Kirk D. Miller

Visceral abdominal-fat accumulation associated with use of indinavir

BACKGROUND After the addition of the protease inhibitor indinavir to combination drug regimens for HIV-1 infection, some patients have experienced an increase in abdominal girth with symptoms of abdominal fullness, distension, or bloating. We aimed to find out whether this collection of symptoms was associated with changes in abdominal fat and whether such changes were associated with indinavir use. METHODS Abdominal computed tomography was used in ten HIV-1-positive patients who had such abdominal symptoms to measure total adipose tissue (TAT) and visceral adipose tissue (VAT) at the umbilicus (L4 vertebral level). The VAT:TAT ratio in the ten cases was compared with that in ten HIV-1-infected patients who had been using indinavir without abdominal symptoms for at least 6 months and ten HIV-1-infected patients who were not using indinavir. FINDINGS The mean VAT:TAT ratios for the three groups-non-users, symptom-free indinavir users, and symptomatic indinavir users-were 0.40 (SD 0.15), 0.59 (0.18), and 0.70 (0.20), respectively (p=0.004). The VAT:TAT ratio correlated with duration of indinavir use (r=0.47, p=0.01). The mean areas of VAT for the three groups were 106 cm2 (SD 72), 141 cm2 (65) and 202 cm2 (93), respectively (p=0.03). The mean body-mass index of the groups was similar, and patients in the two indinavir groups did not gain a significant amount of weight after starting the drug. Serum triglyceride values increased after starting indinavir and correlated with VAT:TAT ratios. INTERPRETATION Our data suggest that some HIV-1-infected patients on indinavir treatment accumulate intra-abdominal fat that may cause abdominal symptoms. Recent evidence suggests that other HIV-1 protease inhibitors may be associated with changes in body-fat distribution. Larger studies of protease-inhibitor treatment are needed to investigate this association further and to investigate metabolic or endocrine mechanisms that may underlie this phenomenon.

Lactic acidosis and hepatic steatosis associated with use of stavudine: report of four cases.

