Of 169 HIV-1-infected patients enrolled between January 2001 and April 2003, 35 (21%) were coinfected with HBV (n = 14) or HCV (n = 21). The baseline patient's characteristics are shown in table . Two thirds of patients were women. Most patients were at an advanced HIV clinical stage (42% were at the CDC stage B and 44% were at stage C). The median CD4 count was 135 cells/mm3 (interquartile range [IQR] 67-218). Fifteen women (13%; 12 monoinfected with HIV and 3 coinfected with HBV or HCV) had a CD4 count above 250 cells/mm3. No man had a CD4 count above 400 cells/mm3. Most characteristics were similar between HIV-monoinfected patients and those coinfected with an hepatitis virus. However, coinfected patients were older (p < 0.001), and had higher liver enzyme levels (p < 0.001). The median viral load was 2.47 × 107 IU/mL for HBV (IQR 3680-1.59 × 108; range 270->2.2 × 108) and 928 000 IU/mL for HCV (IQR 178 400-2.06 × 106; range 640-5.5 × 106) in patients coinfected with the respective virus. The median time of follow-up was 23.9 months (IQR 17.2-24.0) in monoinfected patients and 24.0 months (IQR 20.0-24.0) in coinfected patients. Half the patients received zidovudine, lamivudine and nevirapine at baseline, and the other half received stavudine, lamivudine and nevirapine. Nevirapine was interrupted during follow-up in 16 monoinfected patients (12%) and 4 coinfected patients (11%) because of tuberculosis (n = 9 and 2, respectively), adverse effects (n = 4 and 2, respectively) and antiretroviral drug resistance (n = 3 and 0, respectively).
Baseline characteristics of patients by infection group
A total of 1588 measures of liver enzymes were available. The number of measures per patient was similar in both infection groups (median 10, IQR 9-11, p = 0.2). Two patients only (both were coinfected) had a grade 2 hepatotoxicity at baseline (90 IU/L and 97 IU/L, respectively); at week 2, hepatotoxicity dropped to grade 1 in one patient and remained at grade 2 in the other patient. No patient had a baseline grade 3 or 4 hepatotoxicity.
During follow-up, 39 patients experienced at least one episode of grade 2 or higher hepatotoxicity (22 monoinfected patients [16%] and 17 coinfected patients [49%]). The corresponding incidence rate was 12.4 per 100 person-years (95% confidence interval [CI] 8.2-18.9) in monoinfected patients and 54.0 per 100 person-years (CI 33.6-89.5) in coinfected patients. The Kaplan-Meier analysis showed the higher risk in coinfected patients (p < 0.001; figure ). Of note, all episodes of hepatotoxicity in the coinfected patients occurred in the first six months. In monoinfected patients, such episodes occurred throughout the follow-up (although more frequently in the first months). In multivariate Cox analysis, the risk of grade ≥ 2 hepatotoxicity remained higher in coinfected patients (hazard ratio [HR] 2.94, CI 1.49-5.81, p = 0.002; table ) after adjustement on age (HR 0.90, CI 0.43-1.91, p = 0.8), Karnofsky score (HR 0.41, CI 0.20-0.84, p = 0.01) and liver enzymes levels (HR 1.45, CI 0.74-2.82, p = 0.3). Of the 17 coinfected patients who experienced a grade ≥ 2 hepatotoxicity, 4 were positive for HBV (median viral load 1.80 × 108 IU/mL, IQR 1.04 × 108-2.10 × 108) and 13 were positive for HCV (median viral load 970 000 IU/mL, IQR 173 800-2.06 × 106).
Proportion of patients who experienced episodes of grade ≥ 2 hepatotoxicity by infection group.
Adjusted risks of outcomes associated with the hepatitis coinfection*
Only 12 patients (7%) experienced a grade 3 or 4 hepatotoxicity (7 monoinfected patients [5%] and 5 coinfected patients [14%]). The incidence rates were 3.6 (CI 1.7-7.6) and 9.9 per 100 person-years (CI 4.1-23.7) in monoinfected and coinfected groups, respectively. The risk tended to be higher in coinfected patients but the difference was not significant (HR 2.18, CI 0.61-7.75, p = 0.2; table ) after adjustement on age (HR 1.28, CI 0.36-4.53, p = 0.8) and liver enzymes levels (HR 1.61, CI 0.47-5.46, p = 0.8). All 5 coinfected patients who experienced a grade 3 or 4 hepatotoxicity were HCV positive; their median viral load was 970 000 IU/mL (IQR 320 000-1.22 × 106).
