Michael W. Dunne

Maraviroc for Previously Treated Patients with R5 HIV-1 Infection

BACKGROUND CC chemokine receptor 5 antagonists are a new class of antiretroviral agents. METHODS We conducted two double-blind, placebo-controlled, phase 3 studies--Maraviroc versus Optimized Therapy in Viremic Antiretroviral Treatment-Experienced Patients (MOTIVATE) 1 and MOTIVATE 2--with patients who had R5 human immunodeficiency virus type 1 (HIV-1) only. They had been treated with or had resistance to three antiretroviral-drug classes and had HIV-1 RNA levels of more than 5000 copies per milliliter. The patients were randomly assigned to one of three antiretroviral regimens consisting of maraviroc once daily, maraviroc twice daily, or placebo, each of which included optimized background therapy (OBT) based on treatment history and drug-resistance testing. Safety and efficacy were assessed after 48 weeks. RESULTS A total of 1049 patients received the randomly assigned study drug; the mean baseline HIV-1 RNA level was 72,400 copies per milliliter, and the median CD4 cell count was 169 per cubic millimeter. At 48 weeks, in both studies, the mean change in HIV-1 RNA from baseline was greater with maraviroc than with placebo: -1.66 and -1.82 log(10) copies per milliliter with the once-daily and twice-daily regimens, respectively, versus -0.80 with placebo in MOTIVATE 1, and -1.72 and -1.87 log(10) copies per milliliter, respectively, versus -0.76 with placebo in MOTIVATE 2. More patients receiving maraviroc once or twice daily had HIV-1 RNA levels of less than 50 copies per milliliter (42% and 47%, respectively, vs. 16% in the placebo group in MOTIVATE 1; 45% in both maraviroc groups vs. 18% in MOTIVATE 2; P<0.001 for both comparisons in each study). The change from baseline in CD4 counts was also greater with maraviroc once or twice daily than with placebo (increases of 113 and 122 per cubic millimeter, respectively, vs. 54 in MOTIVATE 1; increases of 122 and 128 per cubic millimeter, respectively, vs. 69 in MOTIVATE 2; P<0.001 for both comparisons in each study). Frequencies of adverse events were similar among the groups. CONCLUSIONS Maraviroc, as compared with placebo, resulted in significantly greater suppression of HIV-1 and greater increases in CD4 cell counts at 48 weeks in previously treated patients with R5 HIV-1 who were receiving OBT. (ClinicalTrials.gov numbers, NCT00098306 and NCT00098722.)

Subgroup analyses of maraviroc in previously treated R5 HIV-1 infection.

BACKGROUND We conducted subanalyses of the combined results of the Maraviroc versus Optimized Therapy in Viremic Antiretroviral Treatment-Experienced Patients (MOTIVATE) 1 and MOTIVATE 2 studies to better characterize the efficacy and safety of maraviroc in key subgroups of patients. METHODS We analyzed pooled data from week 48 from the two studies according to sex, race or ethnic group, clade, CC chemokine receptor 5 (CCR5) delta32 genotype, viral load at the time of screening, the use or nonuse of enfuvirtide in optimized background therapy (OBT), the baseline CD4 cell count, the number of active antiretroviral drugs coadministered, the first use of selected background agents, and tropism at baseline. Changes in viral tropism and the CD4 count at treatment failure were evaluated. Data on aminotransferase levels in patients coinfected with hepatitis B virus (HBV) or hepatitis C virus (HCV) were also analyzed. RESULTS A treatment benefit of maraviroc plus OBT over placebo plus OBT was shown in all subgroups, including patients with a low CD4 cell count at baseline, those with a high viral load at screening, and those who had not received active agents in OBT. Analyses of the virologic response according to the first use of selected background drugs showed the additional benefit of adding a potent new drug to maraviroc at the initiation of maraviroc therapy. More patients in whom maraviroc failed had a virus binding to the CXC chemokine receptor 4 (CXCR4) at failure, but there was no evidence of a decrease in the CD4 cell count at failure in such patients as compared with those in whom placebo failed. Subanalyses involving patients coinfected with HBV or HCV revealed no evidence of excess hepatotoxic effects as compared with baseline. CONCLUSIONS Subanalyses of pooled data from week 48 indicate that maraviroc provides a valuable treatment option for a wide spectrum of patients with R5 HIV-1 infection who have been treated previously. (ClinicalTrials.gov numbers, NCT00098306 and NCT00098722.)