An uncommon but life-threatening syndrome of severe hepatic steatosis and lactic acidosis among patients infected with HIV-1 was first described in the early 1990s (1-3). By early 1994, at least 40 such cases had been reported to regulatory authorities, and an association with use of zidovudine and didanosine was established (4). An underlying mechanism involving impaired replication of mitochondrial DNA was proposed (5). Although stavudine (Zerit, Bristol-Myers Squibb, Princeton, New Jersey) is the second most widely prescribed antiretroviral nucleoside analogue (6, 7), it has rarely been associated with the syndrome of severe hepatic steatosis and lactic acidosis. We report on four patients who developed this syndrome while receiving an antiretroviral regimen containing stavudine. Case Reports In 1997, four patients who had taken stavudine for 3 to 15 months in combination with other antiretroviral drugs presented with severe lactic acidosis, elevated levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and evidence of fatty infiltration of the liver on computed tomography (Table). Two patients had elevated levels of muscle enzymes and two had clinical, laboratory, and computed tomographic evidence of pancreatitis. Two patients underwent liver biopsy, which revealed hepatic steatosis, and two had muscle biopsy that showed evidence of mitochondrial myopathy (Figure). One patient (patient 2) had chronic hepatitis C; none had chronic hepatitis B. Table. Summary of Four Patients Figure. Computed tomographic, biopsy, and electron micrograph findings. A. B. C. D. Patient 1 A 63-year-old obese HIV-infected woman presented with a 1-month history of nausea, vomiting, and abdominal pain. She had severe metabolic acidosis (arterial blood pH, 7.12), a markedly elevated serum lactate level, hepatic steatosis, and pancreatitis (Table). On admission, therapy with stavudine and lamivudine, which the patient had been using for 6 months, was discontinued. After a complicated hospital course, much of which was spent in the intensive care unit, the patient recovered and began taking nelfinavir, saquinavir, and nevirapine. Her illness did not recur. Patient 2 A 54-year-old obese HIV-infected man presented with a 3-month history of nausea, vomiting, and abdominal pain. He had severe metabolic acidosis (arterial blood pH, 7.12), an elevated serum lactate level, and hepatic steatosis (Table). Therapy with stavudine, lamivudine, and indinavir, which the patient had been taking for 15 months, was discontinued. After a complicated 3-week hospitalization, the patient began taking lamivudine, saquinavir, and nelfinavir. His illness did not recur. Patient 3 A 16-year-old HIV-infected girl presented with a 3-day history of nausea, vomiting, and abdominal pain. She had severe metabolic acidosis (arterial blood pH, 7.33), an elevated serum lactate level, hepatic steatosis, pancreatitis, and myopathy (Table). Therapy with stavudine, didanosine, and nelfinavir, which the patient had been taking for 3 months, was discontinued; the patient had previously taken didanosine for 4 years without problems. After a complicated hospital course that included a prolonged stay in the intensive care unit, the patient began receiving zidovudine, nevirapine, and nelfinavir. Her illness did not recur. Patient 4 A 43-year-old HIV-infected man presented with a 2-week history of nausea, vomiting, and diffuse myalgias. His serum lactate level was elevated, and he had hepatic steatosis and myopathy (Table). Therapy with stavudine, lamivudine, saquinavir, and ritonavir was discontinued. The patient had taken stavudine for 15 months, lamivudine for 16 months, ritonavir for 9 months, and saquinavir for 2 weeks. Over the ensuing 4 weeks, his symptoms and laboratory abnormalities gradually resolved; he then began receiving a new antiretroviral regimen consisting of didanosine, lamivudine, and nelfinavir. His illness did not recur. Discussion We report on four patients in whom a syndrome of hepatic steatosis and lactic acidosis developed while they were taking stavudine as part of multidrug antiretroviral regimens. Two of the three patients who were also taking lamivudine at the onset of lactic acidosis subsequently restarted therapy with this drug without recurrence of their illness. One patient was also taking didanosine but had previously taken this drug without difficulty. We therefore believe that hepatic steatosis and lactic acidosis were most likely caused by stavudine. Although stavudine (and the other nucleoside analogues) do not have pharmacokinetic interactions that are likely to contribute to the development of hepatic steatosis and lactic acidosis, the possibility that combinations of agents of this class have additive metabolic toxicity cannot be excluded (8). Two patients developed concurrent acute pancreatitis, and two had biopsy-documented myopathy with prominent lipid accumulations due to mitochondrial dysfunction. Patients who develop