David M. Parenti

Prophylaxis against Disseminated Mycobacterium avium Complex with Weekly Azithromycin, Daily Rifabutin, or Both

BACKGROUND Azithromycin is active in treating Mycobacterium avium complex disease, but it has not been evaluated as primary prophylaxis in patients with human immunodeficiency virus (HIV) infection. Because the drug is concentrated in macrophages and has a long half-life in tissue, there is a rationale for once-weekly dosing. METHODS We compared three prophylactic regimens in a multicenter, double-blind, randomized trial involving 693 HIV-infected patients with fewer than 100 CD4 cells per cubic millimeter. The patients were assigned to receive rifabutin (300 mg daily), azithromycin (1200 mg weekly), or both drugs. They were monitored monthly with blood cultures for M. avium complex. RESULTS In an intention-to-treat analysis, the incidence of disseminated M. avium complex infection at one year was 15.3 percent with rifabutin, 7.6 percent with azithromycin, and 2.8 percent with both drugs. The risk of the infection in the azithromycin group was half that in the rifabutin group (hazard ratio, 0.53; P = 0.008). The risk was even lower when two-drug prophylaxis was compared with rifabutin alone (hazard ratio, 0.28; P<0.001) or azithromycin alone (hazard ratio, 0.53; P = 0.03). Among the patients in whom azithromycin prophylaxis was not successful, 11 percent of M. avium complex isolates were resistant to azithromycin. Dose-limiting toxic effects were more common with the two-drug combination than with azithromycin alone (hazard ratio, 1.67; P=0.03). Survival was similar in all three groups. CONCLUSIONS For protection against disseminated M. avium complex infection, once-weekly azithromycin is more effective than daily rifabutin and infrequently selects for resistant isolates. Rifabutin plus azithromycin is even more effective but is not as well tolerated.

Filgrastim prevents severe neutropenia and reduces infective morbidity in patients with advanced HIV infection : results of a randomized, multicenter, controlled trial

Objective:To assess the effect of filgrastim treatment on the incidence of severe neutropenia in patients with advanced HIV infection, and the effect of initial filgrastim treatment on prevention of infectious morbidity. Design:Randomized, controlled, open-label, multicenter study. Setting:Outpatient centers and physician offices. Patients:Men and women aged > 13 years, who were HIV antibody-positive, and had a CD4 cell count < 200 × 106/l, absolute neutrophil count (ANC) 0.7−1.0 × 109/l, and platelet count ≥ 50 × 109/l within 7 days of randomization were eligible. Two hundred and fifty-eight patients entered and 201 completed the study. Intervention:Daily filgrastim (starting at 1 µg/kg daily, adjusted up to 10 µg/kg daily) or intermittent filgrastim (starting at 300 µg daily one to three times per week to a maximum of 600 µg daily 7 days weekly) was administered to maintain an ANC between 2 and 10 × 109/l. Patients in the control group received filgrastim if severe neutropenia developed. Main outcome measures:Incidence of severe neutropenia (ANC < 0.5 × 109/l) or death, incidence of bacterial and fungal infections, duration of hospitalization and intravenous antibacterial use, and safety. Results:The primary endpoint of severe neutropenia or death was less frequent in patients who received daily (12.8%) or intermittent (8.2%) filgrastim compared with control patients (34.1%; P < 0.002 and P < 0.0001 for comparison with daily and intermittent groups, respectively). Filgrastim-treated patients developed 31% fewer bacterial infections and 54% fewer severe bacterial infections than control patients, required 26% less hospital days including 45% fewer hospital days for bacterial infections, and needed 28% fewer days of intravenous antibacterials. Filgrastim was not associated with an increase in HIV-1 plasma RNA level in a subset of patients in whom this was measured or any new or unexpected adverse events. Conclusion:Filgrastim was safe and effective in preventing severe neutropenia in patients with advanced HIV infection, and may reduce the incidence and duration of bacterial infections, incidence of severe bacterial infections, duration of hospital days for infections, and days of intravenous antibacterial agents.

A comparison of stavudine, didanosine and indinavir with zidovudine, lamivudine and indinavir for the initial treatment of HIV-1 infected individuals : Selection of thymidine analog regimen therapy (START II)