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.

Once-Weekly Dalbavancin versus Daily Conventional Therapy for Skin Infection

BACKGROUND Dalbavancin, a lipoglycopeptide antibiotic agent that is active against gram-positive pathogens, has a long plasma half-life, allowing for once-weekly dosing. DISCOVER 1 and DISCOVER 2 were identically designed noninferiority trials of dalbavancin for the treatment of acute bacterial skin and skin-structure infection. METHODS We randomly assigned patients to receive dalbavancin intravenously on days 1 and 8 or vancomycin intravenously for at least 3 days with the option to switch to oral linezolid to complete 10 to 14 days of therapy. The primary end point, early clinical response, required the cessation of spread of infection-related erythema and the absence of fever at 48 to 72 hours. Secondary end points at the end of therapy included clinical status and investigators assessment of outcome. RESULTS Analysis of the primary end point showed noninferiority of dalbavancin in both DISCOVER 1 and DISCOVER 2. In the pooled analysis, 525 of 659 patients (79.7%) in the dalbavancin group and 521 of 653 (79.8%) in the vancomycin-linezolid group had an early clinical response indicating treatment success (weighted difference, -0.1 percentage point; 95% confidence interval, -4.5 to 4.2). The outcomes were similar in the analyses by study and the pooled analyses of clinical status at the end of therapy and the investigators assessment of outcome. For patients infected with Staphylococcus aureus, including methicillin-resistant S. aureus, clinical success was seen in 90.6% of the patients treated with dalbavancin and 93.8% of those treated with vancomycin-linezolid. Adverse events and study days with an adverse event were less frequent in the dalbavancin group than in the vancomycin-linezolid group. The most common treatment-related adverse events in either group were nausea, diarrhea, and pruritus. CONCLUSIONS Once-weekly intravenous dalbavancin was not inferior to twice-daily intravenous vancomycin followed by oral linezolid for the treatment of acute bacterial skin and skin-structure infection. (Funded by Durata Therapeutics; DISCOVER 1 and DISCOVER 2 ClinicalTrials.gov numbers, NCT01339091 and NCT01431339.).

A Multicenter Study of Azithromycin, Alone and in Combination with Chloroquine, for the Treatment of Acute Uncomplicated Plasmodium falciparum Malaria in India

BACKGROUND Azithromycin has demonstrated in vitro and in vivo activity against Plasmodium falciparum, but small treatment studies have given mixed results. METHODS Participants with fever and with both a blood smear and a rapid diagnostic test positive for falciparum malaria were randomly assigned to groups that were treated with either azithromycin or chloroquine or to matched groups receiving a placebo. After an interim analysis, open-label combination therapy with both drugs was initiated. RESULTS At day 28, 5 (33%) of 15 participants in the azithromycin-treated group had remained free of fever, compared with 4 (27%) of 15 in the chloroquine-treated group. All subsequently enrolled participants then received combination therapy with azithromycin and chloroquine. In 61 (97%) of 67 participants, resolution of fever and parasitemia had occurred by day 7, and, through day 28, no clinical or parasitologic relapse had occurred in them. CONCLUSIONS Resolution of parasitemia was inadequate with monotherapy with either azithromycin or chloroquine, but combination therapy provided substantially improved clinical and parasitologic outcomes. The combination of azithromycin and chloroquine may be an effective alternative treatment for falciparum malaria and deserves further study.

