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Liver Injury and Changes in Hepatitis C Virus (HCV) RNA Load Associated with Protease Inhibitor-Based Antiretroviral Therapy for Treatment-Naive HCV-HIV-Coinfected Patients: Lopinavir-Ritonavir versus Nelfinavir
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Clinical Infectious Diseases Oct 15, 2005;41:1186-1195
Kenneth E. Sherman,1 Norah J. Shire,1 Paul Cernohous,2 Susan D. Rouster,1 Janice H. Omachi,2 Scott Brun,2 and Barbara Da Silva2
1University of Cincinnati College of Medicine, Cincinnati, Ohio; and 2Abbott Laboratories, Abbott Park, Illinois
An HCV/HIV coinfection substudy was conducted among patients enrolled in the phase III study comparing Kaletra to nelfinavir. Patients in the parent study were randomized in a phase III multicenter registration trial to receive either 400 mg of lopinavir and 100 mg of ritonavir (Kaletra) twice daily plus nelfinavir placebo 3 times daily (326 patients) or to receive nelfinavir (Viracept) at a dosage of 750 mg 3 times daily plus lopinavir-ritonavir placebo twice daily (327 patients). All patients also received open-label lamivudine (150 mg twice daily (3TC, Epivir) and stavudine (40 mg twice daily [d4T, Zerit]; patients weighing <60 kg received 30 mg). All subjects were screened for HCV by means of an HCV ELISA. Seventy (11%) of 653 subjects enrolled in the parent clinical trial were HCV-antibody reactive upon HCV ELISA testing.
".....this analysis confirms that HCV loads increase after HAART initiation and that this increase is associated with appropriate immune reconstitution. These increases may be accompanied by flares in the ALT level. The observation that such flares occur after HAART initiation provides a strong rationale for mandatory screening for HCV in all HIV-infected patients infected with HIV before starting treatment. Differential HCV loads and ALT responses between protease inhibitor-treatment groups are noted, especially in patients with low baseline CD4+ cell counts. Future studies should include histologic evaluation at the time of flare, so that the level of liver injury in this setting can be assessed. These observations clearly warrant further evaluation of mechanisms that underlie these observations....
..... By week 24, HCV titers had increased to 6.68 and 6.48 log IU/mL in the lopinavir-ritonavir and nelfinavir groups, respectively (6.1% and 9.6% increases from baseline among patients with measurements at both time points). By week 48, these levels were 6.32 and 6.44 log10 IU/mL, respectively (1.1% and 8.0% increases, respectively, from baseline).....
......8 subjects (19.5%) who were treated with nelfinavir and 2 subjects (6.9%) who were treated with lopinavir-ritonavir had grade 3 or 4 ALT-related adverse events (P = .18).... In subjects without grade 3 or 4 flares in the ALT level, 2 (7%) of 27 lopinavir-ritonavir-treated patients and 5 (15%) of 33 nelfinavir-treated patients had an increase of >0.5 log IU/mL in the HCV load at week 48.....
.... In the subset of patients with a low CD4+ cell count (<100 cells), the mean viral load for patients with a low CD4+ cell count who were receiving lopinavir-ritonavir increased by 6.4% from 5.72 log IU/mL at baseline to 6.75 log IU/mL at week 24 and was 5.95 log IU/mL (5.2% decrease from baseline levels among patients with measurements at both time points) at week 48. In the nelfinavir group, the mean levels were 5.57 log IU/mL at baseline, 6.28 log IU/mL at week 24 (23.3% increase from baseline), and 6.49 log IU/mL at week 48 (26.5% increase from baseline).
...Among patients with a baseline CD4+ cell count of <100 cells/mL, 5 of 11 nelfinavir-treated patients experienced an increase in the HCV load from baseline to week 48 of >0.5 log IU/mL, compared with 0 of 10 lopinavir-ritonavir-treated patients (P = .035).....
..... At week 24, a mean increase in ALT level of 45 U/L (a 111.4% increase from baseline) was observed in the nelfinavir arm, and a mean decrease of 18 U/L (a 5.5% decrease from baseline) was noted for patients receiving lopinavir-ritonavir. After 48 weeks of therapy, the mean ALT levels in both groups did not differ significantly from baseline levels.....
