AIDS-Related Kaposi's Sarcoma Can Occur during Peginterferon-α and Ribavirin Therapy for Chronic Hepatitis C Infection

Introduction

Management of patients infected by both HIV and hepatitis C virus (HCV) remains challenging. Peginterferon-α-2a (pegIFN-α-2a) in association with ribavirin (PegIFN/RBV) is still the backbone treatment for chronic HCV. Combined therapy remains the most efficient strategy to achieve sustained viral response (SVR), despite many side effects particularly in HIV-infected patients. Among them, interferon α-2a (IFN-α2a) therapy has been associated with the decline in CD4 counts ¹ and the development of opportunistic infections (OIs) such as Pneumocystis jiroveci pneumonia, cerebral toxoplasmosis, and oral candidiasis. ^1,2 Nevertheless, for patients with CD4 counts above 500 cells/mm³ and no imperative to begin highly active antiretroviral therapy (HAART), HCV treatment before HAART may avoid cumulative drug toxicity and drug interactions. ³ Interestingly, IFN-α has also been successfully used to treat AIDS-associated Kaposi's sarcoma (KS) in particular before HAART was available but may still today be useful in some patients especially when CD4 counts are above 300 cells/mm³. ^4,5

Case Report

We report here the case of a 50-year-old Caucasian homosexual man who developed KS 6 months after the onset of PegIFN/RBV for genotype 1a HCV infection. The patient had been diagnosed with both HIV and HCV infections in 1997 and had been treated by several different antiretroviral regimens, leading to multiple HIV drug resistance. He had never developed an AIDS-defining illness, and the CD4 count nadir was 350 cells/mm³. Highly active antiretroviral therapy had been stopped in February 2007 because of poor adherence and patient’s choice. CD4 counts remained high between 500 and 750 cells/mm³ (30%-35%). HIV plasma viral load was stable with a median of 4.1 (3.8-4.9) copies/mL from 2007 to November 2009. He was not taking any other medication, neither oral nor local, and had no other medical history. In November 2009, HCV treatment was started (week 0) because of Metavir stage F3 liver fibrosis on liver biopsy and sustained HCV viral replication, while CD4 counts were 541 cells/mm³ (31%) and HIV viral load 4.62 copies/mL. The patient was treated with 180 µg/wk PegIFN (Pegasys, Roche, France) and 800 mg/d ribavirin (Copegus, Roche). Treatment was well tolerated and viral control was reached by week 18 (HCV viral load < 43 UI/mL; Taqman Cobas, Roche).

At week 32, the patient noticed several skin lesions on the torso, abdomen, and palate, typical of KS. Two lesions of gastric KS were also evidenced by endoscopy. Diagnosis was confirmed by pathologic examination including positive staining for human herpesvirus 8 (HHV8). As the CD4 count was 195 cells/mm³ (26%) and the HIV viral load was 5.73 copies/mL, HAART was started by week 36, according to the resistance genotype combined with primary prophylaxis by cotrimoxazole. Peginterferon/ribavirin therapy was initially continued. In 1 month the CD4 count increased to 365 cells/mm³ (31%), while the HIV viral load was <20 copies/mL by week 46. Unfortunately, KS remained active, with new lesions appearing. Peginterferon/ribavirin was discontinued at week 63 (after 48 weeks of control of HCV replication). Finally, 2 courses of liposomal doxorubicine treatment were needed to eventually control KS (weeks 72 and 75). Unfortunately, less than a month after discontinuation of PegIFN/RBV, HCV infection relapsed.

