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Four patients with adult-onset, disseminated mycobacterial infection had 5' UTR mutations in IKBKG without clear physical stigmata of NEMO deficiency. These mutations caused decreased levels of NEMO protein and Toll-like receptor driven cytokine production. Three patients died from disseminated disease. These mutations may be missed by whole exome sequencing.

Summary Background Chloroquine was used for malaria treatment until resistant Plasmodium falciparum was identified. Because 4-aminoquinolines with modified side chains, such as AQ-13, are active against resistant parasites, we compared AQ-13 against artemether plus lumefantrine for treatment of uncomplicated P falciparum malaria. Methods We did a randomised, non-inferiority trial. We screened men (≥18 years) with uncomplicated malaria in Missira (northeast Mali) and Bamako (capital of Mali) for eligibility (≥2000 asexual P falciparum parasites per μL of blood). Eligible participants were randomly assigned to either the artemether plus lumefantrine group or AQ-13 group by permuting blocks of four with a random number generator. Physicians and others caring for the participants were masked, except for participants who received treatment and the research pharmacist who implemented the randomisation and provided treatment. Participants received either 80 mg of oral artemether and 480 mg of oral lumefantrine twice daily for 3 days or 638·50 mg of AQ-13 base (two oral capsules) on days 1 and 2, and 319·25 mg base (one oral capsule) on day 3. Participants were monitored for parasite clearance (50 μL blood samples twice daily at 12 h intervals until two consecutive negative samples were obtained) and interviewed for adverse events (once every day) as inpatients during week 1. During the 5-week outpatient follow-up, participants were examined for adverse events and recurrent infection twice per week. All participants were included in the intention-to-treat analysis and per-protocol analysis, except for those who dropped out in the per-protocol analysis. The composite primary outcome was clearance of asexual parasites and fever by day 7, and absence of recrudescent infection by parasites with the same molecular markers from days 8 to 42 (defined as cure). Non-inferiority was considered established if the proportion of patients who were cured was higher for artemether plus lumefantrine than for AQ-13 and the upper limit of the 95% CI was less than the non-inferiority margin of 15%. This trial is registered at ClinicalTrials.gov, number NCT01614964. Findings Between Aug 6 and Nov 18, 2013, and between Sept 18 and Nov 20, 2015, 66 Malian men with uncomplicated malaria were enrolled. 33 participants were randomly assigned to each group. There were no serious adverse events (grade 2–4) and asexual parasites were cleared by day 7 in both groups. 453 less-severe adverse events (≤grade 1) were reported: 214 in the combination group and 239 in the AQ-13 group. Two participants withdrew from the AQ-13 group after parasite clearance and three were lost to follow-up. In the artemether plus lumefantrine group, two participants had late treatment failures (same markers as original isolates). On the basis of the per-protocol analysis, the AQ-13 and artemether plus lumefantrine groups had similar proportions cured (28 [100%] of 28 vs 31 [93·9%] of 33; p=0·50) and AQ-13 was not inferior to artemether plus lumefantrine (difference −6·1%, 95% CI −14·7 to 2·4). Proportions cured were also similar between the groups in the intention-to-treat analysis (28 of 33, 84·8% for AQ-13 vs 31 of 33, 93·9% for artemether and lumefantrine; p=0·43) but the upper bound of the 95% CI exceeded the 15% non-inferiority margin (difference 9·1%, 95% CI −5·6 to 23·8). Interpretation The per-protocol analysis suggested non-inferiority of AQ-13 to artemether plus lumefantrine. By contrast, the intention-to-treat analysis, which included two participants who withdrew and three who were lost to follow-up from the AQ-13 group, did not meet the criterion for non-inferiority of AQ-13, although there were no AQ-13 treatment failures. Studies with more participants (and non-immune participants) are needed to decide whether widespread use of modified 4-aminoquinolones should be recommended. Funding US Food and Drug Administration Orphan Product Development, National Institutes of Health, US Centers for Disease Control and Prevention, Burroughs-Wellcome Fund, US State Department, and WHO.

