With improved survival of HIV patients in the HAART era, liver disease has emerged as an important cause of morbidity and mortality in co-infected patients. In an analysis of the adverse events of anti-HIV drugs, 1246 patients out of a total of 23 441 died over a 5-year follow-up period; liver failure constituted 15% of the mortality and over 50% of deaths occurred despite adequate HIV suppression[27]. Therefore, effective treatment for both viruses is essential for a favorable outcome in co-infected patients.

The treatment of HCV in HIV infected patients is a challenging undertaking. Management should ideally be provided in a center with experience in treating such patients, preferably under the care of a multidisciplinary team comprised of hepatologists, infectious disease physicians, psychiatrists, pharmacists, social workers, and a substance abuse program.

All HIV patients should be tested for HCV as soon as HIV is diagnosed. An HIV patient negative for anti-HCV, but with significant risk factors for HCV, should be tested for HCV-RNA as a minority of HIV patients may have viremia despite a negative anti-HCV test[28]. Assessment of viral load of HIV and HCV along with a CD4 count should be obtained. The current recommendation is to suppress HIV before starting anti-HCV therapy[29].

Patients positive for HCV RNA with ALT elevation and/or stage 2 disease (or more) on liver biopsy should be considered for treatment. Patients with mild disease (stage 1 fibrosis) may also be considered if they are good treatment candidates (low viral count, genotype-2 and -3). About 25% patients with mild disease on the initial liver biopsy develop significant fibrosis over an average period of 3 years. The occurrence of ALT elevation during the follow up period is an independent predictor of disease progression[30]. Therefore, if the treatment was deferred at the initial evaluation, regular clinical and laboratory follow-up should be pursued. A repeat liver biopsy should be performed after 3 years, especially in patients with ALT elevation on follow up.

Assessment of fibrosis allows treatment to be deferred in patients with mild disease due to genotype-1 or -4 infections. As mentioned earlier, treatment may be considered for genotype-2 or -3 disease as the response to therapy in this population is very good. Liver biopsy is the gold standard for the assessment of fibrosis and cirrhosis. However, liver biopsy has certain disadvantages. Being an invasive procedure, serious complications such as bleeding can occur[31]. Sampling error due to tissue fragmentation and small sample size may provide inaccurate results. Moreover, the procedure adds to the overall cost of the treatment[32].

Non invasive markers of fibrosis are available and may replace liver biopsy in the future. Various surrogate serum markers such as AST to platelet ratio index (APRI), Fibrotest score (comprised of serum bilirubin, α-2 macroglobulin, Apolipoprotein A1, haptoglobin, and gamma glutamyl transpeptidase activity), SHASTA index (hyaluronic acid, AST, and albumin levels), Forn’s index (platelet, GGT, age, and cholesterol), and FIB-4 (age, AST, ALT, and platelets) have been tested in HIV-HCV co-infected patients with generally favorable results[33]. The measurement of liver stiffness by elastography (Fibroscan or Elastoscan) using an ultrasonic transducer is a rapid, simple, non-invasive, and reproducible technique. It is also more accurate than serum markers in the diagnosis of cirrhosis in co-infected patients[34].

A detailed clinical evaluation with history and physical examination is essential before starting anti-HCV therapy (Table 1). Patients with decompensated liver disease; i.e., with presence of ascites, variceal bleeding, jaundice, and encephalopathy (Child Turcotte Pugh or CTP stage B and C), do not tolerate interferon (IFN) based therapy well[35]. Patients should have a hemoglobin level > 11 g/dL in females and > 12 g/dL in males, a platelet count > 75 000/cm and an absolute neutrophil count (ANC) > 1500 before starting treatment. A baseline fundus examination is recommended as pegylated interferon (PEG-IFN) can cause retinopathy with visual disturbances[36]. Combination of Didanosine (DDI) and Zidovudine (AZT) should be avoided to prevent hepatic and mitochondrial toxicity[3738].

