Injecting drug use increases the risk of death in HIV patients on antiretroviral therapy in Vietnam.

The Human Immunodeficiency Virus (HIV) epidemic remains a major public health issue worldwide. In Vietnam, the HIV epidemic is essentially driven by people who inject drugs (PWID). This study aims to compare mortality and loss to follow-up (LTFU) between PWID and other patients. From June 2017 to April 2018, HIV-infected adults were enrolled in a prospective cohort from time of ART initiation in six provinces of North Vietnam. The end date was July 2020. Mortality and LTFU were described using competing-risk survival models. Factors associated with mortality and with LTFU were identified using Cox models with a competing-risk approach. Of the 578 participants, 261 (45.2%) were PWID and almost exclusively male. 49 patients died, corresponding to a mortality rate (95% confidence interval (CI)) of 3.7 (2.8-4.9) per 100 person-months, and 79 were lost to follow-up, corresponding to a rate (95% CI) of 6.0 (4.8-7.4) per 100 person-months. PWID were at higher risk of death but not of LTFU. Overall, LTFU was high in both groups. Latecomers to clinical visits were more at risk of both death and LTFU. Therefore, this should be a warning to clinical teams and preventive actions taken in these patients.Trial registration: ClinicalTrials.gov identifier: NCT03249493..

Molecular Detection of Orthohantavirus puumalaense in Plasma and Urine Samples from Hospitalized Patients Presenting with a Serologically Confirmed Acute Hantavirus Infection in France.

Molecular detection of Orthohantavirus puumalaense (PUUV) RNA during the course of the disease has been studied in blood of patients in Sweden and Slovenia. The use of urine has been poorly investigated. The aims of this work were to study PUUV RNA detection in plasma from a cohort of patients in France where a different PUUV lineage circulates and to assess the use of urine instead of plasma. Matched plasma and urine samples were collected daily from hospitalized patients presenting with fever, pain, and thrombocytopenia within the last 8 days and testing positive for IgM and IgG against PUUV in serum collected at inclusion and/or approximately 1 month after release. RNA was extracted from samples, and PUUV RNA was detected using real-time reverse transcription-PCR for plasma and urine samples. Sixty-seven patients presented a serologically confirmed acute hantavirus infection. At inclusion, PUUV RNA was detected in plasma from 55 of 62 patients (88.7%) sampled within the first week after disease onset, whereas it was detected in 15 of 60 (25.0%) of matched urine samples. It was then detected from 33 (71.7%) and 2 (4.4%) of 46 patients discharged from the hospital during the second week after disease onset, in plasma and urine, respectively. When PUUV RNA was detected in urine it was also detected in plasma, and not vice versa. Detection of PUUV RNA in plasma from hospitalized patients in France is similar to that observed in Sweden and Slovenia. Urine is not an appropriate sample for this detection.

Hospital-based prospective study of pertussis in infants and close contacts in Tehran, Iran.

BACKGROUND: Pertussis remain a global health concern, especially in infants too young to initiate their vaccination. Effective vaccination and high coverage limit the circulation of the pathogen, yet duration of protection is limited and boosters are recommended during a lifetime. In Iran, boosters are given at 18 months and 6 years old using whole pertussis vaccines for which efficacy is not known, and pertussis surveillance is scant with only sporadic biological diagnosis. Burden of pertussis is not well understood and local data are needed. METHODS: Hospital-based prospective study implementing molecular laboratory testing in infants aged ≤6 months and presenting ≥5 days of cough associated to one pertussis-like symptom in Tehran. Household and non-household contact cases of positive infants were evaluated by comprehensive pertussis diagnosis (molecular testing and serology) regardless of clinical signs. Clinical evaluation and source of infection were described. RESULTS: A total of 247 infants and 130 contact cases were enrolled. Pertussis diagnosis result was obtained for 199 infants and 104 contact cases. Infant population was mostly < 3 months old (79.9%; 157/199) and unvaccinated (62.3%; 124/199), 20.1% (40/199) of them were confirmed having B. pertussis infection. Greater cough duration and lymphocyte counts were the only symptoms associated to positivity. Half of the contact cases (51.0%; 53/104) had a B. pertussis infection, median age was 31 years old. A proportion of 28.3% (15/53) positive contacts did not report any symptom. However, 67.9% (36/53) and 3.8% (2/53) of them reported cough at inclusion or during the study, including 20.8% (11/53) who started coughing ≥7 days before infant cough onset. Overall, only five samples were successfully cultured. CONCLUSION: These data evidenced the significant prevalence of pertussis infection among paucy or poorly symptomatic contacts of infants with pertussis infection. Widespread usage of molecular testing should be implemented to identify B. pertussis infections.