Introduction Patients with hematological malignancies (HM) are uniquely immunocompromised and considered at high risk for COVID-19. However, data regarding the diagnosis, clinical course, treatment, and outcomes of these patients is sparse. In particular, the ability to successfully detect SARS-CoV-2 in patients with HM remains unknown. We have previously reported 2 cases of allogeneic stem cell transplant (SCT) diagnosed with COVID-19 using clustered regularly interspaced short palindromic repeats (CRISPR) technique, following multiple negative nasopharyngeal RT-PCR testing (Niu et al. Bone Marrow Transplantation - Nature). Here we examine 29 patients with a variety of HM with high suspicion for COVID-19 based on clinical presentation, lab results, and imaging, whom were tested with CRISPR and/or RT-PCR based techniques. From 3/31/20 to 7/17/20, 29 patients (age 24 to 82) with a variety of HM (20 lymphoid, 9 myeloid; Table 1), 24 of which presented with an undiagnosed respiratory illness and 5 presented while asymptomatic for testing prior to chemotherapy, were evaluated for COVID-19. While 16 patients tested positive for COVID-19 with guideline-directed nasopharyngeal RT-PCR testing (including the 5 asymptomatic patients), 13 patients tested negative with the same technique. However, based on their clinical history, imaging, and disease course, concern for COVID-19 infection remained in these 13 patients. We then used CRISPR technology available at our institution (Huang et al. Biosensors and Bioelectronics) to test 8 patients who initially tested negative by RT-PCR. Surprisingly, 7 of the 8 patients tested positive for COVID-19 with either a blood sample and/or nasal swab for the SARS-CoV-2 specific N gene and ORF1ab gene. Excluding the patients who were negative by RT-PCR and not tested by CRISPR, the rate of false negativity with RT-PCR testing is significantly elevated at 29% (7/24) in our cohort of HM, which compares unfavorably with the expected false negative rates of RT-PCR techniques. A very high fatality rate was observed with 9 out of the 29 patients (31%) ultimately dying. Fifteen patients were undergoing active chemotherapy, 4 had received an autologous SCT, 6 had received an allogeneic SCT, and 4 were on surveillance. Of the 23 COVID-19 positive patients (by RT-PCR or CRISPR), 8 patients received COVID-19-directed therapy with either hydroxychloroquine/azithromycin, remdesivir, and/or Covid-19 convalescent plasma (CCP) depending on their clinical status, and 4 patients expired. Of the 8 treated patients, 7 improved while 1 patient expired. For the 5 patients who were negative for RT-PCR with no CRISPR completed, 1 patient received hydroxychloroquine/azithromycin proactively due to symptoms and imaging and recovered, while 3 patients expired at outside facilities due to unknown causes. Breakdown of testing and treatment is shown in Fig. 1. The majority of our patients had undergone SCT or were actively on chemotherapy, notably lymphodepleting chemotherapy. Associated with the fact that COVID-19 is known to worsen lymphopenia, our patient's symptoms and immune response to COVID-19 is likely to differ from immunocompetent hosts. This translated into an overall worse outcome as seen by the high mortality with our patients. In our limited dataset, patients presented with a variety of symptoms ranging from asymptomatic to acute respiratory failure. Intriguingly, the 5 asymptomatic patients had lymphoid malignancies and were on chemotherapy. It is thus imperative to establish the diagnosis of COVID-19 quickly, as faster initiation of treatment has been associated with better outcomes. The 8 patients who were diagnosed and treated improved substantially. However, as seen by our dataset, a strikingly high false negative rate was observed. Thus, a high clinical suspicion must guide further workup and therapy in patients with HM who present with an undiagnosed respiratory illness consistent with COVID-19. Patients with HM can have a wide variety of presentations when infected with COVID-19. For this select patient population we must establish an algorithm to diagnose COVID-19 efficiently as we reported a high number of initial false negative COVID-19 tests before the more sensitive CRISPR revealed a positive test. In addition, treatment pathways need to be instituted to not only treat COVID-19 infection, but also provide the best treatment for these patient's underlying HM. Disclosures Safah: Amgen: Honoraria; Verastem: Honoraria; Janssen: Speakers Bureau; Astellas: Speakers Bureau. Saba:Kite: Other: Advisory Board; Pharmacyclics: Other: Advisory Board, Speakers Bureau; AbbVie: Consultancy, Other: Advisory Board, Speakers Bureau; Janssen: Other: Advisory Board, Speakers Bureau; Kyowa Kirin: Other: Advisory Board.

