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Papers by Kelly Dooley

Background Adherence to antiretroviral treatment (ART) remains the cornerstone of optimal HIV out... more Background Adherence to antiretroviral treatment (ART) remains the cornerstone of optimal HIV outcomes, including viral suppression (VS), immune recovery, and decreased transmission risk. For many people with HIV (PWH), particularly those with early-acquired HIV, structural, behavioral, and cognitive barriers to adherence and competing priorities related to life events may be difficult to overcome, resulting in nonadherence. Long-acting injectable antiretroviral therapies (LAI-ART) may be a useful strategy to overcome some of these barriers. However, to date, the approved LAI-ART strategies (e.g., cabotegravir and rilpivirine (CAB/RPV)) have targeted those who have already attained viral suppression, precluding their use in the 40% of adolescents and young adults (AYA) that VS has eluded. Case presentation Ms. X is a 30-year-old female with perinatally-acquired HIV and barriers to adherence. Despite many interventions, she remained persistently viremic, with resultant immune suppres...

HIV and Tuberculosis

Having HIV and TB worsens the impact of both. The treatment of HIV-TB coinfection is beset by cha... more Having HIV and TB worsens the impact of both. The treatment of HIV-TB coinfection is beset by challenges, including drug-drug-interactions, coincident toxicities, and the occurrence of the immune reconstitution inflammatory syndrome. These challenges can be overcome with careful attention to evidence-guided practice and clinical pharmacological aspects of co-treatment. There is a clear mortality benefit to treating both infections; the relative timing of initiation of both treatments will be discussed. This chapter will address pharmacologic considerations in the co-treatment of HIV-related latent or active TB of all sensitivity patterns (drug sensitive and multidrug resistant (MDR). The discussion will identify existing gaps in the evidence and include current recommendations for HIV-TB treatment in special populations, including pregnant and lactating women and children.

American Journal of Obstetrics and Gynecology, 2018

OBJECTIVE: While congenital Zika infection may lead to significant fetal neurologic abnormalities... more OBJECTIVE: While congenital Zika infection may lead to significant fetal neurologic abnormalities, little is known about the postnatal consequences of Zika exposure to apparently asymptomatic fetuses. Our aim was to examine the postnatal outcomes of infants exposed to maternal Zika infection during pregnancy.

Clinical Infectious Diseases, 2022

Background Pediatric tuberculous meningitis (TBM) commonly causes death or disability. In adults,... more Background Pediatric tuberculous meningitis (TBM) commonly causes death or disability. In adults, high-dose rifampicin may reduce mortality. The role of fluoroquinolones remains unclear. There have been no antimicrobial treatment trials for pediatric TBM. Methods TBM-KIDS was a phase 2 open-label randomized trial among children with TBM in India and Malawi. Participants received isoniazid and pyrazinamide plus: (i) high-dose rifampicin (30 mg/kg) and ethambutol (R30HZE, arm 1); (ii) high-dose rifampicin and levofloxacin (R30HZL, arm 2); or (iii) standard-dose rifampicin and ethambutol (R15HZE, arm 3) for 8 weeks, followed by 10 months of standard treatment. Functional and neurocognitive outcomes were measured longitudinally using Modified Rankin Scale (MRS) and Mullen Scales of Early Learning (MSEL). Results Of 2487 children prescreened, 79 were screened and 37 enrolled. Median age was 72 months; 49%, 43%, and 8% had stage I, II, and III disease, respectively. Grade 3 or higher adve...

Additional file 1. Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 20... more Additional file 1. Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2013 Checklist: recommended items to address in a clinical trial protocol and related documents.

In this manuscript, the authors address reasons for treatment default among tuberculosis patients... more In this manuscript, the authors address reasons for treatment default among tuberculosis patients in Nairobi, Kenya. As treatment default is a contributor to continued TB transmission and negatively impacts TB control efforts, it is worthwhile to look at region-specific risk factors for default to be able to address them appropriately. In this study, the authors conducted a chart review of defaulters (cases) and completers (controls) of treatment (n=1978) and also conducted an interview with some of the cases and controls to enhance their understanding of risk factors for default (n=274). The article could use some restructuring so the reader can follow which results are from the 1978 and which are from the subset of 274 that underwent interviews. Here are some suggestions:

American Journal of Respiratory and Critical Care Medicine, 2020

GenoType MTBDRplus. rpoB mutations outside the 81-bp rifampicin resistance determining region are... more GenoType MTBDRplus. rpoB mutations outside the 81-bp rifampicin resistance determining region are not covered by these commercial assays. Another, not unusual cause of missed rifampicin resistance is heteroresistance resulting from a mixed population of both susceptible and resistant TB bacilli (3). If patients with resistance to isoniazid and missed rifampicin resistance were treated with the World Health Organization levofloxacin-strengthened first-line regimen, resistance to fluoroquinolone would emerge rapidly. Because the efficacy of second-line TB treatment relies on a fluoroquinolone as a core drug, treatment options would be dramatically reduced. Finally, as shown by Dooley and colleagues, as well as by previous studies (4), high-dose isoniazid may overcome mutations that confer resistance to isoniazid and render normal doses ineffective (4). Excluding isoniazid, which has the highest early bactericidal activity of all first-line drugs, increases the risk of acquiring rifampicin resistance, as mutant bacilli may survive the early phase of TB treatment. Moreover, Boeree and colleagues showed that high-dose rifampicin (35 mg/kg) was safe and reduced time to culture conversion when compared with normal-dose rifampicin (10 mg/kg) (5). Although isoniazid is used for its bactericidal activity against actively replicating bacilli, rifampicin has both a bactericidal effect against rapidly replicating bacilli and a sterilizing effect against dormant bacilli. Both types of action are needed to ensure a relapse-free cure (6). Globally, about 11.6% of patients with recurrent TB have rifampicin-susceptible/isoniazid-resistant TB. Studies should compare high-dose first-line regimens with normal-dose regimens in terms of safety, treatment success, and acquired rifampicin resistance in patients with rifampicin-susceptible/isoniazid-resistant TB. If it is shown to be safe and efficacious, high-dose first-line treatment could be used in all patients with recurrent rifampicin-susceptible TB, regardless of initial isoniazid resistance, thus avoiding delays in retreatment. Such an improved use of first-line anti-TB drugs would have major advantages. No additional susceptibility testing beyond rifampicin testing would be required and there would be no delay between a diagnosis of rifampicin-susceptible recurrent TB and initiation of treatment. If first-line treatment could rely on first-line drugs only, second-line treatment options would be maximally safeguarded. n

The Lancet Infectious Diseases, 2009

The link between diabetes mellitus and tuberculosis has been recognised for centuries. In recent ... more The link between diabetes mellitus and tuberculosis has been recognised for centuries. In recent decades, tuberculosis incidence has declined in high-income countries, but incidence remains high in countries that have high rates of infection with HIV, high prevalence of malnutrition and crowded living conditions, or poor tuberculosis control infrastructure. At the same time, diabetes mellitus prevalence is soaring globally, fuelled by obesity. There is growing evidence that diabetes mellitus is an important risk factor for tuberculosis and might affect disease presentation and treatment response. Furthermore, tuberculosis might induce glucose intolerance and worsen glycaemic control in people with diabetes. We review the epidemiology of the tuberculosis and diabetes epidemics, and provide a synopsis of the evidence for the role of diabetes mellitus in susceptibility to, clinical presentation of, and response to treatment for tuberculosis. In addition, we review potential mechanisms by which diabetes mellitus can cause tuberculosis, the effects of tuberculosis on diabetic control, and pharmacokinetic issues related to the co-management of diabetes and tuberculosis.

