From Alimentary Pharmacology & Therapeutics
The Incidence, Predictors and Management of Anaemia and its Association with Virological Response in HCV/HIV Coinfected Persons Treated with Long-term Pegylated Interferon Alfa 2a and Ribavirin
Posted: 06/22/2011; Alimentary Pharmacology & Therapeutics. 2011;33(1):1234-1244. © 2011 Blackwell Publishing
- Abstract and Introduction
- Methods
- Results
- Discussion Below
Discussion
Anaemia is among the strongest risk factors associated with non-initiation and noncompletion of HCV treatment among HCV and HCV/HIV coinfected persons.[6–8] In our study, 40.4% of the subjects developed anaemia in the first 12–18 weeks of therapy, and only 49.5% of the subjects completed the first 12 weeks without any changes in ribavirin prescription, with 17.3% of the subjects discontinuing ribavirin in this time period. Anaemia developed rapidly, and haemoglobin values reached a nadir by the fourth week of therapy with smaller fluctuations seen in the subsequent period. Among the subjects who stopped ribavirin therapy, haemoglobin values recovered almost as rapidly as the decline in the earlier period. Among Step 1 + 3 subjects (i.e. those who were able to complete the first 12 weeks of therapy, achieved an early virological response at week 12, and continued to receive PEG and WBR), 55.0% developed anaemia over the full duration of study, and only 27.2% were able to maintain the dose of ribavirin throughout the study. These data are remarkable in that such a high proportion of subjects developed anaemia or required ribavirin dose modification or discontinuation. It also demonstrates that anaemia may develop late in therapy, and providers should remain vigilant even after the patients appear to have reached a steady state in the initial weeks of therapy.
We found that lower entry haemoglobin, older age, and zidovudine use were strongly predictive of anaemia on treatment. Controlling for entry haemoglobin which was lower in women, men were more likely to develop anaemia. Unfortunately, the number of women was too small for detailed analyses comparing men and women. Zidovudine is associated with anaemia even in the absence of concomitant ribavirin administration in HIV infected persons as well as healthy volunteers.[15–17] While administration of any effective combination antiretroviral therapy to anaemic HIV infected persons improves haemoglobin levels, the time to improvement is longer among those who receive a zidovudine-based regimen.[18] As the most recent treatment guidelines do not recommend zidovudine as part of a preferred first line antiretroviral regimen, the potentiation of anaemia by co-administration of zidovudine and ribavirin would appear to be of lesser concern in HIV-infected persons contemplating their first antiretroviral regimen. However, among treatment experienced patients who require anti-HCV therapy, the providers need to be mindful of this effect. If treatment for HCV is being contemplated in persons ≥40 years old, more aggressive monitoring of haemoglobin and minimization of any other risk factors should be undertaken. The role of improving pre-treatment haemoglobin using ESA is a potential strategy that has not been adequately tested in this setting.
