Saturday, May 27, 2023
This year, the 45th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) in Washington, DC, clearly had an emphasis on the ongoing controversies and challenges in clinical management of HIV/hepatitis coinfection, which led to numerous presentations in the HIV as well as hepatitis slide sessions and symposia, and also was evaluated in studies in a poster session. Current research is particularly focused on addressing the question of how overall virologic success can be improved in HIV and hepatitis coinfection.
The APRICOT trial[1] has demonstrated that HIV/HCV-coinfected patients can be successfully treated with pegylated interferon and ribavirin, although overall virologic success rates are lower than those observed in patients with hepatitis C monoinfection. Three further analyses of this trial were presented at the 45th ICAAC. The first, by Sulkowski and colleagues,[2] showed that the highest sustained virologic response rates were obtained in the peginterferon alfa-2a + ribavirin arm in APRICOT, even though growth factor use and dose modifications occurred more often in this group. Because no guidelines were provided within the study on when and how to use growth factors, and overall only 13% of study subjects received supportive treatment with growth factors, the implications of these data for clinical care are limited.
The most interesting subanalysis from APRICOT was presented by Opravil and coworkers,[3] who studied the effect of treatment exposure on achieving sustained virologic response (SVR). They found that among HIV/HCV-coinfected patients with HCV genotype 1 who were treated with peginterferon alfa-2a + ribavirin, overall SVR increased from 29% to 39% among those patients with a treatment exposure of at least 80/80/80. (Note: 80/80/80 is shorthand for receipt of 80% of planned ribavirin dose, 80% of planned peginterferon alfa-2a dose, and 80% of planned total treatment duration.)
It is important to recall that in the APRICOT trial, lower ribavirin dosages of just 800 mg were administered to all study subjects -- regardless of genotype -- because of the concern about drug-drug interactions between ribavirin and some regularly used anti-HIV medications. This prompted investigators to consider whether higher ribavirin dosages, such as those recommended in HCV monoinfection, would lead to superior treatment success rates, particularly in genotype 1 patients.
This group also found that in genotype 2/3 patients, overall SVR increased from 59% to 69% among those patients who had a cumulative treatment exposure of at least 70/70/70. Further multiple regression analysis in HCV genotype 1 patients identified baseline HCV RNA and higher body mass index (BMI), as well as reduced treatment exposure, as predictive factors for a reduced SVR rate. The study authors concluded that in order to maximize SVR in genotype 1 patients, 80% of cumulative ribavirin and peginterferon doses should be taken by the patient, and 80% of the duration of treatment should be completed.
Another APRICOT subanalysis presented by Torriani and colleagues[4] looked at the value of early HCV virologic response as a predictor for SVR. Virologic response was defined as at least a 2-log drop in HCV RNA, or HCV RNA negative. Of interest, the positive predictive value was highest for early (week 4) virologic response; 82% of patients with HCV genotype 1 and 94% with HCV genotypes 2/3 were undetectable. The negative predictive value at week 12 remained the best predictor of nonresponse. These data clearly show that HIV/HCV-coinfected patients need HCV treatment for 12 weeks before it is determined whether treatment should be discontinued, as the probability of subsequent virologic response is best assessed by response at this time point.
Tural and associates[5] from Spain presented an interesting late-breaker in which they studied the effect of an increased induction dose of peginterferon on early HCV kinetics in HIV/HCV-coinfected subjects. HIV/HCV patients who were naive to interferon/ribavirin and who had CD4+ cell counts > 200 cells/mcL and elevated alanine transaminase (ALT) were randomized to receive 2 different dosages of peginterferon (270 micrograms [n = 58] vs 180 micrograms [n=60]) subcutaneously once weekly plus ribavirin 1000 mg/1200 mg daily for the first 4 weeks, which was followed by peginterferon 180 micrograms per week and ribavirin 1000 mg/1200 mg daily. Intent-to-treat virologic response at week 12 (defined as negative HCV-RNA or ≥ 2-log drop in HCV RNA) did not differ between the induction and the control arms of the study (69% vs 67.8%). Further subanalyses looking at SVR in different HCV genotypes also could not detect any difference in HCV kinetics between both study arms. Overall, a higher decrease in hematologic parameters -- such as platelets, leukocytes, and neutrophil counts -- occurred from baseline to week 4 in the induction arm of the study. However, this did not lead to a significantly higher discontinuation rate, which at week 12 was 5.4% in the induction arm vs 10% in the control arm. This study suggests that higher interferon doses during the first weeks of HCV therapy will not help to improve overall SVR rates in HIV/HCV-coinfected patients.
A study by Rendon and others[6] determined ribavirin plasma concentrations throughout hepatitis C therapy. Patients (n = 98) achieving SVR under peginterferon and ribavirin had significantly higher ribavirin levels compared with those who did not (3.2 vs 2.7 micrograms/mL; P < .001). In a multivariate analysis, both ribavirin drug level (odds ratio = 3.2; 95% confidence interval: 1.4-7.2; P = .006) and HCV genotype 3 (odds ratio =1.9; 95% confidence interval: 1.1-3.5; P = .03) were independent predictors of SVR. The study authors concluded that therapeutic drug monitoring might help to tailor ribavirin dosages and improve the efficacy of anti-HCV treatment.
Hepatitis B virus (HBV) also remains an important coinfection that is often observed in persons with HIV. Following the first presentation of 24-week efficacy and safety data of entecavir in HIV/HBV-coinfected patients at the Conference on Retroviruses and Opportunistic Infections (CROI) this year, further follow-up of this study up through week 48 was shown at the 45th ICAAC.[7] Entecavir is a potent selective inhibitor of HBV polymerase and has no HIV activity, no mitochondrial toxicity, and no impact on cytochrome P450. HIV/HBV-coinfected patients with at least 24 weeks of prior lamivudine treatment and rebound HBV viremia were randomized to the addition of entecavir 1.0 mg (n = 51) or placebo (n = 17). At 24 weeks, entecavir was superior to placebo in reducing baseline HBV viral load and produced significantly higher rates of viral response and ALT normalization. After 24 weeks, continued entecavir led to a persistent decline in HBV viral load (a decrease of 4.20 log copies/mL at 48 weeks), and no conformed HBV viral rebound was observed. Overall at week 48, 42/51 (82%) patients in the entecavir arm had a HBV-DNA < 300 copies/mL. Tolerability and safety were good and no discontinuation due to adverse events was documented through this follow-up period. Given these favorable data and the fact that entecavir has no anti-HIV activity, entecavir is an attractive choice for first-line HBV treatment in HIV/HBV-coinfected individuals without need for HIV treatment.
Torti and others[8] studied the influence of HCV genotype 3 infection coinfection on liver transaminase elevations (LTE) after commencement of a new highly active antiretroviral therapy (HAART) regimen among persons in the MASTER-EPOKA cohort, which comprised both antiretroviral-naive and -experienced patients. HIV-positive patients with HCV genotype 3 infection displayed a higher risk of hepatotoxicity: incidence of grade 3 or 4 LTE was 31.2 per 100 person-years among patients coinfected with genotype 3 vs 10.5 per 100 person-years among those with other genotypes. Of interest, triglycerides were lower at baseline and remained lower in patients with HCV genotype 3 vs other genotypes. Further studies looking at the relationship between lipids and different genotypes are in progress.
