Effect of prior nucleoside use on the two-year virological response to an initial protease inhibitor regimen in HIV-infected patients.

PURPOSE: This retrospective study investigates the effect of prior nucleoside (nucleoside reverse transcriptase inhibitor [NRTI]) experience on 2-year virologic response to an initial protease inhibitor-highly active antiretroviral therapy (PI-HAART) regimen. METHOD: 152 patients who started a PI (excluding saquinavir hard gel capsule [hgc] as a sole PI) with two NRTIs between January 1996 and May 1998 at two HIV treatment sites were included. RESULTS: 109 patients (71%) were NRTI experienced. 106 patients received two new NRTIs, and 32 received one new NRTI. Overall, 51% of patients had a virologic response (HIV viral load <400 copies/mL); the mean follow-up was 28 months. Virologic response was associated with the use of at least one new NRTI (relative risk [RR] 2.1; p =.031) but not with prior NRTI experience (p =.19). A complete virologic response was most likely to occur when two new NRTIs were used (RR 2.3) rather than one new NRTI (RR 1.8), but this was not significant (p =.12). CONCLUSION: This study suggests that prior nucleoside experience is not a key predictor of 2-year virologic response in patients who receive at least one new NRTI in an initial PI-HAART regimen.

Effect of postoperative atrial fibrillation on length of stay after cardiac surgery (The Postoperative Atrial Fibrillation in Cardiac Surgery study [PACS(2)].

Atrial fibrillation (AF) after cardiac surgery is thought to increase length of stay (LOS). A clinical pathway focused on the management of postoperative AF, including prophylaxis with beta blockers, was implemented to assess the effect of AF on LOS after cardiac surgery. Data were obtained on consecutive cardiac surgery patients in preoperative normal sinus rhythm, no prior history of AF, and no chronic antiarrhythmic therapy from January to May 1995 (control) and November 1996 to June 1997 (pathway). Statistical analysis was performed to assess the effect of postoperative AF on the LOS, clinical outcomes, and cost after cardiac surgery. Despite the clinical pathway, the LOS (7 days for both periods; p = 0.12) and incidence of AF (28.9% vs 28.4%; p = 0.92) remained unchanged. Unadjusted direct costs were 15% higher in the pathway period (p <0.001). Increased rates of beta-blocker therapy had a marginal effect on the incidence of postoperative AF, except in the group who only underwent primary coronary artery bypass graft surgery (31.2% vs 25.3%; p = 0.31). Multivariate analysis revealed that AF contributed only 1 to 1.5 days to the LOS. Thus, this investigation represents the most recent analysis of the effects of postoperative AF on LOS, clinical outcomes, and cost after cardiac surgery. Unlike prior studies, the impact of postoperative AF is less prominent in the current era of cardiac surgical care regardless of the presence of a clinical pathway addressing AF.

Use of cytokines in human immunodeficiency virus-infected patients: colony-stimulating factors, erythropoietin, and interleukin-2.

The recombinant human cytokines granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), erythropoietin, and interleukin-2 (IL-2) have been manufactured and licensed. Studies have been carried out that investigate the use of G-CSF and GM-CSF to reverse leukopenia, as adjunctive therapy for HIV-associated infections and for novel approaches to treat HIV infection, including stem cell mobilization. In addition, studies that identified the role of erythropoietin in the management of anemia have been performed. Furthermore, the abilities of G-CSF and erythropoietin to permit the continued use of marrow suppressive agents that are key in managing HIV infection have been assessed. The aim of this review is to summarize these studies and to describe the reports that evaluate the use of IL-2 to enhance elevation of CD4 cell counts mediated by highly active antiretroviral therapy. This summary is important to the treating clinician in that it identifies the optimal use of these cytokines in current clinical practice as well as their potential future roles.

Pneumocystis carinii cytochrome b mutations are associated with atovaquone exposure in patients with AIDS.

