Liver Damage

“Eleven volunteers started as the first group in this study. No major complaints occurred during day 1–5 (rifampicin only). After addition of [the protease inhibitors] lopinavir/ritonavir, eight volunteers suffered from both nausea and vomiting, one from nausea only, and one from vomiting only. On day 7, increases in [the liver enzymes] aspartate aminotransferase/alanine aminotransferase (AST/ALT) levels were reported in all volunteers and on day 8, the study was prematurely terminated. The AST/ALT levels continued to rise and peaked (grade 2, n=2; grade 3, n=1; grade 4, n=8) on days 9–10. All values returned to normal within 6 weeks. The study showed a high incidence of adverse events when a higher than standard dose of the new lopinavir/ritonavir tablets was combined with rifampicin. In the future, this drug combination should not be given to healthy volunteers [but it’s okay with HIV-positive people? Okay with sick people?]. Liver function should be carefully monitored when rifampicin and lopinavir/ritonavir are combined in patients.”

“Antiretroviral drugs have the potential to cause liver toxicity, especially in hepatitis B virus or hepatitis C virus coinfected patients. Tenofovir [a nucleoside analog] is among the few antiretrovirals that are considered nonhepatotoxic, whereas efavirenz [an NNRTI] can cause liver enzyme elevations. We report three cases of liver enzyme elevations in persistently hepatitis B virus and hepatitis C virus-negative, HIV-infected patients after the addition of tenofovir to an efavirenz-containing regimen.”

“Antiretroviral drug-related liver injury (ARLI) is a common cause of morbidity, mortality and treatment discontinuation in HIV-infected patients…Virtually every licensed antiretroviral medication has been associated with liver enzyme elevations, although certain drugs may cause liver injury more frequently than others…Several major mechanisms of ARLI have been described, including metabolic host-mediated injury, hypersensitivity reactions, mitochondrial toxicity, and immune reconstitution phenomena…The severity of ARLI may range from the absence of symptoms to liver decompensation, and the outcome can range from spontaneous resolution to liver failure and death…After initiating HAART, the reported incidence of severe liver toxicity ranges from 2 to 18%…Mechanisms of drug injury observed with NRTI [nucleoside analogs, such as AZT] mainly include mitochondrial toxicity and hypersensitivity reactions…In patients taking nevirapine, the overall incidence of symptomatic events involving the liver enzymes is approximately 5% [44,88]. However, severe liver toxicity, occurring with early latency, has been reported in HIV-infected and HIV-seronegative individuals. Warnings against the use of nevirapine for postexposure prophylaxis were issued after some individuals developed hepatic failure requiring liver transplantation…The phenomenon of ARLI became more evident after the introduction of PI drugs. Rates of hepatotoxicity from registration trials of various PI have ranged from 1% to 9.5%, but few patients had serious liver-related outcomes. In comparison with other drugs in its class, full-dose ritonavir has consistently been shown to be more hepatotoxic…The clinical development of aplaviroc, a CCR5 antagonist, was halted in 2005 after the occurrence of severe hepatotoxicity”

“In a recent article, Mallet and colleagues reported a series of eight cases of nodular regenerative hyperplasia (NRH) of the liver as a new cause of chronic liver disease in HIV-infected patients. NRH is characterized ‘by the presence of diffuse rather small regenerative nodules in the absence of significant fibrosis’. All patients were treated with HAART and all received didanosine included in one of several lines of antiretroviral drugs they had before the diagnosis of NRH…Our case is very similar to those reported by Mallet et al and emphasizes the seriousness of this complication: the risk of variceal haemorrhage, indication for some patients of transplantation (three out of eight of the cases reported by Mallet et al). Only HIV infection and HAART have been identified as potential co-factors. Nevirapine toxicity is well known, has not been specifically incriminated in NRH pathogenesis, but was also taken by our patient as well as by eight patients reported by Mallet et al.”

“There were 235 deaths among the 4471 patients on HAART (5%)…AIDS-related events were the most common cause of death (n=95; 40%), although they significantly decreased over time, whereas liver diseases and non-AIDS-defining infections significantly increased over time.”

