Design of an observational multi-country cohort study to assess immunogenicity of multiple vaccine platforms (InVITE).

In response to the COVID-19 pandemic, COVID-19 vaccines have been developed, and the World Health Oraganization (WHO) has granted emergency use listing to multiple vaccines. Studies of vaccine immunogenicity data from implementing COVID-19 vaccines by national immunization programs in single studies spanning multiple countries and continents are limited but critically needed to answer public health questions on vaccines, such as comparing immune responses to different vaccines and among different populations.

PREVAIL IV: A Randomized, Double-Blind, 2-Phase, Phase 2 Trial of Remdesivir vs Placebo for Reduction of Ebola Virus RNA in the Semen of Male Survivors.

BACKGROUND: Ebola virus RNA persists in the semen of male Ebola survivors for months to years after the acute infection, and male-to-female sexual transmission of the virus is well documented. We investigated whether remdesivir can safely reduce persistence of seminal Ebola virus RNA. METHODS: We recruited men with persistent seminal Ebola RNA in Liberia and Guinea. Participants were randomized 1:1 to receive intravenous remdesivir (GS-5734; Gilead Sciences) or matching placebo administered once daily by intravenous infusion over 1 hour on 5 consecutive days. Stratification was by country and number of positive (1 or 2) preenrollment semen tests. We evaluated the difference in mean assay negativity rate (ANR), that is, the proportion of negative tests for each participant in each group in the treatment (days 1-28) and follow-up (months 2-6) phases on an intention-to-treat basis. RESULTS: We enrolled 38 men from July 2016 through June 2018. The mean treatment phase ANRs were 85% (standard deviation [SD] = 24%) and 76% (SD = 30%) in the remdesivir and placebo arms, respectively (P = .270). The mean follow-up phase ANRs were 96% (SD = 10%) and 81% (SD = 29%) in the remdesivir and placebo arms, respectively (P = .041). The 5-day remdesivir regimen was well tolerated with no safety concerns. CONCLUSIONS: In this small trial, remdesivir 100 mg/day for 5 days safely reduced the presence of Ebola virus RNA in the semen of Ebola survivors 2 to 6 months after administration. A larger follow-up study is necessary to confirm results. Clinical Trials Registration . NCT02818582.

A Randomized, Controlled Trial of Ebola Virus Disease Therapeutics.

BACKGROUND: Although several experimental therapeutics for Ebola virus disease (EVD) have been developed, the safety and efficacy of the most promising therapies need to be assessed in the context of a randomized, controlled trial. METHODS: We conducted a trial of four investigational therapies for EVD in the Democratic Republic of Congo, where an outbreak began in August 2018. Patients of any age who had a positive result for Ebola virus RNA on reverse-transcriptase-polymerase-chain-reaction assay were enrolled. All patients received standard care and were randomly assigned in a 1:1:1:1 ratio to intravenous administration of the triple monoclonal antibody ZMapp (the control group), the antiviral agent remdesivir, the single monoclonal antibody MAb114, or the triple monoclonal antibody REGN-EB3. The REGN-EB3 group was added in a later version of the protocol, so data from these patients were compared with those of patients in the ZMapp group who were enrolled at or after the time the REGN-EB3 group was added (the ZMapp subgroup). The primary end point was death at 28 days. RESULTS: A total of 681 patients were enrolled from November 20, 2018, to August 9, 2019, at which time the data and safety monitoring board recommended that patients be assigned only to the MAb114 and REGN-EB3 groups for the remainder of the trial; the recommendation was based on the results of an interim analysis that showed superiority of these groups to ZMapp and remdesivir with respect to mortality. At 28 days, death had occurred in 61 of 174 patients (35.1%) in the MAb114 group, as compared with 84 of 169 (49.7%) in the ZMapp group (P = 0.007), and in 52 of 155 (33.5%) in the REGN-EB3 group, as compared with 79 of 154 (51.3%) in the ZMapp subgroup (P = 0.002). A shorter duration of symptoms before admission and lower baseline values for viral load and for serum creatinine and aminotransferase levels each correlated with improved survival. Four serious adverse events were judged to be potentially related to the trial drugs. CONCLUSIONS: Both MAb114 and REGN-EB3 were superior to ZMapp in reducing mortality from EVD. Scientifically and ethically sound clinical research can be conducted during disease outbreaks and can help inform the outbreak response. (Funded by the National Institute of Allergy and Infectious Diseases and others; PALM ClinicalTrials.gov number, NCT03719586.).

Effect of the Ebola-virus-disease epidemic on malaria case management in Guinea, 2014: a cross-sectional survey of health facilities.

