Zika virus infection in European travellers returning from Thailand in 2022: A GeoSentinel case series.

Zika virus is a mosquito-borne flavivirus which caused major epidemics in the Pacific and the Americas between 2013 and 2015. International travellers have previously acted as a sentinel population for Zika virus transmission in endemic areas, where local transmission may be incompletely captured by local surveillance systems. We report five recent European travellers returning from Thailand with Zika virus infection, highlighting the risk of ongoing endemic transmission in this popular tourist destination.

Bedaquiline as Treatment for Disseminated Nontuberculous Mycobacteria Infection in 2 Patients Co-Infected with HIV.

Nontuberculous mycobacteria can cause disseminated infections in immunocompromised patients and are challenging to treat because of antimicrobial resistance and adverse effects of prolonged multidrug treatment. We report successful treatment with bedaquiline, a novel antimycobacterial drug, as part of combination therapy for 2 patients with disseminated nontuberculous mycobacteria co-infected with HIV.

Increased risk of chikungunya infection in travellers to Thailand during ongoing outbreak in tourist areas: cases imported to Europe and the Middle East, early 2019.

We report nine travellers with confirmed chikungunya virus infection, returning from tourist areas of Thailand to Sweden, Switzerland, the United Kingdom, Romania, Israel and France, diagnosed in January and February 2019. These sentinel tourists support the intensification of chikungunya virus circulation in Thailand and highlight the potential for importation to areas at risk of local transmission.

Causes and Timing of Mortality and Morbidity Among Late Presenters Starting Antiretroviral Therapy in the REALITY Trial.

Background: In sub-Saharan Africa, 20%-25% of people starting antiretroviral therapy (ART) have severe immunosuppression; approximately 10% die within 3 months. In the Reduction of EArly mortaLITY (REALITY) randomized trial, a broad enhanced anti-infection prophylaxis bundle reduced mortality vs cotrimoxazole. We investigate the contribution and timing of different causes of mortality/morbidity. Methods: Participants started ART with a CD4 count <100 cells/µL; enhanced prophylaxis comprised cotrimoxazole plus 12 weeks of isoniazid + fluconazole, single-dose albendazole, and 5 days of azithromycin. A blinded committee adjudicated events and causes of death as (non-mutually exclusively) tuberculosis, cryptococcosis, severe bacterial infection (SBI), other potentially azithromycin-responsive infections, other events, and unknown. Results: Median pre-ART CD4 count was 37 cells/µL. Among 1805 participants, 225 (12.7%) died by week 48. Fatal/nonfatal events occurred early (median 4 weeks); rates then declined exponentially. One hundred fifty-four deaths had single and 71 had multiple causes, including tuberculosis in 4.5% participants, cryptococcosis in 1.1%, SBI in 1.9%, other potentially azithromycin-responsive infections in 1.3%, other events in 3.6%, and unknown in 5.0%. Enhanced prophylaxis reduced deaths from cryptococcosis and unknown causes (P < .05) but not tuberculosis, SBI, potentially azithromycin-responsive infections, or other causes (P > .3); and reduced nonfatal/fatal tuberculosis and cryptococcosis (P < .05), but not SBI, other potentially azithromycin-responsive infections, or other events (P > .2). Conclusions: Enhanced prophylaxis reduced mortality from cryptococcosis and unknown causes and nonfatal tuberculosis and cryptococcosis. High early incidence of fatal/nonfatal events highlights the need for starting enhanced-prophylaxis with ART in advanced disease. Clinical Trials Registration: ISRCTN43622374.

Effectiveness of Protease Inhibitor/Nucleos(t)ide Reverse Transcriptase Inhibitor-Based Second-line Antiretroviral Therapy for the Treatment of Human Immunodeficiency Virus Type 1 Infection in Sub-Saharan Africa: A Systematic Review and Meta-analysis.

