronic hepatitis C. Chronic hepatitis C is diagnosed by the detection of HCV viremia (i.e. HCV RNA). It should be noted that HCV antibodies might be lost during the course of HIV infection as a result of the underlying immunosuppression, although nowadays this phenomenon has become rare, probably due to improved test kits. It may therefore be useful to determine HCV RNA levels, even if the anti-HCV test is negative, if there is clinical suspicion or advanced immunodeficiency. Similarly, determination of HCV RNA levels is indicated in cases of suspected acute (primary) HCV infection, as HCV antibodies usually only become detectable one to five months after infection. Patients with HIV/HCV coinfection have significantly higher levels of HCV viremia than patients with HCV monoinfection (about 1 log). However, the level of viremia does not have a prognostic value for the course of hepatitis C. Accordingly, regular testing of HCV-RNA as a routine clinical procedure is not necessary. However, some patients might loose HCV-RNA in parallel to progression of immune deficiency, but experience a flare up of hepatitis C together with clinical symptoms following immune reconstitution under HAART (Kim 2006). Therefore, regular testing around the initiation of HAART seems to be prudent. Otherwise we consider routine measurement of HCV RNA once a year sufficient. It is possible to predict a response to treatment from the level of the HCV viremia: if the concentration of HCV RNA is below 800,000 IU /ml, the probability of treatment success is significantly higher than at levels above 800,000 IU /ml (800,000 IU/ml equals about 2 million copies/ml dependent on the test used). Response rates are influenced by HCV genotype. Six genotypes with numerous subtypes are known, and are seen to have different regional distributions: genotypes 1 and 3 are predominantly found in Europe, whereas genotypes 4 and 5 are found in Africa, and genotype 6 in Asia. Genotypes 2 and 3 in particular are associated with significantly better responses to interferon therapy. Coinfection with several genotypes is possible. Before initiating treatment genotyping should be performed. Grading of liver fibrosis is essential in order to estimate the extent of liver damage. Among non-invasive procedures the Fibroscan system is of special interest. This technique (transelastography) allos to determine liver stiffness that correlates with the extent of liver fibrosis. Due to the development of such non-invasive procedures the role liver biopsy before starting HCV-therapy has to be newly defined. Similarly, follow-up by liver biopsy if no treatment is commenced most likely will not be necessary any more. If a liver biopsy is not available, current consensus recommendations suggest treatment of hepatitis in case of genotypes 2+3, or genotype 1 and low HCV viremia. If a liver biopsy has been performed that shows no significant fibrosis, immediate treatment is usually not required regardless of the underlying genotype. There are several histological classifications used. In Europe the METAVIR-Score is used most often. It distinguishes five stages of fibrosis (0 = no fibrosis, 1 = portal fibrosis without septa, 2 = few septa, 3 = significant septa without cirrhosis, 4 = cirrhosis). Hepatitis activity is graded according to the intensity of necroinflammatory lesions (A0 = no, A1 = mild, A2 = moderate, A3 = severe). Treatment is recommended for grades F2-F4; it may be deferred for grades F0+F1. If there is clinical suspicion requiring the detection or exclusion of extrahepatic manifestations (vasculitis, glomerulonephritis, systemic cryoglobulinemia), appropriate investigations may be necessary (skin biopsy, urine tests, kidney biopsy, detection of serum cryoglobulins). The recommendations for autoantibody testing to exclude autoimmune disease vary and test results are difficult to interpret: up to 60 % of all patients with hepatitis C have autoantibodies such as ANA, RF, anticardiolipin, SMA, and LKM1 antibodies as an accompanying autoimmune phenomenon without any clinical relevance. If the titers of these autoantibodies increase or appear for the first time during interferon therapy, treatment does not usually have to be discontinued, and so the need for routine testing of autoantibodies is arguable. In order to exclude autoimmune hepatitis, however, ANA, SMA, ANCA, and LKM1 antibodies should be