Elizabeth S. Higgs

Paromomycin: No More Effective than Placebo for Treatment of Cryptosporidiosis in Patients with Advanced Human Immunodeficiency Virus Infection

To evaluate the efficacy of paromomycin for the treatment of symptomatic cryptosporidial enteritis in human immunodeficiency virus-infected adults, we conducted a prospective, randomized, double-blind, placebo-controlled trial before the widespread introduction of highly active antiretroviral therapy (HAART). Seven units under the auspices of the AIDS Clinical Trials Group enrolled 35 adults with CD4 cell counts of < or = 150/mm(3). Initially, 17 patients received paromomycin (500 mg 4 times daily) and 18 received matching placebo for 21 days. Then all patients received paromomycin (500 mg q.i.d.) for an additional 21 days. Clinical definitions of response were measured by an average number of bowel movements per day in association with concurrent need for antidiarrheal agents that was lower than that before study entry. There was no treatment response during the placebo-controlled phase of the study according to protocol-defined criteria (P=.88). Three paromomycin recipients (17.6%) versus 2 placebo recipients (14.3%) responded completely. Rates of combined partial and complete responses in the paromomycin arm (8 out of 17, 47.1%) and the placebo arm (5 out of 14, 35.7%) of the study were also similar (P=.72). The clinical course of cryptosporidiosis was quite variable. Paromomycin was not shown to be more effective than placebo for the treatment of symptomatic cryptosporidial enteritis. However, inadequate statistical power prevents definitive rejection of the usefulness of paromomycin as therapy for this infection.

Neurocysticercosis: Neglected but Not Forgotten

Neurocysticercosis (NCC) is an infection of the central nervous system caused by the larval form of the tapeworm Taenia solium. Infections occur following the accidental ingestion of tapeworm ova found in human feces. NCC is a major cause of epilepsy and disability in many of the worlds poorer countries where families raise free-roaming pigs that are able to ingest human feces. It is frequently diagnosed in immigrant populations in the United States and Canada, reflecting the high endemicity of the infection in their countries of origin [1]. Although parenchymal cysts are the most common location in the brain and cause seizures, cysts may also be present in the ventricles, meninges, spinal cord, eye, and subarachnoid spaces. Involvement in these other sites may result in aberrant growth (racemose cysts) and complicated disease that is difficult to treat and may cause increased morbidity and mortality.

End Points for Testing Influenza Antiviral Treatments for Patients at High Risk of Severe and Life-Threatening Disease

Influenza infection results in substantial morbidity and mortality in hospitalized patients, including those who are immunocompromised or pregnant. Antiviral therapy likely provides considerable benefit to these patients, but few studies have been successfully conducted in these high-risk populations, and no drugs are specifically licensed for treating these subgroups. One of the key challenges facing novel antiviral drug development for influenza is determining the appropriate efficacy end points that would enable rapid regulatory approval for drug use in seriously ill patients, for whom risk-benefit assessments differ from those with uncomplicated illness. All available antiviral drugs currently affect viral replication, and respiratory tract viral titers correlate with both symptoms and measures of host inflammatory responses, including cytokine and chemokine expression that are likely responsible for many of the clinical symptoms. Consequently, we outline the evidence to support the use of primary virological end points in studies of antiviral agents involving patients who are hospitalized with severe influenza or those who are at high risk of severe and life-threatening disease.