ObjectiveComparison of stavudine (d4T), didanosine (ddI) and indinavir (IDV) with zidovudine (ZDV), lamivudine (3TC) and IDV in HIV-1 infected patients. DesignRandomized, open-label. SettingFourteen HIV Clinical Research Centers. PatientsTwo-hundred and five patients with less than 4 weeks antiretroviral treatment, naive to 3TC and protease inhibitors and with CD4 cell counts ⩾ 200 × 106/l and plasma HIV-1 RNA levels ⩾ 10 000 copies/ml. InterventionsStavudine 40 mg and ddI 200 mg twice daily plus IDV 800 mg every 8 h compared with ZDV 200 mg every 8 h or 300 mg twice daily, 3TC 150 mg twice daily plus IDV. Main outcome measuresThe proportion of patients with plasma HIV-1 RNA levels < 500 copies/ml and ⩽ 50 copies/ml and changes in CD4 cell counts were compared. ResultsIn an analysis of the primary endpoint, 61% of patients on d4T + ddI + IDV and 45% of patients on ZDV + 3TC + IDV had all HIV-1 RNA values obtained between weeks 40 and 48 < 500 copies/ml [95% confidence interval (CI) for the difference between proportions, 1.7–30.3%;P = 0.038]. In an intent-to-treat analysis, the percentage of all patients randomized with all HIV-1 RNA levels < 500 copies/ml between 40 and 48 weeks were 53% for the d4T + ddI + IDV arm and 41% for the ZDV + 3TC + IDV arm (95% CI, −1.4% to 25.7%;P = 0.068). At 48 weeks 41% and 35% were ⩽ 50 copies/ml for the stavudine- and ZDV-containing arms respectively (P > 0.2). The median time-weighted average increases in CD4 cells count over 48 weeks were 150 × 106/l cells for the d4T arm and 106 × 106/l cells for the ZDV arm (P = 0.001). The occurrence of serious adverse events was not significantly different between arms. ConclusionThe combination of stavudine, ddI and IDV resulted in potent antiretroviral effects over a 48-week period, comparable or superior to zidovudine, 3TC and IDV supporting the use of stavudine, ddI and a protease inhibitor as an initial antiretroviral treatment.

Randomized, placebo-controlled, double-blind trial of the Na-ASP-2 hookworm vaccine in unexposed adults.

Necator americanus Ancylostoma Secreted Protein-2 (Na-ASP-2) is a leading larval-stage hookworm vaccine candidate. Recombinant Na-ASP-2 was expressed in Pichia pastoris and formulated with Alhydrogel. In a phase 1 trial, 36 healthy adults without history of hookworm infection were enrolled into 1 of 3 dose cohorts (n=12 per cohort) and randomized to receive intramuscular injections of either Na-ASP-2 or saline placebo. Nine participants in the first, second and third cohorts were assigned to receive 10, 50 and 100 microg of Na-ASP-2, respectively, on study days 0, 56 and 112, while 3 participants in each cohort received placebo. The most frequent adverse events were mild-to-moderate injection site reactions; in 8 participants these were delayed and occurred up to 10 days after immunization. No serious adverse events occurred. Anti-Na-ASP-2 IgG endpoint titers as determined by ELISA increased from baseline in all vaccine groups and peaked 14 days after the third injection, with geometric mean titers of 1:7066, 1:7611 and 1:11,593 for the 10, 50 and 100 microg doses, respectively, compared to <1:100 for saline controls (p<0.001). Antibody titers remained significantly elevated in all vaccine groups until the end of the study, approximately 8 months after the third vaccination. In vitro stimulation of PBMCs collected from participants with Na-ASP-2 resulted in robust proliferative responses in those who received vaccine, which increased with successive immunizations and remained high in the 50 and 100 microg dose groups through the end of the study. This first trial of a human hookworm vaccine demonstrates that the Na-ASP-2 vaccine is well-tolerated and induces a prolonged immune response in adults not exposed to hookworm, justifying further testing of this vaccine in an endemic area.

Syphilitic Hepatitis in HIV-Infected Patients: A Report of 7 Cases and Review of the Literature

BACKGROUND A recent resurgence of primary and secondary syphilis has been observed in certain population groups, particularly among persons infected with human immunodeficiency virus (HIV). Liver involvement is an infrequently recognized complication of early syphilis, with no previous reports among HIV-infected patients. METHODS We describe 7 cases of syphilitic hepatitis in HIV-positive individuals and review the literature. RESULTS At our institutions, all patients presented with a rash consistent with secondary syphilis. Each case was characterized by a conspicuous increase in serum alkaline phosphatase level (mean level +/- standard deviation, 905 +/- 523.6 IU/L) and milder elevations in serum transaminase levels. The mean CD4+ absolute T cell count was 317 cells/mm3, and the median rapid plasma reagin (RPR) titer was 1 : 128. There was a significant correlation between higher CD4+ cell counts and the RPR titers (R=0.93; P=.002). Symptomatic resolution and biochemical improvement, particularly a significant decrease in serum alkaline phosphatase levels (P=.02), occurred following antibiotic therapy. CONCLUSIONS Hepatic dysfunction is not uncommon in HIV-infected persons and is attributable to multiple causes. In the appropriate clinical setting, syphilitic hepatitis is an easily diagnosed and reversible etiology of liver dysfunction. The recognition of this entity will prevent unnecessary evaluation of abnormal liver enzyme levels in HIV-positive patients.

Mutation in Region III of the DNA Polymerase Gene Conferring Foscarnet Resistance in Cytomegalovirus Isolates from 3 Subjects Receiving Prolonged Antiviral Therapy

Three human immunodeficiency virus-infected subjects with progressive cytomegalovirus (CMV) retinitis despite prolonged antiviral therapy had buffy coat CMV isolates that were resistant to both ganciclovir and foscarnet. Genetic analysis of the resistant isolates showed that each contained a well-known ganciclovir resistance mutation in the viral UL97 phosphotransferase sequence, as well as a mutation (Ala to Val at codon 809, V809) in conserved region III of the DNA polymerase (Pol) sequence. A segment of the Pol sequence from one of the clinical isolates was transferred to CMV laboratory strain AD169 by homologous recombination. The recombinant virus containing V809 showed 6.3-fold increased foscarnet resistance and 2.6-fold increased ganciclovir resistance. Occurrence of the V809 mutation in 3 unrelated cases suggests that it is a clinically significant viral genetic marker for foscarnet resistance and decreased susceptibility to ganciclovir.

