HCV Treatment in HIV-infected Patients

Treatment options for HCV

Dr. David Thomas, from Johns Hopkins University (Baltimore) stated that pegylated IFN plus ribavirin (RBV) is currently the optimal therapy for HCV infection irrespective of HIV status. This has been proven by several randomized studies, showing superiority of pegylated over standard IFN, and of pegylated IFN plus RBV over pegylated IFN monotherapy [19-22].

Common also to HCV-monoinfection, genotypes 2 and 3, and patients with lower baseline viral load ( HCV RNA  ≤ 5.9 log₁₀ IU/mL in the APRICOT study and ≤ 5.7 log₁₀ IU/mL in the RIBAVIC study) respond better [19-22]. In like manner, the value of a 2-log decrease in HCV RNA at 12 weeks versus baseline levels to predict sustained virological response (SVR) is applicable to the HIV-infected population as well. Elevated ALT and age under 40 have been also found to be associated with SVR [21]. However, CD4 counts (although only a few with < 200 CD4 cells were included), weight, and liver histology did not predict SVR in these studies [19, 22].

The results of the four randomized studies evaluating pegylated IFN in HIV/HCV-coinfected patients range from 27% to 40% [19-22]. These different results may be explained by study-to-study differences, person-to-person differences (genotype, age, viral load, race, weight, treatment tolerability, etc..), and by the presence of mitigating factors such as alcohol intake, ongoing intravenous drug use, CD4 counts < 200 cells/mm³, renal failure, and anemia.

Interactions between RBV and some antiretrovirals

HCV treatment in the presence of HIV-infection is more complicated due to the interactions between RBV and some antiretrovirals. This issue was addressed by Dr. Christian Perronne from the University of Versalles (France).

Intracellular levels of some NRTIs are decreased by RBV, but the interactions have no clinical consequences. However, higher toxicity has been seen with the concomitant use of didanosine (ddI) and RBV, and even more when stavudine (D4T), ddI and RBV are used together. This is due to the enhancement of mitochondrial toxicity.

Hepatic decompensation, sometimes with fatal outcome [23] has been described with the co-administration of these drugs in cirrhotic patients. Besides this adverse event, lactic acidosis and pancreatitis have been reported with the combined use of RBV and ddI, and therefore ddI should be avoided in patients receiving anti-HCV therapy [1].

Dr. Perronne also recommended avoiding zidovudine (AZT) in anemic patients at initiation of anti-HCV therapy. AZT might be continued in those subjects without anemia, but they should be closely followed-up within the first 6 weeks of therapy, and epoetin alfa used if needed.

Candidates for HCV therapy

Dr. Vincent Soriano (Hospital Carlos III, Madrid, Spain) undertook the task of defining the candidates for HCV therapy. He stated that all HIV-infected patients with active HCV infection should be considered candidates for treatment, based on the accelerated progression of the HCV-related liver disease in this setting. According to a study presented at the 12th CROI [February 22-25, 2005, Boston], 26% of subjects with mild fibrosis (£ F1 Ishak score) on the first biopsy experienced a 2-stage progression in a repeated biopsy [24].

However, according to recent studies, both the eligibility of HIV/HCV-coinfected subjects for HCV treatment (< 30%), and the proportion of patients actually receiving therapy (<10%) are very low [25,26]. Therefore, efforts are needed to increase the suitability of the coinfected population to be treated for HCV.

Dr. Soriano mentioned that high alcohol intake and active drug use are contraindications for HCV treatment, and in those cases, efforts should focus on detoxification programs. Present or past major psychiatric disorders, and advanced cirrhosis also contraindicate IFN-based treatment.

Regarding HIV infection, stable disease is required, but patients may be under HAART or not. There is no agreement as to the influence of CD4 counts on response to anti-HCV therapy, and not enough data regarding safety of IFN with low CD4 counts. 

For the assessment of candidates to receive anti-HCV treatment, Dr. Soriano stated that liver biopsy should not be mandatory. If liver histology is deemed necessary, he proposed the performance of two non-invasive tests to assess liver damage, FibroScan® and Serum markers, and only in cases of discordance to perform a liver biopsy.