“From January 2003 to June 2006, eight consecutive HIV-infected patients (seven Caucasian and one African) were referred for cryptogenic [unknown cause] liver disease…During the same period, 178 HIV-infected patients were admitted to the same unit for the treatment or the evaluation of chronic liver disease and 97 underwent liver biopsy…With the exception of HIV infection and the associated liver disease, none of these patients had significant co-morbidity, especially considering cardiac or renal pathology. They did not take any other hepatotoxic medication apart from antiretroviral drugs…No patients had had opportunistic infection…A clear nodular architecture was seen in seven patients, whereas in the last one, NRH [nodular regenerative hyperplasia of the liver] was suspected on the presence of sinusoidal dilatation in a clinical context of portal hypertension…To date, all patients are alive, and three are waiting for liver transplantation.”

“We here report a 52-year-old white male (Centers for Disease Control and Prevention stage C3) with a 20-year history of multidrug-resistant HIV. In February 2005 he was started on an antiretroviral regimen with TPV and RTV (500/200 mg twice daily), continuing the existing regimen of zidovudine/lamivudine (300/150 mg twice daily) and T-20 (90 mg twice daily), which was started 12 months before without hepatic disorders…Two weeks after the initiation of the TPV containing regimen, the patient developed elevated liver enzymes…HBV DNA viral load was low with 20 000 copies/ml, autoimmune markers for hepatitis and cirrhosis were negative, excessive alcohol consumption was denied. Percutaneous liver biopsy showed a mild, non-active hepatitis with moderate lymphocyte infiltration in the portal areas and no intrahepatic steatosis. Following the patient’s wish to interrupt the T-20 [enfuvirtide, a fusion inhibitor] treatment because of severe local skin reactions, and under the assumption of a hepatotoxic effect of the antiretroviral regimen T-20 was discontinued for 6 weeks. Shortly after, liver function improved with a 50% decrease in LFT values. Due to a weight loss of 10 kg and an elevation of the viral load treatment with T-20 was recommenced and 2 weeks later after an increase of the G-GT TPV/RTV was discontinued. The liver function tests returned to normal within 4 weeks.”

“Aptivus [tipranavir] co-administered with 200 mg Ritonavir has been associated with reports of clinical hepatitis and hepatic decompensation including some fatalities”

“Considering the 86 patients in the follow-up study, 17 were found to be HBV-DNA positive, 13 on admission and four in the subsequent observation…28 (32.5%) experienced a hepatic flare [at least a tripling of the liver enzyme serum alanine aminotrasferase between two consecutive measurements]…Of the 13 patients who were HBV-DNA positive on admission, two did not receive HAART; one of these two experienced a hepatic flare after a 12-month observation. The other 11 patients were treated with HAART containing lamivudine and were HBV-DNA negative at the subsequent check points. Of these 11, four became HBV-DNA positive under lamivudine treatment and experienced a hepatic flare; two of these four also experienced a hepatic flare after the discontinuation of the drug. Another two of these 11 patients (Fig. 1f, g) became HBV-DNA positive and experienced a hepatic flare, respectively, 4 and 8 months after lamivudine was discontinued because of lack of efficacy of the HAART regimen. The remaining five patients of the 11 treated remained HBV-DNA negative under HAART containing lamivudine and did not experience a hepatic flare…[in summary] in approximately half of the lamivudine treated patients occult HBV replication became detectable again after 12–40 months of lamivudine treatment, always associated with a hepatic flare.”

“Patients with steatosis [fat deposits in the liver] grade 2/3 [severe] were more likely to be receiving antiretroviral therapy than were patients with grade 1 [mild] steatosis (84% versus 77%) and patients without steatosis (69%). NRTI-based [nucleoside reverse-transcriptase inhibitors such as AZT] treatment was more frequent among patients with steatosis grade 2/3 than among patients with grade 1 or grade 0 steatosis (82%, 75% and 68%, respectively)…Lipodystrophy [fat redistribution, also associated with long-term antiretroviral drug use] was present in 15.7% overall, i.e., 21% in patients with grade 2/3 steatosis, 15% in patients with grade 1 steatosis, and 11% in patients with no steatosis.”

“Hepatocellular carcinoma (HCC) is an increasing cause of mortality in HIV-seropositive individuals…All HIV-infected subjects with a diagnosis of HCC included in three cancer registry databases were enrolled in the study [using HCC cases from Brescia, North Italy in 1995-1998 as controls]…41 HIV-infected subjects with HCC were identified…31 patients (77%) were on highly active antiretroviral therapy.”