determined before interferon therapy is initiated. Patients with positive results should be monitored closely for deterioration of liver function on interferon therapy as a sign of active autoimmune hepatitis. If liver function worsens, interferon should be discontinued. The need for immunosuppressive therapy can only be decided on a case-by-case basis. Before treatment with interferon, TSH levels should always be determined to exclude thyroid disease. With normal thyroid function, it is sufficient to monitor TSH at 12-weekly intervals. In cases of hypothyroidism, substitution with levothyroxine is recommended, and thyreostatic treatment is similarly recommended for hyperthyroidism before initiation of interferon therapy. After adequate treatment, interferon therapy can usually be administered under close monitoring of TSH (every 4 weeks). Approximately 5 % of patients develop thyroid dysfunction on interferon therapy. This generally manifests within the first 3 months of treatment. If hypothyroidism is induced, interferon therapy can usually be continued in combination with substituted levothyroxine. The first manifestation of hyperthyroidism is enough cause for most authors to discontinue treatment, although even here it may be possible to continue interferon therapy in certain cases. In the majority of patients, thyroid dysfunction resolves after discontinuation of interferon. However, it may also persist, and therefore cases need to be considered individually. Up to 12 % of patients with hepatitis C have thyroid autoantibodies before treatment with interferon (antibodies against thyroid peroxidase = anti-TPO, anti-thyroglobulin antibodies and TSH receptor antibodies). In these patients, the risk of a deterioration in thyroid function on interferon is significantly higher than in patients without these antibodies. If possible, autoantibodies should be determined in all patients before beginning treatment, but at the very least in those patients with abnormal TSH levels, in order to have a baseline value to allow subsequent monitoring. If no treatment is initiated alpha-Fetoprotein (AFP) and sonography of the liver should be performed every 6-12 months to early detect a hepatocellular carcinoma (HCC). This is particularly relevant for patients with F3/F4-fibrosis. As the course of hepatitis C is accelerated in HIV-coinfection and 10-30 % of the patients will develop HCC without preceding cirrhosis, regular screening should be considered for all patients. Some experts recommend even shorter intervals that are not yet feasible in most circumstances. Table 1: Diagnostic procedures for hepatitis C in HIV-coinfection Diagnosis of hepatitis C HCV-Ab (positive 1-5 months after infection, may be lost with immunosuppression) HCV-RNA (not prognostic for progression, but response to treatment) Status of liver damage Grading of fibrosis (e. g. Fibroscan, liver biopsy) Parameter of synthesis (e. g. coagulation, protein, albumin, CHE) Ultrasound and AFP every half a year Before treatment HCV genotype Autoantibodies (ANA, SMA, ANCA and LKM1) TSH, thyroid autoantibodies if applicable Monitoring of treatment Differential blodd count and liver enzymes every 2-4 weeks HCV-RNA every 12 weeks (and at week 4 to evaluate early virologic response) CD4-count every 12 weeks TSH every 12 weeks Therapy Most important reasons to treat hepatitis C are the unfavourable course in HIV-coinfection, increased life expectancy due to successful HAART, increased liver-related mortality, and an increased risk of hepatotoxicity of HAART. In addition, ist has been shown that successful treatment of hepatitis C improves survival. The goal of hepatitis C treatment is to achieve permanently negative HCV RNA levels. This is generally referred to as a sustained response. It is defined as a negative HCV RNA six months after completion of treatment. Negative HCV RNA at the end of the treatment period is described as an end of treatment response. If transaminases have normalized, this is referred to as a biochemical response. However, the latter does not correlate with the further clinical course of hepatitis C and is therefore no longer used today. Failure to respond to treatment is referred to as a non-response. In the following text, response rates always refer to sustained responses. This is because only sustained responses have been clearly associated with the resolution of liver