Dried blood spots perform well to identify patients with active HCV infection in Vietnam.

Recently, treatment advances in direct-acting antivirals have radically changed the management of HCV patients. However, in resource-limited countries, identification of patients with active HCV infection is still challenging in remote settings due to the limited access to laboratories able to measure HCV viral load. This study evaluated whether dried blood spots (DBS) transferred to a central laboratory could overcome this challenge. A total of 315 HCV-infected patients, naïve to anti-HCV treatment, provided each three type of samples: plasma, DBS with calibrated quantities of venous blood and DBS with uncalibrated quantities of capillary blood. Qualitative comparison was conducted in terms of detection of HCV viral load on DBS as opposed to plasma to estimate sensitivity and specificity. Quantitative comparisons were conducted by means of correlation estimation. Of the 250 patients with detected plasma HCV viral load, 245 also had detectable DBS HCV viral load (capillary or venous) leading to a sensitivity of 98.0% (95% confidence interval (CI): 95.4%-99.3%); importantly, all measurements with a plasma HCV viral load >118 IU/mL were also detected in DBS. When HCV was not detected in plasma, it was also not detected in DBS resulting in 100% specificity (95% CI: 94.5%-100%). Quantitative HCV viral load results were very similar when utilizing plasma or DBS sample types as illustrated by correlations >0.99. In conclusion, DBS sample types, with either uncalibrated capillary blood or calibrated venous blood, performed well to distinguish patients with active HCV infection, and who therefore need treatment, from other patients.

Complications and competing risks of death in compensated viral cirrhosis (ANRS CO12 CirVir prospective cohort).

UNLABELLED: Various critical events, liver related or not, occur in patients with compensated cirrhosis, but their respective burden remains to be prospectively assessed. The aim of this prospective cohort study involving 35 French centers was to capture the whole spectrum of complications occurring in compensated viral cirrhosis (VC) using competing risks analyses. Inclusion criteria were: histologically proven cirrhosis resulting from hepatitis C virus (HCV) or hepatitis B virus (HBV); Child-Pugh A; and no previous hepatic complications. The cohort was considered as a multistate disease model, cumulative incidences (CumIs) of events were estimated in a competing risks framework. A total of 1,654 patients were enrolled from 2006 to 2012 (HCV, 1,308; HBV, 315; HCV-HBV, 31). During a median follow-up of 34 months, at least one liver nodule was detected in 271 patients, confirmed as hepatocellular carcinoma (HCC) in 128 (4-year cumI: 10.5%) and cholangiocarcinoma in 3. HCC incidence was higher in HCV (4-year cumI: 11.4% vs. 7.4%; P = 0.05). HCC fulfilled Milan criteria in 79.3%, leading to curative treatment in 70.4%. Liver decompensation occurred more frequently in HCV patients (4-year cumI: 10.8% vs. 3.6%; P = 0.0004). Virological eradication/control was achieved in 34.1% of HCV and 88.6% of HBV patients and was associated with a marked decrease in HCC, decompensation, and bacterial infection incidences. Survival was shorter in HCV patients (4-year cumI: 91.6% vs. 97.2%; P = 0.0002). Death (n = 102; missing data: 6) was attributed to liver disease in 48 (47%; liver cancer: n = 18; miscellaneous, n = 30) and extrahepatic causes in 48 (47%; bacterial infection: n = 13; extrahepatic cancers: n = 10; cardiovascular events: n = 5; miscellaneous, n = 20). CONCLUSION: After 3 years of follow-up, extrahepatic events still explained half of deaths in patients with compensated VC. A strong decrease in complications was linked to virological eradication/control.