This retrospective cohort study was conducted to determine whether Pneumocystis carinii cytochrome b gene mutations in patients with AIDS and P. carinii pneumonia (PCP) are associated with atovaquone exposure. Portions of the P. carinii cytochrome b genes that were obtained from 60 patients with AIDS and PCP from 6 medical centers between 1995 and 1999 were amplified and sequenced by using polymerase chain reaction. Fifteen patients with previous atovaquone prophylaxis or treatment exposure were matched with 45 patients with no atovaquone exposure. Cytochrome b coenzyme Q binding site mutations were observed in 33% of isolates from patients exposed to atovaquone, compared with 6% from those who were not (P=.018). There was no difference in survival 1 month after treatment between patients with or without cytochrome b mutations (P=.14). Thus, cytochrome b mutations are significantly more common in patients with AIDS and PCP with atovaquone exposure, but the clinical significance of these mutations remains unknown.

Pneumocystis carinii mutations are associated with duration of sulfa or sulfone prophylaxis exposure in AIDS patients.

This study was conducted to determine whether Pneumocystis carinii dyhydropteroate synthase (DHPS) gene mutations in AIDS patients with P. carinii pneumonia (PCP) are affected by duration of sulfa or sulfone prophylaxis and influence response to sulfa or sulfone therapy. The P. carinii DHPS genes from 97 AIDS patients with PCP between 1991 and 1999 from 4 medical centers were amplified, using polymerase chain reaction (PCR), and sequenced. Mutations were observed in 76% of isolates from patients exposed to sulfa or sulfone prophylaxis compared with 23% of isolates from patients not exposed (P=.001). Duration of prophylaxis increased the risk of mutations (relative risk [RR] for each exposure month, 1.06; P=.02). Twenty-eight percent of patients with mutations failed sulfa or sulfone treatment; mutations increased the risk of sulfa or sulfone treatment failure (RR, 2.1; P=0.01). Thus, an increased duration of sulfa or sulfone prophylaxis increases the chance of developing a P. carinii mutation. The majority of patients with mutations respond to sulfa or sulfone therapy.

Recurrence of Mycobacterium avium infection in patients receiving highly active antiretroviral therapy and antimycobacterial agents.

The known effects of highly active antiretroviral therapy (HAART) on opportunistic infections (OIs) range from immune restoration disease to remission of specific OIs. In the present study, Mycobacterium avium complex infection recurred in 3 patients receiving antimycobacterial therapy and HAART. At the time of the initial M. avium infection, the mean CD4 cell count was 22.3 cells/mm3, and the HIV viral load was 181,133 copies/mL. Relapse occurred a mean of 14. 3 months after the first episode; the mean follow-up CD4 cell count was 89/mm3 (mean elevation of 66 cells/mm3), and the HIV viral load was <400 copies/mL in each patient. M. avium was isolated from blood (1 patient), blood and lymph node (1), and small-bowel tissue (1). M. avium infection may recur as a generalized or focal disease in those who are receiving antimycobacterial agents but whose HAART-associated CD4 cell recovery, although significant, is not optimal.

Pneumocystis carinii mutations associated with sulfa and sulfone prophylaxis failures in immunocompromised patients.

Recent studies have shown that mutations in two amino acid positions of the Pneumocystis carinii dihydropteroate synthase gene are significantly more common in immunocompromised patients with P. carinii pneumonia who fail sulfa or sulfone prophylaxis. This paper reviews the studies that suggest that these mutations may be responsible for some failures of prophylaxis in P. carinii.

Granulocyte-macrophage colony-stimulating factor upregulates reduced 5-lipoxygenase metabolism in peripheral blood monocytes and neutrophils in acquired immunodeficiency syndrome.