The higher risk for hepatotoxicity in coinfected patients was confirmed by the multivariate Poisson regression analysis (incidence risk ratio [IRR] 1.83, CI 1.28-2.60, p = 0.001; table ) after adjustement on age (IRR 0.83, CI 0.56-1.24, p = 0.4) and Karnofsky score (IRR 0.54, CI 0.39-0.76, p < 0.001).
Three patients developed a rash in the first four weeks (two women with baseline CD4 counts of 31 and 307 cells/mm3, respectively, and one man with a baseline CD4 count of 18 cells/mm3). Only the male patient was coinfected (HBV viral load 4.88 × 107 IU/mL). Nevirapine was replaced by a protease inhibitor in all three patients. The woman with a high CD4 cell count experienced simultaneously a grade 3 hepatotoxicity. Nevirapine was also replaced by a protease inhibitor in one other (monoinfected) patient with an isolated grade 3 hepatotoxicity. No patient had clinical hepatitis.
The number of CD4 cell counts per patient was comparable between the monoinfected group (median 5, IQR 3-5) and the coinfected group (median 4, IQR 4-5; p = 0.5). As shown in figure , the CD4 cell count increased after treatment initiation from 143 to 325 cells/mm3 in monoinfected patients and from 136 to 297 cells/mm3 in coinfected patients. The square root CD4 cell count increase was not significantly different between monoinfected and coinfected patients (either in the first 6 months [p = 0.9] and thereafter [p = 0.8]; table ) after adjustement on gender (coefficient 1.59, CI 0.41 to 2.77, p = 0.008), age (coefficient -1.07, CI -2.43 to 0.29, p = 0.1), HIV-1 viral load (coefficient 1.55, CI 0.40 to 2.70, p = 0.008), hemoglobin level (coefficient 2.43, CI 1.18 to 3.67, p < 0.001) and total lymphocyte count (coefficient 2.93, CI 1.83 to 4.03, p < 0.001).
Immunological and virological responses to antiretroviral therapy by infection group: mean CD4 cell count (A), and percentage of patients with plasma HIV-1 viral load below 400 copies/mL (B). Bars indicate 95% confidence intervals.
The number of HIV-1 RNA measures per patient was similar in both infection groups (median 5, IQR 4-6, p = 0.8). The proportion of patients with viral load below 400 copies/mL was 91% and 85% after 3 months and 91% and 78% after 24 months in monoinfected and coinfected patients, respectively (figure ). The time for reaching a viral load below 400 copies/mL did not differ between the groups (HR 1.00, CI 0.68-1.47, p = 0.9; table ). No other variable remained in the model.
Deaths or new AIDS-defining events
There were 16 deaths (12%) in monoinfected patients and 3 (9%) in those coinfected. The mortality rates were 7.2 (CI 4.4-11.7) and 4.8 (CI 1.4-15.0) per 100 person-years, respectively. The Kaplan-Meier curves did not differ significantly between the groups (p = 0.6, figure ). In multivariate analysis, death was not associated with coinfection (HR 0.52, CI 0.14-1.93, p = 0.3; table ) after adjustement on gender (HR 0.29, CI 0.11-0.77, p = 0.01), age (HR 1.90, CI 0.68-5.29, p = 0.2), CD4 cell count (HR 0.15, CI 0.04-0.55, p = 0.004) and hemoglobin level (HR 0.28, CI 0.11-0.74, p = 0.01). In the monoinfected group, the deaths were related to advanced HIV disease (n = 5), poor general health (n = 5), multifocal tuberculosis, pulmonary infection, wasting, malaria, pancreatitis and hepatic carcinoma (n = 1 each). In the coinfected group, death was related to advanced HIV disease, poor general health and persistent fever of unknown origin (n = 1 each); the first two patients had taken traditional medicines.
Clinical progression by infection group: progression to death (A), and progression to death or new AIDS-defining event (B).
Deaths or new AIDS-defining events occurred in 25 monoinfected patients (19%) and 5 coinfected patients (14%). The respective incidence rates were 10.6 (CI 7.0-16.1) and 6.7 per 100 person-years (CI 2.5-17.8). The Kaplan-Meier curves showed no significant difference between the groups (p = 0.5, figure ). In multivariate analysis, the occurrence of deaths or new AIDS-defining events was not associated with coinfection (HR 0.37, CI 0.11-1.29, p = 0.1; table ) after adjustement on age (HR 1.33, CI 0.53-3.32, p = 0.5) and body mass index (HR 4.40, CI 1.98-9.78, p < 0.001).