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The Lancet. Infectious Diseases Jun 2018Primaquine and methylene blue are gametocytocidal compounds that could prevent Plasmodium falciparum transmission to mosquitoes. We aimed to assess the efficacy and... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Primaquine and methylene blue are gametocytocidal compounds that could prevent Plasmodium falciparum transmission to mosquitoes. We aimed to assess the efficacy and safety of primaquine and methylene blue in preventing human to mosquito transmission of P falciparum among glucose-6-phosphate dehydrogenase (G6PD)-normal, gametocytaemic male participants.
METHODS
This was a phase 2, single-blind, randomised controlled trial done at the Clinical Research Centre of the Malaria Research and Training Centre (MRTC) of the University of Bamako (Bamako, Mali). We enrolled male participants aged 5-50 years with asymptomatic P falciparum malaria. G6PD-normal participants with gametocytes detected by blood smear were randomised 1:1:1:1 in block sizes of eight, using a sealed-envelope design, to receive either sulfadoxine-pyrimethamine and amodiaquine, sulfadoxine-pyrimethamine and amodiaquine plus a single dose of 0·25 mg/kg primaquine, dihydroartemisinin-piperaquine, or dihydroartemisinin-piperaquine plus 15 mg/kg per day methylene blue for 3 days. Laboratory staff, investigators, and insectary technicians were masked to the treatment group and gametocyte density of study participants. The study pharmacist and treating physician were not masked. Participants could request unmasking. The primary efficacy endpoint, analysed in all infected patients with at least one infectivity measure before and after treatment, was median within-person percentage change in mosquito infectivity 2 and 7 days after treatment, assessed by membrane feeding. This study is registered with ClinicalTrials.gov, number NCT02831023.
FINDINGS
Between June 27, 2016, and Nov 1, 2016, 80 participants were enrolled and assigned to the sulfadoxine-pyrimethamine and amodiaquine (n=20), sulfadoxine-pyrimethamine and amodiaquine plus primaquine (n=20), dihydroartemisinin-piperaquine (n=20), or dihydroartemisinin-piperaquine plus methylene blue (n=20) groups. Among participants infectious at baseline (54 [68%] of 80), those in the sulfadoxine-pyrimethamine and amodiaquine plus primaquine group (n=19) had a median 100% (IQR 100 to 100) within-person reduction in mosquito infectivity on day 2, a larger reduction than was noted with sulfadoxine-pyrimethamine and amodiaquine alone (n=12; -10·2%, IQR -143·9 to 56·6; p<0·0001). The dihydroartemisinin-piperaquine plus methylene blue (n=11) group had a median 100% (IQR 100 to 100) within-person reduction in mosquito infectivity on day 2, a larger reduction than was noted with dihydroartemisinin-piperaquine alone (n=12; -6·0%, IQR -126·1 to 86·9; p<0·0001). Haemoglobin changes were similar between gametocytocidal arms and their respective controls. After exclusion of blue urine, adverse events were similar across all groups (59 [74%] of 80 participants had 162 adverse events overall, 145 [90%] of which were mild).
INTERPRETATION
Adding a single dose of 0·25 mg/kg primaquine to sulfadoxine-pyrimethamine and amodiaquine or 3 days of 15 mg/kg per day methylene blue to dihydroartemisinin-piperaquine was highly efficacious for preventing P falciparum transmission. Both primaquine and methylene blue were well tolerated.
FUNDING
Bill & Melinda Gates Foundation, European Research Council.
Topics: Adolescent; Adult; Amodiaquine; Artemisinins; Child; Child, Preschool; Drug Combinations; Humans; Malaria, Falciparum; Mali; Methylene Blue; Middle Aged; Plasmodium falciparum; Primaquine; Pyrimethamine; Quinolines; Sulfadoxine; Young Adult
PubMed: 29422384
DOI: 10.1016/S1473-3099(18)30044-6 -
Malaria Journal Jun 2019Routine surveillance on the therapeutic efficacy of artemisinin-based combination therapy (ACT) has been ongoing in Ghana since 2005. The sixth round of surveillance was...