acute pancreatitis as part of the syndrome seem to be at particular risk for severe disease and fatal outcome (9). Initial symptoms may be mild and nonspecific, such as nausea and abdominal discomfort; this may lead to a delay in diagnosis until patients are severely ill (10). Of note, hepatic steatosis may be severe despite near-normal ALT and AST levels, and myopathy may be present with only modest elevations of creatine kinase level (1, 2, 9, 10). Two of our patients were obese. Obesity is associated with nonalcoholic steatohepatitis, which may lead to hepatic fibrosis and cirrhosis (11). However, pancreatitis, myopathy, and lactic acidosis are not typical features of this entity. Moreover, the natural history of nonalcoholic steatohepatitis is one of chronicity and poor response to interventions; in contrast, the clinical course of our patients improved after withdrawal of stavudine therapy. It is interesting, however, that nonalcoholic steatohepatitis is predominantly found in women and that women seem to be disproportionately affected by nucleoside analogueassociated toxicity (1-3, 5-7, 9, 10, 12). A similarity to the Reye syndrome was noted in a 1990 report that described a probable case of zidovudine-associated hepatic steatosis (1). The patient in that report had used aspirin, but aspirin use has not been found to be a feature of nucleoside analogueassociated hepatic steatosis. Nor has alcohol abuse been found to be an associated feature. None of our four patients had used aspirin over the long term, and none consumed ethanol heavily. Current evidence suggests that nucleoside analogue toxicity results in mitochondrial injury (13, 14). The earliest signs of mitochondrial dysfunction, which precede structural abnormalities, include reduction of cytochrome oxidase and impaired -oxidation of fatty acids that lead to accumulation of fat droplets within cells. Mitochondrial abnormalities due to nucleoside analogues were first described among HIV-infected patients who developed myopathy after long-term therapy with zidovudine (15). Subsequently, the full syndrome of hepatic steatosis, lactic acidosis, and mitochondrial myopathy was described (2, 16). Studies showed that use of nucleoside analogues led to depletion of mitochondrial DNA by selective inhibition of DNA polymerase-, which is responsible for replication of mitochondrial DNA (17). Depletion of mitochondrial DNA leads to depletion of components of the oxidative phosphorylation system, which in turn leads to a defect in pyruvate metabolism that favors production and accumulation of lactate (14). Thiamine deficiency also leads to defective pyruvate metabolism and accumulation of lactate, and thiamine deficiency has been reported in the setting of HIV infection (18). We did not investigate thiamine deficiency as a cause of lactic acidosis in our patients; however, these patients did not present with the typical cardiovascular or neurologic features of severe thiamine deficiency but rather with atypical features, such as hepatic steatosis and pancreatitis. Nonetheless, the possibility that thiamine and other nutritional deficiencies, such as riboflavin deficiency, might contribute to the development of nucleoside analogueassociated lactic acidosis should not be dismissed. Indeed, riboflavin and thiamine replacement have been proposed as a treatment for this condition (7, 19). Timely confirmation of mitochondrial dysfunction as the mechanism underlying the syndrome of hepatic steatosis, lactic acidosis, and mitochondrial myopathy was facilitated by the intensive investigation that followed the outcome of a 1993 trial of an investigational nucleoside analogue used to treat chronic hepatitis B (20). Whether a given nucleoside analogue causes a highly prevalent and acute catastrophic illness, as did fialuridine, or a relatively rare syndrome of the type described in this report seems to depend on minor differences in molecular structure. Such differences dictate whether an agent will be incorporated into replicating mitochondrial DNA (as in the case of fialuridine) or whether it will lead to termination of replication (as in the case of zidovudine, didanosine, and stavudine) (13). As antiretroviral regimens have become more complex, elevations in ALT and AST levels have become common, especially in patients with concomitant hepatitis B or C infection. Current guidelines for the use of antiretroviral drugs recommend that HIV-1 viral loads and CD4+ T-lymphocyte counts be monitored every 3 to 4 months. Physicians should consider using these opportunities to also monitor ALT and AST levels. Because hepatic steatosis may be life-threatening, physicians should consider it as a possible cause of newly elevated ALT and AST levels among patients using stavudine as well as among those using zidovudine or didanosine. Elevated ALT and AST levels require closer monitoring; levels of serum lactate and pancreatic and muscle enzymes should be measured when