“We report the first observation of acute hepatic cytolysis associated with atazanavir [a new azapeptide protease inhibitor]…transaminase activity gradually increased after the introduction of atazanavir, with a marked increase between weeks 8 and 30 (up to 10 times the normal value). At admission, physical examination showed afebrile subclinical jaundice. The abdominal examination was strictly normal (no hepatomegaly). No signs of chronic liver disease or liver failure were found. Laboratory tests revealed major cytolysis [breakdown of cells in the liver]”

“Abnormalities in hepatic function have become one of the most common complications occurring among human immunodeficiency virus (HIV)-infected individuals receiving highly active antiretroviral therapy (HAART), and liver disease has become an increasingly important cause of morbidity and mortality in HIV-infected patients. We present a case of a patient with HIV infection and hepatotoxicity that exemplifies the complications currently observed during the treatment of such patients…Although coinfection with HCV and HIV has become a common clinical problem, optimal treatment of such patients remains to be defined and must be individualized to maximize benefit and tolerance.”

“during clinical trials of Kaletra [combination of the protease inhibitors Lopinavir and Ritonavir], approximately 1 in 4 treatment experienced patients saw a serious or life-threatening laboratory abnormality.…The most common laboratory abnormalities [found with Kaletra, a combination of the protease inhibitors Lopinavir and Ritonavir] are increases in some tests of liver function…”

“when mortality [in British hemophiliacs] from other [non-HIV] causes was examined separately, a substantial increase over time remained, with the value during 1991–1996 almost double that for 1985–1990 and no appreciable decline in 1997–1999. The increase was entirely caused by an increase in liver disease, which during 1997–1999 was the certified cause of death for over 25% of deaths in HIV-infected individuals…For deaths that were classified neither as HIV related nor from liver disease, mortality remained virtually constant during 1985–1999, albeit at a higher level than that of HIV-uninfected individuals. It seems likely that at least some of these deaths were attributable to HIV, although there was no indication that the individuals concerned had developed an AIDS-defining condition. HAART has been associated with several categories of major toxic effects, but there was no evidence of any deaths occurring as a result of HAART in this population. [but what other explanation is there?]”

“Women with CD4+ counts >250 cells/mm3, including pregnant women receiving chronic treatment for HIV infection, are at considerably higher risk (12 fold) of hepatotoxicity [liver damage]. Some of these events have been fatal…The greatest risk of severe and potentially fatal hepatic events (often associated with rash) occurs in the first 6 weeks of VIRAMUNE [nevirapine] treatment. However, the risk continues after this time and patients should be monitored closely for the first 18 weeks of treatment with VIRAMUNE…In some cases hepatic injury progresses despite discontinuation of treatment. [Boehringer Ingelheim is the manufacturer of Nevirapine]”

“30 non-HIV-infected individuals developed hepatotoxicity [liver toxicity] after 8 to 35 days of single-agent nevirapine (8 people) or a nevirapine-containing PEP regimen (22). Findings included ECOG grade 3 [confined to bed at least half the day] or 4 [completely disabled] hepatotoxicity (n = 14), fevers (n = 11), skin rashes (n = 8), eosinophilia (n = 6), and fulminant hepatic necrosis requiring an orthotopic liver transplant (n = 1). Rates of severe hepatotoxicity (grade 3 or 4) in non-HIV-infected individuals ranged from 10% (4/41) to 62% (5/8). Liver biopsy material from 2 individuals was consistent with a hypersensitivity syndrome.”

“Between December 1996 and December 2001, 2947 patients with a diagnosis of HIV infection were enrolled into 1 of 5 CPCRA [Terry Beim Community Programs for Clinical Research on AIDS] clinical trials…for this analysis…All patients in this cohort were prescribed ART following enrollment…The most common grade 4 events were: liver related (148 patients); neutropenia (89); anemia (64); cardiovascular (51); pancreatitis (50); psychiatric (44); kidney-related (34); thrombocytopenia (32); and hemorrhage (25) [these are much more likely to be therapy-related than HIV-related]…the rate of grade 4 events is greater than the rate of AIDS events, and the risk of death associated with these grade 4 events was very high for many events.”