Prophylaxis with Weekly Versus Daily Fluconazole for Fungal Infections in Patients with AIDS

We compared the efficacy of a 400-mg once-weekly dosage versus a 200-mg daily dosage of fluconazole for the prevention of deep fungal infections in a multicenter, randomized, double-blind trial of 636 human immunodeficiency virus-infected patients to determine if a less intensive fluconazole regimen could prevent these serious but relatively infrequent complications of AIDS. In the intent-to-treat analysis, a deep fungal infection developed in 17 subjects (5.5%) randomly assigned to daily fluconazole treatment and in 24 (7.7%) given weekly fluconazole during 74 weeks of follow-up (risk difference, 2.2%; 95% confidence interval [CI], -1.7% to 6.1%). Thrush occurred twice as frequently in the weekly versus daily fluconazole recipients (hazard ratio, 0.59; 95% CI, 0.40-0.89), and in a subset of patients evaluated, fluconazole resistance was infrequent. Fluconazole administered once weekly is effective in reducing deep fungal infections in patients with AIDS, but this dosage is less effective than the 200-mg-daily dosage in preventing thrush.

Alterations in Serum Levels of Lipids and Lipoproteins with Indinavir Therapy for Human Immunodeficiency Virus—Infected Patients

Alterations in lipid metabolism have been associated with the use of protease inhibitors. Sequential lipid analyses were performed on serum samples from human immunodeficiency virus-infected antiretroviral-naive patients who received indinavir in combination with two nucleoside reverse transcriptase inhibitors. Serum levels of cholesterol, triglycerides, high-density lipoproteins (HDLs), and low-density lipoproteins (LDLs) were measured at baseline and at periodic intervals. After 48 weeks of indinavir therapy, mean serum levels +/- SD rose as follows: cholesterol, from 167.2 +/- 36.0 to 206.3 +/- 32.4 mg/dL (P < .0005); triglycerides, from 110.4 +/- 47.5 to 158.4 +/- 72.5 mg/dL (P < .0101); and LDLs, from 106.6 +/- 35.1 to 136.1 +/- 31.6 mg/dL (P = .0029). There was no significant change in the serum HDL fraction. Mean serum lipoprotein (a) levels +/- SD rose from 6.5 +/- 1.4 to 9.6 +/- 2.0 mg/dL after 30 weeks (P = .0695). Potential mechanisms for the noted increases include alterations in serum lipoprotein lipase activity or changes in hepatic lipid metabolism. The clinical significance of these changes remains to be determined.

Atrial-Esophageal Fistula after Atrial Radiofrequency Catheter Ablation

Atrial-esophageal fistula is a rare but often fatal complication of catheter radiofrequency ablation. Patients occasionally have bacteremia and have been misdiagnosed with endocarditis. Infectious diseases specialists are often consulted and need to be aware of this complication. We report a case of atrial-esophageal fistula after radiofrequency ablation that illustrates the salient features of this illness.

Phase II dose-ranging trial of foscarnet salvage therapy for cytomegalovirus retinitis in AIDS patients intolerant of or resistant to ganciclovir (ACTG protocol 093)

Objective:To document response to foscarnet salvage therapy in patients with cytomegalovirus (CMV) retinitis who are intolerant of or resistant to ganciclovir. Methods:Patients with AIDS and CMV retinitis who had documented hematologic intolerance or resistance to ganciclovir therapy received an induction course of foscarnet, 60mg/kg every 8h for 14 days, and subsequent chronic maintenance foscarnet therapy at a daily dose of 60, 90 or 120 mg/kg/day. The first 87 patients were randomly assigned to receive maintenance foscarnet at a dose of 60 or 90mg/kg/day; all subsequent patients were assigned a maintenance dose of 120 mg/kg/day. Results:A total of 156 evaluable patients were enrolled. Median time to retinitis progression and survival did not differ significantly among groups assigned to different maintenance foscarnet doses. Among patients with retinitis progression documented ophthalmologically occuring at ≤2 week intervals, despite optimal doses of ganciclovir, time to progression on foscarnet therapy was a median 8 weeks at all doses studied. By dose assignment, there were no significant differences in serious drug-associated toxicity, although trends toward increased renal and hypocalcemic adverse events were observed at higher maintenance doses. Conclusion:In patients intolerant of ganciclovir, salvage foscarnet therapy resulted in a longer time to retinitis progression than reported previously in historic controls who terminated ganciclovir therapy. In patients who exhibited clinical resistance to ganciclovir, foscarnet appeared to have efficacy in controlling retinitis. No significant differences in either efficacy or toxicity were observed in the range of foscarnet maintenance doses studied.