High Prevalence of Osteonecrosis of the Femoral Head in HIV-Infected Adults

Context Osteonecrosis (avascular necrosis) of the hip is an uncommon but painful and disabling condition that sometimes requires total hip replacement. Contribution This large survey showed that an unusually high percentage of HIV-infected adults (4.4% [95% CI, 2.5% to 7.2%]) had osteonecrosis of the hip, as detected by magnetic resonance imaging. Implications Although screening asymptomatic HIV-infected patients is not warranted, osteonecrosis should be considered in HIV-infected patients with persistent groin or hip pain. The Editors The natural history of HIV infection has changed substantially with the wide use of highly active antiretroviral regimens that include potent protease inhibitors or non-nucleoside reverse transcriptase inhibitors (1). The incidence of HIV-related deaths and HIV-associated opportunistic infections has decreased dramatically. As survival and quality of life have improved, the focus of health care providers has shifted to management of the increasingly complex drug regimens and their associated drug interactions and toxicities. Previously unrecognized or underrecognized complications related to HIV infection or therapies for HIV infection, such as lactic acidosis, hyperlipidemia, and fat redistribution, are increasingly being recognized (2). Osteonecrosis of the hip (also known as avascular necrosis) is a disabling condition that frequently requires total hip replacement (3-5). Osteonecrosis in HIV-infected patients was first reported in 1990 (6). Subsequent anecdotal reports have suggested that osteonecrosis is being diagnosed with increasing frequency in the setting of HIV infection (7-31). Between May 1999 and November 2000, six HIV-infected patients followed at the Warren Grant Magnuson Clinical Center of the U.S. National Institutes of Health (NIH) presented with groin or hip pain and received a diagnosis of osteonecrosis. The first two of these patients received their diagnosis within a 4-day period and were the first HIV-infected patients ever to receive such a diagnosis at the NIH Clinical Center. We also learned that an increasing number of cases of osteonecrosis were being reported to the U.S. Food and Drug Administrations Adverse Event Reporting System. We were concerned that osteonecrosis might be becoming a major HIV-related complication. We hypothesized that, if this were true, additional patients may have developed clinically silent osteonecrosis. Because magnetic resonance imaging (MRI) has been used to study asymptomatic osteonecrosis of the hip in other high-risk populations (32-37), we undertook a prospective MRI-based study to determine the prevalence of and evaluate possible risk factors for asymptomatic osteonecrosis of the hip in a sample of HIV-infected patients. Methods Participant Recruitment and Questionnaire Between 1 June and 15 December 1999, adults who were enrolled in studies of the treatment or natural history of HIV infection at the NIH Clinical Center or who were receiving health care services at the National Naval Medical Center in Bethesda, Maryland, were invited to participate in an MRI-based screening study of osteonecrosis of the hip. All patients seen in the outpatient clinics of the National Institute of Allergy and Infectious DiseasesNIH Clinical Center HIV program during the study period were informed of the protocol and encouraged to participate. Because this study focused on asymptomatic patients, we excluded persons with current groin or hip pain. Because the incidence of osteonecrosis was unknown, we considered several possible sample sizes (100 to 300 patients) and estimations of the 95% CI for low prevalence rates of asymptomatic osteonecrosis (0.1% to 3.5%). We determined that a sample size of at least 300 HIV-infected participants would be reasonable and attainable. Before undergoing MRI, participants completed a standard questionnaire on joint symptoms; medical history; medication use; and personal habits, including ethanol use, cigarette smoking, and routine exercise regimens. Questions related to medication use made a clear distinction between corticosteroids and other types of steroids, such as androgenic and anabolic steroids. Patients were asked why corticosteroids were prescribed and the route, frequency, and duration of use. The Institutional Review Board of the National Institute of Allergy and Infectious Diseases approved the protocol. All participants gave written informed consent. Data Collection We retrieved laboratory and clinical data from patient databases. Laboratory values obtained within 4 months of the MRI date were used in the analyses; for certain variables, we also analyzed the highest or lowest values recorded in a laboratory database that contained data back to 1984. Physiatrist Evaluation After approximately 150 patients were scanned and asymptomatic osteonecrosis was detected in 4 patients, we prospectively determined whether subtle physical findings might identify patients with MRI evidence of osteonecrosis of the hip. Patients enrolled after 12 July 1999 were asked (but not required) to be examined by a physiatrist who was unaware of the MRI results. The examination included evaluation of range of motion in the hip, which involved testing in all planes to end range with and without resistance and joint-loading maneuvers; pain was assessed in each test (38). MRI Scanning HIV-Infected Participants Magnetic resonance imaging was performed by using an LX Horizon 1.5-T MRI system (General Electric Medical Systems, Milwaukee, Wisconsin). We modeled the protocol for screening MRI on a previously described method for bilateral screening of the hips for osteonecrosis (37). Coronal T1-weighted spin-echo sequences were done with a repetition time of 400 ms and an echo time of 8 ms (using a 256 192 matrix). These were followed by coronal fatsuppressed T2-weighted fast spin-echo inversion recovery sequences with a repetition time of 3266 ms, an echo time of 38 ms, and an inversion time of 150 ms (256 224 matrix). Other variables used for both screening sequences included three excitations, a 40.0 40.0cm field of view, and 5-mm contiguous sections. All MRI scans were initially interpreted by one of the investigators. Positive scans were later intermixed with 35 randomly selected negative scans of HIV-infected participants and were reviewed by a second radiologist, who was unaware of the previous interpretation. Patients with osteonecrosis on the screening MRI underwent dedicated high-resolution MRI of the affected hip or the more abnormal hip. HIV-Negative Participants We assumed that asymptomatic osteonecrosis of the hip detectable only by MRI must occur infrequently in healthy adult humans with no known risk factors. To document this, we recruited persons without hip or groin pain who had no known risk factors for osteonecrosis. Exclusion criteria for this comparison group were a history of alcohol abuse, hip or leg fracture, pancreatitis, diabetes mellitus, hypertriglyceridemia (requiring therapy), systemic lupus erythematosus, blood-clotting disorders, or systemic corticosteroid use during the previous year or for greater than 1 month ever (total lifetime use). We recruited these participants from an NIH healthy volunteer database and by posting flyers at the NIH Clinical Center. The participants in the comparison group were approximately matched for age and sex to participants in the screening study HIV-infected patients; the comparison group underwent the MRI screening and consented to participate using the same protocol and procedures that were used in the HIV group. Hematologic Evaluation Participants with MRI evidence of osteonecrosis were evaluated for a possible hypercoagulable state by using the following assays: two assays for the presence of a lupus anticoagulant (DRVVT, American Diagnostica, Inc., Greenwich, Connecticut, and Staclot, Diagnostica Stago, Asnieres-Sur-Seine, France); assays for immunoglobulin (Ig)G and IgM anticardiolipin antibodies (Quantilite, Innova, San Diego, California); functional assays for protein C, protein S, and antithrombin III levels (Diagnostica Stago; an assay for thrombinantithrombin complex levels [Dade Behring Marburg, Marburg, Germany]; an assay for functional plasma activator inhibitor-1 levels (Biopool, Umea, Sweden); and routine laboratory assays for serum homocysteine and serum lipoprotein(a) levels. These patients were also evaluated for genetic predisposition to hypercoagulability by using restriction enzyme-based genetic tests for factor V Leiden, a prothrombin gene abnormality (G20210A), and for the heat-labile folate reductase (5,10 methylene tetrahydrofolate reductase) gene abnormality, which may lead to hyperhomocystinemia (39-41). For a comparison group, we measured anticardiolipin antibodies, lupus anticoagulant, and protein S levels in a sample of 50 controls with HIV infection who had no evidence of osteonecrosis on MRI. These controls were randomly selected from patients who had been previously scanned as part of the study and who were seen in our clinics for routine visits over a 3-week period (19 November to 9 December 1999). Statistical Analysis We used the method of Clopper and Pearson (42) to calculate exact CIs for proportions. Associations of osteonecrosis with categorical variables were evaluated by using a two-sided Fisher exact test or, for variables with more than two categories, the FisherFreemanHalton test (43). Associations with continuous variables were evaluated by using a two-sided Wilcoxon rank-sum test with continuity correction. Confidence intervals for relative risks for osteonecrosis were estimated by using the likelihood score method (44). For CIs of odds ratios, we estimated variance according to the method of Robins and colleagues (45). For these calculations, we used the NCSS 2000 software package (Number Cruncher Statistical Systems, Kaysville, Utah) and the StatXact 4 software package (Cytel Software Corp., Cambridge, Mass