Characterization of enteroviruses circulating among farm animals and children in Central African Republic.

To characterize enteroviruses (EVs) circulating in farm animals in Central African Republic (CAR), we screened 192 stools of animals under 12 months belonging to family farms located in or near Bangui. To assess whether EV exchanges exist between these animals and humans, we also screened 195 stools of children who lived in contact with farm animals, as well as control stools of 358 children with no contact with farm animals. EVs were typed based on their capsid sequences.In children, all EVs belonged to species A, B and C, with EV-Cs accounting for 60%. Some EV-Cs shared recent common ancestors with lineages of vaccine-derived poliovirus that emerged in the country in 2019-2020. In animals, we identified EV-Gs that belonged to 10 different types, including a previously unknown one that we named EV-G28, while no EV-E or EV-F were observed. The CAR EV-Gs were genetically closely related to specimens sampled in other continents and some of them harboured the torovirus-derived insertion already reported in some EV-Gs. The worldwide circulation of EV-Gs is likely due the massive international trade of live animals. Besides, two human EV-Cs (coxsackievirus A17 and coxsackievirus A24) were detected in pigs, suggesting that these viruses could cross the species barrier. Our work provides original data on the epidemiology and ecology of EVs circulating among herd animals in Africa.

Assessment of HIV viral load monitoring in remote settings in Vietnam - comparing people who inject drugs to the other patients.

INTRODUCTION: Increasing access to viral load (VL) monitoring is essential to fight HIV epidemics. In remote settings in Vietnam, using dried blood spot (DBS) sampling for specimen collection could improve the situation. Here, people who inject drugs (PWID) represent many newly antiretroviral therapy (ART)-initiated patients. The goals of this evaluation were to evaluate if access to VL monitoring and the rate of virological failure differed between PWID and non-PWID. METHODS: Prospective cohort study of patients newly initiated on ART in remote settings in Vietnam. DBS coverage at 6, 12 and 24 months of ART was investigated. Factors associated with DBS coverage were identified through logistic regression, as were factors associated with virological failure (VL ≥1,000 copies/mL) at 6, 12 and 24 months of ART. RESULTS: Overall 578 patients were enrolled in the cohort, of whom 261 (45%) were PWID. DBS coverage improved from 74.7% to 82.9% between 6 and 24 months of ART (p = 0.001). PWID status was not associated with DBS coverage (p = 0.74), but DBS coverage was lower in patients who were late to clinical visits and in those in WHO stage 4 (p = 0.023 and p = 0.001, respectively). The virological failure rate decreased from 15.8% to 6.6% between 6 and 24 months of ART (p<0.001). In multivariate analysis, PWID were more at risk of failure (p = 0.001), as were patients who were late to clinical visits (p<0.001) and not fully adherent (p<0.001). CONCLUSIONS: Despite training and simple procedures, DBS coverage was not perfect. DBS coverage was not associated with PWID status. Close management is required for effective routine HIV VL monitoring. PWID were more at risk of failure, as were patients who were not fully adherent and patients who were late to clinical visits. Specific interventions targeting these patients are needed to improve their outcomes. Overall, efforts in coordination and communication are essential to improve global HIV care. TRIAL REGISTRATION: Clinical Trial Number: NCT03249493.

Safety and immunogenicity of a measles-vectored SARS-CoV-2 vaccine candidate, V591 / TMV-083, in healthy adults: results of a randomized, placebo-controlled Phase I study.

