Efficacy and safety of artemether-lumefantrine for the treatment of uncomplicated falciparum malaria in mainland Tanzania, 2019.

BACKGROUND: Artemisinin-based combination therapy (ACT) has been a major contributor to the substantial reductions in global malaria morbidity and mortality over the last decade. In Tanzania, artemether-lumefantrine (AL) was introduced as the first-line treatment for uncomplicated Plasmodium falciparum malaria in 2006. The World Health Organization (WHO) recommends regular assessment and monitoring of the efficacy of the first-line treatment, specifically considering that artemisinin resistance has been confirmed in the Greater Mekong sub-region. This study's main aim was to assess the efficacy and safety of AL for treating uncomplicated P. falciparum malaria in Tanzania. METHODS: This was a single-arm prospective antimalarial drug efficacy trial conducted in four of the eight National Malaria Control Programme (NMCP) sentinel sites in 2019. The trial was carried out in outpatient health facilities in Karume-Mwanza region, Ipinda-Mbeya region, Simbo-Tabora region, and Nagaga-Mtwara region. Children aged six months to 10 years with microscopy confirmed uncomplicated P. falciparum malaria who met the inclusion criteria were recruited based on the WHO protocol. The children received AL (a 6-dose regimen of AL twice daily for three days). Clinical and parasitological parameters were monitored during follow-up over 28 days to evaluate drug efficacy. RESULTS: A total of 628 children were screened for uncomplicated malaria, and 349 (55.6%) were enrolled between May and September 2019. Of the enrolled children, 343 (98.3%) completed the 28-day follow-up or attained the treatment outcomes. There were no early treatment failures; recurrent infections during follow-up were common at two sites (Karume 29.5%; Simbo 18.2%). PCR-corrected adequate clinical and parasitological response (ACPR) by survival analysis to AL on day 28 of follow-up varied from 97.7% at Karume to 100% at Ipinda and Nagaga sites. The commonly reported adverse events were cough, skin pallor, and abdominal pain. The drug was well tolerated, and no serious adverse event was reported. CONCLUSION: This study showed that AL had adequate efficacy and safety for the treatment of uncomplicated falciparum malaria in Tanzania in 2019. The high recurrent infections were mainly due to new infections, highlighting the potential role of introducing alternative artemisinin-based combinations that offer improved post-treatment prophylaxis, such as artesunate-amodiaquine (ASAQ).

Efficacy and safety of artemether-lumefantrine for the treatment of uncomplicated falciparum malaria in mainland Tanzania, 2018.

BACKGROUND: The use of artemisinin-based combination therapy (ACT) is recommended by the World Health Organization for the treatment of uncomplicated falciparum malaria. Artemether-lumefantrine (AL) is the most widely adopted first-line ACT for uncomplicated malaria in sub-Saharan Africa (SSA), including mainland Tanzania, where it was introduced in December 2006. The WHO recommends regular assessment to monitor the efficacy of the first-line treatment specifically considering that artemisinin partial resistance was reported in Greater Mekong sub-region and has been confirmed in East Africa (Rwanda and Uganda). The main aim of this study was to assess the efficacy and safety of AL for the treatment of uncomplicated falciparum malaria in mainland Tanzania. METHODS: A single-arm prospective anti-malarial drug efficacy trial was conducted in Kibaha, Mlimba, Mkuzi, and Ujiji (in Pwani, Morogoro, Tanga, and Kigoma regions, respectively) in 2018. The sample size of 88 patients per site was determined based on WHO 2009 standard protocol. Participants were febrile patients (documented axillary temperature ≥ 37.5 °C and/or history of fever during the past 24 h) aged 6 months to 10 years. Patients received a 6-dose AL regimen by weight twice a day for 3 days. Clinical and parasitological parameters were monitored during 28 days of follow-up to evaluate the drug efficacy and safety. RESULTS: A total of 653 children were screened for uncomplicated malaria and 349 (53.7%) were enrolled between April and August 2018. Of the enrolled children, 345 (98.9%) completed the 28 days of follow-up or attained the treatment outcomes. There were no early treatment failures, but recurrent infections were higher in Mkuzi (35.2%) and Ujiji (23%). By Kaplan-Meier analysis of polymerase chain reaction (PCR) uncorrected adequate clinical and parasitological response (ACPR) ranged from 63.4% in Mkuzi to 85.9% in Mlimba, while PCR-corrected ACPR on day 28 varied from 97.6% in Ujiji to 100% in Mlimba. The drug was well tolerated; the commonly reported adverse events were cough, runny nose, and abdominal pain. No serious adverse event was reported. CONCLUSION: This study showed that AL had adequate efficacy and safety for the treatment of uncomplicated falciparum malaria. The high number of recurrent infections were mainly due to new infections, indicating the necessity of utilizing alternative artemisinin-based combinations, such as artesunate amodiaquine, which provide a significantly longer post-treatment prophylactic effect.

