Judith A. Aberg

Guidelines for the Evaluation and Management of Dyslipidemia in Human Immunodeficiency Virus (HIV)-Infected Adults Receiving Antiretroviral Therapy: Recommendations of the HIV Medicine Association of the Infectious Disease Society of America and the Adult AIDS Clinical Trials Group

Michael P. Dube, James H. Stein, Judith A. Aberg, Carl J. Fichtenbaum, John G. Gerber, Karen T. Tashima, W. Keith Henry, Judith S. Currier, Dennis Sprecher, and Marshall J. Glesby, for the Adult AIDS Clinical Trials Group Cardiovascular Subcommittee Indiana University, Indianapolis; University of Wisconsin, Madison; Washington University, St. Louis, Missouri; University of Cincinnati and Cleveland Clinic, Ohio; University of Colorado, Denver; Brown University, Providence, Rhode Island; University of Minnesota, St. Paul; University of California at Los Angeles; and Cornell University, New York, New York

Sex Differences in Nevirapine Rash

Nevirapine is a nonnucleoside reverse transcriptase inhibitor (NNRTI) that has the most common treatment limiting side effect of rash. Severe rash has been observed in 3% of patients taking nevirapine in clinical trials, 85% of whom were men. In a multicenter, retrospective cohort study of all patients who received nevirapine over a 5-year period, severe rash was noted in 9 of 95 women and 3 of 263 men (risk ratio [RR], 8.31; 95% confidence interval [CI], 2.3-30.0; P=.005). Women were more likely to discontinue nevirapine therapy because of rash (RR, 4.5; 95% CI, 1. 9-10.5; P=.0005). After adjusting for age and baseline CD4 cell count in multivariate analysis, women had a 7-fold increase in risk for severe rash and were 3.5 times more likely to discontinue nevirapine therapy. In women of reproductive age for whom contraception may occur, nevirapine remains the NNRTI of choice. Recognition of sex differences in this severe adverse event will be important in prescribing nevirapine.

Recombinant Interferon-γlb as Adjunctive Therapy for AIDS-Related Acute Cryptococcal Meningitis

We conducted a phase 2, double-blind, placebo-controlled study to evaluate the safety and antifungal activity of adjuvant recombinant interferon (rIFN)- gamma 1b in patients with acquired immunodeficiency syndrome and acute cryptococcal meningitis. Patients received 100 or 200 microg of rIFN- gamma 1b or placebo, thrice weekly for 10 weeks, plus standard therapy with intravenous amphotericin B, with or without flucytosine, followed by therapy with fluconazole. End points included conversion of cerebrospinal fluid fungal cultures from positive to negative at 2 weeks, resolution of symptoms, and survival. Among 75 patients, 2-week culture conversion occurred in 13% of placebo recipients, 36% of rIFN- gamma 1b (100 microg) recipients, and 32% of rIFN- gamma 1b (200 microg) recipients. There was a trend toward improved combined mycologic and clinical success in rIFN- gamma 1b recipients (26% vs. 8%; P=.078). Therapy with rIFN- gamma 1b was well tolerated, and there was no apparent influence on serial CD4 cell counts and human immunodeficiency virus load measurements. Adjunctive therapy with rIFN- gamma 1b holds promise for patients with acute cryptococcal meningitis and warrants further study.

Phase I Evaluation of the Safety and Pharmacokinetics of Murine-Derived Anticryptococcal Antibody 18B7 in Subjects with Treated Cryptococcal Meningitis

ABSTRACT A promising approach to improving outcomes in patients with cryptococcal meningitis is to use adjunctive passive immunotherapy with a monoclonal antibody (MAb) directed against the capsular polysaccharide of Cryptococcus neoformans. This is the first application of MAb therapy for the treatment of a fungal disease in humans. We determined the safety and maximum tolerated dose of the murine anticryptococcal MAb 18B7 in a phase I dose-escalation study. The subjects were human immunodeficiency virus-infected patients who had been successfully treated for cryptococcal meningitis. Six dosing cohorts received MAb 18B7 at 0.01 to 2 mg/kg of body weight as a single infusion. Three patients each received 0.01, 0.05, 0.2, and 0.5 mg of MAb 18B7 per kg without significant adverse events. Four of the subjects who received the 1-mg/kg dose had mild study drug-associated toxicity, including transient nausea, vomiting, back pain, and urticarial rash. Two of the subjects who received 2 mg/kg developed drug-associated mild to moderate nausea, vomiting, chills, and myalgias. One of the subjects who received 2 mg/kg developed intracranial hypertension 10 weeks after MAb 18B7 administration. Serum cryptococcal antigen titers in the cohorts receiving doses of 1 and 2 mg/kg declined by a median of twofold at 1 week and a median of threefold at 2 weeks postinfusion, but the titers subsequently returned toward the baseline values by week 12. The half-life of MAb 18B7 in serum was approximately 53 h, while the MAb was undetectable in the cerebrospinal fluid of all patients. These data support the continued investigation of MAb 18B7 at a maximum single dose of 1.0 mg/kg.

