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Biomedical subjects

C J Fichtenbaum

Publications and source records attributed to C J Fichtenbaum.

At least 19 recordsLinked to original sources
PubMed2001

HIV protease inhibitor induces fatty acid and sterol biosynthesis in liver and adipose tissues due to the accumulation of activated sterol regulatory element-binding proteins in the nucleus.

The mechanism by which human immunodeficiency virus (HIV) protease inhibitor therapy adversely induces lipodystrophy and hyperlipidemia has not been defined. This study explored the mechanism associated with the adverse effects of the prototype protease inhibitor ritonavir in mice. Ritonavir treatment increased plasma triglyceride and cholesterol levels through increased fatty acid and cholesterol biosynthesis in adipose and liver. Ritonavir treatment also resulted in hepatic steatosis and hepatomegaly. These abnormalities, which were especially pronounced after feeding a Western type high fat diet, were due to ritonavir-induced accumulation of the activated forms of sterol regulatory binding protein (SREBP)-1 and -2 in the nucleus of liver and adipose, resulting in elevated expression of lipid metabolism genes. Interestingly, protease inhibitor treatment did not alter SREBP mRNA levels in these tissues. Thus, the adverse lipid abnormalities associated with protease inhibitor therapy are caused by the constitutive induction of lipid biosynthesis in liver and adipose tissues due to the accumulation of activated SREBP in the nucleus.

Adipose Tissue↗
PubMed2001

Elevated lactate levels in hospitalized persons with HIV infection.

Lactic acidosis has been described in persons with HIV infection particularly in association with the use of nucleoside reverse transcriptase inhibitors (NRTIs). Little is known about the epidemiology of this problem. We reviewed the records of all HIV-infected adults with elevated lactate levels admitted to Barnes-Jewish hospital from 1996 to 1998. There were 37 patients identified with elevated lactate levels. The annual rate of elevated lactate levels was 22.6, 33.9, and 30.8 per 1,000 admissions in 1996, 1997, and 1998, respectively. The median age of the patients was 40.4 years; median CD4(+) count was 148 cells/mm(3); and the median HIV-1 RNA level was 4,401 copies/ml. The median lactate level was 4.5 mmol/liter (range, 2.2-19 mmol/liter). Twenty-nine patients (78%) had elevated lactate levels at admission. Elevated lactate levels were associated with sepsis (48.7%), pancreatitis (13.5%), liver failure (8.1%), multiorgan failure (8.1%), and other conditions. Five patients had lactic acidosis associated with the use of antiretroviral medications; one patient with unexplained lactic acidosis and four patients with pancreatitis. The mortality rate was 45.9% (17/37). Higher lactate levels were associated with increased mortality. In conclusion, elevated lactate levels were uncommon but not rare in hospitalized patients with HIV infection. Sepsis was the most commonly associated condition and antiretroviral medications were the second most frequently associated factor. There was no significant increase in the annual rate of lactic acidosis during this 3-year period.

Acidosis, Lactic↗
PubMed2000

Rifabutin but not clarithromycin prevents cryptosporidiosis in persons with advanced HIV infection.

BACKGROUND: Macrolides have been reported to be effective for the prevention of cryptosporidiosis in persons with HIV infection. OBJECTIVE: To evaluate the efficacy of clarithromycin and rifabutin for the prevention of cryptosporidiosis in persons with advanced HIV infection. DESIGN: Cross-protocol analysis involving 2288 individuals with a history of a CD4 cell counts of < or = 100 x 10(6) cell/l who were enrolled in two prospective clinical trials to prevent Mycobacterium avium complex (MAC) infection and cytomegalovirus (CMV) end-organ disease. INTERVENTIONS: Clarithromycin 500 mg twice daily, rifabutin 300-450 mg daily, the combination of the two or no MAC prophylaxis. MAIN OUTCOME MEASUREMENT: Laboratory-confirmed cryptosporidiosis. Subjects were analyzed in an intent-to-treat and as-treated manner using time-to-event analyses (Cox proportional hazards models). RESULTS: The median length of follow up was 463 days. The median CD4 count at entry was 29 x 10(6) cell/l (range 0-182). There were 60 cases of cryptosporidiosis during the prospective observational period, with an event rate of 2.2 per 100 person-years. In the intent-to-treat [relative risk (RR) 0.50; 95% confidence interval (CI) 0.26-0.96; P = 0.041 and as-treated (RR 0.42; 95% CI 0.20-0.91; P = 0.03) analyses, rifabutin alone was significantly associated with a lower rate of cryptosporidiosis. Clarithromycin alone was not protective in similar analyses (P = 0.98 and 0.90, respectively). CONCLUSIONS: In doses used to prevent MAC infection, rifabutin but not clarithromycin decreases the risk of developing cryptosporidiosis in persons with advanced HIV infection who are not receiving potent combination antiretroviral therapy.