Treatment of severe malaria in the United States with a continuous infusion of quinidine gluconate and exchange transfusion

During the past decade the incidence of Plasmodium falciparum malaria in the United States has increased 10-fold. Treatment may be delayed because the therapy recommended for severe or complicated disease, intravenous quinine dihydrochloride, is available only from the Centers for Disease Control. We studied 17 patients who were treated for severe or complicated P. falciparum malaria in the United States between 1985 and 1987. Five patients were treated with a continuous infusion of quinidine gluconate, 10 with an exchange transfusion in addition to the continuous infusion of quinidine gluconate, and 2 with intermittently administered intravenous quinine dihydrochloride and an exchange transfusion. All 16 patients with P. falciparum malaria (1 patient had P. vivax malaria) had hyperparasitemia at the time of diagnosis (6 to 54 percent of the erythrocytes infected; median, 13 percent). Three patients with marked hyperparasitemia (54, 38, and 30 percent) and multiple other indicators of a poor prognosis, including advanced age, died. The 13 patients who completed their courses of quinidine with or without exchange transfusion had a parasitemia level of 1.1 percent or less 28 to 72 hours (mean, 44.4 hours) after the start of therapy. Side effects of quinidine treatment were observed in only two patients, one of whom had a serum quinidine concentration above the toxic level. We conclude that the continuous infusion of quinidine gluconate is well tolerated alone and with exchange transfusion and is effective in the treatment of severe and complicated malaria.