Algorithm for the treatment of HCV in HIV/HCV-coinfected patients.

Dr. Mark Sulkowski, Johns Hopkins University, Baltimore (US) was in charge of presenting an algorithm for the treatment of HCV in HIV/HCV-coinfected patients. He first summarized the consensus and the contentious issues at the moment (table 5), and then addressed the contentious ones.

Table 5. Consensus and contentious issues regarding anti-HCV therapy in HIV-infection.

ART: antiretroviral therapy

Dr. Sulkowski agreed with Dr Soriano that liver biopsy is not mandatory prior to treatment. Liver biopsy should be used to discard patients with minimal fibrosis, but based on his recent study mentioned above, maybe also those patients should be treated [24].

The effect of alcohol on response to treatment is not known since drinkers have been excluded from the studies. ART had no impact on response to HCV therapy in the APRICOT study, but patients taking PI had lower SVR in the RIBAVIC study [19, 22].

Higher doses of RBV (1,000-1,200 mg/day versus 800 mg/day) have been shown to be more effective in HCV-monoinfected patients with genotype 1 [27]. There are limited data on the safety and efficacy of RBV doses above 800 mg/day in the HIV/HCV-coinfected population, but in one study RBV was given at weight-based dosages (800-1,200 mg/day) without safety concerns [21].

Two recent reports at the 12th CROI [February 22-25, 2005, Boston.] showed higher early and sustained responses in HIV/HCV-coinfected subjects with higher RBV plasma levels, suggesting that also in this setting it is important to maximize the exposure to RBV [28,29].

Higher relapse rates have been reported for HCV-2 and -3 treated for 24 weeks in non-randomized trials, suggesting that longer courses of therapy might be required for these genotypes in the HIV/HCV-coinfected population [30]. More recently, in the randomized trials, 48 weeks of therapy were given to all genotypes. Extended duration for HCV-1 and HCV-4 has also been proposed to increase SVR, but 72 weeks of therapy might increase toxicity and treatment discontinuations.

For non-responders Dr. Sulkowski proposed waiting in cases of minimal disease, and retreat those patients with significant disease with high induction doses of pegylated IFN and RBV in an attempt to achieve SVR, or giving maintenance therapy with low doses of pegylated IFN to reduce liver disease progression.

The rationale to give long-term maintenance pegylated IFN monotherapy is based on the report of histological improvement in 35% of HIV-infected patients failing anti-HCV therapy [20].

For relapsers, extended courses of therapy, higher doses of RBV, and waiting for new drugs are reasonable approaches.

In his treatment algorithm for HCV, Dr. Sulkowski recommended treatment for all HIV/HCV-coinfected patients in whom potential benefits outweighed the risks.

Following guidelines in HCV-moninfection, pegylated IFN should be given combined with RBV at dosages of 800 mg/day for HCV genotypes 2 and 3, and at dosages of 1,000-1,200 mg/day for genotypes 1 and 4 [31].

Safety of anti-HCV therapy

Dr Stefan Mauss (Centre for HIV and Hepatogastroenterology, Düsseldorf, Germany) reviewed the safety of anti-HCV therapy.

Anemia, the most limiting side effect of RBV, might be overcome by the use of epoetin, but large prospective controlled trials are lacking [32].

The new RBV-like drug under development, viramidine, which produces less anemia, is promising [33]. Neutropenia, could also be treated with G-CSF, but Dr Mauss stated that there is no data to support its use. In addition, the occurrence of bacterial infections seems to be infrequent (<2% in the APRICOT study).

He also underlined the importance of the psychiatric side effects, among the most limiting side effects of IFN. Patients with minor psychiatric disorders may be treated for HCV, but they may need preemptive antidepressants before initiating IFN, and should be appropriately followed, preferably by a psychiatrist.

As future research needs in the HCV treatment area, the following were proposed by the speakers:

• Improve outcomes with currently available medications;
• Develop new antiviral compounds that are safer and more efficacious;
• Refine the management of psychiatric and hematological side effects;
• Assess the role of the new drug viramidine;
• Tailor therapy according to early virological response; and

Evaluate treatment of patients with persistently normal transaminases, with low CD4 counts, with acute HCV infection, and of relapsers and non-responders.

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