Phase 2 Placebo-Controlled Trial of Two Vaccines to Prevent Ebola in Liberia

BACKGROUND The safety and efficacy of vaccines to prevent Ebola virus disease (EVD) were unknown when the incidence of EVD was peaking in Liberia. METHODS We initiated a randomized, placebo‐controlled, phase 3 trial of the chimpanzee adenovirus 3 vaccine (ChAd3‐EBO‐Z) and the recombinant vesicular stomatitis virus vaccine (rVSV&Dgr;G‐ZEBOV‐GP) in Liberia. A phase 2 subtrial was embedded to evaluate safety and immunogenicity. Because the incidence of EVD declined in Liberia, the phase 2 component was expanded and the phase 3 component was eliminated. RESULTS A total of 1500 adults underwent randomization and were followed for 12 months. The median age of the participants was 30 years; 36.6% of the participants were women. During the week after the administration of vaccine or placebo, adverse events occurred significantly more often with the active vaccines than with placebo; these events included injection‐site reactions (in 28.5% of the patients in the ChAd3‐EBO‐Z group and 30.9% of those in the rVSV&Dgr;G‐ZEBOV‐GP group, as compared with 6.8% of those in the placebo group), headache (in 25.1% and 31.9%, vs. 16.9%), muscle pain (in 22.3% and 26.9%, vs. 13.3%), feverishness (in 23.9% and 30.5%, vs. 9.0%), and fatigue (in 14.0% and 15.4%, vs. 8.8%) (P<0.001 for all comparisons); these differences were not seen at 1 month. Serious adverse events within 12 months after injection were seen in 40 participants (8.0%) in the ChAd3‐EBO‐Z group, in 47 (9.4%) in the rVSV&Dgr;G‐ZEBOV‐GP group, and in 59 (11.8%) in the placebo group. By 1 month, an antibody response developed in 70.8% of the participants in the ChAd3‐EBO‐Z group and in 83.7% of those in the rVSV&Dgr;G‐ZEBOV‐GP group, as compared with 2.8% of those in the placebo group (P<0.001 for both comparisons). At 12 months, antibody responses in participants in the ChAd3‐EBO‐Z group (63.5%) and in those in the rVSV&Dgr;G‐ZEBOV‐GP group (79.5%) remained significantly greater than in those in the placebo group (6.8%, P<0.001 for both comparisons). CONCLUSIONS A randomized, placebo‐controlled phase 2 trial of two vaccines that was rapidly initiated and completed in Liberia showed the capability of conducting rigorous research during an outbreak. By 1 month after vaccination, the vaccines had elicited immune responses that were largely maintained through 12 months. (Funded by the National Institutes of Allergy and Infectious Diseases and the Liberian Ministry of Health; PREVAIL I ClinicalTrials.gov number, NCT02344407.)

The Southeast Asian Influenza Clinical Research Network: Development and challenges for a new multilateral research endeavor

The Southeast Asia Influenza Clinical Research Network (SEA ICRN) (www.seaclinicalresearch.org) is a recently developed multilateral, collaborative partnership that aims to advance scientific knowledge and management of human influenza through integrated clinical investigation. The partnership of hospitals and institutions in Indonesia, Thailand, United Kingdom, United States, and Viet Nam was established in late 2005 after agreement on the general principles and mission of the initiative and after securing initial financial support. The establishment of the SEA ICRN was both a response to the re-emergence of the highly pathogenic avian influenza A(H5N1) virus in Southeast Asia in late 2003 and an acknowledgment that clinical trials on emerging infectious diseases require prepared and coordinated research capacity. The objectives of the Network also include building sustainable research capacity in the region, compliance with international standards, and prompt dissemination of information and sharing of samples. The scope of research includes diagnosis, pathogenesis, treatment and prevention of human influenza due to seasonal or novel viruses. The Network has overcome numerous logistical and scientific challenges but has now successfully initiated several clinical trials. The establishment of a clinical research network is a vital part of preparedness and an important element during an initial response phase to a pandemic.

Micronutrients and Infectious Diseases: Thoughts on Integration of Mechanistic Approaches into Micronutrient Research

Results of field and laboratory studies provide convincing evidence that micronutrient deficiencies contribute to the mortality and morbidity of infectious diseases. Despite encouraging results in large trials, understanding the mechanisms by which micronutrients contribute to the outcome of the encounter between an individual and an infectious agent requires additional hypothesis-driven research. Presumably, such understanding should lead to translational studies with targeted nutritional therapy. Although these mechanistic studies are varied and complex, they must be done systematically and should include examination of the mechanisms by which micronutrients affect host-pathogen interactions, development of appropriate animal models and reliable methods for the assessment of micronutrient levels, and translation of the results of basic research findings into clinical studies. Moving the frontiers of micronutrient research from the laboratory to the field will be challenging. However, sound scientific research should lead toward better human health.

Ring vaccination with rVSV-ZEBOV under expanded access in response to an outbreak of Ebola virus disease in Guinea, 2016: an operational and vaccine safety report.

Summary Background In March, 2016, a flare-up of Ebola virus disease was reported in Guinea, and in response ring vaccination with the unlicensed rVSV-ZEBOV vaccine was introduced under expanded access, the first time that an Ebola vaccine has been used in an outbreak setting outside a clinical trial. Here we describe the safety of rVSV-ZEBOV candidate vaccine and operational feasibility of ring vaccination as a reactive strategy in a resource-limited rural setting. Methods Approval for expanded access and compassionate use was rapidly sought and obtained from relevant authorities. Vaccination teams and frozen vaccine were flown to the outbreak settings. Rings of contacts and contacts of contacts were defined and eligible individuals, who had given informed consent, were vaccinated and followed up for 21 days under good clinical practice conditions. Findings Between March 17 and April 21, 2016, 1510 individuals were vaccinated in four rings in Guinea, including 303 individuals aged between 6 years and 17 years and 307 front-line workers. It took 10 days to vaccinate the first participant following the confirmation of the first case of Ebola virus disease. No secondary cases of Ebola virus disease occurred among the vaccinees. Adverse events following vaccination were reported in 47 (17%) 6–17 year olds (all mild) and 412 (36%) adults (individuals older than 18 years; 98% were mild). Children reported fewer arthralgia events than adults (one [<1%] of 303 children vs 81 [7%] of 1207 adults). No severe vaccine-related adverse events were reported. Interpretation The results show that a ring vaccination strategy can be rapidly and safely implemented at scale in response to Ebola virus disease outbreaks in rural settings. Funding WHO, Gavi, and the World Food Programme.