BACKGROUND Low CD4 recovery among HIV-positive individuals who achieve virologic suppression is common but has not been studied among individuals initiating treatment at CD4 counts of >500 cells/mm. SETTING United States, Africa, Asia, Europe and Israel, Australia, Latin America. METHODS Among participants randomized to immediate antiretroviral therapy (ART) in the Strategic Timing of AntiRetroviral Therapy trial, low CD4 recovery was defined as a CD4 increase of

On November 7, 2018, the National Rifle Association (NRA) issued a tweet advising “self-important anti-gun doctors to stay in their lane.” The tweet has galvanized physicians to share their experiences with gun violence through the grassroots #ThisISOurLane campaign. Infectious diseases physicians are regularly called upon to manage complications such as infected wounds and osteomyelitis in gunshot victims. Yet, Infectious Diseases as a specialty has been poorly represented in the national dialogue on gun violence. Over 80 medical societies have endorsed statements on gun violence, including the American College of Physicians (ACP) and the American College of Cardiology; the Infectious Diseases Society of America has not. We argue that gun violence does affect the Infectious Diseases community and issue a call to action to engage in the conversation, advocate for our patients, and join with other medical societies in affirming a commitment to gun violence prevention.

Background/purpose The diagnosis of patients with pulmonary infiltrates and human immunodeficiency virus (HIV) infection remains a challenge. In current clinical practice the gold standard for Pneumocystis jirovecii pneumonia (PCP) diagnosis remains the identification of the organism in bronco alveolar lavage (BAL) using microscopy (e.g., silver stain). (1->3)-β -d-glucan (BG) is a polysaccharide that is present within the cell wall of Pneumocystis and other fungi. Methods We analyzed serum and BAL lavage fluid from a cohort of 119 patients that did have HIV, a diagnosis of pneumonia and underwent bronchoscopy (FOB) for diagnosis of PCP. Results The discriminative power of serum BG for the diagnosis of PCP in this group of patients was very high. Using a cutoff of 300 pg/mL, the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were 91%, 92%, 89% and 93% respectively. A model for ROC with just serum BG ( N = 108) had an AUC of 0.95. Serum procalcitonin (PCT) and BAL BG were not as accurate for the diagnosis of PCP. For BAL BG using a cutoff of 783 pg/mL, the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were 72%, 79%, 72% and 79% respectively. The differences between the medians for serum PCT between the group with a without PCP did not reach statistical significance ( p = 0.6137). Conclusion The measurement of serum BG should be incorporated in the diagnostic work up of HIV positive patients with dyspnea and infiltrates on chest X X-ray. Our study confirms the diagnostic value of serum BG previously reported by others but we add a cutoff value that we believe is more accurate for patients with AIDS and suspicion of PCP.

Background Invasive candidiasis is the third most common bloodstream infection in the intensive care unit (ICU) and is associated with morbidity and mortality. Prophylaxis and preemptive therapy are attractive strategies for this setting. Methods We conducted a multicenter, randomized, double-blind, placebo-controlled trial of caspofungin as antifungal prophylaxis in 222 adults who were in the ICU for at least 3 days, were ventilated, received antibiotics, had a central line, and had 1 additional risk factor (parenteral nutrition, dialysis, surgery, pancreatitis, systemic steroids, or other immunosuppressants). Subjects' (1,3)-β-d-glucan levels were monitored twice weekly. The primary endpoint was the incidence of proven or probable invasive candidiasis by EORTC/MSG criteria in patients who did not have disease at baseline. Patients who had invasive candidiasis were allowed to break the blind and receive preemptive therapy with caspofungin. The preemptive approach analysis included patients all patients who received study drug, including those positive at baseline. Results The incidence of proven/probable invasive candidiasis in the placebo and caspofungin arms was 16.7% (14/84) and 9.8% (10/102), respectively, for prophylaxis (P = .14), and 30.4% (31/102) and 18.8% (22/117), respectively, for the preemptive approach (P = .04); however, this analysis included patients with baseline disease. There were no significant differences in the secondary endpoints of mortality, antifungal use, or length of stay. There were no safety differences. Conclusions Caspofungin was safe and tended to reduce the incidence of invasive candidiasis when used for prophylaxis, but the difference was not statistically significant. A preemptive therapy approach deserves further study. Clinical trials registration NCT00520234.