AIDS-Related Opportunistic Infections↗
PubMed2000

Amphotericin B oral suspension for fluconazole-refractory oral candidiasis in persons with HIV infection. Adult AIDS Clinical Trials Group Study Team 295.

OBJECTIVE: To determine the efficacy and safety of amphotericin B oral suspension (ABOS) for the treatment of fluconazole refractory oral candidiasis in persons with HIV infection. DESIGN AND SETTING: A prospective, multicenter, open label trial at 25 study centers within the AIDS Clinical Trials Group. PATIENTS AND METHODS: Individuals with diffuse oral candidiasis after 14 days of treatment with 200 mg of fluconazole daily (more than five plaques or a single plaque > 3 cm largest length) were treated with ABOS, 100 mg/ml, 5 ml swish and swallow, four times daily for 14 days. Thereafter incomplete or non-responders received an additional 14 days of therapy and responders received maintenance ABOS twice daily for up to 6 months. Relapses during maintenance ABOS were treated by increasing the dose to four times daily. MAIN OUTCOME MEASURES: To demonstrate an ABOS clinical response rate > 33% and a treatment-limiting toxicity rate < 50%. Clinical response was defined as the absence of mouth pain and the presence of less than five oral plaques, the largest being < 3 cm largest dimension. RESULTS: Fifty-eight subjects with a median age of 39 years and a median CD4 count of 10 x 10(6) cells/l were enrolled. Four subjects were excluded from the analysis because of inadequate follow-up after randomization (n = 3) or the presence of active esophageal disease (n = 1). Of the remaining 54 subjects, 23 (42.6%; 95% lower confidence interval, 31.1%) were classified as responders after 28 days. Five subjects (9%) stopped treatment due to toxicity. Relapse occurred in 16 responders (70%). CONCLUSIONS: Amphotericin B oral suspension is well tolerated but has limited efficacy for the treatment of fluconazole refractory oral candidiasis.

AIDS-Related Opportunistic Infections↗
PubMed2000

Refractory mucosal candidiasis in advanced human immunodeficiency virus infection.

We conducted a multicenter, prospective study of the risk factors, natural history, and outcome of fluconazole-refractory mucosal candidiasis (FRMC) in 832 persons with advanced human immunodeficiency virus (HIV) infection (median CD4 cell count, 14/mm3) during 1994-1996. FRMC was defined as mucosal candidiasis that failed to resolve despite 14 days of therapy with daily doses (> or =200 mg) of fluconazole. Thirty-six persons (4.3%) had FRMC (35, oral; 1, esophageal), for an incidence of 4.2 per 100 person-years (859.7 total years of follow-up). In a multivariate model, the use of trimethoprim-sulfamethoxazole within 6 months of enrollment (relative risk [RR], 2.39; P=.04) and the use of fluconazole daily or every other day (RR, 5.64; P=.004) were significantly associated with the development of FRMC. The median survival after the development of FRMC was 32.6 weeks. In conclusion, the annual incidence of FRMC was <5%. Refractory candidiasis was a poor prognostic indicator. Daily or every-other-day use of fluconazole was associated with the development of refractory infection.

AIDS-Related Opportunistic Infections↗
PubMed1999

A pilot study of the management of uncomplicated candidemia with a standardized protocol of amphotericin B.

We evaluated an amphotericin treatment strategy on the basis of duration of candidemia and clinical findings. Patients without neutropenia who had uncomplicated candidemia received 200 mg of amphotericin B over 5-7 days if they had had </=1 day of documented positive blood cultures (SC group) or a total of 500 mg of amphotericin B over 14-20 days if they had had >1 day of positive cultures (PC group). The clinical cure rate was 93% (95% confidence interval [CI], 77%-99%; n=29 episodes) in the SC group, with no relapses (median follow-up, 272 days). The clinical cure rate was 83% (95% CI, 64%-94%; n=29 episodes) in the PC group, with 1 relapse (4.2%). The results of this pilot study suggest that patients with candidemia may be stratified into risk groups on the basis of the duration of positive blood cultures and other clinical findings. Decisions about the duration of therapy can be made 4-7 days after initiation of treatment. Carefully selected patients with transient uncomplicated candidemia may be safely treated with a short course of amphotericin B. Further prospective validation of this concept should be undertaken particularly to evaluate the impact on low-frequency late complications (e.g., endophthalmitis).

Adult↗
PubMed1999

Progressive multifocal leukoencephalopathy in patients with AIDS receiving highly active antiretroviral therapy.