Leukotrienes (LT) are mediators derived from the 5-lipoxygenase (5-LO) pathway, which play a role in host defense, and are synthesized by both monocytes (peripheral blood monocyte [PBM]) and neutrophils (PMN). Because 5-LO metabolism is reduced in alveolar macrophages and PMN from acquired immunodeficiency syndrome (AIDS) subjects, we investigated the synthesis of LT by PBM and PMN from these subjects. There was a reduction (74.2% +/- 8.8% of control) in LT synthesis in PBM from human immunodeficiency virus (HIV)-infected compared with normal subjects. Expression of 5-LO (51.2% +/- 8.8% of control), and 5-LO activating protein (FLAP) (48.5% +/- 8.0% of control) was reduced in parallel. We hypothesized that this reduction in LT synthetic capacity in PBM and PMN was due to reduced cytokine production by CD4 T cells, such as granulocyte-macrophage colony-stimulating factor (GM-CSF). We treated 10 AIDS subjects with GM-CSF for 5 days. PBM 5-LO metabolism ex vivo was selectively increased after GM-CSF therapy and was associated with increased 5-LO and FLAP expression. PMN leukotriene B(4) (LTB(4)) synthesis was also augmented and associated with increased 5-LO, FLAP, and cytosolic phospholipase A(2) expression. In conclusion, as previously demonstrated for PMN, PBM from AIDS subjects also demonstrate reduced 5-LO metabolism. GM-CSF therapy reversed this defect in both PBM and PMN. In view of the role of LT in antimicrobial function, cytokine administration in AIDS may play a role as adjunct therapy for infections.

Meal composition effects on the oral bioavailability of indinavir in HIV-infected patients.

PURPOSE: To study the influence of large-volume high-calorie protein, fat, and carbohydrate meals and a non-caloric hydroxypropylmethyl cellulose (HPMC) viscous meal on the oral bioavailability of indinavir in HIV-infected subjects. METHODS: Seven male HIV-infected subjects received caloric meal treatments and control meals in a randomized crossover fashion and the viscosity meal as a final treatment. The total volume of each meal treatment was 500 mL and the caloric meals each contained 680 kcal. Gastric pH was also monitored by radiotelemetry from one hour before to four hours after drug and caloric meal administration. A single Crixivan (indinavir sulfate) dose equivalent to 600 mg indinavir was administrated orally with 100 mL of water immediately following meal administration. Indinavir plasma concentrations were obtained using reverse-phase HPLC. RESULTS: All meal treatments significantly decreased the extent of indinavir absorption as compared to fasted control. AUC0-infinity decreased by 68%, 45%, 34%, and 30% for protein, carbohydrate, fat, and viscosity meal treatments versus fasted control, respectively (p < 0.05). The mean Cmax was significantly decreased 74%, 59%, 46% and 36% (p < 0.05) and the mean tmax was significantly delayed from I hr in fasted controls to 3.8, 3.6, 2.1 and 2.0 hrs (p < 0.05) for protein, carbohydrate, fat, and viscosity meal treatments, respectively. The elimination half-life of indinavir determined in the fasted state was decreased in HIV-infected subjects as compared to the reported half-life in normal healthy subjects. CONCLUSIONS: Reductions in indinavir plasma concentrations compared to drug administration in the fasted state are most severe with the high-calorie protein meal. This is consistent with an influence of elevated gastric pH on drug precipitation. Significant drug plasma concentration reductions observed with administration of the other meals in the absence of appreciably elevated gastric pH profile indicate that other factors are playing a role in the meal effects. The similarity in indinavir plasma profiles with protein and carbohydrate versus fat and viscosity suggests that the latter meals may reduce the impact of drug precipitation compared to the former meals.

Killing of Mycobacterium avium by neutrophils and monocytes from AIDS patients treated with recombinant granulocyte-macrophage colony-stimulating factor.

In this study, 30 AIDS patients without Mycobacterium avium infection were randomized to receive treatment with azithromycin (1200 mg), granulocyte-monocyte colony-stimulating factor (GM-CSF; 250 microg/m2/day for 5 days), or both agents. The M. avium killing capacity of neutrophils and monocytes harvested from each patient before intervention and during (day 4), and after therapy (day 8) was assessed. The mean virus load change in the groups receiving GM-CSF was +0.14 log human immunodeficiency virus RNA. After GM-CSF therapy, neither neutrophils nor monocytes could significantly reduce M. avium growth (P=.96 and.31, respectively). Bone pain, myalgia, presyncope, or fever occurred in 55% of patients receiving GM-CSF. Thus, the GM-CSF regimen used in this study did not affect virus load, frequently caused adverse reactions, and did not improve the M. avium killing capacity of neutrophils and monocytes. Future studies using a different GM-CSF regimen are indicated.