“In multivariate analysis [of 692 Thai HIV patients], predictors of severe hepatotoxicity [liver toxicity] were HBV [Hepatitis B virus] or HCV [Hepatitis C virus] coinfection, and NNRTI[Non-Nucleoside Reverse Transcriptase Inhibitor]-containing therapy. Incidence of severe hepatotoxicity was particularly high among patients receiving nevirapine and nevirapine/efavirenz”

“306 patients started a nevirapine-containing regimen, of whom 8 developed an acute hepatitis (2.6%) in a median of 24 days. Transaminases peaked at 28 days. Injury pattern was in general mixed-hepatocellular. Withdrawal of the antiretroviral agent led to rapid restoration of transaminase levels and resolution of clinical symptoms.”

“In 655 individuals receiving HIV postexposure prophylaxis (PEP), drug-induced aminotransferase alterations were frequent and severe in the nevirapine-including regimen, rare and mild-to-moderate in other combinations, and always reversible. Grade 3–4 incidence in protease inhibitor or nevirapine PEP was 0.5 and 25.0 per 100 person-months, respectively. Apart from nevirapine, continuing PEP appears to be safe [but without long-term follow-up this claim is a bit shaky] even in the case of aminotransferase alterations. The usefulness of routine monitoring of liver function during PEP could be re-considered.”

“Nucleoside reverse transcriptase inhibitors (NRTIs) induce mitochondrial toxic effects resulting in multiple organ disorders. Liver involvement has been associated mainly with severe lactic acidosis and massive steatosis [fatty degeneration]…13 patients with HIV infection treated with NRTI-based regimens had low-grade abnormal liver test results associated with digestive and nonspecific general symptoms. Histologic examination of liver samples showed diffuse steatosis in only 6 cases and mild steatosis in the remaining cases…In all cases, ultrastructural study disclosed mitochondrial abnormalities. Our work demonstrates that NRTI-induced toxic effects in the liver may occur as indolent [without symptoms] nonspecific disease [but probably not forever, as the side effects worsen]”

“755 HIV-seropositive patients consecutively prescribed new [i.e. changed, not necessarily the first] ART [anti-retroviral therapy] were selected…26 cases of SH [severe hepatotoxicity] were observed with an incidence of 4.2% person-years. Liver failure (LF) was rarely seen (1.1 per 100 person-years)…Death occurred during follow-up in 7 of 26 (27%) patients, all of whom showed LF and baseline CD4 count less than 200 cells/mm. Relapse of SH was observed after ART was recommenced in 7 of 17 (41%) patients. [Note that Severe Hepatotoxicity was also somewhat associated with IV drug abuse and alcohol abuse, which may have been contributing factors]”

“the liver-related mortality rate was…twice as high after 1996, when highly active antiretroviral therapy (HAART) was introduced.”

“In this investigation, 492 patients…prescribed antiretroviral drugs between April 1989 and September 2000 were included…The median duration of follow-up of the cohort was 1,392 days. HCV [Hepatitis C] infection was present in 323 (68%). Mortality attributable to AIDS decreased from 4.5 to 1.8 per 100 persons per year. Mortality due to liver failure increased from 0.3 to 0.5 per 100 persons per year. The survival of patients with and without HCV infection was similar. Although liver failure is an increasing cause of death among HIV-infected patients receiving HAART, HCV infection has still no impact on the survival of HIV-infected patients.”

“Liver fat content was significantly higher in the HAART+LD+ group than the HIV-…group [obviously not taking HAART]…The severity of the insulin resistance syndrome in patients with HAART-associated lipodystrophy [abnormal fat distribution] is related to the extent of fat accumulation in the liver”

“We describe a patient in whom disseminated intravascular coagulation (DIC) developed within 6 days after starting abacavir for the treatment of HIV infection [resulting in kidney failure and liver abnormalities]”

“Whether by HAART, viral hepatitis, or alcohol, transaminitis (elevated ALT and AST [liver enzyme levels]) is common among those with HIV infection... In unadjusted analyses, CD4 [immune cell counts], VL [viral load], and AST were significant predictors of survival in both cohorts (p<0.001). ALT was significant only in CHORUS [one cohort]…Transaminitis is a major determinant of survival and should be carefully considered in all phases of HIV therapy [note that the cumulative length of treatment with antiretroviral drugs, which are known to be toxic to the liver, was not considered]”

“The occurrence of a severe elevation of [the liver enzymes] transaminases was associated with poorer survival, although HCV [Hepatitis C Virus] was not. If liver toxicity may be treatment induced, plasma drug concentrations could guide dosage adjustments ofantiretroviral treatments currently prescribed to optimize their use.”