fibrosis and extrahepatic manifestations, as well as with the prevention of further transmission. When HCV RNA becomes detectable again after having been negative, it is referred to as a relapse. The probability of a relapse is highest within the first months following completion of treatment and decreases steadily afterwards. Therefore, the success of therapy is usually determined and evaluated six months after the end of treatment. In individual cases, relapses may occur at later time points, sometimes after years. Therefore, regular monitoring is advisable even following successful treatment (monitoring of transaminases; HCV RNA if there is reason to suspect a relapse). The combination of pegylated interferon with ribavirin is regarded as standard therapy in coinfected patients. Response rates around 50 % can be achieved (Torriani 2004, Nuñez 2006). In patients with genotypes 2 and 3 response rates are significantly higher (about 80 %) than in patients with genotypes 1 and 4 (about 40 %). Duration of treament is tailored acoording to individual factors such as genotype and initial treatment response. In general, duration is 48 weeks. However, patients with genotypes 1 and 4 might benefit from an extended treatment period (Nuñez 2006). On the other hand, in selected patients with genotypes 2 and 3 who respond very quick to the treatment (HCV-RNA negative at week 4) a shorter duration seems to be possible. Liver transplantation may be an option for patients who have cirrhosis and can not be treated with interferon. Concerns that interferon treatment could have a negative effect on HIV infection have not been confirmed in any study. In fact, there is further suppression of detectable HIV viremia in the majority of patients as a result of the antiviral effect of interferon. Absolute CD4+ T-cell counts may drop slightly due to temporary leukopenia, but percentage values usually rise. No treatment study to date has shown a significant deterioration of HIV infection (Soriano 2004). The treatment options remain inadequate for patients with a non-response or relapse. In patients treated earlier with interferon monotherapy, an attempt can be made using a combination of PEG-interferon and ribavirin. There are currently no standard recommendations for treatment of patients after failed PEG-interferon therapy. Some patients will respond to re-treatment, especially in case of bad adherence or suboptimal management of adverse events during the initial treatment. In single patients, a triple combination of PEG-interferon, ribavirin and amantidine (2 x 100 mg/day) has been used successfully, although reliable data are not available. HCV-specific protease inhibitors and polymerase inhibitors, as well as other new substances, will add new options in the next years. Practical tips for management of treatment The following treatment recommendations have been compiled for HIV coinfection: Indications and contraindications As HIV coinfection accelerates the course of hepatitis C and increases the risk of hepatotoxicity after initiation of HAART, the indication for treatment should be determined in every patient with diagnosed HIV/HCV coinfection. In particular, treatment should be discussed for cases with a bioptically confirmed fibrosis of grade F2-F4. Extra-hepatic manifestations of hepatitis C are also an indication for treatment (vasculitis, glomerulonephritis, systemic cryoglobulinemia). The following factors are associated with a more favorable response to treatment: § HCV RNA < 800,000 IU/ml (+ genotype 1) § HCV genotype 2+3 § Age < 50 years § Low grade of fibrosis (either histologically, or by non-invasive technique) § Normal ?-GT § Stable HIV infection In addition, contraindications should be evaluated. The most important are: § Decompensated liver cirrhosis or history of decompensation (but not compensated cirrhosis, i.e. CHILD A cirrhosis!) § Leukopenia (<1,500/µl) § Thrombocytopenia (< 50,000/µl) § Anemia (< 10 g/dl) § Severe, as yet untreated thyroid dysfunction § CD4+ T-cell count < 200/µl (relative contraindication, see below) § Severe psychiatric illnesses § Symptomatic cardiac disease § Active opportunistic infections § Active drug or alcohol abuse § HIV treatment with ddI (AZT and d4T should be avoided too) Methadone or polamidone substitution is not a contraindication if good monitoring can be ensured during the treatment phase. However, patients