Once Weekly Azithromycin Therapy for Prevention of Mycobacterium avium Complex Infection in Patients with AIDS: A Randomized, Double-Blind, Placebo-Controlled Multicenter Trial

We conducted a randomized, double-blind, placebo-controlled multicenter trial of azithromycin (1,200 mg once weekly) for the prevention of Mycobacterium avium complex (MAC) infection in patients with AIDS and a CD4 cell count of < 100/mm3. In an intent-to-treat analysis through the end of therapy plus 30 days, nine (10.6%) of 85 azithromycin recipients and 22 (24.7%) of 89 placebo recipients developed MAC infection (hazard ratio, 0.34; P = .004). There was no difference in the ranges of minimal inhibitory concentrations of either clarithromycin or azithromycin for the five breakthrough (first) MAC isolates from the azithromycin group and the 18 breakthrough MAC isolates from the placebo group. Of the 76 patients who died during the study, four (10.5%) of 38 azithromycin recipients and 12 (31.6%) of 38 placebo recipients had a MAC infection followed by death (P = .025). For deaths due to all causes, there was no difference in time to death or number of deaths between the two groups. Episodes of non-MAC bacterial infection per 100 patient years occurred in 43 azithromycin recipients and 88 placebo recipients (relative risk, 0.49; 95% confidence interval, 0.33-0.73). The most common toxic effect noted during the study was gastrointestinal, reported by 78.9% of azithromycin recipients and 27.5% of placebo recipients. Azithromycin given once weekly is safe and effective in preventing disseminated MAC infection, death due to MAC infection, and respiratory tract infections in patients with AIDS and CD4 cell counts of < 100/mm3.

Rationale and Design of a Secondary Prevention Trial of Antibiotic Use in Patients after Myocardial Infarction: The WIZARD (Weekly Intervention with Zithromax [Azithromycin] for Atherosclerosis and Its Related Disorders) Trial

Mounting evidence supports the contention that atherosclerosis is an inflammatory disease. Recently a possible role for infectious microorganisms has gathered attention. Chlamydia pneumoniae is one possible pathogen. If C. pneumoniae is a target organism, antibiotics with antichlamydial activity may be able to ameliorate plaque instability. The WIZARD trial is a secondary prevention study that is assessing the impact of a 3-month course of azithromycin compared with placebo on the progression of clinical coronary heart disease. The study will enroll 3300 patients who have had a prior myocardial infarction and who have a C. pneumoniae IgG titer of >/=1:16. The primary end point is a composite of time to either recurrent myocardial infarction, death, a revascularization procedure, or hospitalization for angina. This study is the first of a series of adequately powered clinical trials that will attempt to bridge insights from preclinical investigations to interventions applicable to patient care.

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.

Prophylaxis of Plasmodium falciparum Malaria with Azithromycin Administered to Volunteers