“Of the 560 patients, 44 (7.9%) developed grade 4 LEEs [Liver Enzyme Elevation]…9 cases were excluded from the analysis [due to other explanations for their liver problems] leaving 35 cases…6 (17.1%) of 35 patients were symptomatic. The most frequently occurring symptoms were jaundice, dark urine, clay-colored stools, malaise, nausea, vomiting, and right upper quadrant discomfort…the risk factors significantly associated with grade 4 LEE…were higher baseline ALT levels, chronic HBV [Hepatitis B] infection [which could be a surrogate for the user of additional drugs] , chronic HCV [Hepatitis C] infection [also possibly a surrogate for the use of other drugs], the use of first-line potent antiretroviral combination regimens in patients without prior NRTI [Nucleoside Reverse Transcriptase Inhibitor] treatment, recent start of nevirapine or ritonavir, and female sex. Furthermore, among patients chronically coinfected with HBV, discontinuing the use of 3TC was associated with the development of grade 4 LEE…[but] 5 (14%) had recently discontinued the use of 3TC while a chronic HBV infection was present [which could indicate that 3TC caused the liver problems, but that 3TC was stopped before the LEE worsened to grade 4]”

“Current highly active antiretroviral therapy (HAART) is based on combination regimens with substances from three different classes: nucleoside reverse transcriptase inhibitors (NRTI), non-nucleoside reverse transcriptase inhibitors (NNRTI) and protease inhibitors (PI)…HAART-associated toxicity has evolved as the main reason to discontinue or modify antiretroviral therapy. Hepatotoxicity [liver damage] appears to be of particular importance in this context as it can occur with any antiretroviral regimen currently in use. Most remarkably, longitudinal surveys have not only reported an increased incidence of hepatic injury in HAART-treated patients but also identified life-threatening hepatotoxic events and end-stage liver disease in patients on antiretroviral treatment. Since rational alternatives to HAART [i.e. not taking HAART is not rational] are currently not available to control HIV infection, understanding the pathophysiology as well as a profound knowledge of how to prevent and to treat HAART-related liver damage will be a continuous challenge [and source of income] for the present and future generations of hepatologists.”

“In a case-control study, 70 patients taking nevirapine (200 mg twice a day) triple combinations were chosen and classified into two groups, one including subjects who developed any grade of hepatotoxicity [liver disease], and a control group including subjects without transaminase elevations. The use of nucleoside analogs was comparable in both groups...The peak in transaminase levels [surrogate marker for liver toxicity] among the 33 subjects of the first group occurred at a median time of 6.1 months after beginning nevirapine-based therapy...our preliminary findings support the theory that nevirapine-associated liver toxicity occurring after several months on therapy is not part of a systemic hypersensitivity reaction, and seems to be correlated with higher plasma drug concentrations involving a dose-dependent mechanism”

“A number of patients experienced grade 3-4 laboratory abnormalities in liver function tests, cholesterol, and triglycerides while receiving this drug combination”

“In conclusion, we believe that our patient developed liver failure and portal hypertension in the absence of cirrhosis because of long-term nucleoside-analogue therapy without development of symptomatic lactic acidaemia. Gliclazide and metformin are not related to hepatocellular damage; however, tuberculostatic drugs used might have accelerated this process. This case suggests that even mild hyperlactaemia, which occurs in 15-35% of nucleoside-analogue-treated patients, can be associated with progressive liver damage”

“We describe four instances of reversible hepatocellular [liver] damage associated with the use of nevirapine in patients with HIV infection...Evidence of malaise, skin rash, and icteric hepatitis [jaundice] with pruritis [skin rash] occurred 4-6 weeks after the beginning of nevirapine therapy...In all cases, liver test results declined to normal or near normal levels, and pruritus disappeared 4-6 weeks after discontinuation of the medication. No patient was rechallenged with the drug.”