BACKGROUND
Routine surveillance on the therapeutic efficacy of artemisinin-based combination therapy (ACT) has been ongoing in Ghana since 2005. The sixth round of surveillance was conducted between 2015 and 2017 to determine the therapeutic efficacy of artesunate-amodiaquine (AS-AQ) and artemether-lumefantrine (AL) in 10 sentinel sites across the country.
METHODS
The study was a one-arm, prospective, evaluation of the clinical, parasitological, and haematological responses to directly observed treatment with AS-AQ and AL among children 6 months to 9 years old with uncomplicated falciparum malaria. The WHO 2009 protocol on surveillance of anti-malaria drug efficacy was used for the study with primary outcomes as prevalence of day 3 parasitaemia and clinical and parasitological cure rates on day 28. Secondary outcomes assessed included patterns of fever and parasite clearance as well as changes in haemoglobin concentration.
RESULTS
Day 3 parasitaemia was absent in all sites following treatment with AS-AQ whilst only one person (0.2%) was parasitaemic on day 3 following treatment with AL. Day 28 PCR-corrected cure rates following treatment with AS-AQ ranged between 96.7% (95% CI 88.5-99.6) and 100%, yielding a national rate of 99.2% (95% CI 97.7-99.7). Day 28 PCR-corrected cure rates following treatment with AL ranged between 91.3% (95% CI 79.2-97.6) and 100%, yielding a national rate of 96% (95% CI 93.5-97.6). Prevalence of fever declined by 88.4 and 80.4% after first day of treatment with AS-AQ and AL, respectively, whilst prevalence of parasitaemia on day 2 was 2.1% for AS-AQ and 1.5% for AL. Gametocytaemia was maintained at low levels (< 5%) during the 3 days of treatment. Post-treatment mean haemoglobin concentration was significantly higher than pre-treatment concentration following treatment with either AS-AQ or AL.
CONCLUSIONS
The therapeutic efficacy of AS-AQ and AL is over 90% in sentinel sites across Ghana. The two anti-malarial drugs therefore remain efficacious in the treatment of uncomplicated malaria in the country and continue to achieve rapid fever and parasite clearance as well as low gametocyte carriage rates and improved post-treatment mean haemoglobin concentration.
Topics: Amodiaquine; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; Drug Combinations; Female; Ghana; Humans; Infant; Malaria, Falciparum; Male; Prospective Studies; Treatment Outcome
PubMed: 31234874
DOI: 10.1186/s12936-019-2848-1 -
Antiviral Research Dec 2018Ebola virus disease is a severe disease caused by highly pathogenic Ebolaviruses. Although it shows a high mortality rate in humans, currently there is no licensed...
Ebola virus disease is a severe disease caused by highly pathogenic Ebolaviruses. Although it shows a high mortality rate in humans, currently there is no licensed therapeutic. During the recent epidemic in West Africa, it was demonstrated that administration of antimalarial medication containing amodiaquine significantly lowered mortality rate of patients infected with the virus. Here, in order to improve its antiviral activity, a series of amodiaquine derivatives were synthesized and tested for Ebola virus infection. We found that multiple compounds were more potent than amodiaquine. The structure-activity relationship analysis revealed that the two independent parts, which are the alkyl chains extending from the aminomethyl group and a halogen bonded to the quinoline ring, were keys for enhancing antiviral potency without increasing toxicity. When these modifications were combined, the antiviral efficacy could be further improved with the selectivity indexes being over 10-times higher than amodiaquine. Mechanistic evaluation demonstrated that the potent derivatives blocked host cell entry of Ebola virus, like the parental amodiaquine. Taken together, our work identified novel potent amodiaquine derivatives, which will aid in further development of effective antiviral therapeutics.
Topics: Amodiaquine; Antimalarials; Antiviral Agents; Ebolavirus; Structure-Activity Relationship; Virus Internalization
PubMed: 30395872
DOI: 10.1016/j.antiviral.2018.10.025 -
Malaria Journal Feb 2022In 2012, seasonal malaria chemoprevention (SMC) was recommended as policy for malaria control by the World Health Organization (WHO) in areas of highly seasonal malaria...
Effect of three years' seasonal malaria chemoprevention on molecular markers of resistance of Plasmodium falciparum to sulfadoxine-pyrimethamine and amodiaquine in Ouelessebougou, Mali.