SCHISTOACT: a protocol for an open-label, five-arm, non-inferiority, individually randomized controlled trial of the efficacy and safety of praziquantel plus artemisinin-based combinations in the treatment of Schistosoma mansoni infection.

BACKGROUND: Schistosomiasis control relies on praziquantel for preventive chemotherapy. Alternative drugs are needed for the treatment and control of schistosomiasis. Praziquantel is effective against adult schistosome worms but ineffective against larval stages of the parasite and cannot prevent re-infection or interrupt the transmission of infection. Continued reliance on praziquantel for wide-scale schistosomiasis control will likely accelerate the emergence of drug resistance. Artemisinin derivatives are effective against the juvenile stages but ineffective against adult worms. The SCHISTOACT study aimed to evaluate the efficacy and safety of praziquantel plus one of four artemisinin-based combinations in treating Schistosoma mansoni infection in Kenya. METHODS: The SCHISTOACT study is an open-label, head-to-head, five-arm, proof-of-concept, non-inferiority, individually randomized controlled trial with a follow-up of 12 weeks. A total of 540 primary school-aged children from the Mwea area, Kirinyaga County in central Kenya, diagnosed with S. mansoni infection (by Kato-Katz method) are randomly allocated (1:1:1:1:1) to a single dose of praziquantel plus a 3-day course of artesunate-sulfalene/pyrimethamine, or artesunate-amodiaquine, or artesunate plus mefloquine, or dihydroartemisinin-piperaquine, or praziquantel control arm. The primary endpoints are efficacy (cure rate, assessed by microscopy) and safety (adverse events) of each study arm 6 weeks after treatment. Secondary endpoints include cumulative cure rate, egg reduction rate, and re-infection 12 weeks after treatment. The non-inferiority margin is set at - 10 for the risk difference in cure rates between praziquantel and the combined treatment. DISCUSSION: This study assesses a strategy for repurposing artemisinin-based combination therapies (ACTs) for treating schistosomiasis. It adopts a head-to-head comparison of four different ACTs to test a non-inferiority hypothesis and to strengthen local capacity to conduct clinical trials for interventions against neglected tropical diseases. TRIAL REGISTRATION: Pan-African Clinical Trials Registry PACTR202001919442161 . Retrospectively registered on 6 January 2020.

Reinfection rates, change in antibody titers and adverse events after COVID-19 vaccination among patients previously infected with COVID-19 in Metro Manila, Philippines: a secondary analysis of a completed cohort study.

BACKGROUND: Variation in immune response to COVID-19 vaccines is observed among different ethnicities. We aimed to describe the reinfection rates, change in antibody titers, and adverse events among Filipinos. METHODS: This is a secondary analysis of a cohort study of 307 participants within one year of having COVID-19 infection. We measured COVID-19 antibody levels at pre-determined timepoints (Days 21, 90, 180, 270, and 360 from initial infection). We monitored for COVID-19 symptoms and obtained details on COVID-19 vaccination. An adjudication committee classified the participants as probable, possible, or unlikely COVID-19 reinfection. We determined the probable reinfection rate, adverse events, and the geometric mean titer (GMT) ratio of pre- and post-vaccination antibody levels according to type and brand of COVID-19 vaccine. RESULTS: At the end of the follow-up period, 287 (93.5%) out of 307 study participants were fully vaccinated, 1 was partially vaccinated (0.3%), and 19 were unvaccinated (6.2%). Among the fully vaccinated participants, those given mRNA vaccines had the lowest reinfection rate (19.2 cases/100 person-years, 95% CI 9.6, 38.4), followed by viral vector vaccines (29.8 cases/100 person-years, 95% CI 16.9, 52.4). We observed the highest reinfection rate among those given inactivated virus vaccines (32.7 cases/100 person-years, 95% CI 23.6, 45.3). The reinfection rate was 8.6 cases/100 person-years (95% CI 4.1, 17.9) for unvaccinated participants and 3.6 cases/100 person-years (95% CI 0.5, 25.3) for partially vaccinated participants. We observed the largest rise in antibody titers among those given mRNA vaccines (GMT ratio 288.5), and the smallest rise among those given inactivated virus vaccines (GMT ratio 16.7). We observed the highest percentage of adverse events following immunization with viral vector vaccines (63.8%), followed by mRNA vaccines (62.7%), and the lowest for inactivated virus vaccines (34.7%). No serious adverse events were reported. CONCLUSION: Vaccinees given the mRNA vaccines had the lowest reinfection rate and the highest rise in antibody titers. Vaccinees given inactivated virus vaccines had the highest reinfection rate, smallest rise in antibody titers, and lowest percentage of adverse events. The small sample size and imbalanced distribution of the type of vaccines received limits the external generalizability of our results. STUDY REGISTRATION: The cohort study was registered at the Philippine Health Research Registry on December 14, 2020 (PHRR201214-003199).