In order to explore the clinical significance and risk factors for true bacteremia caused by coagulase-negative staphylococci (CNS) other than Staphylococcus epidermidis, a retrospective cohort study of 160 patients with at least one blood culture positive for non- epidermidis CNS was performed. True bacteremia was diagnosed in 32 (20%) of the patients. On multivariate analysis the following factors were associated with true bacteremia: (i) more than one positive blood culture, (ii) presence of a central venous catheter, and (iii) methicillin resistance. The results of this study indicate that non- epidermidis CNS can cause significant bloodstream infections.

High-level penicillin resistance has been associated with treatment failure in patients with Streptococcus pneumoniae infections. To identify a subgroup of patients at low risk for high-level penicillin-nonsusceptible S. pneumoniae bacteremia, a cross-sectional study of 303 patients was performed. For the total study population, penicillin resistance was observed in 98 (32%) of 303 patients; high-level resistance was seen in 33 (11%). A predictive model was created by using 3 baseline variables that were independently associated with high-level penicillin resistance: previous beta -lactam antibiotic use, previous stay in a risk area (defined as stay in day care facilities, prisons, homeless shelters, nursing homes, or other long-term care facilities), and previous respiratory tract infection. The model was used to identify patients at low and high risk for high-level penicillin-resistant pneumococcal bacteremia. None of the isolates of patients in the low-risk subgroup had ceftriaxone resistance. Patients in the low-risk subgroup could be empirically treated with fluoroquinolone-sparing regimens.

The 24-week extension of AIDS Clinical Trials Group Protocol 359, a study of human immunodeficiency virus (HIV)‐infected, indinavir-experienced patients, was designed to study the durability of “salvage” treatment regimens. Patients received saquinavir in combination with either ritonavir or nelfinavir and, in addition, delavirdine, adefovir, or both. Patients who demonstrated a virologic response at weeks 12‐16 were eligible to continue therapy in the extension through week 48. Of the 105 eligible subjects who were enrolled in the extension, 86 (82%) completed 48 weeks, and 49 (57%) of those 86 had HIV RNA levels 500 copies/ mL at week 48. For these 86 subjects who completed 48 weeks, the median change in CD4 cell count from baseline was +72 cells/mm 3 . Greater body weight, higher CD4 cell count, and greater degree of phenotypic susceptibility to indinavir and saquinavir at baseline were significantly associated with durable virologic suppression. These results show that some patients who experience treatment failure can demonstrate durable virologic and immunologic responses with salvage antiretroviral regimens. Current treatment guidelines recommend starting therapy for human immunodeficiency virus (HIV) infection with 2 nucleoside analogue reverse-transcriptase inhibitors in combination with 1 or 2 protease inhibitors or a nonnucleoside analogue reversetranscriptase inhibitor [1, 2]. However, 20%‐63% of patients from clinical cohorts experience virologic treatment failure while receiving combination antiretroviral therapy [3‐7]. Recent prospective studies have attempted to identify strategies for treatment of the treatment-experienced patient [8‐13], but these studies have focused primarily on 8‐24-week virologic responses to treatment. The durability of virologic and immunologic re

In April 2008, the Infectious Diseases Society of America (IDSA) entered into an agreement with Connecticut Attorney General Richard Blumenthal to voluntarily undertake a special review of its 2006 Lyme disease guidelines. This agreement ended the Attorney General's investigation into the process by which the guidelines were developed. The IDSA agreed to convene an independent panel to conduct a one-time review of the guidelines. The Review Panel members, vetted by an ombudsman for potential conflicts of interest, reviewed the entirety of the 2006 guidelines, with particular attention to the recommendations devoted to post-Lyme disease syndromes. After multiple meetings, a public hearing, and extensive review of research and other information, the Review Panel concluded that the recommendations contained in the 2006 guidelines were medically and scientifically justified on the basis of all of the available evidence and that no changes to the guidelines were necessary.