The introduction of interferon (INF) in 1991 has revolutionized the treatment of HCV infection. In HIV/HCV co-infected patients, results obtained with PEG-IFN + ribavirin (RBV)[39–54] were superior to those with PEG-IFN alone, standard IFN alone[48], or standard IFN + RBV (Table 2). A meta-analyses of 6 randomized controlled studies showed superior sustained virologic response (SVR) with PEG-IFN + RBV compared with IFN + RBV and PEG-IFN monotherapy. The response was more favorable in males, patients with CD4 > 500, HCV load < 100 0000, and in non drinkers[55]. Currently, PEG-IFN and RBV combination is the standard of care for the treatment of HCV in HIV patients.

In an intention to treat analysis, the end of treatment response (ETR); i.e., negative HCV-RNA at the end of treatment, and SVR; i.e., negative HCV-RNA 24 wk after discontinuation of treatment with PEG-IFN + RBV, in IFN naïve HIV/HCV co-infected patients were 29%-62% and 17%-53%, respectively (Table 2). The large difference in the response rates is due to variable frequency of baseline characteristics, such as the presence of cirrhosis, frequency of genotype-1 (GT-1), baseline HIV parameters, dose of RBV, and treatment discontinuation rate. The ETR and SVR rates were superior for the GT-2/3 (44%-81% and 24%-62%, respectively) compared to GT-1/4 (19%-47% and 9%-38%, respectively)[444647]. In a recent study, the treatment response rates were similar with the use of PEG-IFN 2a and 2b[56].

The highest SVR rate of 53% was reported by Hopkins et al[49], which may be related to the lower proportion of GT-1 patients (33%) compared with other studies (48%-77%) (Table 2). The pooled SVR rate with the use of PEG-IFN + RBV obtained from 7 randomized controlled trials or prospective cohort studies involving 784 HIV + HCV co-infected patients was 33.3% (27.3%-44.2%)[57]. The SVR rate in HCV mono-infection with PEG-IFN + RBV was much better (52% for GT-1 and 80% for GT-3)[58]. A head-to-head comparison of the two groups also showed superior ETR and SVR rates for GT-1 infection (46% vs 25%, P < 0.05 and 37% vs 17%, P < 0.05, respectively)[50]. These inferior response rates in co-infected patients can be explained to some extent by the greater number of patients with cirrhosis (43% vs 11%, P = 0.0001), and lower doses of RBV used (12.75 ± 1.46 vs 14.10 ± 1.88, P = 0.0001) in these patients.

Another important reason for the lower SVR in the co-infected population is the high treatment dropout rate (12%-51%) (Table 3). The importance of medication compliance was shown in a recent retrospective analysis on HCV mono-infected patients[59]. Patients who consumed > 80% of the medications (PEG-IFN + RBV), had a superior SVR compared to those with < 80% compliance (Figure 1). The difference in SVR was noted for GT-1 but not for GT-2/3 infection. The treatment discontinuation rates were 39% in both the APRICOT and RIBAVIC trials, and 12% in the ACTG study[444647]. Discontinuation of treatment due to adverse effects was observed in 13%, 17%, and 12% of patients, respectively. These figures are similar to discontinuation rates in the HIV negative population[60]. Other reasons for treatment discontinuation were patient refusal (4%), lack of follow up (4%), and violation of the study protocol (1%) in the APRICOT study. Another reason was relapse of substance abuse in 1%-4% patients[4148].

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Figure 1 Patients who consumed > 80% of their anti-HCV medications showed a trend towards better sustained virologic response (SVR) compared to those with < 80% drug compliance (72% vs 57%, P = 0. 06). The SVR was much better in GT-1 infections (63% vs 34%, P = 0.008) but not in GT-2 or -3 infections (94% vs 95%, P = 0.88). Wk: Week.

The barriers to anti-HCV treatment may be patient as well as physician related (Table 3). Education and motivation of patients with intensive training and provision of better infrastructure for the treating physicians may improve the outcome. Most studies to date have excluded patients with active substance abuse (Table 3). A recent NIH consensus conference has recommended that active substance abuse should not be considered a contraindication to anti-HCV treatment[61]. Instead, greater integration of HCV treatment in HIV clinics and detoxification programs and provision of additional social support should be encouraged[62]. In a retrospective analysis of 73 patients with HCV infection (32% with HIV) treated at a methadone maintenance treatment program, encouraging ETR and SVR rates of 55% and 45%, respectively, were obtained[63].