Background: In sub-Saharan Africa, 25.5 million people are living with human immunodeficiency virus (HIV), representing 70% of the global total. The need for second-line antiretroviral therapy (ART) is projected to increase in the next decade in keeping with the expansion of treatment provision. Outcome data are required to inform policy. Methods: We performed a systematic review and meta-analysis of studies reporting the virological outcomes of protease inhibitor (PI)-based second-line ART in sub-Saharan Africa. The primary outcome was virological suppression (HIV-1 RNA <400 copies/mL) after 48 and 96 weeks of treatment. The secondary outcome was the proportion of patients with PI resistance. Pooled aggregate data were analyzed using a DerSimonian-Laird random effects model. Results: By intention-to-treat analysis, virological suppression occurred in 69.3% (95% confidence interval [CI], 58.2%-79.3%) of patients at week 48 (4558 participants, 14 studies), and in 61.5% (95% CI, 47.2%-74.9%) at week 96 (2145 participants, 8 studies). Preexisting resistance to nucleos(t)ide reverse transcriptase inhibitors (NRTIs) increased the likelihood of virological suppression. Major protease resistance mutations occurred in a median of 17% (interquartile range, 0-25%) of the virological failure population and increased with duration of second-line ART. Conclusions: One-third of patients receiving PI-based second-line ART with continued NRTI use in sub-Saharan Africa did not achieve virological suppression, although among viremic patients, protease resistance was infrequent. Significant challenges remain in implementation of viral load monitoring. Optimizing definitions and strategies for management of second-line ART failure is a research priority. Prospero Registration: CRD42016048985.

Viral suppression following switch to second-line antiretroviral therapy: associations with nucleoside reverse transcriptase inhibitor resistance and subtherapeutic drug concentrations prior to switch.

BACKGROUND: High rates of second-line antiretroviral treatment (ART) failure are reported. The association with resistance and nonadherence on switching to second-line ART requires clarification. METHODS: Using prospectively collected data from patients in South Africa, we constructed a cohort of patients switched to second-line ART (1 January 2003 through 31 December 2008). Genotyping and drug concentrations (lamivudine, nevirapine, and efavirenz) were measured on stored samples preswitch. Their association with viral load (VL) <400 copies/mL by 15 months was assessed using modified Poisson regression. RESULTS: One hundred twenty-two of 417 patients (49% male; median age, 36 years) had genotyping (n = 115) and/or drug concentrations (n = 80) measured. Median CD4 count and VL at switch were 177 cells/µL (interquartile range [IQR], 77-263) and 4.3 log10 copies/mL (IQR, 3.8-4.7), respectively. Fifty-five percent (n = 44/80) had subtherapeutic drug concentrations preswitch. More patients with therapeutic vs subtherapeutic ART had resistance (n = 73): no major mutations (3% vs 51%), nonnucleoside reverse transcriptase inhibitor (94% vs 44%), M184V/I (94% vs 26%), and ≥ 1 thymidine analogue mutations (47% vs 18%), all P = .01; and nucleoside reverse transcriptase inhibitor (NRTI) cross-resistance mutations (26% vs 13%, P = .23). Following switch, 68% (n = 83/122) achieved VL <400 copies/mL. Absence of NRTI mutations and subtherapeutic ART preswitch were associated with failure to achieve VL <400 copies/mL. CONCLUSIONS: Nonadherence, suggested by subtherapeutic ART with/without major resistance mutations, significantly contributed to failure when switching regimen. Unresolved nonadherence, not NRTI resistance, drives early second-line failure.

Anti-inflammatory therapy with nebulized dornase alfa for severe COVID-19 pneumonia: a randomized unblinded trial.