with active drug or alcohol abuse should first be introduced to the appropriate programs. When to treat If a decision to treat hepatitis C is made, the immune status of the patient and current antiretroviral therapy must be considered.The following scheme is suggested: Patients without HAART If possible, HCV should be treated before HIV. Reasons for this include the increased hepatotoxicity of HAART with concurrent hepatitis C; possibly impaired immune reconstitution resulting from hepatitis C; better compliance; and finally, prevention of drug interactions. If the CD4+ T-cell count is above 350/µl, treatment of hepatitis C can be started. It is unclear whether a high viral load (> 50,000/ml) requires initiation of HAART. If the CD4+ T-cell count is between 200 and 350/µl, the patient might benefit from treatment of hepatitis C if HIV RNA is below 5,000 copies/ml. If it is higher, initiation of HAART should be considered. A CD4+ T-cell count below 200/µl is a relative contraindication. HAART should be initiated first. When there is an adequate increase in the CD4 count, interferon therapy can be reconsidered. Patients on HAART If CD4+ T-cells are above 350/µl under stable HAART and the viral load is below the level of detection, treatment can be started. If CD4+ T-cells are between 200 and 350/µl and the viral load is stable below the limit of detection, the decision should be dependent on the overall situation (with consideration of severity of hepatitis, HCV genotype and status of HIV infection). A CD4+ T-cell count below 200/µl is a relative contraindication. It is a judgement call to decide whether to take the risk of a treatment attempt with interferon (with the likelihood of a poor response and the danger of a further decline in the CD4+ T-cell count as a result of interferon treatment). If necessary, antiretroviral treatment should ideally be modified several weeks before HCV therapy is initiated. ddI is contraindicated with concurrent HCV therapy (as it can lead to pancreatitis, mitochondrial toxicity, and more cases of liver decompensation). AZT and d4T should also be avoided if possible, in order to prevent additive toxicities (zidovudine: anemia and leukopenia; stavudine: mitochondrial toxicity). Before modifying HAART, it should be insured that the treatment success of HIV therapy is not going to be compromised. In such cases, HCV treatment should only be started if the overall clinical situation is stable, i.e. good viral suppression has been achieved and side effects have been evaluated or treated. Treatment practice The combination of PEG-interferon with ribavirin over a period of 48 weeks is recommended as the standard therapy (Rockstroh 2004, Alberti 2005). However, this standard duration has to be adapted according to genotype and speed of viral response (Soriano 2007). Two interferons are currently available as PEG-interferons: PEG-Intron™ and Pegasys™. PEG-Intron™ is administered subcutaneously and the dose is based on body weight at 1.5 µg/kg. Pegasys™ is injected subcutaneously at a fixed dose of 180 µg. Both substances are administered once a week, and must be kept refrigerated. The dosage of ribavirin should be adapted to body weight: patients below 75 kg should receive 1,000 mg daily, patients above 75 kg 1,200 mg daily regardless of genotype. The capsules can be taken once daily, or spread over the day. Patients must be made aware of the fact that both interferon and ribavirin are potentially teratogenic. A reliable method of contraception for at least six months after treatment is therefore important. All patients require regular clinical monitoring. This should initially take place every 2 weeks; later at least every 4 weeks. Laboratory monitoring should include (see table 1): § A complete blood count and transaminases every 2-4 weeks § Thyroid function tests every 12 weeks (more frequently with pre-existing dysfunction) § Immune status every 12 weeks § Lactate levels every four weeks in patients on stavudine comedication HCV RNA is the most important parameter for measuring the treatment response and is determined after 4, 12, and 24 weeks to decide on the duration of treatment. The duration of treatment depends on the individual treatment response (see figure 1). If a very early response can be achieved (HCV-RNA negative at week 4), a shorter duration of treatment may be possible in genotypes 2 and 3 (in patients with low viral load at baseline and only minimal fibrosis). If in all other cases the viral load has not dropped by at least 2 logs after 12 weeks, treatment should be discontinued, as there will be no response ("2 log stopping rule"). Figure 1: Hepatitis C treatment algorithm; modified after Soriano 2007 Management of adverse events The management of possible side effects is often the decisive factor for the success of treatment (s. table 2). A high discontinuation rate of up to 30 % in numerous (older) clinical studies is likely also to have been due to a lack of experience with combination therapy. Proper management of side effects probably results in significantly better treatment success rates. It is often helpful to indicate to patients that side effects are reversible after stopping therapy. Patients should be counseled extensively on the expected side effects before beginning treatment. Following main aspects should be explicitly addressed: Almost all patients experience influenza-like symptoms or malaise when beginning treatment. As the severity of symptoms cannot be predicted beforehand, treatment should be initiated at a time when there are no important private or professional events pending (e.g. before a weekend). The administering physician should be readily available during the first days of treatment. In addition, paracetamol should be prescribed (dosage has to be adjusted individually; single dose = 1,000 mg). Symptoms usually improve within the first two to four weeks. Most patients tolerate treatment quite well and can continue their daily activities normally. However, it is possible that particularly in the initial stages of treatment, they may be unable to work for several days. In rare cases, the side effects may be so grave that patients are unable to work for the entire duration of treatment. This also needs to be discussed with the patient in advance. Ribavirin causes hemolytic anemia in up to 20 % of patients. This can be treated with epoetin alfa. Dose recommendations differ: usually approximately 100 IE/kg body weight are injected subcutaneously three times a week. 40,000 IE once a week also significantly improve ribavirin-induced anemia (Sulkowski 2005). Alternatively, halving the dose (hemoglobin below 10 g/dl) or discontinuing ribavirin altogether (hemoglobin below 8.5 g/dl) are possible options. However, dose reductions, frequently used in the past, should only be made if epoetin does not help. Studies have shown that the correct dosing of ribavirin is associated with a better treatment response. A daily 5 mg dose of folic acid is recommended to reduce hematoxicity. Treatment with granulocyte colony stimulation factor (GCSF) may ameliorate an interferon-induced leukopenia. Clinical experience is very limited so far. However, so that the required dose of interferon can be maintained in case of severe leukopenia (neutrophil count below 500/µl), this recommendation seems to be justified. Doses have to be adjusted individually. In most instances low doses are adequate, as hematopoiesis itself is not impaired (e.g. Filgrastim 30 Mio IE once a week). The evaluation of psychological side effects is made at every clinic visit. Observations made by others, such as family members, may also be very helpful. Mild depression whilst on interferon can be treated with well-tolerated antidepressants (e.g. paroxetin 20 mg daily). In case of relevant history prophylactic use of paroxetin can be discussed. Therapy should be stopped immediately in cases of severe depression or on development of suicidal thoughts. The frequent occurrence of weight loss can be lessened with dietary counseling. It is important to ensure a regular diet that is tailored to the patient's wishes (e.g. in-patients with drug addiction). It is possible that the weight loss is a form of lipoatrophy, and therefore nucleoside analogs with a lower risk for development of lipodystrophy should be used if possible. Thyroid dysfunction may develop during treatment with interferon (see above), but does not always require discontinuation of interferon. In the majority of cases hyperthyroidism develops at first, that may progress to hypothyroidism in the further course. Manifestation of hyperthyroidism is enough cause for most authors to discontinue treatment. If discontinued timely, prognosis is excellent. If interferon treatment is continued, irreversible