Metabolic and anthropometric consequences of interruption of highly active antiretroviral therapy.

BackgroundHAART has been associated with metabolic abnormalities (hyperlipidemia, insulin resistance, alterations in cortisol metabolism) and fat redistribution. SettingA prospective study of 26 Caucasian men (median age 43.5 years) with HIV-1 viral loads < 500 copies/ml for 12 months while on highly active antiretroviral therapy (HAART) who interrupted treatment for a median of 7.0 weeks (range 4.9–10.3 weeks). Seventeen (65.4%) patients reported at least one fat redistribution symptom at baseline. MethodSerum lipids, glucose and insulin levels during an oral glucose tolerance test, 24-h urinary free cortisol and 17-hydroxycorticosteroids, and anthropometric parameters were measured before HAART cessation and prior to its reinstitution. ResultsWhen baseline values were compared with those obtained after HAART interruption (means ± SD), there was a significant decrease in total cholesterol (194 ± 47.3 versus 159 ± 29.3 mg/dl;P < 0.0001), low density lipoprotein (LDL) cholesterol (114 ± 32.6 versus 96 ± 24.7 mg/dl;P = 0.0013), triglycerides (261 ± 244.3 versus 185 ± 165.4 mg/dl;P = 0.008), and 24-hour urinary 17-hydroxycorticosteroids (15 ± 7.9 versus 5 ± 2.5 mg/24 h, P < 0.0001) and a significant increase in 24-hour urinary free cortisol (45 ± 34.1 versus 62 ± 32.2 μg/24 h;P = 0.016). There were no significant changes in glucose or insulin levels or in anthropometric measurements. ConclusionsA relatively brief interruption of HAART resulted in significant improvements in total cholesterol, LDL cholesterol, and triglyceride levels. No changes were observed in insulin resistance profiles or anthropometric measurements, perhaps because of the brief duration of HAART interruption. These results suggest that hyperlipidemia and alterations in corticosteroid metabolism in the setting of HAART are a direct drug effect that reverses with drug withdrawal. However, glucose metabolism and fat redistribution do not change over the short term.

Lymph node architecture preceding and following 6 months of potent antiviral therapy: follicular hyperplasia persists in parallel with p24 antigen restoration after involution and CD4 cell depletion in an AIDS patient.

OBJECTIVES To evaluate changes in architecture, viral RNA, and viral protein over 6 months in lymph nodes from retroviral-naïve HIV-infected persons before and after commencing highly active antiretroviral therapy (HAART). METHODS Nine antiretroviral-naïve HIV-infected persons had lymph nodes excised at baseline and at 2 and 6-8 months after beginning a four-drug combination regimen containing zidovudine, lamivudine, nevirapine, and indinavir. Two patients had AIDS. Lymph nodes were examined by immunohistochemical staining for Gag p24 HIV, CD3, CD21, CD20, HAM 56, and Ki67 antigens and by in-situ hybridization (ISH) for HIV RNA and H3-histone RNA. RESULTS Eight of nine baseline lymph nodes showed follicular hyperplasia and germinal center and paracortical mononuclear cell activation. At 2 months, the lymph nodes from seven patients, including the AIDS patients, showed more follicular hyperplasia and activation than their baseline specimens but with decreased mononuclear cell activation. By 6 months, seven lymph nodes were less hyperplastic and activated than their corresponding 2 month specimens. Combined ISH/immunohistochemical staining of baseline lymph nodes revealed productively infected T (CD3) and B (CD20) cells and macrophages (HAM56+). HIV RNA-positive mononuclear cells were infrequent at 2 months, and rare at 6 months. HIV RNA was still associated with follicular dendritic cells (FDC) at 2 months, but not at 6 months. HIV p24-positive antigen in germinal centers persisted through all 6, and the one 8 month specimens. The baseline lymph nodes from one of the AIDS patients was involuted and T cell depleted, whereas the follow-up lymph nodes were hyperplastic with normal T cell levels. CONCLUSION Follicular hyperplasia and cell activation, possibly caused by persistent viral protein in germinal centers, may help explain why HIV viremia rebounds so rapidly after the interruption of HAART. Restoration of architecture may follow the treatment of patients with AIDS who initially had involuted and CD4 cell-depleted lymph nodes.