Background: Prinflammatory extracellular chromatin from neutrophil extracellular traps (NETs) and other cellular sources is found in COVID-19 patients and may promote pathology. We determined whether pulmonary administration of the endonuclease dornase alfa reduced systemic inflammation by clearing extracellular chromatin. Methods: Eligible patients were randomized (3:1) to the best available care including dexamethasone (R-BAC) or to BAC with twice-daily nebulized dornase alfa (R-BAC + DA) for seven days or until discharge. A 2:1 ratio of matched contemporary controls (CC-BAC) provided additional comparators. The primary endpoint was the improvement in C-reactive protein (CRP) over time, analyzed using a repeated-measures mixed model, adjusted for baseline factors. Results: We recruited 39 evaluable participants: 30 randomized to dornase alfa (R-BAC +DA), 9 randomized to BAC (R-BAC), and included 60 CC-BAC participants. Dornase alfa was well tolerated and reduced CRP by 33% compared to the combined BAC groups (T-BAC). Least squares (LS) mean post-dexamethasone CRP fell from 101.9 mg/L to 23.23 mg/L in R-BAC +DA participants versus a 99.5 mg/L to 34.82 mg/L reduction in the T-BAC group at 7 days; p=0.01. The anti-inflammatory effect of dornase alfa was further confirmed with subgroup and sensitivity analyses on randomised participants only, mitigating potential biases associated with the use of CC-BAC participants. Dornase alfa increased live discharge rates by 63% (HR 1.63, 95% CI 1.01-2.61, p=0.03), increased lymphocyte counts (LS mean: 1.08 vs 0.87, p=0.02) and reduced circulating cf-DNA and the coagulopathy marker D-dimer (LS mean: 570.78 vs 1656.96 µg/mL, p=0.004). Conclusions: Dornase alfa reduces pathogenic inflammation in COVID-19 pneumonia, demonstrating the benefit of cost-effective therapies that target extracellular chromatin. Funding: LifeArc, Breathing Matters, The Francis Crick Institute (CRUK, Medical Research Council, Wellcome Trust). Clinical trial number: NCT04359654.

Assessment of returning travellers with fever.

Millions of people travel to the tropics each year and a significant minority of them become ill, either during their stay or shortly after their return. Most have mild, self-limiting illnesses, but a few have a life-threatening condition. This article outlines how to evaluate fever in the returning traveller and discusses important infection control and public health measures. A detailed travel history, which takes into account travel destinations, specific activities and risk factors in relation to the onset of symptoms, is essential for constructing a comprehensive list of differential diagnoses and guiding appropriate investigations. Importantly, all travellers returning from the tropics with a fever should be investigated for malaria.

Tuberculosis in travellers.

Tuberculosis (TB) incidence is increasing in many countries which are popular with international travellers. The development of active TB is a two-stage process; the risk of acquiring new TB infection depends primarily on the risk of contact with an individual with infectious TB, and the risk of disease on the immune status of the newly infected person. The risk of TB infection is low for most holiday-makers, but among long-term travellers to countries with high TB incidence, the risk may be similar to that experienced by the local population (0.5-2.5% per year); the risk to people working in health care is particularly high. Effective pre-travel advice involves assessing the traveller's risk of TB infection and disease. Recommendations on the prevention of TB in travellers vary between countries. Possible strategies include avoidance of exposure; BCG vaccination; and tuberculin skin testing before and after travel, with preventive therapy for those whose post-travel skin tests indicate recent infection. For those at highest risk of progression to disease, there may be value in preventive therapy during travel to reduce the risk of new TB infection. Further information on the contribution of recent travel to incident TB in industrialised countries would be valuable.

Assessment of returning travellers with fever.

Millions of people travel to the tropics each year and a significant minority of them become ill, either during their stay, or shortly after their return. Most have mild, self-limiting illnesses, but a few will have a life-threatening condition. This article outlines how to evaluate fever in the returning traveller and discusses important infection control and public health measures. A detailed travel history, which takes into account travel destinations, specific activities and risk factors in relation to the onset of symptoms, is essential for constructing a comprehensive list of differential diagnoses and guiding appropriate investigations. Importantly, all travellers returning from the tropics with a fever should be investigated for malaria, even if their return was 3 months ago or longer.