We retrospectively determined, in plasma stored at −80°C, HHV8 serology using indirect immunofluorescence (antibodies against latent and lytic HHV8 antigens) and HHV8 DNA viral load using a real-time quantitative polymerase chain reaction described elsewhere (lower limit of quantification 100 copies/mL). ⁶ Human herpesvirus 8 immunoglobulin G (IgG) antibodies were present prior to the onset of PegIFNa/RBV therapy. Human herpesvirus 8 viral load before pegIFN/RBV was <100 copies/mL. Four weeks before the first KS lesions appeared, the HHV8 became detectable in plasma and progressively increased until the beginning of HAART (Figure 1). Six months after the onset of HAART, the HHV8 viral load was <100 copies/mL and remained so thereafter.

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Figure 1.

Plasma levels of HHV8 DNA, HIV-1 RNA, and CD4 count during peginterferon/ribavirin treatment and HAART. HHV indicates human herpesvirus; HAART, highly active antiretroviral therapy.

Discussion

Kaposi's sarcoma is an AIDS-defining illness associated with chronic HHV8 infection. The development of KS in HIV-positive patients is closely linked to the host T-cell immune status and in particular CD4 counts. Decrease in CD4 counts in HIV-infected patients treated by IFN-α for chronic hepatitis C infection has been described since the early 1990s. ¹ Thereafter, IFN-α therapy was not recommended in severely immunocompromised patients and immune restoration was warranted before starting HCV treatment. ⁴ Today, despite adequate control of HIV replication, PegIFN/RBV therapy in HCV-coinfected patients is associated with a decrease in total lymphocyte counts and in the absolute number of CD4 cells, similar to what occurred in our patient. ⁷ In the large randomized trials that permitted the approval of PegIFN/RBV association in HIV-HCV-coinfected patients, the occurrence of AIDS-defining illnesses was very rare (<1%), and no case of KS was ever reported despite a decrease in CD4 counts. ^8,9 Patients with controlled HIV replication are indeed at lower risk of developing OI, even when CD4 counts are low, ¹⁰ which was not the case for this patient. Recommendations concerning HIV treatment in coinfected patients before starting PegIFN/RBV are not straightforward when the CD4 counts are above 500 cells/mm³, though the guidelines recommend to start HAART between 350 and 500 cells/mm³ in case of HCV coinfection. ³ The Strategies for Management of Antiretroviral Therapy (SMART) study has taught us that HAART discontinuation puts patients at risk of developing AIDS and AIDS-related KS in particular. ¹¹ Nevertheless, to our knowledge, no case of onset of AIDS-associated KS has yet been described during PegIFN/RBV therapy.

Nevertheless, it is still surprising that PegIFN therapy was unable to prevent the occurrence of KS. Indeed, as soon as 1981, INF-α has been successfully used for the treatment of AIDS-associated KS itself. High-dose interferon (36 million units daily) was active against KS, whereas lower doses (3 million units daily) rarely induced KS regression. ¹² With the better understanding of KS physiopathology, a strong rationale for treating KS with interferon accumulated. Indeed, interferon is a strong inhibitor of angiogenesis, which is one of the main features of KS. Additionally, interferon has shown specific antiviral activity against HHV8 in vitro and in animal models. ¹³ In one report of HHV8 viral load measurement in 4 patients undergoing interferon therapy and HAART at different doses, for the treatment of KS, no specific anti-HHV8 activity of IFN was found in vitro. None of 5 patients showed durable clearance of HHV8 viral load from either plasma or peripheral blood mononuclear cells, although 1 patient experienced partial response. ¹⁴ Replication of HHV8 correlates with the clinical outcome of KS as witnessed in this case: HHV8 replication began before any KS lesion was visible. Increase in CD4 count, thanks to HAART, permitted the control of HHV8 replication.

Today, the incidence of KS has been markedly reduced with the availability of HAART, but PegIFN is still used with some efficiency in the management of refractory AIDS-related KS. ^4,5 The lack of HAART combined with a rapid decrease in absolute CD4 counts (despite a persistent satisfactory percentage), due to PegIFN treatment, was responsible for the development of KS in this HHV8-seropositive patient. Despite its potential activity on KS, PegIFN was unable to prevent the occurrence of KS and HHV8 replication.