Bongiovanni, Marco MD; Ranieri, Roberto MD; Casana, Maddalena MD; Tordato, Federica MD; Cicconi, Paola MD; Tincati, Camilla MD; Bini, Teresa MD; Monforte, Antonella d'Arminio MD
Clinic of Infectious Diseases San Paolo Hospital University of Milan Milan, Italy
To the Editor:
The use of highly active antiretroviral therapy (HAART) has been associated with an increased frequency of insulin resistance (IR) and of its clinical correlates, such as glucose intolerance and type-2 diabetes.1 A direct role of protease inhibitors (PIs) has been proposed;2 however, traditional risk factors for IR other than HIV infection and HAART use may also predict glucose intolerance or type-2 diabetes in HIV-infected population.3
In the general population, a correlation between hepatitis C virus (HCV) infection and IR has been demonstrated;4 the possible mechanisms at the basis of this finding seem to be increased tumor necrosis factor (TNF) production, together with the enhancement of suppressor cytokines (SOC-3), both blocking PI3K and Akt phosphorylation.5 In HIV-negative patients with chronic HCV receiving pegylated interferon plus ribavirin, IR, as measured by the hemostatic model of assessment (HOMA) index, has been related to the 6-month virologic response. In addition, subjects with a sustained virologic response had lower HOMA values compared with others.6,7 Whether IR represents a marker of difficult-to-cure subjects or whether it acts through a pathogenic mechanism by blocking the antiviral activity of interferon is unknown.8
HCV infection is often a comorbidity in HIV-infected subjects, especially if they are intravenous drug abusers.9 It has often been associated with IR and hyperglycemia in HIV-infected patients receiving HAART.10
At the moment, few data are available on the role of IR in influencing the virologic response to anti-HCV treatment in the HIV-infected population. The aim of this study is to evaluate the correlation between IR and early virologic response (EVR) in HIV/HCV-coinfected subjects receiving pegylated interferon plus ribavirin.
We included in this study 29 consecutive HIV-infected subjects followed at our clinic who started an anti-HCV treatment with pegylated interferon α-2a plus ribavirin (at a dosage of 1000 to 1200 mg according to body weight) in January 2006. The following variables were collected at baseline (time of starting anti-HCV treatment): gender, age, race, body mass index (BMI), platelet count, aspartate aminotransferase (AST), alanine aminotransferase (ALT), serum glucose, insulin, total cholesterol, triglycerides, CD4 cell count, HIV RNA level, HCV RNA level, HCV genotype, and use of HAART (defined as use of ≥2 nucleoside reverse transcriptase inhibitors with any PI or nonnucleoside reverse transcriptase inhibitors). Serum insulin levels were measured by electrochemiluminescence immunoassay using an autoanalyser (Elecsys 1010/2010; Elecsys Modular Analytics E170; Roche, Basel, Switzerland). HIV-RNA load was assessed using the reverse transcriptase (RT) polymerase chain reaction (PCR), with a detection limit <60 copies/mL (Arthus Qiagen, Heiden, Germany). Qualitative PCR analysis for HCV was performed by nested PCR (Amplicor Roche, Basel, Switzerland; detection limit <15 IU/L). HCV genotyping was performed using a line-probe assay (INNO-LiPA HCV II; Immunogenetics, Belgium). IR was calculated through the HOMA equation: fasting insulin (mIU/L) × fasting glucose (mmol/L)/22.5.11 IR was defined as a HOMA value >3.8, according to other studies on white populations with low risk for diabetes.12 EVR was defined as HCV RNA level <15 IU/mL after 3 months of anti-HCV treatment; additionally, we evaluated the rapid virologic response (RVR), defined as HCV RNA level <15 IU/L after 1 month of anti-HCV treatment. Differences between variables were calculated using the χ2 and Student t tests when appropriate.
Table 1 shows the demographics and clinical characteristics of the subjects included in our study according to the HOMA values at baseline. All the patients were white. Ten subjects (34.5%) had a HOMA index >3.8, and 19 (65.5%) had values ≤3.8. No statistically significant differences were observed in the 2 groups according to the variables considered. After 3 months of anti-HCV treatment, median AST and ALT levels decreased in both groups. In subjects with IR at baseline, median AST and ALT levels decreased from 109 (interquartile range [IQR]: 60 to 141) IU/L to 54 (IQR: 42 to 65) IU/L (P < 0.01) and from 105 (IQR: 76 to 124) IU/L to 53 (IQR: 45 to 88) IU/L (P < 0.01), whereas in subjects without IR, AST and ALT levels decreased from 108 (IQR: 61 to 147) IU/L to 37 (IQR: 30 to 50) IU/L (P < 0.01) and from 101 (IQR: 68 to 109) IU/L to 33 (IQR: 27 to 48) IU/L (P < 0.01), respectively. RVR was achieved in 8 (42.1%) of 19 subjects without IR and in 0 of 10 with IR at baseline (P < 0.001); EVR was observed in 16 (84.2%) of 19 subjects without IR and in 0 of 10 with IR (P < 0.001). The 3 subjects who did not achieve EVR had genotype 1a, 3a, and 4c/4d, respectively.
HCV infection and HAART are conditions associated with a higher probability of developing IR. Such a condition is a known predictor of reduced sustained virologic response to anti-HCV treatment in HCV-infected subjects. Conversely, the achievement of RVR and EVR is a strong predictor of recovery from HCV infection; therefore, subjects who do not achieve this endpoint may be discontinued from anti-HCV treatment because of a low probability of sustained virologic response.13
In the present study, including only HIV/HCV-coinfected subjects, we found that subjects without IR at baseline are more likely to reach RVR and EVR than the others. Also, in subjects with genotype 3, which is known to respond better to anti-HCV treatments,13 the presence of IR does not allow for the achievement of RVR or EVR. These results, obtained on a limited number of subjects, suggest that IR should always be evaluated before starting anti-HCV treatment. Therefore, the correction of IR, and the consequent recovery of insulin sensitivity, could improve RVR and EVR in the HIV/HCV-coinfected population treated with pegylated interferon and ribavirin, and thus should be tentatively attempted before initiating such a regimen.
Marco Bongiovanni, MD
Roberto Ranieri, MD
Maddalena Casana, MD
Federica Tordato, MD
Paola Cicconi, MD
Camilla Tincati, MD
Teresa Bini, MD
Antonella d'Arminio Monforte, MD
Clinic of Infectious Diseases San Paolo Hospital University of Milan Milan, Italy
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© 2008 Lippincott Williams & Wilkins, Inc.