....Among 7 patients in the lopinavir-ritonavir group and 11 patients in the nelfinavir group with a CD4+ cell count of <100 cells/mm3, the mean ALT level decreased by 26 U/L (40.2%) and 15.1 U/L (48.3%), respectively, between baseline and week 24 (P = .012)...."
Author Discussion extracts:
--Increases in mean HCV load after HAART initiation were clearly demonstrated in this analysis. Chung et al. [4] previously reported that patients with CD4+ cell counts <350 cells/mL demonstrated increased HCV loads after week 24 of HAART initiation, but that this effect was not observed in patients who began HAART with a CD4+ cell count of >350 cell/mm3. These observations may help explain the observation [in this study] that HCV RNA levels among subjects with very low baseline CD4+ cell count (<100 cells/mL) demonstrated a drug-specific differential response (i.e., flares in HCV RNA loads were more prolonged in the nelfinavir arm than in the lopinavir-ritonavir arm).
Some authors have argued that mild or moderate increases in HCV loads are not clinically relevant, particularly considering the variability of commercially available assays for measuring the HCV load [16]. However, our analysis clearly demonstrates changes in HCV load over time, and HCV load has been identified as the second most important factor, after HCV genotype, affecting the response to HCV treatment [17]. Furthermore, viral kinetics modeling suggests that even an increase of 0.5 log IU/mL significantly alters the predicted time to viral clearance
HIV responses and associated CD4+ cell count increases were somewhat blunted in the nelfinavir arm, compared with the lopinavir-ritonavir arm. This suggests that the increase in the HCV RNA load might be tied to relative effects on HIV suppression or immunologic recovery. The mechanism of this increase is unclear.
BACKGROUND
In the United States, >20% of HIV-infected patients are also chronically infected with HCV [1] (ED NOTE: most estimates are 25-30% coinfection rate). Coinfection with these agents leads to increased liver-associated morbidity and mortality [2]. Furthermore, concerns regarding use of potentially hepatotoxic antiretroviral agents may limit appropriate drug intervention in HIV-positive individuals with HCV infection
ABSTRACT
Background. Highly active antiretroviral therapy (HAART) initiation in patients coinfected with human immunodeficiency virus type 1 (HIV-1) and hepatitis C virus (HCV) has been associated with transaminase and HCV viral load flares. Previous studies have included highly variable antiretroviral regimens. We compared effects of 2 protease inhibitor-based regimens on alanine aminotransferase (ALT) levels and HCV loads in HCV-HIV-coinfected patients initiating HAART.
Methods. Seventy HIV-infected patients with positive baseline results of HCV enzyme-linked immunosorbant assay from a treatment trial comparing lopinavir-ritonavir with nelfinavir were evaluated during a 48-week period. HCV and HIV titers were analyzed at baseline, at weeks 24 and 48 of treatment, and during flares in the ALT level of >5 times the upper limit of normal.
Results.
--Use of the Division of AIDS table for grading adult adverse experiences revealed that 8 subjects (19.5%) who were treated with nelfinavir and 2 subjects (6.9%) who were treated with lopinavir-ritonavir had grade 3 or 4 ALT-related adverse events (P = .18) [8]. Flares in ALT levels tended to occur later among the lopinavir-ritonavir-treated subjects than among nelfinavir-treated subjects (hazard ratio, 2.93; 95% CI, 0.62-13.8; P = .18).
--We also reviewed the association between increases in the ALT level and changes in the HCV RNA load. For the 2 lopinavir-ritonavir-treated subjects with grade 3 or 4 flares in the ALT level, there appeared to be a concomitant increase of >0.5 log IU/mL in the HCV load. One of these patients, however, had a very low HCV titer at baseline (<2.7 log IU/mL) and experienced a dramatic increase in HCV load, whereas the other patient had a baseline HCV load of 6.6 log IU/mL that increased to 7.4 log IU/mL. In the nelfinavir-treated group, 5 of 8 patients with grade 3 or 4 flares in ALT levels either had no change or a slight decrease in HCV load, whereas 3 of 8 patients had clear increases. In subjects without grade 3 or 4 flares in the ALT level, 2 (7%) of 27 lopinavir-ritonavir-treated patients and 5 (15%) of 33 nelfinavir-treated patients had an increase of >0.5 log IU/mL in the HCV load at week 48.