Slow extended daily dialysis (SLEDD) is the newest form of dialysis that is being used increasingly to replace continuous venovenous hemodialysis (CVVHD) for critically ill patients; it is less expensive to administer and has similar safety for patients who are prone to hemodynamic instability. Unfortunately, there are limited data regarding the appropriate dosing of antimicrobial agents for patients undergoing SLEDD. Furthermore, many nonnephrologists are not familiar with the differences between SLEDD, other continuous renal replacement therapies--for example, CVVHD--and routine hemodialysis. Thus, there is potential for inaccurate and, at worst, inadequate dosing of critical antimicrobial agents for this patient population. We review the available pharmacokinetic data on SLEDD and give preliminary recommendations for how to approach dosing in this situation.

Diseases of the head and neck often are the first sign of Human Immunodeficiency Virus (HIV) infection. As current treatment increases the survival time of HIV-positive patients, the physician may encounter patients with a greater variety and number of diseases related to the primary HIV infection. Some entities are harbingers of HIV infection, such as Kaposi's sarcoma and parotid cystic enlargement. Other manifestations, such as Mycobacterium avium complex infection, may be used to determine the stage of HIV infection. The advent of highly active anti-retroviral therapy (HAART) has transformed the prevalence of HIV-associated head and neck disease. This article reviews the clinical presentations and treatments of common and uncommon head and neck manifestations in HIV infection. Accurate assessment of these conditions may allow the physician to identify HIV infection in previously undiagnosed patients, and, as a result, provide more timely treatment.

This multicenter study evaluated the tolerance and potential pharmacokinetic interactions between azithromycin and rifabutin in volunteers with or without human immunodeficiency virus infection. Daily dosing with the combination of azithromycin and rifabutin was poorly tolerated, primarily because of gastrointestinal symptoms and neutropenia. No significant pharmacokinetic interactions were found between these drugs.

Even at the turn of the millennium, respiratory infections exact a heavy toll on the American public. Pneumonia is the leading infectious disease cause of death, and influenza costs Medicare more than $1 billion each year. This article highlights some of the advances this past year in antimicrobial therapy for respiratory tract infections. Efforts are targeted at shortening the length of treatment and reducing costs for pneumonia. A promising new class of antivirals has been introduced for the treatment of influenza, and alternative medicine continues to receive more scientific scrutiny. Antimicrobials alone are not the answer, and preliminary work on immunomodulatory therapies may usher in a new era of multifaceted treatment approaches.

This study evaluated the tolerance and potential pharmacokinetic interactions between clarithromycin (500 mg every 12 h) and rifabutin (300 mg daily) in clinically stable human immunodeficiency virus-infected volunteers with CD4 counts of 3 . Thirty-four subjects were randomized equally to either regimen A or regimen B. On days 1 to 14, subjects assigned to regimen A received clarithromycin and subjects assigned to regimen B received rifabutin, and then both groups received both drugs on days 15 to 42. Of the 14 regimen A and the 15 regimen B subjects who started combination therapy, 1 subject in each group prematurely discontinued therapy due to toxicity, but 19 of 29 subjects reported nausea, vomiting, and/or diarrhea. Pharmacokinetic analysis included data for 11 regimen A and 14 regimen B subjects. Steady-state pharmacokinetic parameters for single-agent therapy (day 14) and combination therapy (day 42) were compared. Regimen A resulted in a mean decrease of 44% ( P = 0.003) in the clarithromycin area under the plasma concentration-time curve (AUC), while there was a mean increase of 57% ( P = 0.004) in the AUC of the clarithromycin metabolite 14-OH-clarithromycin. Regimen B resulted in a mean increase of 99% ( P = 0.001) in the rifabutin AUC and a mean increase of 375% ( P < 0.001) in the AUC of the rifabutin metabolite 25- O -desacetyl-rifabutin. The usefulness of this combination for prophylaxis of Mycobacterium avium infections is limited by frequent gastrointestinal adverse events. Coadministration of clarithromycin and rifabutin results in significant bidirectional pharmacokinetic interactions. The resulting increase in rifabutin levels may explain the increased frequency of uveitis observed with concomitant use of these drugs.