“The cases of 2 patients with nevirapine-associated hepatotoxicity [liver damage]…are reported here. Both patients' conditions improved following withdrawal of nevirapine.…Until a better understanding of the clinical spectrum and pathophysiology of nevirapine-associated hepatotoxicity is realized, treatment will remain largely empiric [translation: we are not too sure what we are doing, but we never like to take a drug away from a patient]”

“A comprehensive retrospective review of more than 10,000 adult AIDS patients participating in 21 different AIDS Clinical Trials Group (ACTG) studies [confirms]... that antiretroviral therapy is associated with a high rate of severe hepatotoxicity [liver damage], regardless of drug class or combination. Dr. Chung of Massachusetts General Hospital in Boston presented the findings to the Digestive Disease Week annual meeting...The researchers evaluated data for AIDS patients, enrolled in ACTG studies between 1991 and 2000. The subjects were taking a variety of drug combinations including one or more nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs)...Overall, 10% of patients developed grade 3 and 4 hepatotoxicity and 23% of them had to discontinue therapy permanently. According to the data, 2.5% of all deaths in the study period were liver related. NNRTI[non-nucleoside reverse-transcriptase inhibitors]-containing regimens, especially those including nevirapine and efavirenz, were particularly hard on the liver, with high rates of discontinuation.”

“Acute hepatitis with lactic acidosis is a life-threatening but [sometimes] reversible toxic effect on mitochondria of HIV-1 nucleoside-analogue treatment [later this letter notes that 80% of patients with lactate greater than 10 mmol/L die]. We report fatal portal hypertension, liver failure, and persistent mitochondrial dysfunction in a man aged 65 years with HIV-1 infection who had recovered from nucleoside-analogue-induced acute hepatitis and lactic acidaemia more than 18 months previously. We believe that symptom-free patients who receive nucleoside-analogue therapy should have hepatic [liver] function constantly monitored, especially those with past or present lactic acidaemia.”

“The antiretroviral drugs used to fight HIV, particularly the protease inhibitors, place a great strain on the liver, the organ whose function it is to metabolize them...When Brian Klein of San Francisco found out that he was HIV-positive in 1996, he immediately started on a three-drug regimen that included a protease inhibitor. "Within two weeks I got extremely sick," he recalled. "I became jaundiced. I lost 15 pounds. They did some tests, and, lo and behold, I had hepatitis C [or liver damage from the protease inhibitors generated auto-antibodies misidentified as from Hepatitis C]. They pulled me off the medications because this was all new at the time and they didn't know what to do.”

“In 1998-1999, 11 (50%) of 22 deaths were due to end-stage liver disease, compared with 3 (11.5%) of 26 in 1991 and 5 (13.9%) of 36 in 1996 (P = .003). In 1998-1999, 55% of patients had nondetectable plasma HIV RNA levels and/or CD4 cell counts of >200 cells/mm3 within the year before death. Most of the patients that were tested had detectable antibodies to hepatitis C virus (75% of patients who died in 1991, 57.7% who died in 1996, and 93.8% who died in 1998-1999; P = NS). In 1998-1999, 7 patients (31.8%) discontinued antiretroviral therapy because of hepatotoxicity, compared with 0 in 1991 and 2 (5.6%) in 1996. End-stage liver disease is now the leading cause of death in our hospitalized HIV-seropositive population.”

“We retrospectively examined the causes of death of HIV-seropositive patients at our institution in 1991, 1996, and 1998–1999. In 1998–1999, 11 (50%) of 22 deaths were due to end-stage liver disease, compared with 3 (11.5%) of 26 in 1991 and 5 (13.9%) of 36 in 1996…In 1998–1999, 7 patients (31.8%) discontinued antiretroviral therapy because of hepatotoxicity, compared with 0 in 1991 and 2 (5.6%) in 1996. End-stage liver disease is now the leading cause of death in our hospitalized HIV-seropositive population.”