HIV protease inhibitors: advances in therapy and adverse reactions, including metabolic complications.

Protease inhibitors (PIs) effectively inhibit replication of the human immunodeficiency virus (HIV), and reduce mortality and prolong survival in patients with HIV infection. Newer PIs saquinavir (soft gelatin capsule) and amprenavir, as well as other PIs, may be effective when administered twice/day. Adverse reactions may occur, as well as metabolic complications and interactions between PIs and other drugs, including other PIs. The strategy of combining PIs is based on specific pharmacologic interactions among the agents.

Human immunodeficiency virus-associated fever of unknown origin: a study of 70 patients in the United States and review.

To characterize the clinical features of human immunodeficiency virus (HIV)-associated fever of unknown origin (FUO) in the United States, we performed a retrospective analysis of cases that fulfilled specific criteria (published by Durack and Street in 1991) at two medical centers in the United States between 1992 and 1997. Seventy cases met criteria for HIV-associated FUO; the mean CD4 cell count was 58/mm3, and the mean duration of fever was 42 days. A cause of FUO was found in 56 of the 70 cases; 43 were of a single etiology, and in 13 cases multiple conditions were established. The most common diagnoses were disseminated Mycobacterium avium infection (DMAC; 31%), Pneumocystis carinii pneumonia (13%), cytomegalovirus infection (11%), disseminated histoplasmosis (7%), and lymphoma (7%). In this United States series, FUO occurs most often in the late stage of HIV infection, individual cases often have multiple etiologies, and DMAC is the most common diagnosis.

Sequence polymorphisms in the Pneumocystis carinii cytochrome b gene and their association with atovaquone prophylaxis failure.

Atovaquone (Mepron, 566c80) is an effective agent against Pneumocystis carinii, which probably acts by binding to cytochrome b and inhibiting electron transport. To assess the possibility that atovaquone resistance might be developing, the genes for the cytochrome b from P. carinii sp. f. carinii and P. carinii sp. f. hominis were partially sequenced. Eight of 10 patient isolates had cytochrome b genes with the same amino acid sequence. The P. carinii cytochrome b genes from 2 of 4 patients who had atovaquone prophylaxis failure contained mutations resulting in amino acid changes in one of the ubiquinone (coenzyme Q) binding sites (Qo). These mutations are homologous to mutations in other microorganisms that confer resistance to similar inhibitors. Variations in the sequence of the P. carinii cytochrome b gene suggest but do not prove the development of drug resistance.

Neutrophils from AIDS patients treated with granulocyte colony-stimulating factor demonstrate enhanced killing of Mycobacterium avium.

Neutrophils isolated from AIDS patients have demonstrated improved growth inhibition of Mycobacterium avium when incubated with exogenous granulocyte colony-stimulating factor (G-CSF). In this clinical study, 30 AIDS patients without M. avium infection were randomized to receive 5 days of treatment with rifabutin, G-CSF, or both agents. The M. avium killing capacity of neutrophils harvested from each patient before intervention, during (day 4), and after therapy (day 7) was assessed. The mean change in human immunodeficiency virus load in the group receiving G-CSF alone was -0.07 log of viral RNA. There was a 90% reduction in M. avium growth after therapy for patients treated with G-CSF alone (P=.01), 59% for patients treated with both agents (P=.06), and 11% for patients treated with rifabutin alone (P=.84). Thus, neutrophils isolated from AIDS patients treated with G-CSF demonstrated a significant enhancement of killing of M. avium; there was no notable effect on virus load.

Granulocyte colony-stimulating factor administration to HIV-infected subjects augments reduced leukotriene synthesis and anticryptococcal activity in neutrophils.