--The mean HCV load for HCV-positive subjects in both treatment groups increased after initiation of HAART. By week 24, HCV titers had increased to 6.68 and 6.48 log IU/mL in the lopinavir-ritonavir and nelfinavir groups, respectively (6.1% and 9.6% increases from baseline among patients with measurements at both time points). By week 48, these levels were 6.32 and 6.44 log10 IU/mL, respectively (1.1% and 8.0% increases, respectively, from baseline).
--In the subset of patients with a low CD4+ cell count (<100 cells), HAART initiation was associated with larger increases in HCV load. The mean viral load for patients with a low CD4+ cell count who were receiving lopinavir-ritonavir increased by 6.4% from 5.72 log IU/mL at baseline to 6.75 log IU/mL at week 24 and was 5.95 log IU/mL (5.2% decrease from baseline levels among patients with measurements at both time points) at week 48. In the nelfinavir group, the mean levels were 5.57 log IU/mL at baseline, 6.28 log IU/mL at week 24 (23.3% increase from baseline), and 6.49 log IU/mL at week 48 (26.5% increase from baseline).
--Among patients with a baseline CD4+ cell count of <100 cells/mL, 5 of 11 nelfinavir-treated patients experienced an increase in the HCV load from baseline to week 48 of >0.5 log IU/mL, compared with 0 of 10 lopinavir-ritonavir-treated patients (P = .035). (ED NOTE: perhaps, HCV viral load changes comparing between patients on nelfinavir vs Kaletra suggest that greater viral suppression by HAART translates into lower HCV viral load. The same could be said about ALT changes comparing between patients on nelfinavir vs Kaletra).
--Liver injury.
Hepatocellular injury was evaluated by assessment of serum ALT levels before, during, and after HAART initiation in all 70 subjects with positive ELISA results. The mean ALT at baseline was 55 U/L for the lopinavir-ritonavir group and 47 U/L for the nelfinavir group (P = not significant). Of the 57 patients with detectable HCV RNA loads at baseline, the mean ALT level at baseline was 61 U/L in the lopinavir-ritonavir arm and 51 U/L in the nelfinavir arm (P = not significant). Statistically significant differences in ALT concentrations were observed between treatment groups at week 24 after HAART initiation. At week 24, a mean increase in ALT level of 45 U/L (a 111.4% increase from baseline) was observed in the nelfinavir arm, and a mean decrease of 18 U/L (a 5.5% decrease from baseline) was noted for patients receiving lopinavir-ritonavir. After 48 weeks of therapy, the mean ALT levels in both groups did not differ significantly from baseline levels.
Among 7 patients in the lopinavir-ritonavir group and 11 patients in the nelfinavir group with a CD4+ cell count of <100 cells/mm3, the mean ALT level decreased by 26 U/L (40.2%) and 15.1 U/L (48.3%), respectively, between baseline and week 24 (P = .012). Similar to the findings for all patients in the substudy, mean ALT levels among HCV-infected patients with a CD4+ cell count of <100 cells/mm3 were comparable at 48 weeks.
Patients in each treatment arm of the HCV substudy experienced dramatic decreases in HIV loads. By week 48 of therapy, 100% of subjects treated with lopinavir-ritonavir and 87% of subjects randomized to receive nelfinavir achieved HIV RNA loads of <400 copies/mL (P = .274). Similar results were observed between groups when a decrease to 50 copies/mL was used as an end point; 100% of lopinavir-ritonavir-treated subjects and 73% of nelfinavir-treated subjects reached this end point by week 48 (P = .308).
A comparison of HCV-infected patients with HCV-uninfected patients in the parent cohort revealed no significant differences in virologic or immunologic response. In contrast, among subjects infected with HCV who were treated with lopinavir-ritonavir, the mean increase in the CD4+ cell count was 234 cells/mm3 at 48 weeks, compared with 184 cell/mm3 for those treated with nelfinavir. This difference was not statistically significant. However, among subjects with a CD4+ cell count of <100 cells/mm3 at baseline, the mean increase in the CD4+ cell count from baseline to week 48 was 221 cells/mL in the lopinavir-ritonavir group versus 147 cells/mL in the nelfinavir group (P = .049).
