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Low incidence of hepatotoxicity in a cohort of HIV patients treated with lopinavir/ritonavir
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AIDS: Volume 19(13) 2 September 2005 p 1433-1434
Bonfanti, Paoloa; Ricci, Elenaa; Penco, Giovannib; Orofino, Giancarloc; Bini, Teresad; Sfara, Claudioe; Miccolis, Sebastianof; Cristina, Giovannig; Quirino, Tizianah; for the CISAI Study Group
aI Divisione di Malattie Infettive, Ospedale Luigi Sacco, Milan, Italy
bDivisione di Malattie Infettive, Ospedale Galliera, Genoa, Italy
cDivisione A di Malattie Infettive, Ospedale Amedeo di Savoia, Turin, Italy
dClinica di Malattie Infettive, Ospedale Luigi Sacco, Milan, Italy
eClinica di Malattie Infettive, Perugia, Italy
fDivisione di Malattie Infettive, Cremona, Italy
gDivisione di Malattie Infettive, Vercelli, Italy
hDivisione di Malattie Infettive, Busto Arsizio, Italy.
Abstract
We describe the hepatotoxicity encountered in a cohort of HIV-positive patients treated with lopinavir/ritonavir. We used the database from the SCOLTA project, an on-line pharmacovigilance programme involving 25 Italian infectious disease centres. A total of 755 patients were followed, over a mean observation period of 16 months. The incidence of severe events was low despite the high prevalence of patients co-infected with hepatitis virus at enrolment.
Hepatotoxicity has always been one of the most serious adverse reactions to highly active antiretroviral therapy, often making it necessary to stop the treatment and even, fortunately rarely, putting the patient's life at risk [1,2]. This is an important consideration in the Italian population in which the prevalence of HIV-positive patients with chronic viral hepatitis [hepatitis C virus (HCV) and hepatitis B virus] reaches 50% [3], and these individuals have a greater risk of hepatic toxicity [4].
All the families of antiretroviral drugs have this drawback. If one had to list the drug groups in order of their hepatic toxicity, the non-nucleosidic reverse transcriptase inhibitors (nevirapine and efavirenz) are the most risky classes, followed by the protease inhibitors and the reverse transcriptase inhibitors [5]. Lopinavir/ritonavir is at present the most widely used protease inhibitor, with confirmed efficacy. The incidence of severe hepatotoxicity in patients given this drug ranges in different studies from 2 to 11% [6-8].
The present study investigated the incidence of severe hepatic toxicity in a cohort of patients treated with lopinavir/ritonavir, using data obtained in the SCOLTA (Surveillance COhort Long-term Toxicity Antiretrovirals) project. This is an on-line reporting system for adverse reactions to antiretroviral drugs, designed by the CISAI (Coordinamento Italiano per lo Studio Allergia e Infezione da HIV; Italian coordination for the study of allergy and HIV infection) group. It originated as a pharmacovigilance system for newly introduced drugs, and as a sentinel scheme for unexpected or late adverse reactions arising during any antiretroviral treatment. It works through the internet site www.cisai.info and involves 25 Italian infectious disease centres. Cohorts of patients are established for each new drug as it comes onto the market, and these patients are followed prospectively. Data collection and follow-up procedures for the cohorts are described elsewhere [9].
We only analysed grade III and IV events, using the AIDS Clinical Trial Group scale [10]. A total of 755 patients were enrolled; Table 1 summarizes their main features. A large proportion (44.4%) had co-infection with hepatitis viruses. The mean observation period was 16.7 months (± 9.6 SD). The incidence of adverse reactions was 11.0 [95% confidence interval (CI) 10.8-11.2] events per 100 person-years; the incidence was lower in previously untreated (naive) patients than those who had already received treatment, respectively 7.0 (95% CI 6.6-7.4) and 11.9 (95% CI 11.6-12.1). Metabolic adverse events were the most common, with an incidence of 5.4 (95% CI 5.2-5.5).
Hepatic toxicity was not frequent, at 0.59 (95% CI 0.54-0.63) events per 100 person-years for the whole series, 0.54 (95% CI 0.43-0.64) in naive patients, and 0.48 (95% CI 0.43-0.53) in 'experienced' patients. Only one severe event was recorded among naive patients, compared with four in the experienced group. Four of these five patients had HCV co-infection. Two events arose after one month of treatment and the other three after a year, confirming the multifaceted mechanisms causing this toxicity. In all these cases the treatment had to be stopped, and the patients regressed.
To the best of our knowledge, this study comprises the biggest series to date of patients treated with lopinavir/ritonavir and followed prospectively outside clinical trials. In addition, this HIV-positive population had a high prevalence of co-infection with hepatitis viruses.
The frequency of hepatotoxicity was actually low, unlike in other studies. This might partly be the result of methodological differences, reflecting how the data were collected. Retrospective studies can suffer major selection bias. Gonzalez-Requena et al. [11] also reported a low incidence of adverse events, but their case series was small and was followed up for not more than one year.
In conclusion, the present study found that lopinavir/ritonavir caused only limited hepatic toxicity in this population of HIV-positive patients with a high prevalence of co-infection with hepatitis B virus or HCV.
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