BACKGROUND: V591 (TMV-083) is a live recombinant measles vector-based vaccine candidate expressing a pre-fusion stabilized SARS-CoV-2 spike protein. METHODS: We performed a randomized, placebo-controlled Phase I trial with an unblinded dose escalation and a double-blind treatment phase at 2 sites in France and Belgium to evaluate the safety and immunogenicity of V591. Ninety healthy SARS-CoV-2 sero-negative adults (18-55 years of age) were randomized into 3 cohorts, each comprising 24 vaccinees and 6 placebo recipients. Participants received two intramuscular injections of a low dose vaccine (1 × 105 median Tissue Culture Infectious Dose [TCID50]), one or two injections of a high dose vaccine (1 × 106 TCID50), or placebo with a 28 day interval. Safety was assessed by solicited and unsolicited adverse events. Immunogenicity was measured by SARS-CoV-2 spike protein-binding antibodies, neutralizing antibodies, spike-specific T cell responses, and anti-measles antibodies. ClinicalTrials.gov, NCT04497298. FINDINGS: Between Aug 10 and Oct 13, 2020, 148 volunteers were screened of whom 90 were randomized. V591 showed a good safety profile at both dose levels. No serious adverse events were reported. At least one treatment-related adverse event was reported by 15 (20.8%) participants receiving V591 vs. 6 (33.3%) of participants receiving placebo. Eighty-one percent of participants receiving two injections of V591 developed spike-binding antibodies after the second injection. However, neutralizing antibodies were detectable on day 56 only in 17% of participants receiving the low dose and 61% receiving the high dose (2 injections). Spike-specific T cell responses were not detected. Pre-existing anti-measles immunity had a statistically significant impact on the immune response to V591, which was in contrast to previous results with the measles vector-based chikungunya vaccine. INTERPRETATION: While V591 was generally well tolerated, the immunogenicity was not sufficient to support further development. FUNDING: Themis Bioscience GmbH, a subsidiary of Merck & Co. Inc., Kenilworth, NJ, USA; Coalition for Epidemic Preparedness Innovations (CEPI).

Circulation of Bordetella pertussis in vaccinated Cambodian children: A transversal serological study.

BACKGROUND: The Cambodia pertussis immunization schedule includes three doses given at age 6, 10 and 14 weeks using a whole-pertussis vaccine. No booster doses are included. Pertussis biological diagnosis is unavailable in Cambodia and its burden remains unclear. This study aimed to provide accurate data on pertussis serological status of Cambodian children and adolescents, and to evaluate vaccination timeliness. METHODS: Fully vaccinated children aged 3-15 years were recruited at the Rabies Prevention Center, Institut Pasteur in Cambodia, Phnom Penh. Capillary blood samples and information on pertussis vaccination history were collected. Anti-pertussis toxin (PT) IgG titers were quantified by ELISA. RESULTS: Compliance with the national immunization schedule was 95.1%. Initiation of vaccination after 8 weeks of age was observed for 29.0% of the children, but was less frequent in the youngest children (13.0%) compared with the oldest ones (46.4%). Rate of children exhibiting anti-PT IgG varied across age groups, and increased from 35.7% to 55.0% in 3-5 and 12-15 years age groups, respectively. CONCLUSION: Pertussis circulates among vaccinated Cambodian children and adolescents. These data support the need for public health authorities to strengthen pertussis surveillance and use local epidemiological data to make evidence-based decision for the establishment of an optimal vaccination strategy.

Transversal sero-epidemiological study of Bordetella pertussis in Tehran, Iran.

OBJECTIVES: Pertussis remains endemic despite high vaccine coverage in infants and toddlers. Pertussis vaccines confer protection but immunity wanes overtime and boosters are needed in a lifetime. Iran, eligible for the Expanded Program on Immunization that includes the primary immunization, implemented two additional booster doses using a whole-cell vaccine (wPV) at 18 months-old and about 6 years-old. Duration of protection induced by the wPVs currently in use and their impact as pre-school booster are not well documented. This study aimed at assessing vaccination compliance and at estimating the duration of protection conferred by vaccination with wPV in children aged < 15 years in Tehran, Iran. METHODS: Detailed information on vaccination history and capillary blood samples were obtained from 1047 children aged 3-15 years who completed the 3 doses-primary pertussis immunization, in Tehran. Anti-pertussis toxin IgG levels were quantified by ELISA. RESULTS: Compliance was very high with 93.3% of children who received the three primary and 1st booster doses in a timely manner. Timeliness of the 2nd booster was lower (63.3%). Rate of seropositive samples continuously and significantly increased from 1-2 to 5-6 years after 1st booster attaining 30.4% of children exhibiting serological sign of recent contact with B. pertussis. Second booster dating back 1 or 2 years was associated with high antibody titers, which significantly decreased within 3 years from injection. Among children who received 2nd booster injection more than 2 years before serum analysis, seroprevalence of pertussis infection was 8.4% and seropositivity rate was higher from the 10 years-old group. CONCLUSION: Seropositivity in children aged 6-7 years with no 2nd booster supports the need for a vaccination at that age. Adolescent booster may also be considered.

