Brief report: Circulating markers of fibrosis are associated with immune reconstitution status in HIV-infected men.

INTRODUCTION: Lymphoid tissue fibrosis may contribute to incomplete immune reconstitution on antiretroviral therapy (ART) via local CD4+ T lymphocyte (CD4) depletion. Hyaluronic acid (HA) increases with fibrotic burden. CXCL4 concentrations increase in response to pro-fibrotic stimuli, but lower CXCL4 concentrations in HIV-infected individuals may reflect successful immune evasion by HIV. We investigated relationships between circulating HA and CXCL4 concentrations and immune reconstitution on ART in HIV-infected Multicenter AIDS Cohort Study participants. METHODS: HIV-infected men on ART for >1 year with cryopreserved plasma samples and suppressed post-ART HIV-1 RNA were included. Men with post-ART CD4 <200 cells/mm3 were defined as immunologic non-responders (n = 25). Age-/race-matched men with post-ART CD4 >500 cells/mm3 served as controls (n = 49). HA and CXCL4 concentrations were measured via ELISA. RESULTS: Median pre-ART CD4 was 297 cells/mm3 for non-responders vs 386 cells/mm3 for controls. Median post-ART CD4 was 141 cells/mm3 for non-responders and 815 cells/mm3 for controls. HIV infection duration was 23 years, with median time on ART 13 years for non-responders vs 11 years for controls. Pre-ART HA and CXCL4 concentrations did not vary by eventual immune reconstitution status. Post-ART HA concentrations tended to be higher (85 vs 36 ng/mL, p = 0.07) and CXCL4 concentrations were lower (563 vs 1459 ng/mL, p = 0.01) among non-responders. Among men with paired pre-/post-ART samples, non-responders had greater HA increases and CXCL4 decreases than controls (HA: 50 vs 12 ng/mL, p = 0.04; CXCL4: -1258 vs -405 ng/mL, p = 0.01). CONCLUSIONS: Higher circulating concentrations of HA and lower concentrations of CXCL4 are associated with failure of immune reconstitution on ART.

Incidence rate of and factors associated with loss to follow-up in a longitudinal cohort of antiretroviral-treated HIV-infected persons: an AIDS Clinical Trials Group (ACTG) Longitudinal Linked Randomized Trials (ALLRT) analysis.

PURPOSE: Examine incidence and factors associated with loss to follow-up (LTFU) in the AIDS Clinical Trials Group (ACTG) Longitudinal Linked Randomized Trials (ALLRT) cohort. METHOD: ALLRT is a prospective cohort of HIV-infected persons randomized to antiretroviral (ARV) regimens/strategies in ACTG trials and followed long-term after the trial ends. Person-years were calculated from ALLRT entry until loss to follow-up (LTFU; defined using off-study reasons or ≥ 3 consecutive missed visits), death/ severe debilitation/site closures, or June 2009 (censored). Poisson regression was used to examine LTFU factors separately among participants who were ARV naïve or ARV experienced at trial entry. RESULTS: Among 4,630 participants (22,524 person-years), 1,140 were lost to follow-up, 237 died, 29 were severely debilitated, and 443 were at sites that closed. The LTFU incidence was 5.5 and 4.2 per 100 person-years among previously ARV-naïve and ARV-experienced participants, respectively. In both groups, age ≤ 50, site location, being off ARVs, and viral load ≥ 400 copies/mL were associated with a higher risk of LTFU. Among ARV-naïve participants, male sex, education <16 years, intravenous drug use, and cigarette smoking were also associated with LTFU. CONCLUSION: Knowledge of differential LTFU can help researchers identify participants at risk of LTFU in longitudinal HIV cohorts and design retention strategies, thereby limiting study bias. The identified factors should be included in inverse probability of weighting models to account for LTFU.

Skin test reactivity and cellular immune responses to Mycobacterium avium sensitin in AIDS patients at risk for disseminated M. avium infection.

Skin tests and lymphocyte proliferation assays (LPA) were performed with Mycobacterium avium sensitin on patients with AIDS. Among 139 subjects, 13% had positive skin test results and 32% had positive LPA results. The LPA may be a more sensitive indicator of prior M. avium infection in this population.

A prospective study of discontinuing primary and secondary Pneumocystis carinii pneumonia prophylaxis after CD4 cell count increase to > 200 x 106 /l.