Safety of Discontinuation of Maintenance Therapy for Disseminated Histoplasmosis after Immunologic Response to Antiretroviral Therapy

We performed a prospective observational study to assess the safety of stopping maintenance therapy for disseminated histoplasmosis among human immunodeficiency virus infected patients after response to antiretroviral therapy. All subjects received at least 12 months of antifungal therapy and 6 months of antiretroviral therapy before entry. Negative results of fungal blood cultures, urine and serum Histoplasma antigen level of <4.1 units, and CD4+ T cell count of >150 cells/mm3 were required for eligibility. Thirty-two subjects were enrolled; the median CD4+ T cell count at study entry was 289 cells/mm3. No relapses of histoplasmosis occurred after a median duration of follow-up of 24 months. This corresponded to an observed relapse rate of 0 cases per 65 person-years. The median CD4+ T cell count at final study visit was 338 cells/mm3. Discontinuation of antifungal maintenance therapy appears to be safe for patients with acquired immunodeficiency syndrome with previously treated disseminated histoplasmosis and sustained immunologic improvement in response to antiretroviral therapy.

Discontinuation of Maintenance Therapy for Cryptococcal Meningitis in Patients with AIDS Treated with Highly Active Antiretroviral Therapy: An International Observational Study

We conducted a retrospective, multicenter study evaluating the safety of discontinuing maintenance therapy for cryptococcal meningitis after immune reconstitution. Inclusion criteria were a previous definitive diagnosis of cryptococcal meningitis, a CD4 cell count of >100 cells/microL while receiving highly active antiretroviral therapy (HAART), and the subsequent discontinuation of maintenance therapy for cryptococcal meningitis. The primary end point was relapse of cryptococcal disease. As of July 2002, 100 patients were enrolled. When maintenance therapy was discontinued, the median CD4 cell count was 259 cells/microL and the median plasma virus load was <2.30 log10 copies/mL, and serum cryptococcal antigen was undetectable in 56 patients. During a median follow-up period of 28.4 months (range, 6.7-64.5; 262 person-years), 4 events were observed (incidence, 1.53 events per 100 person-years; 95% confidence interval, 0.42-3.92). Three of these patients had a CD4 cell count of >100 cells/microL and a positive serum cryptococcal antigen test result during the recurrent episode. In conclusion, discontinuation of maintenance therapy for cryptococcal meningitis is safe if the CD4 cell count increases to >100 cells/microL while receiving HAART. Recurrent cryptococcal infection should be suspected in patients whose serum cryptococcal antigen test results revert back to positive after discontinuation of maintenance therapy.

Effect of ritonavir/saquinavir on stereoselective pharmacokinetics of methadone : Results of AIDS clinical trials group (ACTG) 401

The effect of ritonavir 400 mg/saquinavir 400 mg twice daily on the stereoselective pharmacokinetics of methadone was examined in 12 HIV‐infected, methadone‐using study subjects. Design: A 24‐hour methadone pharmacokinetic study was performed before antiretroviral therapy was begun and after 15 days of therapy. Methadone concentration was measured by a chiral plasma assay because the drug is administered as a racemic mixture of R‐ and S‐methadone, but only the R‐isomer is active. Both changes in plasma protein binding and changes in objective and subjective opioid effect were monitored. Results: Ritonavir/saquinavir administration was associated with 40% decrease in total S‐methadone AUC0‐24hr and 32% decrease in R‐methadone area under the curve (AUC)0‐24hr, and both changes were statistically significant (p = .001 for both). When AUC was corrected for the changes in protein binding induced by ritonavir/saquinavir, R‐methadone free AUC0‐24hr decreased 19.6% whereas the S‐methadone decreased 24.6%, neither of these changes was statistically significant (p = .129 and p = .0537, respectively). This change in methadone exposure was not associated with any evidence of withdrawal from narcotics and no modification of methadone dose was required. Conclusions: Our data indicate that ritonavir/saquinavir administration is associated with induction of metabolism of methadone but this is greater for the inactive S‐methadone. However, approximately 37% of the decrease in the total R‐methadone exposure can be explained by protein binding displacement. Ritonavir/saquinavir can be used in HIV‐infected people taking methadone without routine dose adjustments.