BACKGROUND
In 2012, seasonal malaria chemoprevention (SMC) was recommended as policy for malaria control by the World Health Organization (WHO) in areas of highly seasonal malaria transmission across the Sahel sub-region in Africa along with monitoring of drug resistance. We assessed the long-term impact of SMC on Plasmodium falciparum resistance to sulfadoxine-pyrimethamine (SP) and amodiaquine (AQ) over a 3-year period of SMC implementation in the health district of Ouelessebougou, Mali.
METHODS
In 8 randomly selected sub-districts of Ouelessebougou, Mali, children aged 0-5 years were randomly selected during cross-sectional surveys at baseline (August 2014) and 1, 2 and 3 years post-SMC, at the beginning and end of the malaria transmission season. Blood smears and blood spots on filter paper were obtained and frequencies of mutation in P. falciparum genes related to resistance to SP and AQ (Pfdhfr, Pfdhps, Pfmdr1, and Pfcrt) were assessed by PCR amplification on individual samples and PCR amplification followed by deep sequencing on pooled (by site and year) samples.
RESULTS
At each survey, approximately 50-100 individual samples were analysed by PCR amplification and a total of 1,164 samples were analysed by deep sequencing with an average read depth of 18,018-36,918 after pooling by site and year. Most molecular markers of resistance did not increase in frequency over the period of study (2014-2016). After 3 years of SMC, the frequencies of Pfdhps 540E, Pfdhps 437G and Pfcrt K76T remained similar compared to baseline (4.0 vs 1.4%, p = 0.41; 74.5 vs 64.6%, p = 0.22; 71.3 vs 67.4%, p = 0.69). Nearly all samples tested carried Pfdhfr 59R, and this proportion remained similar 3 years after SMC implementation (98.8 vs 100%, p = 1). The frequency of Pfmdr1 N86Y increased significantly over time from 5.6% at baseline to 18.6% after 3 years of SMC (p = 0.016). Results of pooled analysis using deep sequencing were consistent with those by individual analysis with standard PCR, but also indicated for the first time the presence of mutations at the Pfdhps A581G allele at a frequency of 11.7% after 2 years of SMC, as well as the Pfdhps I431V allele at frequencies of 1.6-9.3% following 1 and 2 years of SMC, respectively.
CONCLUSION
Two and 3 years of SMC implementation were associated with increased frequency of the Pfmdr1 N86Y mutation but not Pfdhps 540E, Pfdhps 437G and Pfcrt K76T. The first-time detection of the Pfdhps haplotype bearing the I431V and A581G mutations in Mali, even at low frequency, warrants further long-term surveillance.
Topics: Amodiaquine; Antimalarials; Chemoprevention; Child; Child, Preschool; Cross-Sectional Studies; Drug Combinations; Drug Resistance; Humans; Infant; Infant, Newborn; Malaria; Malaria, Falciparum; Mali; Plasmodium falciparum; Pyrimethamine; Seasons; Sulfadoxine
PubMed: 35135546
DOI: 10.1186/s12936-022-04059-z -
Malaria Journal Oct 2018Artemisinin-based combination therapy (ACT) is the first-line anti-malarial treatment of uncomplicated malaria in most malaria endemic countries, including Tanzania....
BACKGROUND
Artemisinin-based combination therapy (ACT) is the first-line anti-malarial treatment of uncomplicated malaria in most malaria endemic countries, including Tanzania. Unfortunately, there have been reports of artemisinin resistance and ACT failure from South East Asia highlighting the need to monitor therapeutic efficacy of ACT in these countries as recommended by World Health Organization.
METHODS
Open-label single arm studies in mainland Tanzania were conducted in nine sentinel sites in 2011, 2012 and 2015 to assess the efficacy and safety of artemether/lumefantrine (AL) and artesunate/amodiaquine (ASAQ) using 28 days follow-up and dihydroartemisinin/piperaquine (DHAPQ) using 42 days follow-up. Mutations in the propeller domain of the Plasmodium falciparum kelch 13 (k13) gene and amplification of the P. falciparum plasmepsin 2 (pm2) gene, associated with artemisinin and piperaquine (PQ) resistance, were also investigated.