OBJECTIVE: To assess the incidence of Pneumocystis carinii pneumonia (PCP) after discontinuation of either primary or secondary prophylaxis. DESIGN: This was a prospective, non-randomized, non-blinded study. SETTING: Twenty-five University-based AIDS Clinical Trials Group units. PARTICIPANTS: Participants either had a CD4 cell count < or = 100 x 106/l at any time in the past and no history of confirmed PCP (group I; n = 144), or had a confirmed episode of PCP > or = 6 months prior to study entry (group II; n = 129). All subjects had sustained CD4 cell counts > 200 x 106/l in response to antiretroviral therapy. INTERVENTIONS: Subjects discontinued PCP prophylaxis within 3 months or at the time of study entry. Evaluations for symptoms of PCP and CD4 cell counts were performed every 8 weeks. Prophylaxis was resumed if two consecutive CD4 cell counts were < 200 x 106/l. MAIN OUTCOME MEASURE(S): The main outcome was development of PCP. RESULTS: No cases of PCP occurred in 144 subjects (median follow-up, 82 weeks) in group I or in the 129 subjects (median follow-up, 63 weeks) in group II (95% upper confidence limits on the rates of 1.3 per 100 person-years and 1.96 per 100 person-years for groups I and II, respectively). Eight subjects (five in group I and three in group II) resumed PCP prophylaxis after two consecutive CD4 cell counts < 200 x 106/l. CONCLUSIONS: The risk of developing initial or recurrent PCP after discontinuing prophylaxis is low in HIV-infected individuals who have sustained CD4 cell count increases in response to antiretroviral therapy. Neither lifelong primary nor secondary PCP prophylaxis is necessary.

Discontinuation of Mycobacterium avium complex prophylaxis in patients with antiretroviral therapy-induced increases in CD4+ cell count. A randomized, double-blind, placebo-controlled trial. AIDS Clinical Trials Group 362 Study Team.

BACKGROUND: Patients infected with HIV who experience increases in CD4(+) cell counts are at reduced risk for opportunistic infections. However, the safety of discontinuing prophylaxis against Mycobacterium avium complex has been uncertain. OBJECTIVE: To compare the rate of M. avium complex infection in patients with increased CD4(+) cell counts who receive azithromycin and those receiving placebo. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: 29 university-based clinical centers in the United States. PARTICIPANTS: 643 HIV-1-infected patients with a previous CD4(+) cell count less than 0.05 x 10(9) cells/L and a sustained increase to greater than 0.10 x 10(9) cells/L during antiretroviral therapy. INTERVENTION: Azithromycin, 1200 mg once weekly (n = 321), or matching placebo (n = 322). MEASUREMENTS: Mycobacterium avium complex cultures, CD4(+) cell counts, and clinical evaluations for AIDS-defining illnesses and bacterial infections were done every 8 weeks. Plasma HIV-1 RNA levels were measured at 16-week intervals. RESULTS: During follow-up (median, 16 months), 2 cases of M. avium complex infection were reported among the 321 patients assigned to placebo (incidence rate, 0.5 event per 100 person-years [95% CI, 0.06 to 1.83 events per 100 person-years]) compared with no cases among the 322 patients assigned to azithromycin (CI, 0 to 0.92 events per 100 person-years), resulting in a treatment difference of 0.5 event per 100 person-years (CI, -0.20 to 1.21 events per 100 person-years) for placebo versus azithromycin. Both cases were atypical in that M. avium complex was localized to the vertebral spine. Patients receiving azithromycin were more likely than those receiving placebo to discontinue treatment with the study drug permanently because of adverse events (8% vs. 2%; hazard ratio, 0.24 [CI, 0.10 to 0.57]). CONCLUSIONS: Prophylaxis against Mycobacterium avium complex can safely be withdrawn or withheld in adults with HIV infection who experience increases in CD4(+) cell count while receiving antiretroviral therapy.

Azithromycin as treatment for disseminated Mycobacterium avium complex in AIDS patients.

This multicenter, randomized, dose-ranging study was performed to determine the safety and efficacy of two different doses of azithromycin for treating disseminated Mycobacterium avium complex (MAC) in patients with AIDS. Eighty-eight AIDS patients with symptoms and blood cultures consistent with disseminated MAC were treated with 600 or 1,200 mg of azithromycin daily for 6 weeks; 62 patients completed the entire 6 weeks of study. Of note, this study was done prior to the time when combination antiretroviral or anti-MAC regimens were the standard of care. Over the 6-week study period, symptomatic improvement was noted in both dose groups. Microbiological responses were comparable, with mean decreases of 1. 5 and 2.0 log CFU/ml in the high- and low-dose groups, respectively. Sterilization of blood cultures occurred in 54% of samples; patients with lower baseline colony counts were more likely to achieve culture negativity. Resistance developed in one patient. Gastrointestinal symptoms were the most common side effects and were more frequent in patients receiving 1,200 mg. Azithromycin is a useful alternative treatment for disseminated MAC infection in AIDS patients. Symptomatic improvement correlates with measurable decreases in mycobacterial load.