Prevalence of mutations in the cysteine desulfurase IscS (Pfnfs1) gene in recurrent Plasmodium falciparum infections following artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DP) treatment in Matayos, Western Kenya.

BACKGROUND: Malaria remains a public health concern globally. Resistance to anti-malarial drugs has consistently threatened the gains in controlling the malaria parasites. Currently, artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DP) are the treatment regimens against Plasmodium falciparum infections in many African countries, including Kenya. Recurrent infections have been reported in patients treated with AL or DP, suggesting the possibility of reinfection or parasite recrudescence associated with the development of resistance against the two therapies. The Plasmodium falciparum cysteine desulfurase IscS (Pfnfs1) K65 selection marker has previously been associated with decreased lumefantrine susceptibility. This study evaluated the frequency of the Pfnfs1 K65 resistance marker and associated K65Q resistant allele in recurrent infections collected from P. falciparum-infected individuals living in Matayos, Busia County, in western Kenya. METHODS: Archived dried blood spots (DBS) of patients with recurrent malaria infection on clinical follow-up days after treatment with either AL or DP were used in the study. After extraction of genomic DNA, PCR amplification and sequencing analysis were employed to determine the frequencies of the Pfnfs1 K65 resistance marker and K65Q mutant allele in the recurrent infections. Plasmodium falciparum msp1 and P. falciparum msp2 genetic markers were used to distinguish recrudescent infections from new infections. RESULTS: The K65 wild-type allele was detected at a frequency of 41% while the K65Q mutant allele was detected at a frequency of 22% in the recurrent samples. 58% of the samples containing the K65 wild-type allele were AL treated samples and while 42% were DP treated samples. 79% of the samples with the K65Q mutation were AL treated samples and 21% were DP treated samples. The K65 wild-type allele was detected in three recrudescent infections (100%) identified from the AL treated samples. The K65 wild-type allele was detected in two recrudescent DP treated samples (67%) while the K65Q mutant allele was identified in one DP treated (33%) recrudescent sample. CONCLUSIONS: The data demonstrate a higher frequency of the K65 resistance marker in patients with recurrent infection during the study period. The study underscores the need for consistent monitoring of molecular markers of resistance in regions of high malaria transmission.

COVID-19 disease frequency, risk factors, and re-infection rates in patients with autoimmune rheumatic disease receiving rituximab.

INTRODUCTION: Rituximab, which is used in autoimmune rheumatic diseases (ARD), can cause both an increased risk of development of COVID-19 disease and re-infection due to its potent and long-acting immunosuppression. So, we aimed to evaluate the frequency, risk factors and re-infection rates of COVID-19 in ARD patients receiving rituximab. METHODS: A single-center retrospective study was performed with patients receiving rituximab for ARD in 12 months before the onset of COVID-19 in Turkey. The data regarding severe acute respiratory syndrome-coronavirus 2 reverse transcription polymerized chain reaction (RT-PCR) test, clinical, laboratory, and mortality data of all patients were collected from medical records. Logistic regression analysis was used for predictors of COVID-19 disease. COVID-19 re-infection was defined as RT-PCR positivity and recurrence of acute COVID-19 symptoms after at least 1 negative RT-PCR in patients with clinical improvement. RESULTS: Ninety-eight ARD patients with rituximab were evaluated and 23 (23%) of them had COVID-19. The presence of hypogammaglobulinemia increased the risk of COVID-19 disease 8-fold. COVID-19 pneumonia occurred in 13 (57%) and these patients' age was higher than those without pneumonia (59.6 ± 11.8 vs 44.9 ± 14.2 years, P = 0.013). Mortality due to COVID-19 was 13% and COVID-19 re-infection was seen in 20% of survivors. CONCLUSION: Regardless of the underlying rheumatic disease and organ involvements, hypogammaglobulinemia in ARD could be a risk factor for COVID-19 development, and advanced age could be for COVID-19 severity. Moreover, COVID-19 re-infection rates are high.

