Outcome of HCV Genotype 1 Treatment in HIV-Coinfected Patients with Chronic Kidney Disease

Abstract

Chronic renal insufficiency is a barrier for the treatment of hepatitis C virus (HCV), and yet virus clearance is desirable prior to kidney transplantation. Several reports document success of kidney transplantation in the setting of HIV infection. We analyzed the treatment outcome of patients with HIV and HCV genotype 1 infections and chronic kidney disease, who received pegylated interferon with or without ribavirin in our center. Of the 7 patients, 2 achieved sustained virological response. None of the responders had end-stage renal disease, suggesting that HCV treatment is most likely to be successful in earlier stages of renal disease.

Treatment of chronic hepatitis C virus (HCV) infection in HIV-coinfected patients is complicated by toxicities associated with interferon, ribavirin, and poor response. ¹ Since ribavirin is slowly eliminated from the body with a substantial renal component, chronic kidney disease (CKD) confers increased risk of accumulation and anemia. ² The objective of this retrospective study was to assess the outcome of HCV treatment with pegylated interferon with or without ribavirin in HIV-coinfected patients with CKD.

Approval by the local institutional review board was obtained. Baseline data included demographics, CD4 counts, HIV RNA, blood cell counts, renal function tests, transaminases, HCV RNA, HCV genotype, albumin, prothrombin time, and results of liver biopsy and image studies. Treatment data included doses of pegylated interferon and ribavirin, indices of hematological toxicity, major side effects, and virological response (HCV RNA determinations at weeks 4 [if available], 12, 24, and 48 of treatment, and 24 weeks after treatment discontinuation). Futility rules at weeks 12 and 24 of treatment were applied. Data are presented as means (range) for continuous variables.

Of the 265 patients with chronic HCV and HIV infections in the HIV database, 95 had elevated creatinine, 7 of whom met the following criteria for this study: CKD stage II or more as defined by the National Kidney Foundation of glomerular filtration rate <60 mL/min/1.73 m² for ≥3 months ³ and treated with pegylated interferon between January 2005 and December 2010. Table 1 summarizes patients’ characteristics and HCV treatment data. Of the 7 patients, all but 1 were African American and their mean age was 52 years (range, 42-61 years). Time since diagnosis of HIV infection ranged from 4 to 20 years. All were on highly active antiretroviral treatment ([HAART] duration 6 years; range, 2-10 years) except for 1 patient. Mean CD4 nadir was 182 cells/mm³ (range, 20-410 cells/mm³). All patients carried HCV genotype 1 and had liver synthesis function preserved. Steatosis was identified in 2 participants. The degree of renal insufficiency varied, but all patients had proteinuria, and 3 were on hemodialysis because of end-stage renal disease (ESRD). Evaluation for kidney transplantation prompted HCV therapy in 2 cases. Two patients received renal transplants after HCV treatment failure.

Table 1.

Patients’ Characteristics and HCV Treatment Data.

Patient	Race, sex	Age, y	GFR at Treatment Baseline, CKD Class	HCV RNA, IU/mL	METAVIR Score	Year of HCV Therapy	Weeks of Therapy	Pegylated Interferon alfa, mcg/wk	RBV Dose Titration, mg/d a	RVR	EVR	CD4, cells/mm3, Before/After	HGB drop, g/dL
1	Black, F	44	<10, V	1 741 000	A1F1	2009	12	2a 135	200→100→30	N	N	510/320	3.9
2 b	Black, M	58	30, III/IV	259 000	–	2006	48	2a 180	200→400→600	N	Y	120/90	5.2
3	Black, M	61	<10, V	7 000 000	A2F1	2006	12	2b 80	None	N	N	470/390	3
4	Black, M	50	<10, V	167 900	A2F1	2007	12	2a 135	200	N	N	520/120	5.6
5	Black, M	54	58, III	2 110 000	A2f3	2009	24	2b 120	1000→600→400	N	N	630/330	5.4
6	White, TG (M to F)	54	39, III	703 200	A1F3	2010	8	2b 94	400	N	N	480/480	3
7 b	Black, M	42	60, II	79 360	A1F2	2010	48	2b 120	1200→1000→400	Y	Y	330/280	5.1

Abbreviations: CKD, chronic kidney disease; EVR, early virologic response F, female; GFR, glomerular filtration rate; HCV, hepatitis C virus; M, male; RVR, rapid virologic response; SVR, sustained virologic response; TG, transgender.