RESULTS
Of the 428 patients enrolled, 328 patients provided study endpoint. For AL, the PCR corrected per-protocol analysis showed adequate clinical and parasitological response (ACPR) of 90.3% (n = 28; 95% CI 74.2-98.0) in Kyela 2012, 95.7% (n = 22; 95% CI 78.1-99.0) in Chamwino, 100% in Muheza (n = 29; 95% CI 88.1-100), 100% in Nagaga (n = 39; 95% CI 91.0-100) and Kyela 2015 (n = 60; 95% CI 94.0-100). For ASAQ, PCR corrected ACPR of 98% (n = 49; 95% CI 89.4-99.9) and 100% (n = 25; 95% CI 86.3-100) were observed in 2011 in Ujiji and Kibaha, respectively. For DHAPQ, the ACPR was 100% (n = 71; 95% CI 94.9-100). Of the 235 samples with genetic interpretable results, only 7 (3%) had non-synonymous k13 mutations. None of these are candidate or validated markers of artemisinin resistance and all patients carrying these alleles cleared the parasites on day 3. Of the DHAPQ group, 10% (3/29) of the samples with interpretable results had pm2 multiple copies and none of them was associated with treatment failure.
CONCLUSION
All the tested ACT in mainland Tanzania were highly efficacious and none of validated k13 mutants associated with artemisinin resistance was observed. However, three isolates with multiple copy numbers of pm2 gene associated with PQ resistance among the limited samples tested successfully calls for further investigation. Trial registration Number ACTRN12615000159550. Registered 18th February 2015, https://www.anzctr.org.au/trial/MyTrial.aspx.
Topics: Adolescent; Amodiaquine; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; Drug Combinations; Female; Humans; Infant; Malaria, Falciparum; Male; Plasmodium falciparum; Prospective Studies; Quinolines; Tanzania
PubMed: 30333022
DOI: 10.1186/s12936-018-2524-x -
Design, Implementation, and Coordination of Malaria Therapeutic Efficacy Studies in Nigeria in 2018.The American Journal of Tropical... Jun 2023Prior to 2018, malaria therapeutic efficacy studies (TESs) in Nigeria were implemented separately at different sites, as assigned by the National Malaria Elimination...
Prior to 2018, malaria therapeutic efficacy studies (TESs) in Nigeria were implemented separately at different sites, as assigned by the National Malaria Elimination Program (NMEP). In 2018, however, the NMEP engaged the Nigerian Institute of Medical Research to coordinate the 2018 TESs in 3 of 14 sentinel sites with the objective of standardizing their conduct across all three sites: Enugu, Kano, and Plateau states in three of six geopolitical zones. Artemether-lumefantrine and artesunate-amodiaquine, the two first-line drugs for treatment of acute uncomplicated malaria in Nigeria, were tested in both Kano and Plateau states. In Enugu State, however, artemether-lumefantrine and dihydroartemisinin-piperaquine were the test drugs, with dihydroartemisinin-piperaquine being tested for potential inclusion in Nigerian treatment policy. The TES was conducted in 6-month to 8-year-old children and was funded by the Global Fund with additional support from the WHO. A multipartite core team comprised of the NMEP, the WHO, the U.S. Presidential Malaria Initiative, academia, and the Nigerian Institute of Medical Research was set up to oversee the execution of the 2018 TES. This communication reports best practices adopted to guide its coordination, and lessons learned during in the process, including applying developed standard operating procedures, powering the sample size adequately for each site to report independently, training the investigating team for fieldwork, facilitating stratification of decisions, determining efficiencies derived from monitoring and quality assessment, and optimizing logistics. The planning and coordination of the 2018 TES activities is a model of a consultative process for the sustainability of antimalarial resistance surveillance in Nigeria.
Topics: Child; Humans; Antimalarials; Nigeria; Malaria, Falciparum; Artemether; Drug Combinations; Artemether, Lumefantrine Drug Combination; Malaria; Amodiaquine; Ethanolamines; Fluorenes
PubMed: 37094786
DOI: 10.4269/ajtmh.21-1261 -
The Cochrane Database of Systematic... Jan 2006Artemisinin-based combination treatments are strongly advocated, but supplies are limited. Sulfadoxine combined with amodiaquine is an alternative non-artemisinin... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Artemisinin-based combination treatments are strongly advocated, but supplies are limited. Sulfadoxine combined with amodiaquine is an alternative non-artemisinin combination.