Recent reports suggest that human immunodeficiency virus (HIV)-associated progressive multifocal leukoencephalopathy (PML) may improve with highly active antiretroviral therapy (HAART). We observed three patients who developed PML while receiving HAART. All patients received HAART for 4-11 months and had low plasma levels of HIV-1 RNA before the onset of symptoms of PML. Antiretroviral therapy was changed in two patients, and their plasma HIV-1 RNA levels declined significantly. Despite this virologic response, PML did not improve in these patients. The third patient's HIV-1 RNA level became undetectable while he was receiving HAART, and his symptoms of PML improved after the addition of interferon alpha. Our observations suggest that PML can develop in patients who have shown clinical response to HAART. Furthermore, PML may not improve despite an adequate virologic response to HAART. Definitive therapy is still needed for PML.

AIDS-Related Opportunistic Infections↗
PubMed1998

Refractory mucosal candidiasis in patients with human immunodeficiency virus infection.

Difficult-to-manage mucosal candidal infection has been a hallmark of individuals with advanced infection due to human immunodeficiency virus type 1. In this AIDS Commentary, Drs. Fichtenbaum and Powderly comprehensively review the literature and their experience with refractory candidiasis in such patients. Of interest is their delineation of resistance, a lack of susceptibility to an antifungal agent in vitro among patients with refractory or clinically unresponsive disease. These authors believe that the establishment of resistance should be based upon standards established by the National Committee on Clinical Laboratory Standards, which they propose to define as a failure to respond to systematic therapy with specific doses of itraconazole, fluconazole, or parenterally or orally administered amphotericin B within 14 days. There have been many definitions of "refractory candidiasis," and the one proposed by these authors will be debated; however, this definition has the advantage of establishing a standard by which to judge the efficacy of their proposed algorithm for the treatment of persistent or refractory oropharyngeal candidal infections. Drs. Fichtenbaum and Powderly have performed a useful service in their attempt to bring coherence to the management of this common and often vexing problem.

AIDS-Related Opportunistic Infections↗
PubMed1998

Genotypic and phenotypic characterization of Cryptosporidium parvum isolates from people with AIDS.

Genotypic analysis of Cryptosporidium parvum has demonstrated the presence of two subgroups within the species, whereas biochemical and antigenic characterization have shown more heterogeneity. The clinical relevance of these observations is unknown. C. parvum isolates from people with AIDS were studied with respect to parasite genotypes and virulence in cell monolayers and laboratory animals. Ten of 13 oocyst samples had a characteristic human-associated (H) genotype; 3 had a genotype typical of calf-excreted oocysts (C). Virulence in cell culture was mildly or markedly lower in the 5 isolates tested (4 H and 1 C) compared with the GCH1 reference isolate. H isolates did not infect newborn ICR mice, whereas 1 of the 2 C isolates tested did. These findings reinforce the concept of C. parvum genetic subgroupings that correlate to some extent with infectivity and suggest that additional heterogeneity is present within the subgroups.

AIDS-Related Opportunistic Infections↗
PubMed1997

The effect of mode of administration on medical outcomes study health ratings and EuroQol scores in AIDS.

Brief measures of health-related quality of life are being used with increased frequency in AIDS clinical trials. Self-administration of questionnaires can reduce costs in this setting because they require little time. However, the equivalence between self- and interview-administered responses in clinical trials is not known. We evaluated patient and proxy responses to the Medical Outcomes Study HIV Health Survey (MOS-HIV) and the EuroQol. We randomized 68 patients with advanced HIV disease on (1) mode of administration (self vs. interview); (2) type of interview (face-to-face vs. telephone); (3) questionnaire order (MOS-first vs. EuroQol-first); and (4) 2- vs. 3-item response categories for physical limitations. There were few differences in scores between self and interview administration and type of interview. Proxy respondents viewed patients as more impaired than did patients themselves on subjective aspects of health including mental health (63.8 vs. 75.7, p < 0.001), health distress (67.3 vs. 77.1, p = 0.007), pain (64.4 vs. 70.0, p = 0.04), and vitality (48.4 vs. 55.5, p = 0.04). Results concerning questionnaire order and number of response categories were not conclusive. Our results suggest that for patients with advanced HIV disease, data from the MOS-HIV and the EuroQol collected using different modes may be pooled, but that proxy responses should be calibrated.

Adult↗
PubMed1995

Risk factors for dideoxynucleoside-induced toxic neuropathy in patients with the human immunodeficiency virus infection.