New effective and well-tolerated prophylactic agents against P. falciparum malaria need to be developed. Chloroquine and proguanil are now relatively ineffective [1, 2]. Although the efficacy of mefloquine is approximately 90% [1], this rate may decline as resistance spreads [3], and mefloquine is currently not recommended for pregnant women, infants weighing less than 15 kg, and persons with neuropsychiatric disorders [2]. Sulfadoxine-pyrimethamine (Fansidar, Roche, Nutley, New Jersey) is no longer recommended for prophylaxis [2] because of the possibility of fatal toxic epidermal necrolysis. Doxycycline, 100 mg/d, is approximately 90% effective [4], but this agent is contraindicated in pregnant women and children younger than 8 years old and has gastrointestinal side effects. Plasmodium falciparum initially infects the liver, and, after approximately 7 days, parasites begin to emerge from the liver to parasitize red cells. A prophylactic agent against the liver stage of infection (causal prophylactic agent) needs to be administered for only approximately 7 days or less after infection, whereas an agent effective solely against the blood stage of the infection (suppressive prophylactic agent) needs to be administered for several weeks after infection. Mefloquine and doxycycline are insufficiently effective against liver-stage parasites, and patients require dosing for 4 weeks after leaving the endemic area. Azithromycin is an azalide analog of erythromycin that was recently licensed for the treatment of bacterial and chlamydial diseases. In a rodent model, we found that azithromycin has a causal prophylactic efficacy superior to that of doxycycline [5]. In addition, we did a study in which volunteers were exposed to the bites of P. falciparum-infected mosquitoes and given azithromycin for as long as 5 days after exposure to the bites. Azithromycin, 500 mg administered 2 days before exposure to the bites followed by 250 mg/d administered for 5 days after exposure to the bites, was successful prophylaxis for three of four persons [6]. Because the previous clinical study involved only 4 drug recipients, we did a new study of causal prophylaxis using 10 drug recipients. Because we obtained results showing unexpectedly poor efficacy, we subsequently entered another cohort of 10 drug recipients to determine the combined causal efficacy as well as the suppressive efficacy of azithromycin against P. falciparum malaria in the challenge model. Methods Study Design We did an open-label, controlled phase II study in which two cohorts were entered sequentially. In cohort 1, we evaluated the causal prophylactic efficacy of azithromycin. Ten persons received 500 mg of the drug on day 14 before the challenge, followed by 250 mg/d from day 13 before the challenge through day 7 after the challenge. Dosing from day 14 before the challenge to day 0 was intended to allow serum concentrations to reach a steady state; dosing from days 1 to 7 after the challenge was intended to provide causal prophylaxis. In the 12 preceding experiments at our clinical research center, all of approximately 40 control volunteers inoculated with this strain of P. falciparum became infected. In our present study, two controls did not receive azithromycin and were concomitantly infected to verify that the parasitologic challenge was infectious. In cohort 2, we evaluated the combined causal and suppressive prophylactic efficacy of azithromycin. Ten persons received 500 mg of the agent on day 14 before the challenge, followed by 250 mg/d from day 13 before the challenge through day 28 after the challenge. Dosing from days 8 through 28 was intended to provide suppressive prophylaxis. Two controls were concomitantly challenged. Inclusion and Exclusion Criteria Men and women aged 18 through 46 years were eligible if they were healthy on the basis of history, physical examination, and results of laboratory tests (complete blood count; serum levels of sodium, potassium, chloride, urea nitrogen, creatinine, calcium phosphate, total protein, albumin, aspartate aminotransferase, alkaline phosphatase, total bilirubin, lactate dehydrogenase, and uric acid) and had no history of exposure to malaria in the previous 2 years. Persons who did not object to the high likelihood of becoming parasitemic were permitted to be controls. Study Procedures For each cohort of 12 volunteers, all persons were infected [7] by exposure to the bites of five female Anopheles stephensi mosquitoes infected with the chloroquine-sensitive, mefloquine-resistant NF54 strain of P. falciparum. During drug administration, adverse reactions and symptoms of malaria were assessed by means of daily interviews for subjective symptoms (chills, headache, photophobia, back pain, muscle ache, stomach ache, anorexia, nausea, vomiting, diarrhea, vaginal itching), by daily recording of body temperature, and by repetition of the entrance laboratory tests on day 4 before the challenge and day 5 after the challenge. To make the definitive diagnosis of malaria, on days 5 through 28 (for cohort 1) or on days 5 through 35 (for cohort 2), thick blood smears were obtained, stained with Giemsa, and