The recommended dose of PEG-IFN 2a is 180 μg/wk and for PEG-IFN 2b is 1.5 μg/kg per week (Table 2). Because of the wider systemic distribution of PEG-IFN 2b, it is essential to adjust the dose for body weight, as compared to PEG-IFN 2a, which is restricted to blood and interstitial fluids only. In most studies, RBV has been used at a dose of 800 mg/d or 10.6 mg/kg per day in co-infected patients (Table 2). Virologic response at weeks 4 and 12 were superior with the use of 1000-1200 mg of RBV compared to 800 mg/d of RBV (Figure 2). Improved SVR rates, similar to that seen in HCV mono-infection, were observed when RBV was used at a dose of 1000-1200 mg[496465]. Based on the current data, it is recommended that weight-based RBV (1000 mg/d for < 75/kg and 1200 mg/d for 75 kg and above) should be used in co-infected patients.

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Figure 2 Results of virologic response in different studies. PRESCO study 33% and 84%, respectively, at weeks 4 and 12 for GT-1 infections; APRICOT study 13% and 34%; PISG study 31% and 71% respectively. Similar figures for GT-2 and -3 infections were 47% and 92%, 37% and 72%, 84% and 96%, respectively.

The use of PEG-IFN + RBV for 48 wk in GT-1/4 and 24 wk in GT-2/3 infections yielded ETR in 53%-82% and SVR in 42%-75% patients (Table 2). On the other hand, treatment for 48 wk for all GTs achieved an ETR in 50%-80% and SVR in 44%-73% co-infected patients[444647]. In the recently completed PRESCO trial, PEG-IFN and weight-based RBV were used for 48 wk or 72 wk for GT-1/4 and 24 wk or 48 wk for GT-2/3[65]. The overall SVR was 49.6% (72.4% in GT-2/3 and 35% in GT-1/4, P < 0.001). In patients with GT-2/3, a higher relapse rate was seen in patients treated for 24 wk compared to those receiving 48 wk of treatment (40% vs 10%, P = 0.02). Patients treated for 48 wk were 5.4 times more likely to achieve SVR. If these data are confirmed in other studies, the standard of care in co-infected patients will be 48 wk of treatment with PEG-IFN and weight based RBV, irrespective of the GT.

Adverse effects are seen in the majority of patients (Tables 4 and 5). The most common adverse effects are influenza-like symptoms (Table 4). About one third of patients experience a drop in hematologic parameters. In most cases, the adverse effects are mild, but, treatment discontinuation was needed in 12%-17% of patients and dose modification of PEG-IFN and RBV, due to either adverse events or a change in laboratory values (neutropenia or thrombocytopenia with PEG-IFN and anemia with RBV), was required in 25%-33% patients[3547]. RBV-induced anemia is exacerbated with the concomitant use of AZT[38]. This was confirmed in the PRESCO study where RBV-induced anemia was observed in only 2.6% patients, despite using weight-based higher doses of RBV[65]. Every effort should be made to maintain patients on the medications, while simultaneously managing the hematologic abnormalities using blood products and growth factors. In a recent study, the use of Eicosapentaenoic acid prevented RBV dose reduction during first 12 wk of treatment[66].

To ensure the safety of treatment, patients should have regular assessment with complete blood count and liver tests. Efficacy of treatment is assessed by quantitative HCV-RNA at weeks 4, 12, 24, 48, and 72. The goal of therapy is to achieve a SVR as this is associated with < 1% recurrence of infection at 5 years[67]. Assessment of a 2 log reduction in the HCV viral load at week 12 is crucial; lack of such a reduction has a 98%-100% probability of not achieving a SVR. Recently, data have emerged that patients who become HCV-RNA negative at wk 4 (rapid virologic response or RVR) have a SVR rate of 82%, while 99% of those who fail to achieve a 1-log reduction at week 4 are unlikely to have a SVR[68]. However, the current recommendation is to stop further treatment in patients who fail to achieve a 2-log reduction at week 12 of treatment.