Resistance to tenofovir-based regimens during treatment failure of subtype C HIV-1 in South Africa.

BACKGROUND: Tenofovir disoproxil fumarate (TDF) is increasingly available for patients infected with subtype C HIV-1. This subtype is reported to develop the principal TDF resistance mutation in the HIV reverse transcriptase, K65R, with greater propensity than other subtypes. We sought to describe K65R development during TDF use in a cohort of patients infected with subtype C HIV. METHODS: Using a prospectively followed cohort with 6 monthly HIV RNA assays, we identified virological failure (defined as an HIV RNA > 1,000 copies/ml) during treatment that included TDF. Residual serum, stored at the time of the HIV RNA assay, was used for consensus sequencing and allele-specific PCR. We assessed prevalence of resistance at failure during TDF-containing treatment and associated factors. RESULTS: Among 1,682 patients on a TDF-containing regimen, 270 developed failure of which 40 were assessed for resistance. By sequencing, the K65R was identified in 5 (12%), major non-nucleoside reverse transcriptase inhibitor mutations in 24 (57%) and the M184V/I in 12 (28%) patients. The K65R was associated with lower HIV RNA at failure (HIV RNA 3.3 versus 4.2 log10 copies/ml) and prior stavudine exposure. An additional five patients had minority K65R populations identified by allele-specific PCR. CONCLUSIONS: These data suggest that the K65R prevalence at virological failure is moderately higher in our subtype C population than some non-subtype C HIV cohorts. However, we did not find that the K65R was highly selected in HIV-1 subtype-C-infected patients with up to 6 months of failure of a TDF-containing regimen.

Quantifying and addressing losses along the continuum of care for people living with HIV infection in sub-Saharan Africa: a systematic review.

INTRODUCTION: Recent years have seen an increasing recognition of the need to improve access and retention in care for people living with HIV/AIDS. This review aims to quantify patients along the continuum of care in sub-Saharan Africa and review possible interventions. METHODS: We defined the different steps making up the care pathway and quantified losses at each step between acquisition of HIV infection and retention in care on antiretroviral therapy (ART). We conducted a systematic review of data from studies conducted in sub-Saharan Africa and published between 2000 and June 2011 for four of these steps and performed a meta-analysis when indicated; existing data syntheses were used for the remaining two steps. RESULTS: The World Health Organization estimates that only 39% of HIV-positive individuals are aware of their status. Among patients who know their HIV-positive status, just 57% (95% CI, 48 to 66%) completed assessment of ART eligibility. Of eight studies using an ART eligibility threshold of ≤200 cells/µL, 41% of patients (95% CI, 27% to 55%) were eligible for treatment, while of six studies using an ART eligibility threshold of ≤350 cells/µL, 57% of patients (95% CI, 50 to 63%) were eligible. Of those not yet eligible for ART, the median proportion remaining in pre-ART care was 45%. Of eligible individuals, just 66% (95% CI, 58 to 73%) started ART and the proportion remaining on therapy after three years has previously been estimated as 65%. However, recent studies highlight that this is not a simple linear pathway, as patients cycle in and out of care. Published studies of interventions have mainly focused on reducing losses at HIV testing and during ART care, whereas few have addressed linkage and retention during the pre-ART period. CONCLUSIONS: Losses occur throughout the care pathway, especially prior to ART initiation, and for some patients this is a transient event, as they may re-engage in care at a later time. However, data regarding interventions to address this issue are scarce. Research is urgently needed to identify effective solutions so that a far greater proportion of infected individuals can benefit from long-term ART.

Outcomes following virological failure and predictors of switching to second-line antiretroviral therapy in a South African treatment program.