BACKGROUND: The ongoing west Africa Ebola-virus-disease epidemic has disrupted the entire health-care system in affected countries. Because of the overlap of symptoms of Ebola virus disease and malaria, the care delivery of malaria is particularly sensitive to the indirect effects of the current Ebola-virus-disease epidemic. We therefore characterise malaria case management in the context of the Ebola-virus-disease epidemic and document the effect of the Ebola-virus-disease epidemic on malaria case management. METHODS: We did a cross-sectional survey of public health facilities in Guinea in December, 2014. We selected the four prefectures most affected by Ebola virus disease and selected four randomly from prefectures without any reported cases of the disease. 60 health facilities were sampled in Ebola-affected and 60 in Ebola-unaffected prefectures. Study teams abstracted malaria case management indicators from registers for January to November for 2013 and 2014 and interviewed health-care workers. Nationwide weekly surveillance data for suspect malaria cases reported between 2011 and 2014 were analysed independently. Data for malaria indicators in 2014 were compared with previous years. FINDINGS: We noted substantial reductions in all-cause outpatient visits (by 23 103 [11%] of 214 899), cases of fever (by 20249 [15%] of 131 330), and patients treated with oral (by 22 655 [24%] of 94 785) and injectable (by 5219 [30%] of 17 684) antimalarial drugs in surveyed health facilities. In Ebola-affected prefectures, 73 of 98 interviewed community health workers were operational (74%, 95% CI 65-83) and 35 of 73 were actively treating malaria cases (48%, 36-60) compared with 106 of 112 (95%, 89-98) and 102 of 106 (96%, 91-99), respectively, in Ebola-unaffected prefectures. Nationwide, the Ebola-virus-disease epidemic was estimated to have resulted in 74 000 (71 000-77 000) fewer malaria cases seen at health facilities in 2014. INTERPRETATION: The reduction in the delivery of malaria care because of the Ebola-virus-disease epidemic threatens malaria control in Guinea. Untreated and inappropriately treated malaria cases lead to excess malaria mortality and more fever cases in the community, impeding the Ebola-virus-disease response. FUNDING: Global Fund to Fight AIDS, Tuberculosis and Malaria, and President's Malaria Initiative.

Lipodystrophy in a cohort of human immunodeficiency virus-infected Asian patients: prevalence, associated factors, and psychological impact.

We investigated the prevalence of and factors associated with lipodystrophy in a cohort of human immunodeficiency virus (HIV)-infected patients in Singapore. A standardized questionnaire was administered to 410 consecutive patients (mainly Chinese men), and blood samples were obtained for metabolic measurements for fasting patients. Peripheral fat loss was reported by 46% of subjects, central fat gain was reported by 32%, and 8% of patients overall had a mixed clinical presentation. Levels of total cholesterol, triglycerides, glucose, and lactate were elevated in 19%, 38%, 12%, and 16% of patients, respectively. A mixture of drug-related and non-drug-related factors was associated with these changes. The body-shape changes affected the mood of 36% of patients and the work and/or social activity of 23% of patients, but only <1% of affected subjects reported a desire to stop receipt of antiretroviral therapy because of these changes. We conclude that the prevalence of and factors associated with body-shape changes and metabolic abnormalities in HIV-infected Asian patients are similar to those reported for Western cohorts, but the changes did not appear to have a major psychosocial impact on this patient population.

Validation of the Medical Outcomes Study HIV Health Survey as a measure of quality of life in HIV-infected patients in Singapore.

Measurement of quality of life is crucial to assess the full impact of antiretroviral therapy on patient morbidity. No quality of life instruments have been validated in an Asian HIV-infected patient population, but it is important to do so given the increasing involvement of the region in clinical trials. We set out to validate the Medical Outcomes Study HIV Health Survey (MOS-HIV) in HIV infected patients in Singapore. Clinically stable outpatients were asked to complete the 30-item MOS-HIV (English or Chinese translation). Patients were also asked about the frequency of selected disease symptoms, and clinical and demographic data were recorded from the case sheet. 163 patients (90% Chinese, 96% male, mean age 38 years, mean CD4 count 159 cells/mm(3)) participated in the study and completed the questionnaire to a satisfactory standard. The questionnaire showed good internal consistency (Cronbach's alpha >0.7 in all cases). There were significant differences in quality of life scores between Centers for Disease Control disease stages, and significant correlations with CD4 count and symptom score, confirming the discriminant validity of the MOS-HIV. Factor analysis revealed two components corresponding to physical and mental health which were similar to those of studies in Western countries except that pain was more closely related to mental than physical health. Linear regression analysis identified symptom burden as the major predictor of physical and mental health. We concluded that the MOS-HIV is a valid measure of quality of life in this HIV patient population in Singapore, and is therefore likely to be useful in future clinical trials in the region. In the era of chronic HIV disease, close attention to symptoms (disease or drug-related) is warranted due to their major adverse influence on mental and physical aspects of quality of life.

Hydroxychloroquine, hydroxycarbamide, and didanosine as economic treatment for HIV-1.

Most people who have HIV-1 and live in less-developed countries cannot afford standard combination antiretroviral therapy, and more economical approaches to treatment are therefore needed. We treated 22 patients who were infected with HIV-1 (viral load < 100000 copies/mL and CD4 count >150 cells/microL) with hydroxychloroquine (200 mg), hydroxycarbamide (hydroxyurea) (500 mg), and didanosine (125-200 mg), taken twice daily. Treatment was well tolerated, with few serious adverse events. Viral load showed a sustained decrease of 1 3 log, and CD4 count was maintained (percentage increase; 2 9%) over 48 weeks in the 16 evaluable patients. This new combination of drugs could be suitable for countries that have restricted resources, but should first be further investigated.