Faculty Bibliography

OBJECTIVE: To identify baseline characteristics predictive of a sustained virological response (SVR) in patients with HIV-hepatitis C virus (HCV) co-infection treated with interferon-based therapy. DESIGN/METHODS: A stepwise multiple logistic regression analysis was used to explore the prognostic factors associated with SVR [undetectable HCV-RNA (< 50 IU/ml) at the end of untreated follow-up in week 72]. RESULTS: In all patients (n = 853), in addition to the HCV therapy received, the factors most predictive of SVR were baseline HCV-RNA [< or = versus > 400 000 IU/ml; odds ratio (OR) 4.77; 95% confidence interval (CI) 3.15-7.22; P < 0.0001] and HCV genotype (OR 2.87; 95% CI 2.00-4.12; P < 0.0001). HIV treatment (with a protease inhibitor or non-nucleoside reverse transcriptase inhibitor; P = 0.034), race (P = 0.027), and body mass index (P = 0.039) were also weak predictors of HCV treatment response. CONCLUSIONS: In the AIDS PEGASYS Ribavirin International Co-infection Trial (APRICOT), the predictors of SVR among HIV-HCV co-infected patients treated with peginterferon alfa-2a plus ribavirin were similar to those in patients with HCV mono-infection. The HCV genotype and pretreatment HCV-RNA level had the greatest influence on SVR

Coinfection with HIV and hepatitis B virus (HBV) substantially alters the natural course of HBV infection as well as its management. Therapy for HBV infection in HIV-coinfected patients requires several factors to be taken into consideration, such as whether the antiviral activity of a particular agent is specific for HBV (that is, adefovir, entecavir, telbivudine and pegylated interferon) or for both viruses (that is, lamivudine, emtricitabine and tenofovir), whether the chosen drug has the potential for inducing drug resistance and cross-resistance, and whether use of the agent is associated with hepatotoxicity. For coinfected patients who do not require therapy for their HIV infection, clinicians should avoid prescribing monotherapy with agents that have activity against HIV (that is, tenofovir, entecavir, emtricitabine or lamivudine) so as not to compromise future HIV care. This review discusses the current status of treatment of hepatitis B in the setting of HIV infection. It describes emerging therapeutic strategies and addresses challenges in the treatment of coinfection

BACKGROUND: In patients with chronic hepatitis B, long-term use of lamivudine is limited by resistance mutations. Adefovir dipivoxil has a very low rate of resistance, but there have been recent reports describing resistance mutations. Tenofovir disoproxil fumarate and emtricitabine show potent activity against wild-type and lamivudine-resistant hepatitis B virus. METHODS: We describe a series of seven HIV-seronegative patients who failed to achieve undetectable hepatitis B viral DNA on adefovir. No lamivudine resistance testing was performed. The antiviral regimen was changed to tenofovir (300 mg daily) and emtricitabine (200 mg daily). Variables collected included levels of hepatitis B viral DNA by polymerase chain reaction, alanine and aspartate aminotransferase, hepatitis B e antigen and hepatitis B e antibody. RESULTS: The median hepatitis B viral DNA level while on adefovir was 430,000 copies/ml with a median fall in hepatitis B viral DNA levels of 2.0 log10 copies/ml. Patients were on adefovir for a median period of 10 months before a change in regimen to tenofovir and emtricitabine. This regimen change resulted in a median fall in hepatitis B viral DNA levels of 3.0 log10 copies/ml (range, 2-4) after a median treatment duration of 23 months (range, 14-28). All patients (100%) had achieved undetectable hepatitis B viral DNA levels following combination therapy. Anti-hepatitis B e seroconversion occurred in one patient. No change in serum creatinine was observed during therapy, and no significant adverse events were reported. CONCLUSIONS: In patients failing to respond to adefovir monotherapy or an adefovir-containing regimen for chronic hepatitis B virus, a combination of tenofovir and emtricitabine resulted in undetectable hepatitis B viral DNA levels without any renal toxicity. Tenofovir, in combination with emtricitabine, may be an alternative treatment for those with detectable hepatitis B viral DNA on adefovir