OBJECTIVES: Without resistance tests, deciding which patients with virological failure should switch to second-line antiretroviral therapy (ART) is difficult. The factors influencing this decision are poorly understood. We assess predictors of switching regimens after virological failure. DESIGN: Retrospective cohort study using clinical data from a South African ART program with 6-monthly viral load (VL) monitoring. METHODS: We constructed a dataset of patient visits occurring following first-line virological failure, and used random effects logistic regression (accounting for individual-level and clinic-level clustering) to assess predictors of switching at each visit. RESULTS: One thousand six hundred sixty-eight patients with virological failure (73% male, mean age 41 years, median CD4 184 cells/mm, mean log10 VL 4.3) contributed 1922 person-years of viremia. 12 months after failure, the cumulative incidence of switching regimen, viral resuppression, or death was 16.9%, 13.2%, and 4.6%, respectively. In adjusted analysis, switching was more likely at the third or subsequent visit after failure; in visits occurring in 2008 versus 2003 to 2007; and in patients with ART experience pre-programme, current high VL or low CD4 count. Switching was less likely in patients with no clinic contact for 4 months, or declining VL. Switching rates varied between clinics with clinic-level clustering evident in the final model (P <0.001). CONCLUSIONS: Despite 6-monthly virological monitoring and recommendations to switch after adherence interventions and confirmed viremia, patients experienced delayed switching. Individual-level covariates influenced switching but did not account for variable switching rates between clinics, suggesting differences in guideline implementation. In certain circumstances delays may be warranted; however understanding barriers to guideline implementation will limit unnecessary delays.

Second-line antiretroviral therapy in a workplace and community-based treatment programme in South Africa: determinants of virological outcome.

BACKGROUND: As antiretroviral treatment (ART) programmes in resource-limited settings mature, more patients are experiencing virological failure. Without resistance testing, deciding who should switch to second-line ART can be difficult. The consequences for second-line outcomes are unclear. In a workplace- and community-based multi-site programme, with 6-monthly virological monitoring, we describe outcomes and predictors of viral suppression on second-line, protease inhibitor-based ART. METHODS: We used prospectively collected clinic data from patients commencing first-line ART between 1/1/03 and 31/12/08 to construct a study cohort of patients switched to second-line ART in the presence of a viral load (VL) ≥ 400 copies/ml. Predictors of VL<400 copies/ml within 15 months of switch were assessed using modified Poisson regression to estimate risk ratios. RESULTS: 205 workplace patients (91.7% male; median age 43 yrs) and 212 community patients (38.7% male; median age 36 yrs) switched regimens. At switch compared to community patients, workplace patients had a longer duration of viraemia, higher VL, lower CD4 count, and higher reported non-adherence on first-line ART. Non-adherence was the reported reason for switching in a higher proportion of workplace patients. Following switch, 48.3% (workplace) and 72.0% (community) achieved VL<400, with non-adherence (17.9% vs. 1.4%) and virological rebound (35.6% vs. 13.2% with available measures) reported more commonly in the workplace programme. In adjusted analysis of the workplace programme, lower switch VL and younger age were associated with VL<400. In the community programme, shorter duration of viraemia, higher CD4 count and transfers into programme on ART were associated with VL<400. CONCLUSION: High levels of viral suppression on second-line ART can be, but are not always, achieved in multi-site treatment programmes with both individual- and programme-level factors influencing outcomes. Strategies to support both healthcare workers and patients during this switch period need to be evaluated; sub-optimal adherence, particularly in the workplace programme must be addressed.

Changing predictors of mortality over time from cART start: implications for care.