We conducted a retrospective study to further elucidate the clinical presentations and prognosis of disease due to Mycobacterium kansasii in patients infected with human immunodeficiency virus (HIV). Forty-nine HIV-infected patients first had M. kansasii isolated at a mean CD4 cell count of 62/mm 3 and at a mean interval of 17 months after the diagnosis of AIDS. Seventeen of the 49 patients had disseminated disease caused by M. kansasii. Twenty-nine patients had a positive acid-fast smear of sputum, and 35 were known to be cigarette smokers. At the time of initial isolation of M. kansasii, 13 patients had other concurrent pulmonary isolates and 15 had another mycobacterial species concurrently isolated (the Mycobacterium avium complex in 13 instances). Patients who received antimycobacterial treatment survived longer than those who did not. Only one of the 49 patients was definitively determined to be colonized with M. kansasii without disease ; therefore, it appears that pulmonary isolates of M. kansasii in HIV-infected patients are almost always associated with disease. The increase in rates of M. kansasii disease among HIV-infected patients has paralleled the rise of AIDS in Louisiana. So far, this state has recorded more coinfections with M. kansasii and HIV than any other.

A case of a total knee arthroplasty infection with Actinomyces naeslundii is described. The difficulties of therapeutic decision-making are emphasized.

Objectives: To determine: (1) the pharmacokinetics and safety of an investigational aminoquinoline active against multidrug–resistant malaria parasites (AQ-13), including its effects on the QT interval, and (2) whether it has pharmacokinetic and safety profiles similar to chloroquine (CQ) in humans. Design: Phase I double-blind, randomized controlled trials to compare AQ-13 and CQ in healthy volunteers. Randomizations were performed at each step after completion of the previous dose. Setting: Tulane–Louisiana State University–Charity Hospital General Clinical Research Center in New Orleans. Participants: 126 healthy adults 21–45 years of age. Interventions: 10, 100, 300, 600, and 1,500 mg oral doses of CQ base in comparison with equivalent doses of AQ-13. Outcome Measures: Clinical and laboratory adverse events (AEs), pharmacokinetic parameters, and QT prolongation. Results: No hematologic, hepatic, renal, or other organ toxicity was observed with AQ-13 or CQ at any dose tested. Headache, lightheadedness/dizziness, and gastrointestinal (GI) tract–related symptoms were the most common AEs. Although symptoms were more frequent with AQ-13, the numbers of volunteers who experienced symptoms with AQ-13 and CQ were similar (for AQ-13 and CQ, respectively: headache, 17/63 and 10/63, p = 0.2; lightheadedness/dizziness, 11/63 and 8/63, p = 0.6; GI symptoms, 14/63 and 13/63; p = 0.9). Both AQ-13 and CQ exhibited linear pharmacokinetics. However, AQ-13 was cleared more rapidly than CQ (respectively, median oral clearance 14.0–14.7 l/h versus 9.5–11.3 l/h; p ≤ 0.03). QTc prolongation was greater with CQ than AQ-13 (CQ: mean increase of 28 ms; 95% confidence interval [CI], 18 to 38 ms, versus AQ-13: mean increase of 10 ms; 95% CI, 2 to 17 ms; p = 0.01). There were no arrhythmias or other cardiac AEs with either AQ-13 or CQ. Conclusions: These studies revealed minimal differences in toxicity between AQ-13 and CQ, and similar linear pharmacokinetics., Editorial Commentary Background: Chloroquine (CQ) is a drug that has been widely used for over 40 years for the treatment and prevention of malaria. It is cheap, safe, and, except in areas where resistant malaria parasites exist, effective. However, the spread of resistant malaria parasites in most malarial regions of the world has meant that this drug, and many others, can no longer be relied upon to control disease. New drug candidates are therefore needed, and ideally should be cheap to produce as well as safe and effective. Some research groups are working on potential drug candidates from the aminoquinoline family of compounds, which includes chloroquine. One candidate, AQ-13 (aminoquinoline-13) has already been studied in animal and in vitro experiments, and seemed to be a good candidate for further testing in humans. Therefore, as the first stage in evaluating AQ-13 further, this group of researchers carried out a Phase I trial in healthy humans. The researchers specifically wanted to compare how often people given AQ-13, as compared to those given CQ, had side effects, and to find out how AQ-13 is handled in the body (i.e., how quickly the compound is taken into the bloodstream, gets broken down, and how it affects normal body functions). These sorts of studies do not tell researchers anything about the efficacy of the drug in treating malaria, but the results are absolutely essential before trials can be done that do test efficacy in people with malaria. 126 healthy volunteers were recruited into the study, and each received capsules containing a different dosage of either AQ-13 or CQ. Side effects data were collected for four weeks after the drugs were given. What this trial shows: The most common side effects experienced by volunteers in the trial were headache, light-headedness, dizziness, and gastrointestinal symptoms such as nausea, vomiting, and diarrhea. Overall, the frequencies of such events were roughly similar among people receiving AQ-13 and those receiving CQ, but due to the small numbers of participants in the trial, it is not possible to say whether any observed differences in frequency of side effects between the two groups are meaningful or not. The data collected in this trial also showed that both AQ-13 and CQ were absorbed into the bloodstream in a similar way, but AQ-13 was absorbed more slowly than CQ. On ECG testing, both compounds increased the QT interval (part of the heart's electrical cycle, and used as a measure of heart function), particularly at high dosage levels, and volunteers given CQ experienced a greater increase in QT interval than those receiving AQ-13. No volunteers experienced any symptoms related to heart function. The researchers concluded that on the basis of these data, AQ-13 could proceed to further trials to evaluate the drug's efficacy in treating clinical malaria. Strengths and limitations: The trial was appropriately designed as a randomized controlled Phase I study, allowing the researchers to assess safety and physiological outcomes after giving AQ-13 as compared to an existing and widely used drug, CQ. A key limitation inherent to such studies is the small number of participants studied. This means that the study cannot prove that AQ-13 is safe, or even as safe as CQ, but rather simply that the findings do not raise immediate safety concerns. Contribution to the evidence: Data from animal experiments suggest that AQ-13 could potentially be a safe and effective antimalarial compound. The results reported here provide crucial safety data from the first study known to this research group that evaluates the effects of AQ-13 in humans.