Over one-third of the subjects were prescribed an ESA during the initial period of treatment, with a significant proportion being prescribed an ESA prior to meeting the definition of anaemia by haemoglobin criteria. Among those who achieved early virological response and continued on PEG and WBR to complete the total of 72 weeks of treatment almost a half received ESA. Use of ESA is a costly strategy, but has been associated with enhanced rates of maintained ribavirin dosing,[19] improvements in target haemoglobin levels,[20] and improved health-related quality of life measures.[19] Compared with ribavirin dose reduction, treatment with ESA has been advocated as cost effective, with estimates ranging from US$33 382 to 64 311 per additional quality-adjusted life-year gain, depending on the agent used.[21] These potential benefits should be carefully weighed against possible risks of ESA use demonstrated in the non-HCV population.[22–24] In a recent small study, ESA use was not associated with increased risk of cardiovascular events, malignancy, thrombosis, or death in HCV-infected patients during receipt of HCV therapy or in the period after completion.[20]
A major concern regarding development of anaemia and subsequent reduction in RBV dosing or its temporary or permanent discontinuation is the potential for virological failure. However, we did not see evidence of a difference in EVR or SVR among those with and without anaemia, although the rates of both EVR and SVR were slightly higher among subjects who did not experience anaemia. We also did not observe an effect of ESA prescription upon virological response. The role of anaemia upon SVR is controversial. A study by Nunez et al. found no association between development of anaemia and SVR in HCV/HIV coinfected persons enrolled in the PRESCO trial.[11] This is in contrast to two recent studies in HCV monoinfected subjects which reported higher rate of SVR among those who developed anaemia.[9,10] In the study by Sulkowski et al. [9] subjects who received an ESA in the first 8 weeks of therapy and did not require dose reduction of RBV had higher SVR compared with those who did not receive an ESA. The percentage of intended dose of RBV delivered was significantly higher among those who received an ESA compared with those who did not, 64% vs. 43% (P < 0.001) suggesting that the effect is primarily mediated through a higher RBV exposure. In the study by Sievert et al.,[10] subject who developed anaemia during week 5–48 of therapy had a higher SVR, but those who developed anaemia in the first 4 weeks had no association with SVR. The reason for this remains unclear, but it is possible that subjects who developed anaemia in the first 4 weeks may have had dose reductions in RBV or treatment discontinuation, and the rest of the subjects had a higher exposure to RBV.
Other than zidovudine use, HIV-related factors were not associated with an increased risk of anaemia. Although reasonable control of HIV replication and a relatively preserved CD4+ lymphocyte count are usually required for enrolment in many clinical trials as well as in actual clinical setting when treating HCV infected persons, evidence supporting this practice is sparse. Similarly, no HCV-specific factors were associated with the risk of anaemia in our study. Recently, genetic variants leading to inosine triphosphatase (ITPA) deficiency have been shown to protect against anaemia in patients treated for HCV.[25] Such information was not available at the time our study was conducted, and the prevalence and effect of such gene variants among our study subjects remain unknown.
There is some discrepancy in the rates of anaemia in our study compared with some previously published studies, which have reported the rate of anaemia to be in the 12–16% range.[10,16,17] This is likely due to the different definition of anaemia. Most studies define anaemia as a drop in haemoglobin to <10 g/dL, without accounting for gender differences or baseline haemoglobin. The definition of anaemia has long been debated and was discussed by Beutler et al. in an elegant and critical review.[26] One consistent aspect of defining a 'normal' haemoglobin has been the difference based on gender. Numerous studies cited in the above article unanimously use different levels for men and women. Most studies that have attempted to define the 'normal' haemoglobin have consistently found the lower limit of normal to be 13–14 g/dL for men and on average 1 g/dL lower for women. Additionally, a drop in haemoglobin to less than 10 g/dL translates to a nearly 30% drop in haemoglobin for men based on average baseline haemoglobin for most studies. The median baseline haemoglobin in our study was 14.8 g/dL for men and 13.1 g/dL for women, and a drop to 11 g/dL and 10 g/dL for men and women represents a 26% and 24% drop from baseline respectively. On the basis of these data, we felt that using a uniform definition for men and women is not appropriate and that our defined limits are more clinically relevant and appropriate. When we compare studies which reported a drop in haemoglobin from baseline, our results are closer to the previously results. For example, compared to 64% of subjects who had a drop in haemoglobin >3 g/dL in our study, 61% of subjects on an AZT-based regimen in the study by Alvarez et al.,[16] and 76% of the subjects in the CHARIOT study had at 3 g/dL decline in haemoglobin.[10] In the RIBAVIC study, 24% of the subjects had at least 25% drop in haemoglobin on treatment.[17]
In summary, anaemia is very common in HCV/HIV-infected persons who are treated with PEG and WBR. While anaemia develops in a majority of subjects in the first 12 weeks of therapy, a substantial portion develop late anaemia. Baseline haemoglobin, lower BMI, age over 40 years and zidovudine use are strong predictors of anaemia. The majority of subjects are not able to maintain the originally prescribed dose of ribavirin. Strategies to improve management of anaemia are urgently required in the HIV-coinfected population.
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