OBJECTIVES
To compare sulfadoxine-pyrimethamine plus amodiaquine (SP plus AQ) with sulfadoxine-pyrimethamine plus artesunate (SP plus AS) for treating uncomplicated Plasmodium falciparum malaria.
SEARCH STRATEGY
We searched the Cochrane Infectious Diseases Group Specialized Register (October 2005), CENTRAL (The Cochrane Library 2005, Issue 4), MEDLINE (1966 to October 2005), EMBASE (1988 to October 2005), LILACS (October 2005), and reference lists. We also contacted researchers and organizations working in this field.
SELECTION CRITERIA
Randomized controlled trials comparing SP plus AS with SP plus AQ for treating uncomplicated P. falciparum malaria.
DATA COLLECTION AND ANALYSIS
Two authors independently applied the inclusion criteria, extracted data, and assessed methodological quality. The primary outcome measure was treatment failure (parasitological or clinical evidence of treatment failure between start of treatment and day 28). We calculated the relative risk (RR) with 95% confidence intervals (CI) for dichotomous data.
MAIN RESULTS
Four trials (775 participants) met the inclusion criteria. All were from areas of high and seasonal malaria transmission in Africa. Fewer participants using SP plus AQ failed treatment by day 28 (RR 0.59, 95% CI 0.42 to 0.83; 652 participants, 3 trials). Even excluding new infections, SP plus AQ performed better (RR 0.62, 95% CI 0.40 to 0.96; 649 participants, 3 trials). There was no statistically significant difference between the two treatments for treatment failure at day 14 (RR 1.14, 95% CI 0.47 to 2.78; 775 participants, 4 trials). SP plus AS was more effective at reducing gametocyte carriage at day seven (RR 2.31, 95% CI 1.36 to 3.92; 220 participants, 1 trial). One trial reported that one person - in the SP plus AQ group - developed severe malaria. Adverse events were poorly reported, but did not seem to differ in type and number between the two treatment combinations.
AUTHORS' CONCLUSIONS
SP plus AQ performed better at controlling treatment failure at day 28, but was not as good as SP plus AS at reducing gametocyte carriage at day seven. Careful consideration of local resistance patterns is required because resistance to sulfadoxine-pyrimethamine and amodiaquine are high in many areas. In order to delay development of resistance to artesunate, the combination with sulfadoxine-pyrimethamine should only be considered where both drugs are known to be effective. Data on adverse events are still lacking.
Topics: Amodiaquine; Artemisinins; Artesunate; Drug Combinations; Drug Therapy, Combination; Humans; Malaria, Falciparum; Pyrimethamine; Randomized Controlled Trials as Topic; Sesquiterpenes; Sulfadoxine
PubMed: 16437507
DOI: 10.1002/14651858.CD004966.pub2 -
The Pan African Medical Journal 2020Artemether-lumefantrine (AL) and artesunate-amodiaquine (ASAQ) are the first line therapy of uncomplicated malaria in Burkina Faso. We assessed the treatment efficacy,... (Comparative Study)
Comparative Study Randomized Controlled Trial
INTRODUCTION
Artemether-lumefantrine (AL) and artesunate-amodiaquine (ASAQ) are the first line therapy of uncomplicated malaria in Burkina Faso. We assessed the treatment efficacy, tolerability of these drugs 11 years following its adoption as first line treatment.
METHODS
In this opened randomized controlled trial carried out in 2016, participants with age over 6 months who consented to participate were randomly assigned treatment with artemether-lumefantrine or artesunate-amodiaquine and followed up for 28 days. Primary endpoint was the treatment efficacy over 28 days of follow up unadjusted by Polymerase chain reaction (PCR).
RESULTS
Two hundred and eighty-one (281) participants were enrolled and the completion rate was 92.9%. No early treatment failure was found. Adequate clinical and parasitological responses were significantly higher in artesunate-amodiaquine group (97% versus 85.2%, p = 0.0008). On day 28, the risk of failure was 4 times higher in AL group 20.14%, 95% CI (13-30.47) against 5.16%, 95% CI (1.91-13.54) in ASAQ group. All treatments had a similar and good tolerability profile.