Feasibility of dried blood spots for HIV viral load monitoring in decentralized area in North Vietnam in a test-and-treat era, the MOVIDA project.

BACKGROUND: Access to HIV viral load is crucial to efficiently monitor patients on antiretroviral treatment (ART) and prevent HIV drug resistance acquisition. However, in some remote settings, access to viral load monitoring is still complex due to logistical and financial constraints. Use of dried blood spots (DBS) for blood collection could overcome these difficulties. This study aims to describe feasibility and operability of DBS use for routine viral load monitoring. METHODS: From June 2017 to April 2018, HIV-infected adults who initiated ART were enrolled in a prospective cohort in 43 clinical sites across 6 provinces in North Vietnam. Following national guidelines, the first viral load monitoring was planned 6 months after ART initiation. DBS were collected at the clinical site and sent by post to a central laboratory in Hanoi for viral load measurement. RESULTS: Of the 578 patients enrolled, 537 were still followed 6 months after ART initiation, of which DBS was collected for 397 (73.9%). The median (inter quartile range) delay between DBS collection at site level and reception at the central laboratory was 8 (6-19) days and for 70.0% viral load was measured ≤30 days after blood collection. The proportion of patients with viral load ≥1000 copies/mL at the 6 month evaluation was 15.9% (n = 59). Of these, a DBS was collected again to confirm virological failure in 15 (24.4%) of which virological failure was confirmed in 11 (73.3%). CONCLUSION: Delay of DBS transfer to the central laboratory was acceptable and most viral loads were measured in ≤30 days, in-line with routine follow-up. However, the level of DBS coverage and the proportion of patients in failure for whom a confirmatory viral load was available were suboptimal, indicating that integration of viral load monitoring in the field requires, among other things, careful training and strong involvement of the local teams. The proportion of patients experiencing virological failure was in line with other reports; interestingly those who reported being non-adherent and those with a low BMI were more at risk of failure.

Primary liver cancer is more aggressive in HIV-HCV coinfection than in HCV infection. A prospective study (ANRS CO13 Hepavih and CO12 Cirvir).

OBJECTIVE: Since HAART, primary liver cancer has emerged as an increasing cause of morbidity and mortality in patients with HIV infection. Our aim was to compare characteristics and outcome of primary liver cancer according to HIV status in HCV cirrhotic patients submitted to periodic ultrasonographic surveillance. METHODS: All patients with primary liver cancer and cirrhosis were selected from two prospective cohorts (ANRS CO12 Cirvir, viral cirrhosis, n=1081; ANRS CO13 Hepavih, HIV-HCV coinfection, n=1175). Cirrhosis was diagnosed by liver biopsy in monoHCV group and biopsy and/or non-invasive tests in HIV-HCV group. Ultrasonographic surveillance was performed every 6 months. Diagnosis of primary liver cancer was established according to EASL-AASLD guidelines. RESULTS: Primary liver cancer was diagnosed in 32 patients, 16 in each group, and corresponded to hepatocellular carcinoma in all except for two cholangiocarcinomas in HIV-HCV patients. Ultrasonographic follow-up was similar (median time since last ultrasonographic without focal lesion: 237 days in HIV-HCV group (n=12) versus 208 days in HCV group, NS). At primary liver cancer diagnosis HIV-HCV patients were markedly younger (48 vs. 60 yrs, P<0.001), primary liver cancer was more advanced in HIV-HCV patients (single nodule: 43% vs. 75%, P=0.07; mean diameter of main nodule: 24 vs. 16 mm, P=0.006; portal obstruction: 3 vs. 0). Curative treatment was performed in four HIV-HCV patients versus 11 HCV patients (P=0.017). During follow-up, 10 HIV-HCV patients died versus only one HCV patient (P=0.0005). CONCLUSIONS: This result suggests more aggressiveness for tumors in HIV infected patients and, if confirmed, could result in shortening the length between ultrasonographic examinations.