The role of induction therapy using a higher IFN dose was tested in the CORAL-1 study[69]. The use of PEG-IFN α-2a at a dose of 270 μg for 4 wk followed by 180 μg for 8 wk was compared with the standard dose of 180 μg for 12 wk. Both groups received 1000-1200 mg/d of weight-based RBV. Although the induction dose was safe and well tolerated, it failed to provide any efficacy benefit. Treatment for an extended duration was assessed in another study in which patients who failed to achieve a 2-log reduction at 12 wk were randomized to receive either 48 wk or 72 wk of PEG-IFN + RBV. This approach also lacked efficacy as only one (2.5%) patient achieved an SVR.

The lack of an animal model has hampered the development of a vaccine against HCV. Several new drugs for treating HCV are under various stages of development[70]. These include improved IFN molecules (albumin fused with IFN-α, Ω IFN, sequential treatment with IFN-α and IFN-γ), improved RBV molecules (Viramidine with a lower potential for hemolysis, and Levovirin), immunomodulators (histamine dihydrochloride, thymosin α, and isatoribine), and directly acting anti-HCV agents (HCV protease inhibitors, HCV entry inhibitors, ribozymes, and antisense nucleotides)[70].

The anti-fibrotic effect of IFN, with the potential of reducing fibrosis and HCC, is the basis for its use as a maintenance therapy. A beneficial histological response (HR) was observed in all 3 trials with co-infected patients who did not achieve a SVR (Figure 3). In the ACTG and APRICOT studies, HR was defined as an improvement of ≥ 2 points in the HAI[3544], and an improvement of ≥ 1 point in the Metavir score in the RIBAVIC study[47]. Currently, other studies (SLAM-C and ENDURE) are in progress to confirm the role of maintenance therapy in HIV patients who fail anti-HCV treatment[71].

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Figure 3 A beneficial histological response was seen in 35% and 43%, respectively, in patients with no sustained virologic response (SVR) in the ACTG and APRICOT trials. Worsening histology was seen in 18% patients with no SVR in the APRICOT study; similar data were not available in the ACTG study. In the RIBAVIC study, histological worsening was seen in 23% without SVR while histology remained stable in the remaining patients.

Patients should be counseled on treatment compliance, and should be encouraged to consume a healthy diet. Patients should abstain from alcohol as HCV and alcohol have a synergistic effect on liver injury[72]. Patients with active substance abuse use should be enrolled in drug detoxification programs. Safe sex practices should be encouraged amongst high risk populations, such as multiple sexual partners, active sexually transmitted disease, and MSM. Patients should be instructed to report to their physician if they experience any unusual symptoms, and should avoid herbal or over the counter medications. Patients who are negative for anti-HBs and antibodies to hepatitis A virus (HAV) should be vaccinated against HAV and HBV[73].

PNAL is defined as the presence of at least 3 normal ALT values, each at least 2 mo apart, over a period of 12 mo. The prevalence of PNAL in co-infected patients is 8%-30%[74–76]. Although, the prevalence of stage 3-4 disease in patients with HCV mono-infection and PNAL was lower compared to patients with elevated ALT (5% vs 20%, P = 0.01), the prevalence was similar in co-infected patients (37% vs 32%, P =0.6)[77]. Five year follow-up of 27 co-infected patients with PNAL showed intermittent or persistent elevation of ALT in more than one third of the patients, with the development of decompensated cirrhosis in 2 patients and death in one patient[75].

Treatment of every co-infected patient with PNAL is a daunting task, with considerable expenditure of time and cost. Therefore, it is important to identify factors that may induce rapid FPR in these patients. Currently, it is recommended that treatment should be considered in highly motivated patients and/or those with GT-2/3 infection[29].

In the US, about 30 000 cases of acute HCV infection occur annually with increasing incidence in MSM[78–80]. The diagnosis is important since unrecognized infection tends to become chronic in 90%-95% co-infected patients[79]. The criteria for diagnosis are: elevation of ALT > 10 times the upper limit of normal (ULN), a positive HCV-RNA test and exposure to HCV during the preceding 2-12 mo[78]. A high index of suspicion is required, and acute HCV should be excluded before attributing the elevated of ALT to HAART.