examined for P. falciparum by an investigator blinded to whether or not the study participant had received azithromycin. Positive results were confirmed by two other investigators. In addition, all persons not already diagnosed as having malaria were instructed to contact study personnel until day 70 if they had symptoms that suggested malaria. In each thick smear, 200 fields were examined. Patent malaria was defined as the presence of at least two parasites per smear. If the volunteer had patent parasitemia, he or she was treated with chloroquine (1500-mg base given over 3 days). Treatment Agents Azithromycin in the form of 250-mg tablets was provided by Pfizer Central Research. Groton, Connecticut. Chloroquine in the form of Aralen Phosphate tablets was purchased from Winthrop Pharmaceuticals. New York, New York. Protocol Approval Our protocol was approved by the Office of the Surgeon General of the United States Army and filed under IND with the U.S. Food and Drug Administration. All volunteers gave written informed consent. Statistical Methods Computation of exact CIs of a proportion was done using the binomial distribution. Results Prophylactic Efficacy of Azithromycin Cohort 1 consisted of 10 volunteers who received azithromycin until 7 days after challenge with P. falciparum sporozoites and 2 volunteers who were challenged with sporozoites but received no treatment. Both of the controls who received no treatment and 6 of the 10 volunteers who received treatment with the drug developed parasitemia. One participant was removed from the study on day 25 because of noncompliance with follow-up. He was not patent (parasitemic) on that day, and no other participant became patent between day 23 and the end of the study on day 70. We consider this participant to be a prophylactic success. All but one of the persons who received treatment with the drug and in whom prophylaxis failed had delayed patency (mean day of patency, 19 days; range, 11 to 23 days) compared with the controls (mean day of patency, 10 days; range, 9 to 11 days). In cohort 1, the efficacy of treatment was 40% (95% CI, 12% to 74%). Cohort 2 consisted of 10 persons who received azithromycin until 28 days after exposure to sporozoites and 2 controls who received no treatment. Both controls became patent (on days 11 and 13); none of the participants who received drug treatment became patent. In cohort 2, the efficacy of azithromycin was 100% (lower 95% CI, 70%). Of the 10 participants in both cohorts who became parasitemic, only 3 had temperatures greater than 37.7 C, and 7 had symptoms characterized by chills, headache, myalgia, and anorexia. No volunteer required hospitalization. Adverse Effects of Azithromycin Although each day during the period of drug administration, study participants were interviewed for subjective side effects, we found only four instances of headache, four instances of stomach ache, and one instance of diarrhea not temporally linked to parasitemia. Each of these events was mild and lasted at most 1 day. In addition, one patient developed flulike symptoms 2 days after receiving the last dose of the drug. Neither the one woman in cohort 1 nor the three women in cohort 2 reported symptoms of vaginitis. The only abnormality in laboratory variables was total bilirubin values somewhat higher than the upper limit of normal (24 mol/L) in 3 participants. In 1 volunteer, the value on day 4 before the challenge (37.6 mol/L) had returned to normal by day 5 after the challenge (15.4 mol/L) while the participant was still receiving the drug. In 1 participant, the values were relatively constant during therapy (27.4 mol/L on day 4 before the challenge and 34.2 mol/L on day 5 after the challenge) and then returned to normal after therapy. In the third participant, a value of 30.8 mol/L was first recorded on day 5 and levels returned to normal after therapy. Discussion A causal and suppressive prophylactic regimen of azithromycin, 250 mg/d for 28 days after a single challenge with P. falciparum sporozoites, was successful in 10 of 10 persons studied. In contrast, a causal prophylactic regimen of azithromycin, 250 mg/d for 7 days after challenge, was successful in only 4 of 10 persons. We had hoped that azithromycin would be sufficiently concentrated in the liver to be completely causally prophylactic, because it has been reported that azithromycin liver concentrations are approximately 10 times that of serum concentrations [8]. The results of treatment for 7 days after the challenge show that, as with doxycycline [9], azithromycin has only partial causal prophylactic activity in the human challenge model. The mean percent efficacy determined here (40% [CI, 12% to 74%]) is much less than that recently achieved by Kuschner and colleagues [6] in a tria

A Randomized Clinical Trial of Single-Dose Versus Weekly Dalbavancin for Treatment of Acute Bacterial Skin and Skin Structure Infection

Dalbavancin when delivered as a single 1500-mg infusion is noninferior to the same total dose given as a 2-dose regimen, removing the logistical constraints related to the second dose while improving compliance and patient convenience.