A total of 57 of 70 patients tested positive for HCV RNA at baseline. HCV titers for patients in lopinavir-ritonavir and nelfinavir groups, respectively, were as follows: baseline, 6.07 and 6.22 log IU/mL; week 24 of treatment, 6.68 and 6.48 log IU/mL; and week 48 of treatment, 6.32 and 6.44 log IU/mL.
Of patients with a CD4+ cell count of <100 cells/mm3 at baseline, 5 of 11 in the nelfinavir group and 0 of 10 in the lopinavir-ritonavir group had an increase in the HCV load of >0.5 log IU/mL from baseline to week 48.
Mean baseline ALT and aspartate aminotransferase levels in the 70 subjects with ELISA results positive for HCV RNA were 50.6 and 52.3 U/L, respectively, compared with 35.4 and 33.2 U/L, respectively, in the HIV-infected subjects (P < .001 for both comparisons).
The mean ALT level increased by 45 U/L at 24 weeks and 18 U/L at 48 weeks in the nelfinavir group but decreased by 18 U/L at 24 weeks and 7 U/L at 48 weeks in the lopinavir-ritonavir group.
Eight patients in the nelfinavir group and 2 patients in the lopinavir-ritonavir group had grade 3 or 4 flares in the ALT level.
Conclusions. HAART initiation is associated with increased HCV loads and ALT levels. A low baseline CD4+ cell count is associated with persistent increases in the HCV RNA load in nelfinavir-treated patients. These results warrant careful interpretation of abnormalities in the ALT load after HAART initiation in HCV-HIV-coinfected patients to prevent premature discontinuation of treatment.
RESULTS
Demographic characteristics. Seventy (11%) of 653 subjects enrolled in the parent clinical trial were HCV-antibody reactive upon HCV ELISA testing. Of this group, 57 subjects (81%) had HCV RNA detectable by either the quantitative or the qualitative assay. Whereas the majority of patients (56 [ 98%] of 57) had a viral titer sufficiently large enough to be detected by the less sensitive quantitative methodology, 1 subject (2%) had very low viral titer identifiable only by the qualitative PCR assay. No patient tested positive for hepatitis B virus. Table 1 displays the characteristics of the HCV substudy group relative to the parent study group classified by treatment arms. There were no statistically significant differences between the HCV RNA-positive subjects after randomization. Of note, 41% to 57% of patients were reported to be current alcohol users, and an additional 14% to 31% were past users. Regarding risk factors for coinfection: 55% IVDU; gay or bisexual man 20%; HIV+ sex partner 14-27%. Patients self-designated as drinkers of alcohol were not permitted to consume alcohol during the study.
Additional author discussion:
--The data presented herein suggest that choice of a protease inhibitor may lead to downstream laboratory findings with the potential to result in treatment modification. It is also possible that ALT increases after initiation of HAART may lead to antiretroviral drug discontinuation or to dose modification [19]. Formal recommendations regarding evaluation and management of hepatotoxicity have been promulgated by expert panels in the field and have been widely distributed to practicing clinicians. These recommendations suggest that patients with new antiretroviral therapy regimens undergo ALT and/or aspartate aminotransferase testing 4 weeks after drug initiation. If grade 3 toxicity is present, drug should be stopped if any symptoms are evident or retested weekly if no symptoms are discernible. If grade 4 toxicity is present, the drug should be stopped, and expert consultation should be sought [20]. In our cohort, application of these rules might have significantly altered treatment regimens. Although clinical outcomes were not significantly different between these 2 regimens after 48 weeks, clinicians seeing flares in ALT levels and/or HCV loads might have altered their choice of treatment regimen at the time of the flare, resulting in suboptimal therapeutic efficacy. The choice of an initial antiretroviral regimen is generally based on a combination of availability, tolerability, resistance profiles, cost, and ease of administration [21].
concern about additive hepatotoxicity in HCV-HIV-coinfected patients has resulted in reluctance by some health care professionals to initiate HAART in patients with HCV infection. Furthermore, observations that HCV-HIV-coinfected patients are more likely to exhibit higher grades of toxicity may lead to premature discontinuation of antiretroviral therapy [12].