The current data on the treatment of acute hepatitis C in HIV patients is limited to a few case studies with SVR of 59% to 91%[81–83]. The large difference in the response rates may be due to factors such as clinical presentation (anicteric vs symptomatic) and compliance with therapy. The timing of treatment in co-infected patients is not clear. In HCV mono-infection, a 12 wk waiting period is recommended to allow spontaneous clearance of the virus. Consideration should be given to early treatment of acute HCV in HIV patients because of a higher frequency of chronic disease. However, issues such as the timing of treatment, treatment with PEG-IFN alone, and the role of extended treatment can only be determined by properly conducted controlled trials. Until then, it is recommended that acute HCV infection in HIV positive subjects should be treated with PEG-IFN and RBV for a total of 24 wk, irrespective of the GT[14].

With the reduction in occurrence of opportunistic infections with the use of HAART, HCV-induced end-stage liver disease (ESLD) is now one of the leading causes of death (denominator effect) in these patients[84]. Indeed, HCV is considered as an OI in HIV patients[85]. The development of HCC is an important reason for high mortality in co-infected patients, and its incidence has increased from 4.7% in 1995 to 25% in 2000[86]. Whether co-infected patients with cirrhosis and end-stage liver disease (ESLD) should be screened for HCC every 6 mo or earlier is not clear. In one study, 5 of 8 patients diagnosed with advanced HCC were tumor negative 6 mo earlier[18]. Until more data on the screening interval and the factors that influence progression to HCC becomes available, we recommend that co-infected patients should be screened for HCC every 6 mo[87].

Previously, HIV infection was considered a contraindication for liver transplantation (LT). However, in the HAART era, the outcome after LT has improved considerably, with survival at 1 year and 3 years of 87%-91% and 64%-73% ,respectively[88]. A recent retrospective analysis of the United Network for Organ Sharing (UNOS) database showed that although the 2 year survival of HIV patients (n = 138) was inferior to HIV -ve patients (70% vs 81%), the survival was similar in HIV -ve patients and HIV +ve patients without HCV or HBV co-infection[89]. Similar poor outcome in HIV patients with concomitant HCV infection has been observed in other studies[8890–95]. Survival of co-infected patients was inferior to HCV mono-infected patients at 1 year, 3 years, and 5 years (68%-80% vs 76%-87%, 56%-57% vs 72%-81%, and 33%-51% vs 72%-81%, respectively)[889394]. Poor survival with co-infection has been attributed to the recurrence of HCV, which runs an aggressive course, with frequent development of fibrosing cholestatic hepatitis[93]. Moreover, the treatment of recurrent HCV is associated with inferior results (SVR of 27%-28%) compared with treatment of post-LT HCV recurrence in mono-infected patients[9396]. Other factors affecting post-LT survival were intolerance to HAART, CD4 < 200, HIV viral load > 400 cpm, African American race, and model of end-stage liver disease (MELD) score of > 20[8893]. Whether such patients should be treated with pre-emptive anti-HCV therapy or maintenance treatment is unclear. Moreover, the ethical consideration of performing LT in HIV/HCV patients is questionable given the short supply of organ donors in the US[97]. An NIH sponsored prospective study on OLT in co-infected patients reported 1 year and 3 year patient survival of 91% and 64%, with graft survival of 82% and 64%, respectively[98]. Based on these data, it can be concluded that OLT should be performed only on selected HIV patients in centers with adequate expertise.

The criteria for LT are the same as for HIV -ve patients, including abstinence from drugs for ≥ 2 years and abstinence from alcohol for ≥ 6 mo. HIV should be adequately controlled with VL < 400 cpm and CD4 > 100. OIs precluding LT are multifocal leucoencephalopathy and multi-drug resistant fungal infections[99]. The major issues after LT in co-infected patients are the interaction of HAART with immunosuppressive drugs and recurrence of HCV disease. Most of the immunosuppressive medications are metabolized by the cytochrome P450 system. Protease inhibitors, such as ritonavir, can reduce metabolism of calcineurin inhibitors (CIs), such as cyclosporine and tacrolimus. Therefore, the doses of CIs need to be reduced by about 50%-75% with concomitant administration of PIs. On the other hand, drugs like mycophenolate mofetil interact with nucleoside analogues with decreases in efficacy of zidovudine and stavudine and increases in activity of abacavir and didanosine[100].