^a Arrow indicates the monthly dose adjustments.

^b Patients with SVR.

In all, 4 patients were treated with pegylated interferon alfa-2b and 3 with pegylated interferon alfa-2a. Ribavirin was not given to 1 patient with ESRD, and the remaining received dosages from 200 to 1200 mg daily. Mean hemoglobin drop was 4.5 g/dL (range, 3-5.6 g/dL). The 3 patients on hemodialysis were receiving epoetin (EPO) as part of CKD management. In all, 4 patients underwent decreases in ribavirin dose, based on hemoglobin levels. Patient #1 received a transfusion because of severe anemia. Pneumocystis prophylaxis was given in 1 case because of low CD4 counts. Treatment was interrupted based on futility rules in 5 patients. In all, 2 patients achieved sustained virologic response (SVR) after 48 weeks of therapy. One of the 2 patients who eventually achieved SVR had rapid virologic response and the other achieved undetectable viral load by week 12 of treatment.

A relative increase in the number of deaths in HIV-HCV-coinfected patients in the post-HAART era has been reported. ^4,5 Patients with ESRD with HCV also have increased mortality because of liver disease. ^{6 –8} After kidney transplantation, HCV infection is associated with decreased graft and patient survival. ⁷ Since kidney transplantation has been successful in HIV-infected patients, efforts to eradicate HCV are of utmost importance to improve survival in patients with HIV-HCV and CKD. Response to standard HCV therapy, that is, combination of pegylated interferon alfa and ribavirin, is impaired in HIV-HCV-coinfected patients. ¹ In CKD, elimination of ribavirin is reduced, increasing the risk of anemia, and adequate plasma levels are not achieved in ESRD. ² Most patients in our study were of African American descent, an additional factor that makes response to HCV treatment less likely. ⁹ Nonetheless, 2 patients of 7, who were African American, achieved SVR.

Consistent with previous reports, individuals who cleared their HCV had relatively low levels of HCV replication and were treated with maximum doses of pegylated interferon. ¹⁰ It is noteworthy that none of the patients with ESRD and on hemodialysis achieved SVR, suggesting that patients with CKD should be treated for HCV early on. Connected with this, our study suggests that the presence of ribavirin is an important component of the treatment, as reported in non-HIV patients with CKD and in HIV-HCV-coinfected patients. ^{2,6,11 –13} Our group was heterogeneous in the degree of renal insufficiency and in the doses of ribavirin and in the way it was used. While most patients underwent downward titration in dose, upward titration was employed for 1 patient, a strategy previously reported. ¹¹ Some experts select pegylated interferon alfa-2a because of its partial clearance by nonrenal mechanisms ^11,14,15 ; however, both interferons alfa-2a and alfa-2b were used in our series. Severe adverse events occurred but were not in any case the reason for therapy discontinuation, supporting the notion of treatment feasibility in this setting. Like in other studies, anemia required several approaches including EPO use, dose reduction, and transfusion. ^2,11

Our study has several limitations such as the heterogeneity of patients with varied degrees of renal insufficiency and diverse treatment approaches. Interleukin (IL)-28b polymorphisms were not assessed, however, being that most of our patients were of black ethnicity, we assume that unfavorable IL-28b polymorphisms were most prevalent in our series. Because of small sample size, inferences cannot be made on optimal dosages of interferon or ribavirin. Addition of HCV direct-acting antivirals to the current standard of care will likely improve outcomes, but the safety and efficacy of these therapies has not been studied in the setting of renal insufficiency. Additional studies are needed to clarify the above issues.

In summary, to our knowledge, this is the first report on the management of HIV-coinfected patients with renal disease undergoing anti-HCV treatment. The challenges posed by patients with HIV, HCV, and CKD for HCV therapy explain the small sample of our study. Although only a minority of patients responded, following the treatment futility rules we identified the patients who benefited from it while medication exposure in the nonresponders was minimized. None of the responders had ESRD, suggesting that HCV treatment is most likely to be successful in earlier stages of renal disease. While changes in ribavirin doses were frequent, there were no treatment discontinuations due to anemia, suggesting that larger investigations are possible from a toxicity standpoint. This is likely justified, even in the absence of significant liver fibrosis, since HCV treatment in anticipation of kidney transplantation will likely improve survival in patients with HIV, HCV, and CKD.