The Journal of Infectious Diseases, 2008

Clinical Infectious Diseases, 2003

Fluoroquinolones are widely used for the treatment of bacterial infections and are also second-li... more Fluoroquinolones are widely used for the treatment of bacterial infections and are also second-line therapy for tuberculosis. However, fluoroquinolone resistance in patients with newly diagnosed cases of tuberculosis is not routinely assessed. We performed in vitro susceptibility testing of Mycobacterium tuberculosis to fluoroquinolones for all culture-confirmed tuberculosis cases in adults that were diagnosed at Johns Hopkins Hospital (Baltimore) between January 1998 and March 2002. Fifty-five patients were included in the study; 19 received fluoroquinolone monotherapy before the initiation of antituberculosis therapy. Two of 55 M. tuberculosis isolates (4%; 95% CI, 1%-13%) had decreased susceptibility to fluoroquinolones, including 2 of 19 of those from patients who had received fluoroquinolones (11%; 95% CI, 1%-33%) and 0 of 36 isolates from those who had not (95% CI, 0%-10%). The 2 fluoroquinolone-resistant M. tuberculosis strains were both from patients with acquired immunodeficiency syndrome and a CD4 + lymphocyte count of !50 cells/mm 3. The incidence of M. tuberculosis fluoroquinolone resistance in this small sample of patients with newly diagnosed tuberculosis was high, particularly among patients with prior fluoroquinolone exposure. Fluoroquinolones are broad-spectrum antimicrobial agents that have been used with increasing frequency over the past decade. As of August 2002, fluoroquinolones accounted for 11% of all antibiotic sales in the United States (IMS Health, personal communication). The particular advantages of fluoroquinolones are their high bioavailability, convenient dosing intervals, and efficacy against a wide array of bacterial infections, including community-acquired pneumonia [1, 2]. Fluor

BMC Public Health, 2011

Background: Patients with tuberculosis require retreatment if they fail or default from initial t... more Background: Patients with tuberculosis require retreatment if they fail or default from initial treatment or if they relapse following initial treatment success. Outcomes among patients receiving a standard World Health Organization Category II retreatment regimen are suboptimal, resulting in increased risk of morbidity, drug resistance, and transmission. In this study, we evaluated the risk factors for initial treatment failure, default, or early relapse leading to the need for tuberculosis retreatment in Morocco. We also assessed retreatment outcomes and drug susceptibility testing use for retreatment patients in urban centers in Morocco, where tuberculosis incidence is stubbornly high. Methods: Patients with smear-or culture-positive pulmonary tuberculosis presenting for retreatment were identified using clinic registries in nine urban public clinics in Morocco. Demographic and outcomes data were collected from clinical charts and reference laboratories. To identify factors that had put these individuals at risk for failure, default, or early relapse in the first place, initial treatment records were also abstracted (if retreatment began within two years of initial treatment), and patient characteristics were compared with controls who successfully completed initial treatment without early relapse. Results: 291 patients presenting for retreatment were included; 93% received a standard Category II regimen. Retreatment was successful in 74% of relapse patients, 48% of failure patients, and 41% of default patients. 25% of retreatment patients defaulted, higher than previous estimates. Retreatment failure was most common among patients who had failed initial treatment (24%), and default from retreatment was most frequent among patients with initial treatment default (57%). Drug susceptibility testing was performed in only 10% of retreatment patients. Independent risk factors for failure, default, or early relapse after initial treatment included male gender (aOR = 2.29, 95% CI 1.10-4.77), positive sputum smear after 3 months of treatment (OR 7.14, 95% CI 4.04-13.2), and hospitalization (OR 2.09, 95% CI 1.01-4.34). Higher weight at treatment initiation was protective. Male sex, substance use, missed doses, and hospitalization appeared to be risk factors for default, but subgroup analyses were limited by small numbers.

BMC Infectious Diseases, 2009

Background Immune responses to Mycobacterium tuberculosis antigens could serve as surrogate marke... more Background Immune responses to Mycobacterium tuberculosis antigens could serve as surrogate markers of treatment response. Methods Using the T-SPOT.TB assay and frozen peripheral blood mononuclear cells, we enumerated ESAT-6- and CFP-10-specific IFN-γ-producing T cells over time in pulmonary TB patients receiving directly observed treatment. T cell responses (measured as "spot forming cells" or "SFCs") were assessed prior to treatment and at 16 and 24 weeks of treatment. Results 58 patients were evaluated, of whom 57 were HIV seronegative. Mean (SD) ESAT-6, CFP-10, and summed RD1 specific SFCs declined from 42.7 (72.7), 41.2 (66.4), and 83.8 (105.7) at baseline to 23.3 (39.4, p = 0.01), 23.2 (29.4, p = 0.18), and 46.5 (59.5, p = 0.02) at completion of 24 weeks of treatment, respectively. Only 10% of individuals with a baseline reactive test reverted to negative at treatment week 24. For the group that was culture positive at completion of 8 weeks of treatment com...