OBJECTIVE: To determine predictors of mortality and changes in those predictors over time on combination antiretroviral therapy (cART) in South Africa. DESIGN: A cohort study. METHODS: Using routine clinic data with up to 4 years follow-up after antiretroviral therapy initiation and with death ascertainment from a national vital statistics register, we used proportional hazards modeling to assess baseline and time-updated predictors of mortality and changes in strength of those predictors over time on cART. Furthermore, we compared CD4 count among individuals who died by duration on cART. RESULTS: Fifteen thousand sixty subjects (64% men, median CD4 count 127 cells/mm³) started antiretroviral therapy between January 2003 and January 2008. Over a median follow-up of 1.8 years, 2658 subjects died. The baseline characteristics of WHO stage, hemoglobin, CD4 count, HIV RNA level, and symptoms were all associated with mortality during the first 12 months of cART but lost association thereafter. However, time-updated factors of CD4 count, body mass index, symptoms, anemia, and HIV RNA suppression remained strong predictors of death. Most recent CD4 count before death rose from 71 during the first 3 months of cART to 175 cells per cubic millimeter after >3 years of cART. CONCLUSION: Over 4 years of cART, risk of death declined and associations with mortality changed. An increase in CD4 count at death and changing associations with mortality may suggest a shift in causes of death, possibly from opportunistic infections to other infections and chronic illnesses.

Fever in returned travellers presenting in the United Kingdom: recommendations for investigation and initial management.

International travel is increasing. Most physicians and general practitioners will encounter returned travellers with fever and the majority of travel-related infection is associated with travel to the tropics. In those returning from the tropics malaria must always be excluded, and HIV considered, from all settings. Common causes of non-malarial fever include from Africa rickettsial diseases, amoebic liver abscess and Katayama syndrome; from South and South East Asia, enteric fever and arboviral infection; from the Middle East, brucellosis and from the Horn of Africa visceral leishmaniasis. Other rare but important diseases from particular geographical areas include leptospirosis, trypanosomiasis and viral haemorrhagic fever. North and South America, Europe and Australia also have infections which are geographically concentrated. Empirical treatment may have to be started based on epidemiological probability of infection whilst waiting for results to return. The evidence base for much of the management of tropical infections is limited. These recommendations provide a pragmatic approach to the initial diagnosis and management of fever in returned travellers, based on evidence where it is available and on consensus of expert opinion where it is not. With early diagnosis and treatment the majority of patients with a potentially fatal infection related to travel will make a rapid and full recovery.

Global epidemiology and control of Trichomonas vaginalis.

PURPOSE OF REVIEW: Trichomonas vaginalis is the most common curable sexually transmitted infection. Despite a number of serious health consequences including facilitation of HIV transmission, pelvic inflammatory disease and adverse outcomes of pregnancy it remains an under-recognized condition. This review aims to update the reader on the global epidemiology and control of T. vaginalis. RECENT FINDINGS: The burden of T. vaginalis infection is found in resource-limited settings and high-risk groups in industrialized settings. Utilization of polymerase chain reaction-based diagnostics has enhanced our understanding of the epidemiology of T. vaginalis both at the population level and in sexual partners. High rates of asymptomatic infection in male partners of infected females and subsequent re-infection have significant implications for control programmes. Further studies investigating the role of T. vaginalis in facilitating HIV transmission has highlighted its significance and the need to develop and implement control interventions. SUMMARY: Future research to develop cheap, point-of-care diagnostic tests will allow a greater understanding of T. vaginalis epidemiology. In addition, the effect of treatment on outcome of pregnancy and HIV acquisition requires further study. This will in turn facilitate operational studies evaluating optimal control strategies and their impact on the complications of T. vaginalis.

Prevalence of Chlamydia trachomatis infection among 'high risk' young people in New South Wales.

International research on homeless adolescents has found that incidence and prevalence of sexually transmissible infections is relatively high. This study reports on a chlamydia prevalence survey conducted among high-risk young people (14-25 years) in New South Wales. The participants were recruited from youth health centres, which target homeless and high-risk youth. Of 333 clients (42.6% male), 84.1% were sexually active and mean number of sexual partners over the preceding 3 months was 1.4. Among sexually active participants, 24.6% claimed to use condoms always and 25% never. Sixteen of 274 available urine samples tested positive for Chlamydia trachomatis infection. Further research is warranted to better define high-risk groups and clarify the nature of associations between various factors impacting on sexual health. Most importantly, research is now called for into effective strategies for engaging and attracting young people to screening, treatment and contact tracing.