Progress of Hepatitis C elimination in Viennese people living with HIV after two decades of increasing cure rates.

BACKGROUND & AIMS: Interferon(IFN)-based hepatitis C virus (HCV) therapy has been replaced by direct-acting antivirals (DAAs). We assessed temporal trends in patient characteristics, transmission risks, treatment initiation, and cure rates in eras of IFN, restricted DAA-access, and unrestricted DAA-access in Viennese HCV/HIV-coinfected patients (HIV/HCV). METHODS: Consecutive HIV/HCV-coinfected patients starting HCV treatment at the Vienna General Hospital between 2002 and 2020 were retrospectively enrolled. RESULTS: Of all N = 508 HIV/HCV, 78% (398/508) were male and the mean age was 41.8 ± 9.5 years. 'People-who-inject-drugs' (PWID) accounted for 61% (311/508), while 31% (156/508) were 'men who have sex with men' (MSM). In the IFN-era, restricted DAA-era and unrestricted DAA-era, N = 152, N = 129, and N = 227 HCV treatments were started and 49% (74/152), 95% (122/129), and 88% (200/227) achieved sustained virologic response, respectively. Treatment during the IFN-era was a strong predictor for virologic non-response (aOR 12.69; 6.93-23.24) and loss-to-follow-up (aOR 6.12; 2.99-12.54), while virologic non-response was less common in 'MSM' (aOR 0.28; 0.13-0.62). Ninety three percent (50/54) of the observed HCV reinfections occurred in the unrestricted DAA-era. A substantial increase in 'MSM' transmission was observed since 2010 with 66% (107/161) in the DAA-era versus 15% (49/330) prior to the DAA-era. CONCLUSIONS: HCV cure rates in Viennese HIV patients increased from 49% in the IFN-era to 88-95% in the DAA-era. MSM-related risk behaviour and reinfections became the key challenges towards HCV elimination in HIV-coinfected patients.

Abatacept is second to rituximab at risk of HBsAg reverse seroconversion in patients with rheumatic disease.

BACKGROUND: Hepatitis B surface antigen (HBsAg) reverse seroconversion (RS) can happen in patients with rheumatoid arthritis (RA) with resolved hepatitis B (RHB) undergoing biological disease-modifying antirheumatic drugs (bDMARDs). But the incidence and risk factors need to be delineated. METHODS: From 2003 to 2019, 1937 patients with RA with available HBsAg and antibody to hepatitis B virus (HBV) core antigen data were retrospectively reviewed, and 489 patients with RHB undergoing bDMARDs treatment were identified. Factors associated with HBsAg RS were analysed. RESULTS: During 67 828 person-months of follow-up, 27 (5.5%) patients developed HBsAg RS after bDMARD treatment. As compared with those without HBsAg RS, patients with HBsAg RS were older, had lower frequency of antibody to HBsAg (anti-HBs), and lower baseline anti-HBs levels. In multivariate analysis, rituximab, abatacept and baseline negative for anti-HBs were the independent risk factors for HBsAg RS (adjusted HR: 87.76, 95% CI: 11.50 to 669.73, p<0.001; adjusted HR: 60.57, 95% CI: 6.99 to 525.15, p<0.001; adjusted HR: 5.15, 95% CI: 2.21 to 12.02, p<0.001, respectively). The risk of HBsAg RS was inversely related to the level of anti-HBs. Both rituximab and abatacept might result in anti-HBs loss, and abatacept had a cumulative incidence of HBsAg RS of 35.4%-62.5% in patients with low titers or negative of anti-HBs. CONCLUSIONS: Not only rituximab, but also abatacept has a high risk of HBV reactivation in patient with RA with RHB. Anti-HBs positivity cannot confer HBV reactivation-free status if the anti-HBs levels are not high enough for patients with RHB on rituximab and abatacept treatment.