Neutrophil (PMN) dysfunction occurs in HIV infection. Leukotrienes (LT) are mediators derived from the 5-lipoxygenase (5-LO) pathway that play a role in host defense and are synthesized by PMN. We investigated the synthesis of LT by PMN from HIV-infected subjects. There was a reduction (4.0+/-1.3% of control) in LT synthesis in PMN from HIV-infected compared with normal subjects. This was associated with reduced expression of 5-LO-activating protein (31.2+/-9.6% of normal), but not of 5-LO itself. Since HIV does not directly infect PMN, we considered that these effects were due to reduced release of cytokines, such as granulocyte colony-stimulating factor (G-CSF). We examined the effect of G-CSF treatment (300 microgram daily for 5 d) on eight HIV-infected subjects. PMN were studied in vitro before therapy (day 1) and on days 4 and 7. LTB4 synthesis was increased on day 4 of G-CSF treatment, and returned toward day 1 levels on day 7. 5-LO and 5-LO-activating protein expression were increased in parallel. As a functional correlate to this increase in PMN LT synthesis by G-CSF, we examined the effects on killing of Cryptococcus neoformans. Anticryptococcal activity of PMN from HIV-infected subjects was less than that of PMN from normal subjects. G-CSF treatment improved fungistatic activity of PMN. This increase in antifungal activity was attenuated by in vitro treatment with the LT synthesis inhibitor, MK-886. In conclusion, PMN from HIV-infected subjects demonstrate reduced 5-LO metabolism and antifungal activity in vitro, which was reversed by in vivo G-CSF therapy.

Pneumocystis carinii mutations associated with sulfa and sulfone prophylaxis failures in AIDS patients.

BACKGROUND: Failures of prophylaxis against Pneumocystis carinii pneumonia (PCP) in AIDS patients do occur, but no evidence for drug resistance has yet been presented. OBJECTIVE: To determine whether mutations in the sulfa and sulfone drug target are associated with failure of prophylaxis using a sulfa-containing agent. METHODS: Portions of the gene for P. carinii dihydropteroate synthase (DHPS), the sulfa and sulfone target, from 27 patients (20 of whom had AIDS) diagnosed with PCP between 1976 and 1997 were amplified using polymerase chain reaction and sequenced. Seven of the 27 patients (all of whom had AIDS) were receiving sulfa or sulfone drugs as prophylaxis for PCP. RESULTS: Mutations were found at only two amino-acid positions and were significantly more common in patients who received sulfa/sulfone prophylaxis. Mutations were observed in five (71%) out of seven isolates from AIDS patients receiving sulfa/sulfone as prophylaxis compared with only two (15%) out of 13 specimens from AIDS patients who did not (P = 0.022). No mutations were seen in isolates from seven non-HIV-infected patients, none of whom were on prophylaxis. Mutations were only observed in specimens obtained in 1995-1997. CONCLUSIONS: Mutations in two amino-acid positions were significantly more common in AIDS patients with PCP who failed sulfa/sulfone prophylaxis. These amino acids appeared to be directly involved in both substrate and sulfa binding, based on homology to the Escherichia coli DHPS crystal structure. Thus, the results were consistent with the possibility that mutations in the P. carinii DHPS are responsible for some of the failures of sulfa/sulfone prophylaxis in AIDS patients.

Spinal cord infection: myelitis and abscess formation.

PURPOSE: Our purpose was to describe the MR findings and evolution of spinal cord abscess and to define those MR features that allow differentiation of cord infection from other intramedullary abnormalities. METHODS: We retrospectively reviewed the MR studies of all patients in whom intramedullary spinal cord abscess was proved either by blood or cerebrospinal fluid culture or by serologic examination at our institution between January 1988 and January 1996. The study group included four adults and two children, 7 to 74 years old (mean age, 38 years). RESULTS: Initial MR studies showed intramedullary high signal on T2-weighted sequences with poorly defined marginal enhancement on T1-weighted images. On follow-up contrast-enhanced T1-weighted studies, the lesions had well-defined enhancing margins with central low signal intensity. After the initiation of therapy, T2 signal abnormalities decreased markedly and contrast-enhanced studies showed ring enhancement. These T1 findings resolved with treatment over serial studies in four patients. The organisms identified were Streptococcus milleria, S pyogenes, atypical mycobacteria, Mycobacterium tuberculosis, and Schistosoma mansoni (both children). CONCLUSION: A characteristic sequence of imaging findings aids in the differentiation of cord infection from other intramedullary lesions.