hypothyroidism requiring lifelong hormone replacement may develop. In case of preexisting hypothyroidism interferon treatment usually can be continued with ongoing substitution of levothyroxine. Table 2: Most important adverse events with PEG-interferon/Ribavirin Adverse event Management Interferon-associated Influenza-like symptoms Paracetamol Leukopenia, Thrombopenia Dose reduction of IFN, G-CSF Psychiatric Symptoms Antidepressants, Discontinuation of IFN Weight loss Well balanced nutrition Autoimmune Phenomena Discontinuation IFN Ribavirin-associated Hemolysis Folic acid, Erythropoetin, Dose reduction of Ribavirin Recommendations for treatment of hepatitis C are constantly evolving. Therefore an experienced treatment center should always be contacted if clarifications are needed. Due to the complexities of HIV/HCV coinfection, patients should be treated within clinical studies wherever possible. Acute Hepatitis C During recent years a constantly growing number of cases of acute hepatitis C has been observed in homosexual men. These mainly had had contacts with high risk of infection (e.g. use of sex toys, fisting). As HCV-antibodies are produced only long time after infection, diagnosis of acute hepatitis C is made according to history, elevated transaminases (ideally normal before) and positive HCV-RNA. The optimal management of acute hepatitis C remains unclear. Data available so far show an improved response rate of about 60 % (up to 80 % in genotype 2/3) if treatment is initiated early (Vogel 2005). These data support early treatment even in the presence of HIV coinfection. On the other hand spontaneous clearance after acute infection might be better than previously expected. The following aopproach might be feasible: In case of symptomatic acute hepatitis C (especially jaundice), patients are followed for 12 weeks in order to await possible spontaneous clearance. Patients with asymptomatic acute hepatitis C can be treated immediately. We treat for a period of 24 weeks with peg-interferon alone for genotypes 2+3, and peg-interferon plus ribavirin for genotypes 1+4. However, the optimal strategy is unclear at the moment. If possible, patients should be treated within prospective clinical studies. References 1. Alberti A, Clumeck N, Collins S, 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; 42:615-624. http://amedeo.com/lit.php?id=15916745 2. Kim AY, zur Wiesch JS, Kuntzen T, et al. Impaired hepatitis C virus-specific T cell responses and recurrent hepatitis C virus in HIV coinfection. PLoS Med 2006; 3:e492. http://amedeo.com/lit.php?id=17194190 3. Nuñez M, Miralles C, Berdún MA, et al. The PRESCO trial: role of extended duration of therapy with pegylated interferon alfa-2a plus weight-based ribavirin dose in 389 HCV/HIV co-infected patients. 8th International Congress on Drug Therapy in HIV Infection, Glasgow 2006; PL13.1 4. Pembrey L, Newell ML, Tovo PA, EPHN Collaborators. The management of HCV infected pregnant women and their children European paediatric HCV network. J Hepatol 2005; 43:515-25. http://amedeo.com/lit.php?id=16144064 5. Rockstroh JK, Spengler U. HIV and hepatitis C virus co-infection. Lancet Infect Dis 2004; 4:437-44. http://amedeo.com/lit.php?id=15219554 6. Rockstroh JK, Mocroft A, Soriano V, et al. Influence of hepatitis C virus infection on HIV-1 disease progression and response to highly active antiretroviral therapy. J Infect Dis 2005; 192:992-1002. http://amedeo.com/lit.php?id=16107951 7. Sulkowski MS, Dieterich DT, Bini EJ, et al. Epoetin alfa once weekly improves anemia in HIV/Hepatitis C virus-coinfected patients treated with interferon/ribavirin: a randomized controled trial. J Acquir Immune Defic Syndr 2005; 39:504-506. http://amedeo.com/lit.php?id=16010180 8. Soriano V, Puoti M, Sulkowski M, et al. Care of patients with hepatitis C and HIV co-infection. AIDS 2004,18:1-12. http://amedeo.com/lit.php?id=15090824 9. Soriano V, Puoti M, Sulkowski 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. http://amedeo.com/lit.php?id= 17502718 10. Torriani FJ, Rodriguez-Torres M, Rockstroh JK, 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. http://amedeo.com/lit.php?id=15282351 11. Vogel M, Biniek B, Jessen H, et al. Treatment of acute hepatitis C infection in HIV-infected patients: a retrospective analysis of eleven cases. J Viral Hepat 2005; 12:207-211. http://amedeo.com/lit.php?id=15720537