Use of Existing Diagnostic Reverse-Transcription Polymerase Chain Reaction Assays for Detection of Ebola Virus RNA in Semen

Sexual transmission of Ebola virus in Liberia has now been documented and associated with new clusters in regions previously declared Ebola free. Assays that have Emergency Use Authorization (EUA) and are routinely used to detect Ebola virus RNA in whole blood and plasma specimens at the Liberian Institute for Biomedical Research were tested for their suitability in detecting the presence of Ebola virus RNA in semen. Qiagen AVL extraction protocols, as well as the Ebola Zaire Target 1 and major groove binder quantitative reverse-transcription polymerase chain reaction assays, were demonstrably suitable for this purpose and should facilitate epidemiologic investigations, including those involving long-term survivors of Ebola.

Evidence acquisition and evaluation for a U.S. Government Evidence Summit on Protecting Children Outside Family Care.

Recognizing the need for evidence to inform policies, strategies, and programs to care for vulnerable children, the U.S. Government convened an Evidence Summit on Protecting Children Outside of Family Care on December 12-13, 2011, in Washington, DC, USA. This paper summarizes the background and methods for the acquisition and evaluation of the evidence used to achieve the goals of the Summit. A multistep process was undertaken to identify the appropriate evidence for review. It began by identifying crucial focal questions intended to inform low and middle income governments and the U.S. Government about effective systems for protecting children outside family care. This was followed by a systematic attempt to gather relevant peer reviewed and gray literature that would inform these focal questions. The search processes, methods used for screening and quality reviews are described. In addition, members of the Evidence Review Teams were invited to add relevant papers not identified in the initial literature review to complete the bibliographies. These teams were asked to comply with a specific evaluation framework for recommendations on practice and policy based on both expert opinion and the quality of the data. This was the first U.S. Government Evidence Summit originating in the U.S. Agency for International Development Global Health Bureau and valuable lessons were learned on the identification and assessment of evidence informing complex development challenges.

Pregnancy outcomes in Liberian women who conceived after recovery from Ebola virus disease

BACKGROUND: Postpartum haemorrhage complicates approximately 10% of all deliveries and contributes to at least a quarter of all maternal deaths worldwide. The competency-based Helping Mothers Survive Bleeding after Birth (HMS BAB) training was developed to support evidence-based management of postpartum haemorrhage. This one-day training includes low-cost MamaNatalie(R) birthing simulators and addresses both prevention and first-line treatment of haemorrhage. While evidence is accumulating that the training improves health providers knowledge skills and confidence evidence is missing as to whether this translates into improved practices and reduced maternal morbidity and mortality. This cluster-randomised trial aims to assess whether this training package - involving a one-day competency-based HMS BAB in-facility training provided by certified trainers followed by 8 weeks of in-service peer-based practice - has an effect on the occurrence of haemorrhage-related morbidity and mortality. METHODS/DESIGN: In Tanzania and Uganda we randomise 20 and 18 districts (clusters) respectively with half receiving the training intervention. We use unblinded matched-pair randomisation to balance district health system characteristics and the main outcome which is in-facility severe morbidity due to haemorrhage defined by the World Health Organizationation-promoted disease and management-based near-miss criteria. Data are collected continuously in the intervention and comparison districts throughout the 6-month baseline and the 9-month intervention phase which commences after the training intervention. Trained facility midwives or clinicians review severe maternal complications to identify near misses on a daily basis. They abstract the case information from case notes and enter it onto programmed tablets where it is uploaded. Intention-to-treat analysis will be used taking the matched design into consideration using paired t test statistics to compare the outcomes between the intervention and comparison districts. We also assess the impact pathway from the effects of the training on the health providers skills care and interventions and health system readiness. DISCUSSION: This trial aims to generate evidence on the effect and limitations of this well-designed training package supported by birthing simulations. While the lack of blinding of participants and data collectors provides an inevitable limitation of this trial the additional evaluation along the pathway of implementation will provide solid evidence on the effects of this HMS BAB training package. TRIAL REGISTRATION: Pan African Clinical Trials Registry PACTR201604001582128 . Registered on 12 April 2016.