Antimicrobial Agents and Chemotherapy, 2008

Moxifloxacin- and rifapentine-based regimens are under investigation for the treatment of tubercu... more Moxifloxacin- and rifapentine-based regimens are under investigation for the treatment of tuberculosis. However, rifapentine may induce enzymes that metabolize moxifloxacin, resulting in decreased moxifloxacin concentrations. In this phase I, two-period, sequential-design study, 13 subjects received 400 mg moxifloxacin daily for 4 days followed by daily moxifloxacin coadministered with 900 mg rifapentine thrice weekly. Pharmacokinetic analyses were performed after the 4th and 19th doses of moxifloxacin and after the 1st and 7th doses of rifapentine. For moxifloxacin, the mean area under the concentration-time curve from 0 to 24 h (AUC 0-24 ) decreased by 17.2% ( P = 0.0006) when the drug was coadministered with rifapentine, and the mean half-life ( t 1/2 ) decreased from 11.1 to 8.9 h ( P = 0.0033). For rifapentine, the mean AUC 0-48 after seven thrice-weekly doses decreased by 20.3% ( P = 0.0035) compared to the AUC 0-48 after the first dose, and the mean t 1/2 decreased from 18.5 ...

Antimicrobial Agents and Chemotherapy, 2019

Central nervous system tuberculosis (TB) is devastating and affects vulnerable populations. Multi... more Central nervous system tuberculosis (TB) is devastating and affects vulnerable populations. Multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculous meningitis (TBM) specifically are nearly uniformly fatal, with little information being available to guide the treatment of these patients. Delamanid (DLM), a nitro-dihydro-imidazooxazole, is a new, well-tolerated anti-TB drug with a low MIC (1 to 12 ng/ml) against Mycobacterium tuberculosis .

Clinical Infectious Diseases, 2002

This is an Open Access article distributed under the terms of the Creative Commons Attribution Li... more This is an Open Access article distributed under the terms of the Creative Commons Attribution License

Tuberculosis (TB) is the leading cause of death among people living with HIV and/or AIDS (PLWHA) ... more Tuberculosis (TB) is the leading cause of death among people living with HIV and/or AIDS (PLWHA) globally [1]. In 2014, of 9.6 million people with incident cases of TB worldwide, 1.2 million (12 %) were HIV infected. And of the 1.5 million TB-related deaths, 400,000 (33 %) had HIV coinfection [2]. Clearly, PLWHA bear a disproportionate burden of TB disease. Unlike other opportunistic infections in which the risk of disease is generally not elevated among those individuals with HIV infection with high CD4 counts, TB incidence increases substantially even within the first year of HIV infection, when CD4 counts are generally high [3]. Risk rises further with progressive immunodeficiency [4]. The annual risk of development of TB disease among persons with latent TB infection (LTBI) and untreated HIV infection is approximately 10 % [5].

Received 8 November 2018; editorial decision 25 January 2019; accepted 5 April 2019; published on... more Received 8 November 2018; editorial decision 25 January 2019; accepted 5 April 2019; published online March 28, 2019. Correspondence: K. E. Dooley, Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Osler 527, Baltimore, MD, USA (kdooley1@jhmi.edu). Clinical Infectious Diseases 2019;XX(XX):1–8 © The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. DOI: 10.1093/cid/ciz256 Dolutegravir-based Antiretroviral Therapy for Patients Coinfected With Tuberculosis and Human Immunodeficiency Virus: A Multicenter, Noncomparative, Open-label, Randomized Trial

Annual Review of Medicine

Tuberculosis (TB) is one of the oldest infections afflicting humans yet remains the number one in... more Tuberculosis (TB) is one of the oldest infections afflicting humans yet remains the number one infectious disease killer worldwide. Despite decades of experience treating this disease, TB regimens require months of multidrug therapy, even for latent infections. There have been important recent advances in treatment options across the spectrum of TB, from latent infection to extensively drug-resistant (XDR) TB disease. In addition, new, potent drugs are emerging out of the development pipeline and are being tested in novel regimens in multiple currently enrolling trials. Shorter, safer regimens for many forms of TB are now available or are in our near-term vision. We review recent advances in TB therapeutics and provide an overview of the upcoming clinical trials landscape that will help define the future of worldwide TB treatment.