Localized Osteomyelitis Due to Mycobacterium avium Complex in Patients with Human Immunodeficiency Virus Receiving Highly Active Antiretroviral TherapyLocalized Osteomyelitis Due to Mycobacterium avium Complex in Patients with Human Immunodeficiency Virus Receiving Highly Active Antiretroviral Therapy

We describe 3 patients who developed atypical manifestations of Mycobacterium avium complex (MAC) infection >10 months (range, 3-16 months) after attaining sustained CD4(+) T cell counts of >100 cells/microL while receiving antiretroviral therapy and not receiving MAC prophylaxis. The common features of these cases include the degree of immune reconstitution, the unusual locations of the infections, and the absence of a systemic inflammatory response. The low rate of these unusual MAC infections does not warrant continuation of primary or secondary prophylaxis after presumed immune reconstitution.

The impact of sex and contraceptive therapy on the plasma and intracellular pharmacokinetics of zidovudine.

Objectives:Zidovudine remains part of combination antiretroviral therapy. Pharmacological studies rely on quantitation of active triphosphates in peripheral blood mononuclear cells. This study evaluated the impact of female sex and contraceptive therapy on zidovudine plasma and intracellular pharmacokinetics and the impact of contraceptive therapy on HIV viral load. Methods:Serial plasma and intracellular zidovudine pharmacokinetics following oral and intravenous dosing were determined in 18 men and 20 women treated with zidovudine. Women could repeat pharmacokinetics assessment following 2 months oral or injectable contraceptive therapy. Zidovudine plasma and intracellular mono-, di- and triphosphate concentrations were determined by liquid chromatography tandem mass spectrometry. Plasma and cervical viral loads were determined preceding and following 2 months of contraceptive therapy in women. Results:Men exhibited higher area under the concentration versus time curve for intracellular zidovudine and zidovudine-monophosphate following oral and intravenous dosing and higher zidovudine triphosphate following oral dosing. There was no difference between men and women in plasma zidovudine parameters. Furthermore, contraceptive therapy had no effect on zidovudine plasma or intracellular pharmacokinetics or on plasma or cervical HIV-1 RNA levels. Conclusions:Using an optimized pharmacokinetic design, this study indicated men exhibit significantly higher zidovudine-monophosphate and zidovudine-triphosphate exposure following zidovudine oral administration, having implications for drug toxicity and overall tolerance of zidovudine therapy. The lack of an effect of contraceptive therapy on zidovudine pharmacokinetics is surprising in light of previous pharmacokinetic studies for drugs eliminated primarily through glucuronidation. Contraceptive therapy had no effect on plasma or cervical viral load, results consistent with previous findings.

A study of discontinuing maintenance therapy in human immunodeficiency virus-infected subjects with disseminated Mycobacterium avium complex: AIDS clinical trial group 393 study team

The present nonrandomized prospective study evaluated whether antimycobacterial therapy for disseminated Mycobacterium avium complex (MAC) could be withdrawn from human immunodeficiency virus-infected subjects who experienced immunologic recovery while receiving highly active antiretroviral therapy (HAART). Eligible subjects had received macrolide-based therapy for least 12 months, were asymptomatic for MAC, had received HAART for at least 16 weeks, and had CD4+ T cell counts >100 cells/microL. Forty-eight subjects were enrolled, with a median CD4+ T cell count of 240 cells/microL at the time of discontinuation of MAC therapy. Forty-seven subjects remained MAC free, whereas 1 subject developed localized MAC osteomyelitis. The median duration of follow-up while not receiving therapy was 77 weeks, and the incidence of MAC infection was 1.44/100 person-years (95% confidence interval, 0.04-8.01). Withdrawal of anti-MAC therapy appears to be safe in patients who have been treated with a macrolide-based regimen for at least 1 year and have an immunologic response on HAART.