Background: We conducted a trial to compare treatment with zidovudine or didanosine in patients with advanced human immunodeficiency virus type 1 (HIV-1) infection who had received little or no previous therapy with zidovudine. Methods: Six hundred seventeen patients with acquired immunodeficiency syndrome (AIDS), advanced AIDS-related complex (CD4 cell count, ≤0.30× 10 9 /L [300/μL]), or asymptomatic HIV (CD4 cell count, ≤0.20× 10 9 /L) received zidovudine, 500 mg/d of didanosine, or 750 mg/d of didanosine in a randomized, double-blind allocation, with cross-over to alternative medication after development of an end point or serious toxic effect. To be eligible, patients must have received either no or up to 16 weeks of zidovudine therapy before entry into the study. Primary end points were development of a new AIDS-defining event or death. Secondary clinical end points were new or recurrent AIDS-defining events, or death, and survival. Results: In the study as a whole, there were no differences in the relative risks (RRs) of the development of end points between treatment groups. However, there was a strong interaction between the relative efficacies of zidovudine and didanosine and previous experience with zidovudine. Among 380 patients with no previous zidovudine therapy, zidovudine was more effective than 750 mg/d of didanosine (RR, 1.43; 90% confidence interval [CI], 1.02 to 2.00), with a similar trend for zidovudine compared with 500 mg/d of didanosine (RR, 1.21; 90% CI, 0.86 to 1.71). However, among 118 patients with more than 8 weeks but no more than 16 weeks of previous zidovudine therapy, 500 mg/d of didanosine was more effective than zidovudine (RR, 0.48; 90% CI, 0.27 to 0.86); there was a similar trend for increased effectiveness of 750 mg/d of didanosine compared with zidovudine (RR, 0.61; 90% CI, 0.36 to 1.03). Among 119 patients who had some but no more than 8 weeks of previous zidovudine therapy, there were no significant differences among the treatment arms. Similar findings were noted in the analysis of the two secondary clinical end points. No significant differences were found in efficacy between the groups receiving 500 and 750 mg/d of didanosine. The major toxic effect associated with zidovudine was hematopoietic (granulocytopenia) and that associated with didanosine was pancreatitis (dosage, 750 mg/d). Conclusions: In patients with advanced HIV disease, zidovudine appears to be more effective than didanosine as initial therapy; however, some patients with advanced HIV disease may benefit from a change to didanosine therapy after as little as 8 to 16 weeks of therapy with zidovudine. (Arch Intern Med. 1995;155:961-974)