CONCLUSION
Eleven years following artemether-lumefantrine and artesunate-amodiaquine adoption as first line therapy for uncomplicated malaria in Burkina Faso, artemether-lumefantrine retained fairly good efficacy even though its efficacy fell below WHO threshold of 90% considering uncorrected outcome.
Topics: Adolescent; Amodiaquine; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Burkina Faso; Child; Child, Preschool; Drug Combinations; Female; Follow-Up Studies; Humans; Infant; Malaria; Male; Polymerase Chain Reaction; Treatment Failure; Treatment Outcome
PubMed: 32537072
DOI: 10.11604/pamj.2020.35.68.20849 -
Antimicrobial Agents and Chemotherapy Mar 2010Sulfadoxine-pyrimethamine with amodiaquine (SP-AQ) is a highly efficacious regimen for intermittent preventive treatment to prevent malaria in children (IPTc), but the... (Clinical Trial)
Clinical Trial
Sulfadoxine-pyrimethamine with amodiaquine (SP-AQ) is a highly efficacious regimen for intermittent preventive treatment to prevent malaria in children (IPTc), but the amodiaquine component is not always well tolerated. We determined the association between amodiaquine dosage by body weight and mild adverse events (AEs) and investigated whether alternative age-based regimens could improve dosing accuracy and tolerability, using data from two trials of IPTc in Senegal, one in which AQ dose was determined by age and the other in which it was determined by weight category. Both dosage strategies resulted in some children receiving AQ doses above the recommended therapeutic range. The odds of vomiting increased with increasing amodiaquine dosage. In one study, incidence of fever also increased with increasing dosage. Anthropometric data from 1,956 children were used to predict the dosing accuracy of existing and optimal alternative regimens. Logistic regression models describing the probability of AEs by dosage were used to predict the potential reductions in mild AEs for each regimen. Simple amendments to current AQ dosing schedules based on the child's age could substantially increase dosing accuracy and thus improve the tolerability of IPTc using SP-amodiaquine in situations where weighing the child is impractical.
Topics: Age Factors; Amodiaquine; Antimalarials; Body Weight; Child; Child, Preschool; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Combinations; Drug Therapy, Combination; Humans; Infant; Malaria; Pyrimethamine; Seasons; Sulfadoxine; Treatment Outcome
PubMed: 20065053
DOI: 10.1128/AAC.01161-09 -
Antimicrobial Agents and Chemotherapy Nov 2004The in vitro activity of the prodrug amodiaquine and its metabolite monodesethyl-amodiaquine has been studied for three strains of Plasmodium falciparum: LS-2, LS-3, and...
The in vitro activity of the prodrug amodiaquine and its metabolite monodesethyl-amodiaquine has been studied for three strains of Plasmodium falciparum: LS-2, LS-3, and LS-1. Both compounds showed significant activity against all three strains; the activity of amodiaquine was slightly higher than that of the metabolite. By use of a checkerboard design, interaction studies with both compounds yielded evidence of significant synergism; means of the sums of the fractional inhibitory concentrations were 0.0392 to 0.0746 for strain LS-2, 0.1567 to 0.3102 for strain LS-3, and 0.025 to 0.3369 for strain LS-1. In further investigations, the interaction of amodiaquine with monodesethyl-amodiaquine was tested at clinically relevant concentrations of both compounds. In these studies, involving amodiaquine at picomolar and femtomolar concentrations, the compound was found to exert high potentiating activity on monodesethyl-amodiaquine. This interaction produced mean ratios of observed to expected activity of 0.0505 to 0.0642 for strain LS-2, 0.0882 to 0.3820 for strain LS-3, and 0.0752 to 0.2924 for strain LS-1. The synergistic activity was most marked at monodesethyl-amodiaquine/amodiaquine ratios up to 100,000:1 but was still evident at higher ratios.
Topics: Amodiaquine; Animals; Antimalarials; Culture Media; Drug Synergism; Genes, MDR; Genotype; Membrane Proteins; Membrane Transport Proteins; Plasmodium falciparum; Protozoan Proteins; Reverse Transcriptase Polymerase Chain Reaction
PubMed: 15504826
DOI: 10.1128/AAC.48.11.4089-4096.2004