Itraconazole oral solution versus clotrimazole troches for the treatment of oropharyngeal candidiasis in immunocompromised patients.

This multicenter, open-label, third-party-masked trial compared the efficacy and safety of itraconazole oral solution (200 mg once daily) and clotrimazole troches (10 mg five times daily) in a population of immunocompromised subjects composed primarily of patients with human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS). Patients were treated for 14 days; patients who exhibited a clinical response were followed up for an additional month to document the occurrence of relapse. Efficacy was judged by changes from baseline in symptoms of oropharyngeal candidiasis (erythema, soreness/burning), extent of oral lesions, and the presence/absence of Candida species on fungal culture. A total of 162 patients were randomized, and 149 were evaluated for efficacy. The percentage of patients with negative cultures at the end of treatment was significantly greater in the itraconazole group than in the clotrimazole group (60% vs 32%, respectively). Negative culture plus clinical response was achieved in significantly more itraconazole-treated patients (53%) than clotrimazole-treated patients (30%); results were similar in the subgroup of patients with HIV/AIDS. Both drugs were well tolerated, with the most frequently reported adverse events for both agents involving the gastrointestinal system. In conclusion, systemic therapy with intraconazole oral solution is efficacious and well tolerated in immunocompromised patients, including those with HIV/AIDS, when administered once daily for 14 days for the treatment of oral candidiasis.

Exposure to domestic cats: risk factor for Pasteurella multocida peritonitis in liver cirrhosis?

Pasteurella multocida is most commonly associated with acute skin and soft tissue infections following an animal bite or scratch. Peritonitis caused by P. multocida in patients with cirrhosis is rarely reported. We present a case of spontaneous bacterial peritonitis with P. multocida in a patient with cirrhosis, squamous cell cancer of the head and neck, and nontraumatic domestic cat exposure. Nasopharyngeal colonization with P. multocida, with subsequent transient bacteremia and seeding of the peritoneum in immunocompromised (particularly cirrhotic) cat-owners, could play an important pathogenetic role in the development of spontaneous bacterial peritonitis. A review of the literature showed that in nine of 13 patients with cirrhosis and P. multocida peritonitis, exposure to domestic animals was reported. The mortality rate is high in this setting, even with prompt antibiotic treatment. Preventive strategies for immuno-compromised patients should include minimization of animal contact, especially cats, which have a high carriage rate (70-90%) of P. multocida.

Cirrhosis: a risk factor for cryptococcal peritonitis.

Cryptococcal peritonitis is usually associated with end-stage renal disease and peritoneal dialysis. Significant liver disease has not been well recognized as a risk factor for its development. We report two patients with cirrhosis who developed peritoneal infections with Cryptococcus neoformans. We also retrospectively review all cases of cryptococcal illness at the Ohio State University Medical Center from October 1990 to January 1994 and present a review of the literature regarding cryptococcal peritonitis associated with hepatic dysfunction. Cirrhotic patients with this entity present with subtle, nonspecific complaints resulting in delayed diagnoses, dissemination, and death. We suggest that clinicians maintain an increased awareness of this unusual but lethal entity in patients with liver impairment. Early and frequent abdominal paracenteses with bedside inoculations of fungal culture medium, India ink preparations, and serum cryptococcal antigen testing may hasten the diagnosis and institution of appropriate therapy.

A randomized trial comparing fluconazole with clotrimazole troches for the prevention of fungal infections in patients with advanced human immunodeficiency virus infection. NIAID AIDS Clinical Trials Group.

BACKGROUND: Cryptococcal meningitis and other serious fungal infections are common complications in patients infected with the human immunodeficiency virus (HIV). Fluconazole is effective for long-term suppression of many fungal infections, but its effectiveness as primary prophylaxis had not been adequately evaluated. METHODS: We conducted a prospective, randomized trial that compared fluconazole (200 mg per day) with clotrimazole troches (10 mg taken five times daily) in patients who were also participating in a randomized trial of primary prophylaxis for Pneumocystis carinii pneumonia. RESULTS: After a median follow-up of 35 months, invasive fungal infections had developed in 4.1 percent of the patients in the fluconazole group (9 of 217) and in 10.9 percent of those in the clotrimazole group (23 of 211; relative hazard, as adjusted for the CD4+ count, 3.3; 95 percent confidence interval, 1.5 to 7.6). Of the 32 invasive fungal infections, 17 were cryptococcosis (2 in the fluconazole group and 15 in the clotrimazole group; adjusted relative hazard, 8.5; 95 percent confidence interval, 1.9 to 37.6). The benefit of fluconazole was greater for the patients with 50 or fewer CD4+ cells per cubic millimeter than for the patients with higher counts. Fluconazole was also effective in preventing esophageal candidiasis (adjusted relative hazard, 5.8; 95 percent confidence interval, 1.7 to 20.0; P = 0.004) and confirmed and presumed oropharyngeal candidiasis (5.7 and 38.1 cases per 100 years of follow-up in the fluconazole and clotrimazole groups, respectively; P < 0.001). Survival was similar in the two groups. CONCLUSIONS: Fluconazole taken prophylactically reduces the frequency of cryptococcosis, esophageal candidiasis, and superficial fungal infections in HIV-infected patients, especially those with 50 or fewer CD4+ lymphocytes per cubic millimeter, but the drug does not reduce overall mortality.