Indinavir-Associated Interstitial Nephritis and Urothelial Inflammation: Clinical and Cytologic Findings

The objective of the present study was to characterize the genitourinary syndromes that accompany indinavir-associated pyuria. Of 23 indinavir-treated patients with persistent pyuria, 4 had isolated interstitial nephritis, 10 had both interstitial nephritis and urothelial inflammation, 7 had isolated urothelial inflammation, and 2 had pyuria with nonspecific urinary tract inflammation. A total of 21 patients had multinucleated histiocytes identified by cytologic testing of urine specimens. Urine abnormalities resolved in all 20 patients who stopped receiving indinavir therapy. Pyuria continued in the 3 patients who continued receiving indinavir. Six patients had elevated serum creatinine levels, which returned to baseline levels when indinavir was discontinued. In conclusion, indinavir-associated pyuria was frequently associated with evidence of interstitial nephritis and/or urothelial inflammation, multinucleated histiocytes were commonly present in urine specimens, and cessation of indinavir therapy was associated with prompt resolution of urine abnormalities.

Acute hepatitis caused by a novel strain of hepatitis E virus most closely related to United States strains

A unique hepatitis E virus (HEV) strain was identified as the aetiological agent of acute hepatitis in a United States (US) patient who had recently returned from vacation in Thailand, a country in which HEV is endemic. Sequence comparison showed that this HEV strain was most similar, but not identical, to the swine and human HEV strains recovered in the US. Phylogenetic analysis revealed that this new HEV isolate was closer to genotype 3 strains than to the genotype 1 strains common in Asia. The fact that this HEV was closely related to strains recovered in countries where HEV is not endemic and was highly divergent from Asian HEV strains raises the questions of where the patients infection was acquired and of whether strains are geographically as localized as once thought.

Guide to Major Clinical Trials of Antiretroviral Therapy in Human Immunodeficiency Virus-Infected Patients: Protease Inhibitors, Non-Nucleoside Reverse Transcriptase Inhibitors, and Nucleotide Reverse Transcriptase Inhibitors

In this AIDS Commentary, Drs. Tavel, Miller, and Masur of the National Institutes of Health present this compilation of clinical trials of antiretroviral therapy in HIV-infected patients, which complements two similar reviews published as AIDS Commentaries in Clinical Infectious Diseases (1995;20:1145-51 and 1996;23:15-27). Whereas the previous compilations focused on trials of nucleoside analogues, this review is based on published articles and abstracts of clinical trials of protease inhibitors, non-nucleoside reverse transcriptase inhibitors, and nucleotide reverse transcriptase inhibitors in HIV-infected patients. The intent is to present a thorough, but not necessarily exhaustive, review of studies that have shaped our principles of antiretroviral therapy. Preference is given to clinical endpoint trials, proof-of-concept trials that have influenced the standard of care for HIV treatment, double-blind, randomized trials, and large trials with long-term patient follow-up. Smaller trials that address important questions are also included.

Fatal Hepatic Necrosis Due to Pyrimethamine-Sulfadoxine (Fansidar)

Pyrimethamine-sulfadoxine has been associated with severe and fatal cutaneous reactions as well as transient liver damage. We report the case of a patient who died of progressive hepatic failure caused by pyrimethamine-sulfadoxine administration. In addition, we summarize reports made to the Food and Drug Administration since 1982 that focus on hepatotoxic reactions to pyrimethamine-sulfadoxine. We suggest that fatal hepatic injury can occur after treatment with pyrimethamine-sulfadoxine and that physicians who prescribe the drug should be aware of this possibility.