Dideoxynucleosides induce a dose-related toxic neuropathy; however, there is a paucity of information on whether other risk factors influence the development of neuropathy. We reviewed the records of 103 patients at an AIDS Clinical Trials Unit who were taking didanosine and/or zalcitabine to determine the risk factors for dideoxynucleoside-induced toxic neuropathy. Most were homosexual or bisexual (85%) men with a mean age of 39 years. The median CD4+ lymphocyte count was 59 cells/mm3, and 35% had a previous diagnosis of AIDS. Toxic neuropathy was more common in patients taking zalcitabine compared with those taking didanosine (14 of 51 versus seven of 55, p = 0.08). In the patients who took zalcitabine, those who had a low baseline serum cobalamin level, a history of heavy ethanol consumption, or a history of symptoms of peripheral nerve dysfunction were more likely to develop a toxic neuropathy (10 of 14 versus 12 of 37, p = 0.01). Conversely, there were no factors associated with the development of didanosine-induced toxic neuropathy. Dideoxynucleoside-induced toxic neuropathy is a common problem that can be disabling but is usually reversible. A history of symptoms of peripheral nervous system disease, heavy ethanol consumption, or a low serum cobalamin level may be useful in distinguishing patients at higher risk of developing zalcitabine-induced toxic neuropathy.

Acquired Immunodeficiency Syndrome↗
PubMed1995

Bacteremia in hospitalized patients infected with the human immunodeficiency virus: a case-control study of risk factors and outcome.

We reviewed all episodes of nonmycobacterial bacteremias in human immunodeficiency virus (HIV)-infected patients from 1990 to 1991 to determine the incidence, risk factors, and outcome. Forty-five patients had a total of 63 episodes of bacteremia (9% of 689 HIV-related hospitalizations). In this cohort, the median CD4+ lymphocyte count was 17 cells/mm3, 71% had AIDS, and 78% were homosexual men. The most frequently isolated bacteria were Staphylococcus aureus (25%) and coagulase-negative staphylococci (22%). The most common site of infection was intravenous catheter-related, accounting for 35% of the bacteremias. Compared to HIV-infected, nonbacteremic controls, patients with bacteremia detected at admission were more likely to have an indwelling intravenous catheter (p = 0.003) and less likely to be likely zidovudine (p = 0.04). The overall in-hospital mortality rate was 24%. There was no significant difference in the in-hospital mortality rates in bacteremic patients with or without HIV infection. Seventeen patients had more than one episode of bacteremia (71% had recurrence with the same organism). We conclude that bacteremia is a significant problem in HIV-infected persons with low CD4+ lymphocyte counts, often related to the presence of an intravenous catheter; recurrence is common. In addition, HIV infection does not appear to increase the mortality rate for bacteremia.

Adult↗
PubMed1995

Level of cytomegalovirus (CMV) DNA in cerebrospinal fluid of subjects with AIDS and CMV infection of the central nervous system.

The objective of this study was to correlate cytomegalovirus (CMV) DNA levels in the cerebrospinal fluid (CSF) of subjects with AIDS with clinical and pathologic findings attributable to CMV infection of the central nervous system (CNS). CMV polymerase chain reaction (PCR) was done on serial dilutions of CSF samples from 24 AIDS patients with autopsy-proven CNS disorders. CMV DNA was detected in CSF from 12 of 13 subjects with evidence of CMV infection of the brain or spinal cord but in none of 11 subjects without autopsy evidence of CMV CNS infection. Subjects whose CSF contained > 10(3) CMV DNA molecules/8 microL of CSF had severe CMV CNS disease (e.g., ventriculoencephalitis). PCR appears to be more useful than clinical and neuroradiologic findings for documenting CMV infection of the CNS in patients with AIDS. Quantitation of CMV DNA in CSF shows promise for evaluation of the extent of involvement.

AIDS-Related Opportunistic Infections↗
PubMed1995

Detection of Epstein-Barr virus DNA in cerebrospinal fluid for diagnosis of AIDS-related central nervous system lymphoma.

The diagnostic utility of Epstein-Barr virus (EBV) DNA detection in cerebrospinal fluid for the diagnosis of central nervous system lymphoma was evaluated with two different PCR assays to test a collection of cerebrospinal fluid samples from 24 AIDS patients with central nervous system disorders. A PCR assay amplifying a fragment from the BamHI-W region had the highest clinical and analytic sensitivity. The BamHI-W PCR assay detected EBV DNA in cerebrospinal fluid from 83% (5 of 6) of patients with pathologically proven primary central nervous system lymphoma and 7% (1 of 16) of controls with autopsy-proven nonlymphomatous central nervous system disorders. EBV DNA was also detected in one patient with autopsy-proven systemic lymphoma involving the central nervous system and one patient with probable primary central nervous system lymphoma. EBV DNA was detected consistently when central nervous system lymphoma involved meningeal surfaces. PCR for EBV in cerebrospinal fluid appears to be useful for diagnosis of AIDS-related central nervous system lymphoma, but additional studies are required to better define the sensitivity of the assay and to understand the significance of a positive test in the absence of lymphoma.

Central Nervous System Neoplasms↗