Anaemia during peginterferon (PEG-IFN) and ribavirin (RBV) therapy is common in human immunodeficiency virus/hepatitis C virus (HIV/HCV)-coinfected patients despite the use of lower doses of RBV than are recommended for HIV-seronegative persons. In addition, concurrent zidovudine (ZDV) may exacerbate the anaemia caused by PEG-IFN and RBV. We retrospectively analysed the incidence of anaemia, RBV dose reduction and epoetin-alpha (EPO) use among coinfected patients treated with PEG-IFN and weight-based RBV (800-1400 mg/day) who enrolled in two clinical trials and had haemoglobin (Hb) levels assessed at baseline and after 4 and/or 12 weeks of HCV treatment. Overall, 217 patients were included; pre-treatment Hb levels (mean 14.7 g/dL) were similar in all patients, including ZDV users (29% of patients). After 4 weeks of therapy, the mean Hb decline was greater among ZDV recipients (3.13 g/dL) compared with those on other anti-retroviral treatment (ART) (2.13 g/dL) or on no ART (1.47 g/dL) (P < 0.0001). RBV dose reduction and EPO use were more common in patients taking ZDV compared with those not taking ZDV (P < 0.0001). RBV dose was not associated with Hb reduction, RBV dose reduction or EPO use. Virologic response after 12 weeks of therapy and the treatment discontinuation rate did not differ by ZDV use. The use of ZDV but not weight-based RBV dosing was associated with an increased risk of anaemia, RBV dose reduction or EPO use in coinfected patients treated with PEG-IFN/RBV. However, ZDV use was not associated with higher rates of treatment discontinuation or lower early virologic response rates. HIV and hepatitis C care providers should be cognizant of these data

Chronic hepatitis B (CHB) is an important public health problem worldwide and in the United States, with approximately 25% of patients infected as neonates dying prematurely from cirrhosis or liver cancer. A treatment algorithm for CHB previously developed and published by a panel of United States hepatologists was revised based on new developments in the understanding of CHB, the availability of more sensitive molecular diagnostic testing, the addition of new treatments, and better understanding of the advantages and disadvantages of approved therapies. This updated algorithm is based on available evidence using a systematic review of the scientific literature. Where data are lacking, the panel relied on clinical experience and consensus expert opinion. Serum HBV DNA can be detected at levels as low as 10 IU/mL using molecular assays and should be determined to establish a baseline level before treatment, monitor response to antiviral therapy, and survey for the development of drug resistance. The primary aim of antiviral therapy is durable suppression of serum HBV DNA to the lowest levels possible. The threshold level of HBV DNA for determination of candidacy for therapy is 20,000 IU/mL or more for patients with hepatitis B e antigen-positive CHB. A lower serum HBV DNA threshold of 2000 IU/mL or more is recommended for patients with hepatitis B e antigen-negative CHB, and 200 IU/mL or more for those with decompensated cirrhosis. Interferon alfa-2b, lamivudine, adefovir, entecavir, and peginterferon alfa-2a all are approved as initial therapy for CHB and have certain advantages and disadvantages. Issues for consideration include efficacy, safety, incidence of resistance, method of administration, and cost