“In a cohort of 1,047 human immunodeficiency virus type 1-infected patients started on protease inhibitors (PIs), the incidence of severe hepatic [liver] cytolysis (alanine aminotransferase concentration five times or more above the upper limit of the normal level>=5N) was 5% patient-years after a mean follow-up of 5 months...At the onset of severe cytolysis, 2 patients were receiving Saquinavir (SQV), 5...Ritonavir (RTV), 7...Indinavir (IDV), 5...Nelfinavir (NFV), 1...SQV and RTV, 1...IDV and NFV, and 1...RTV and NFV”

“treatment with certain PIs [Protease Inhibitors] is associated with fat redistribution, hyperlipidemia (high fat levels in the blood), or both...we examined the effects of PIs on lipid synthesis in cultured hepatocytes [liver cells] and AKR/J mice. The results showed that NFV [nelfinavir] and RTV [ritonavir] increased serum TG [triglyceride] levels in mice...ABT-378, NFV, RTV, and SQV [saquinavir], but not APV [amprenavir] or IDV [indinavir], increased TG synthesis and RTV increased CH [cholesterol] synthesis in HepG2 [liver] cells...select PIs affect multiple, distinct metabolic pathways, perhaps accounting for the different side effects observed for each PI”

“While the risk of transmission of HIV via a needlestick is approximately 0.3%, the risk of serious adverse effects of these preventive strategies remains undefined. We report a case of a health care worker who experienced serious morbidity from PEP [post-exposure prophylaxis]...A 43-year-old female, African American phlebotomist sustained a needlestick injury after drawing blood from an HIV- and hepatitis C virus (HCV) infected patient. She received PEP with zidovudine, lamivudine, and nevirapine. Triple therapy including nevirapine was selected based on the source patient's advanced disease, antiretroviral treatment history, and severity of the exposure...The patient required an orthotopic liver transplant 35 days following initiation of PEP. Pathology of the native liver showed confluent hepatic necrosis...We think that this patient had a severe hypersensitivity reaction to nevirapine that resulted in hepatic failure...This case raises the question of whether the safety profile of nevirapine warrants its use as a prophylactic medication in health care workers who are exposed to HIV when the risk of transmission is low.”

“The existing sections [of the product label for Nevirapine/Viramune] have been updated to provide additional warning information about the risk of severe, life-threatening and in some cases, fatal hepatotoxicity [liver damage] that have been reported in patients treated with Viramune. Although clinical presentation varied among patients, frequently occurring features included non-specific prodromal [early] signs and symptoms of fatigue, malaise, anorexia and nausea, with or without abnormal serum transaminase levels. In these reports, symptoms progressed to jaundice, hepatomegaly [enlarged liver], elevation of transaminase levels and hepatic [liver] failure over several days.”

“severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including Ziagen and other antiretrovirals”

“Severe hepatotoxicity was observed in 31 (10.4%) of 298 patients...Risk of severe hepatoxicity was 5-fold higher for patients taking [the protease inhibitor] ritonavir, which accounted for half of all cases...Likewise, more than half of cases of severe hyperbilirubinemia [excess of bilirubin] were associated with indinavir use”

“Liver disease has become the leading cause of death among HIV patients at a Massachusetts hospital, a report issued on Friday...[by] Dr. Barbara McGovern, a professor at Tufts University School of Medicine and a member of staff at Lemuel Shattuck Hospital in Jamaica Plains, Mass. The findings were reported on Friday at the annual meeting of the Infectious Diseases Society of America in Philadelphia. McGovern said HIV patients who take a powerful combination of AIDS drugs called highly active antiretroviral therapy (HAART) were at particular risk because of the drug's potential toxicity to the liver. One-third of HIV patients with underlying liver disease at Lemuel Shattuck have had to stop taking HAART.”

“hepatotoxicity is frequently seen in patients under HAART, and can force the withdrawal of antiviral treatment in a significant proportion of patients, occasionally resulting in fatal outcome.”

“We analysed the first 187 patients who began highly active antiretroviral therapy (HAART) in a reference centre for HIV/AIDS located in Madrid. Examination of liver function was made at baseline and after 1 month of starting treatment…A significant increase in transaminases (more than twofold) was recognized in 26 (13.9%) patients, whereas bilirubin increases above 2.5 g/l were seen in seven (3.7%) individuals. Eleven (5.9%) subjects needed to stop the medication because of either hepatic cytolysis [liver cell death] (nine patients), or hyperbilirubinaemia (one patient), or both (one patient). Four (2.1%) individuals developed clinical hepatic decompensation, and one of them died. This patient was receiving stavudine, lamivudine plus indinavir, and he had been diagnosed with multiple chronic hepatitis (hepatitis B, C and D), although this was his first episode of clinical liver failure…In conclusion, hepatotoxicity is frequently seen in patients under HAART, and can force the withdrawal of antiviral treatment in a significant proportion of patients, occasionally resulting in fatal outcome.”