Several series suggest that HCV loads may increase with HAART initiation, but these observations have been limited by variability in treatment regimens, small sample sizes, and post hoc analysis. In the analysis described herein, the study cohort was uniquely suited to address several of these issues. Treatment-naive patients were randomized to 1 of 2 treatment arms that differed only in the protease inhibitor component and used a stable nucleoside reverse-transcriptase inhibitor backbone, thus allowing a direct comparison between protease inhibitors regarding their effect on HCV. Samples were collected in an organized manner on a predefined schedule. Finally, all HCV loads and ALT levels were determined in a single laboratory, thus reducing risk of interlaboratory and interbatch bias.
The results demonstrate several important points. The prevalence of HCV coinfection in this HIV-infected cohort was 11%. This is somewhat lower than that described by Sherman et al. [1] in the AIDS Clinical Trial Group (16.1%) and significantly lower than prevalences observed in high-risk inner-city cohorts (76.9%) [13]. Nearly 80% of subjects with HCV antibodies had evidence of active viral replication detected by sensitive PCR-based assays. Although it is possible that some HCV RNA-negative subjects had very low titers below the level of detectability, this observation more likely represents spontaneous clearance. Messick et al. [14] reported similar levels of spontaneous clearance among coinfected hemophiliacs.
There are limitations to this study that should be acknowledged. The HCV-HIV-coinfected patients were a subset of an HIV treatment trial and therefore included a higher proportional of gay or bisexual men relative to the general HCV-HIV-coinfected population. The rate of coinfection is lower than that seen in other cohorts with a greater proportion of injection drug users. HCV load was measured at 3 predetermined time points during the study (at baseline and at weeks 24 and 48 after treatment), unless a flare in the ALT level was noted. This limited the ability to correlate HCV titer with ALT level and CD4+ cell counts over time. It is also possible that patients with flares in the ALT level experienced confounding events that may have contributed to the flares, although this is unlikely, because subjects were not active alcohol users and because only 1 subject was taking corticosteroids at the time of the flare.
Subjects.
The parent study enrolled 653 patients recruited from 93 centers in 13 countries in North America, South America, Europe, Africa, and Australia [8]. Inclusion criteria were age of >12 years, HIV RNA load of at least 400 copies/mL (as measured by the Amplicor HIV-1 Monitor [Roche]), a Karnofsky score of >70, and no previous treatment with stavudine or lamivudine or with any other antiretroviral therapy for >14 consecutive days. There was no restriction on the CD4+ cell count. Exclusion criteria included treatment for an opportunistic infection within 30 days before screening, pregnancy, and alanine aminotransferase (ALT) or aspartate aminotransferase levels >3 times the upper limit of normal.
Treatment regimens.
Patients in the parent cohort were randomized in a phase III multicenter registration trial to receive either 400 mg of lopinavir and 100 mg of ritonavir (Kaletra; Abbott Laboratories) twice daily plus nelfinavir placebo 3 times daily (326 patients) or to receive nelfinavir (Viracept; Agouron) at a dosage of 750 mg 3 times daily plus lopinavir-ritonavir placebo twice daily (327 patients) [8]. All patients also received open-label lamivudine (150 mg twice daily [Epivir; GlaxoSmithKline]) and stavudine (40 mg twice daily [Zerit; Bristol-Myers Squibb]; patients weighing <60 kg received 30 mg). If adverse events related to stavudine or lamivudine occurred, the drug could be discontinued and replaced with another nucleoside reverse-transcriptase inhibitor at the discretion of the investigator.
HCV RNA detection, quantitation.
All HCV ELISA-reactive samples were initially evaluated using the Amplicor Monitor assay, which has a linear range of 600-500,000 IU/mL for detection of HCV RNA. Aliquots in which HCV RNA was not detected were retested using the Amplicor Qualitative HCV RNA assay (Roche), which has a sensitivity of 50 IU/mL. HCV load was measured at baseline, at weeks 24 and 48, and when the ALT level was >5 times the upper limit of normal (170 U/L for women and 215 U/L for men, specified as grade 3+ elevations in the Division of AIDS table for grading adult adverse experiences [10]). HCV RNA genotypes were determined at baseline using the InnoLipa reverse hybridization assay (Bayer), in accordance with the manufacturer's instructions.
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