BACKGROUND: A multinational trial (APRICOT) showed that peginterferon alfa-2a (40kDa) plus ribavirin is efficacious for treatment of HIV-HCV co-infection. The cost-effectiveness of treating these patients with peginterferon alfa-2a/ribavirin has yet to be explored from a US societal perspective. OBJECTIVE: To predict the cost-effectiveness of peginterferon alfa-2a/ribavirin with interferon/ribavirin (IFN/RBV) or no treatment in HIV-HCV co-infected patients. STUDY DESIGN: A Markov model was constructed with liver progression estimates based on published literature. Sustained virological response and baseline characteristics of the reference case were based on APRICOT. Quality of life and costs in 2004 US dollars (US$) were based on literature estimates and discounted at 3%. RESULTS: Peginterferon alfa-2a/ribavirin compared with IFN/RBV or no treatment is predicted to increase quality-adjusted life-years (QALYs) by 0.73 and 0.94 years, respectively, in HCV-genotype-1 patients. The incremental cost-effectiveness ratio of peginterferon alfa-2a/ribavirin compared with IFN/RBV and no treatment for all patients is respectively US$ 2,082 and 5,187/QALY gained. CONCLUSIONS: Anti-HCV treatment is predicted to decrease the risk of cirrhosis and increase quality-adjusted survival of HIV-HCV co-infected patients compared with IFN/RBV and no treatment. Peginterferon alfa-2a/ribavirin's cost per QALY gained relative to these options falls within the cost-effectiveness level of many health technologies commonly adopted in the US

OBJECTIVE: To evaluate the prevalence of and risk factors for immune recovery uveitis (IRU) in eyes of patients with AIDS and cytomegalovirus (CMV) retinitis. DESIGN: Enrollment data from a 19-clinical center cohort study. PARTICIPANTS: Three hundred seventy-four patients with AIDS and CMV retinitis affecting 539 eyes. METHODS: Patients with AIDS were enrolled at 19 United States AIDS ophthalmology clinics. Data were collected by interview, review of medical records, ophthalmic examination, and phlebotomy. MAIN OUTCOME MEASURE: Immune recovery uveitis. RESULTS: Thirty-six patients (9.6%) were diagnosed with IRU involving 50 eyes. The CD4+ T-cell count of 31 of these had risen by > or =50 cells per microliter above nadir to a level > or = 100 cells per microliter (immune recovery), making up 17.6% of the patients known to have immune recovery after diagnosis of CMV retinitis (95% confidence interval, 12.3%-24.1%). No patients with IRU were observed to have active retinitis or detectable CMV DNA in peripheral blood (P<0.001 and P<0.001 with respect to patients without IRU). Other factors associated with IRU were > or =25% retinal area (odds ratio [OR], 2.72; P = 0.014) or posterior pole involvement with CMV retinitis (odds ratio, 0.43; P = 0.039), treatment with intravitreous injection of cidofovir (OR, 10.6 with respect to eyes never exposed to intravitreous or IV cidofovir; P<0.001), and male gender (OR, 0.26; P = 0.012). More eyes with IRU had visual acuity (VA) of 20/50 or worse (38.0% vs. 26.3%, P = 0.077) relative to eyes without IRU, but the proportions with VA of 20/200 or worse were similar (14.0% vs. 13.8%, P = 0.96). Eyes with IRU more commonly had cystoid macular edema (CME) (45.5% vs. 3.7%, P<0.001) and epiretinal membrane (48.9% vs. 13.3%, P<0.001) than eyes without IRU. CONCLUSIONS: Among eyes of patients with immune recovery, the prevalence of IRU is substantial. Eyes with IRU have a high risk of additional morbidity over and above that seen with CMV retinitis, with several-fold higher risk of CME and epiretinal membrane. Large CMV lesions and use of intravitreous cidofovir are risk factors for IRU

The current recommendation for the duration of treatment of patients infected with chronic hepatitis C virus (HCV) genotype 1 is 48 weeks; however, the standard regimen of peginterferon plus ribavirin bears significant adverse effects, which make completion of treatment exceedingly difficult. Reported here are 2 cases of HIV-HCV-coinfected genotype-1 patients who discontinued treatment early (after 3 and 8 weeks) because of adverse effects yet had a sustained virologic response with undetectable HCV viral loads at follow-up

Coinfection of hepatitis C virus (HCV), hepatitis B virus (HBV), and HIV is common due to shared modes of transmission. These coinfections accelerate the course of chronic liver disease and facilitate progression to cirrhosis and hepatocellular carcinoma. The viral interactions between these viruses are complex, and their treatment may be challenging for clinicians