Isolation of fluconazole-resistant Candida albicans from human immunodeficiency virus-negative patients never treated with azoles.

Isolation of fluconazole-resistant strains of Candida species from human immunodeficiency virus (HIV)-infected patients after repeated or continuous courses of treatment has been reported with increasing frequency. During 1991-1992, MICs of fluconazole for 139 Candida albicans isolates from our institution were bimodally distributed: 102 strains were susceptible (MICs, < or = 4 micrograms/mL) and 37 were resistant (MICs, > or = 8 micrograms/mL). There was incomplete cross-resistance between fluconazole and ketoconazole or miconazole, and there was no cross-resistance between azoles and amphotericin B or flucytosine. Twenty of the 37 fluconazole-resistant strains were isolated from 17 HIV-negative patients, some with systemic infections, who had never been treated with azoles. There were no differences in characteristics or risk factors for those patients as compared with those for an equal number of HIV-negative patients from whom fluconazole-susceptible strains were isolated. Among patients with systemic infection, 6 (50%) of 12 with infection caused by fluconazole-resistant strains survived and 11 (69%) of 16 with infection caused by fluconazole-susceptible strains survived (P = .54). Survival was not found to be related to treatment regimen, but the number of patients was small. The emergence of fluconazole-resistant C. albicans among HIV-negative patients never exposed to azoles is of concern.

Intraorbital injection of amphotericin B for palliative treatment of Aspergillus orbital abscess.

We report successful palliative treatment of an Aspergillus fumigatus orbital mass in a patient with acquired immunodeficiency syndrome by direct injection of amphotericin B into the abscess cavity. This case presents intraorbital injection of amphotericin B as an alternative to surgical debridement of Aspergillus orbital infection. In patients who are unable or unwilling to undergo more aggressive treatment, this procedure appears to limit morbidity while still providing effective palliative therapy.

Comparison of oral fluconazole and clotrimazole troches as treatment for oral candidiasis in patients infected with human immunodeficiency virus.

Thirty-nine adult patients with human immunodeficiency virus infection and oral candidiasis were randomly assigned to receive either one fluconazole capsule (100 mg) or five clotrimazole troches (10 mg each) daily for 14 days. Among 36 evaluable patients, clinical resolution rates were 100 and 65%, respectively (P = 0.018). Mycological eradication rates were 75 and 20%, respectively (P = 0.004). Fluconazole-treated patients were more likely to remain disease free during follow-up than those treated with clotrimazole (P = 0.014 at 2 weeks). Prolonged clinical responses correlated with mycological eradication at the end of therapy (P = 0.043).

Topography of cerebellar corticonuclear fibers of the albino rat. Vermis of anterior and posterior lobes.

The distribution of cerebellar corticonuclear fibers of the vermis of anterior and posterior lobes was determined for the albino rat using the Fink and Heimer method. Efferent fibers from vermal cortex terminate in the ipsilateral medial cerebellar nucleus (NM) in an organized circumferential manner. Rostral lobules (I--III) project to rostroventral and rostrocentral NM, more central lobules (IV, V, VI) project to rostrodorsal, dorsocentral and caudodorsal areas of the nucleus respectively, while caudal lobules (VII, VIII, IX) send fibers into caudal and ventrocaudal NM. No evidence was seen to corroborate the contention that individual lobules of the vermis may project essentially throughout the rostrocaudal extent of the nucleus. Although species differences are apparent the arrangement of terminal fields in the NM for vermal cortex of rats is similar to that reported for other mammals. Degenerated fibers from medial aspects of each lesion primarily enter the NM while those coursing into the juxtarestiform body originate from more lateral portions of the cortical injury. This suggests that the arrangement of cortical zones in rat is fundamentally similar to that described in other mammals.