Neena Valecha

Global extent of chloroquine-resistant Plasmodium vivax: a systematic review and meta-analysis.

Summary Background Chloroquine is the first-line treatment for Plasmodium vivax malaria in most endemic countries, but resistance is increasing. Monitoring of antimalarial efficacy is essential, but in P vivax infections the assessment of treatment efficacy is confounded by relapse from the dormant liver stages. We systematically reviewed P vivax malaria treatment efficacy studies to establish the global extent of chloroquine resistance. Methods We searched Medline, Web of Science, Embase, and the Cochrane Database of Systematic Reviews to identify studies published in English between Jan 1, 1960, and April 30, 2014, which investigated antimalarial treatment efficacy in P vivax malaria. We excluded studies that did not include supervised schizonticidal treatment without primaquine. We determined rates of chloroquine resistance according to P vivax malaria recurrence rates by day 28 whole-blood chloroquine concentrations at the time of recurrence and study enrolment criteria. Findings We identified 129 eligible clinical trials involving 21 694 patients at 179 study sites and 26 case reports describing 54 patients. Chloroquine resistance was present in 58 (53%) of 113 assessable study sites, spread across most countries that are endemic for P vivax. Clearance of parasitaemia assessed by microscopy in 95% of patients by day 2, or all patients by day 3, was 100% predictive of chloroquine sensitivity. Interpretation Heterogeneity of study design and analysis has confounded global surveillance of chloroquine-resistant P vivax, which is now present across most countries endemic for P vivax. Improved methods for monitoring of drug resistance are needed to inform antimalarial policy in these regions. Funding Wellcome Trust (UK).

Malaria in India: Challenges and opportunities

India contributes about 70% of malaria in the South East Asian Region of WHO. Although annually India reports about two million cases and 1000 deaths attributable to malaria, there is an increasing trend in the proportion of Plasmodium falciparum as the agent. There exists heterogeneity and variability in the risk of malaria transmission between and within the states of the country as many ecotypes/paradigms of malaria have been recognized. The pattern of clinical presentation of severe malaria has also changed and while multi-organ failure is more frequently observed in falciparum malaria, there are reports of vivax malaria presenting with severe manifestations. The high burden populations are ethnic tribes living in the forested pockets of the states like Orissa, Jharkhand, Madhya Pradesh, Chhattisgarh and the North Eastern states which contribute bulk of morbidity and mortality due to malaria in the country. Drug resistance, insecticide resistance, lack of knowledge of actual disease burden along with new paradigms of malaria pose a challenge for malaria control in the country. Considering the existing gaps in reported and estimated morbidity and mortality, need for estimation of true burden of malaria has been stressed. Administrative, financial, technical and operational challenges faced by the national programme have been elucidated. Approaches and priorities that may be helpful in tackling serious issues confronting malaria programme have been outlined.

A Multicenter Study of Azithromycin, Alone and in Combination with Chloroquine, for the Treatment of Acute Uncomplicated Plasmodium falciparum Malaria in India

BACKGROUND Azithromycin has demonstrated in vitro and in vivo activity against Plasmodium falciparum, but small treatment studies have given mixed results. METHODS Participants with fever and with both a blood smear and a rapid diagnostic test positive for falciparum malaria were randomly assigned to groups that were treated with either azithromycin or chloroquine or to matched groups receiving a placebo. After an interim analysis, open-label combination therapy with both drugs was initiated. RESULTS At day 28, 5 (33%) of 15 participants in the azithromycin-treated group had remained free of fever, compared with 4 (27%) of 15 in the chloroquine-treated group. All subsequently enrolled participants then received combination therapy with azithromycin and chloroquine. In 61 (97%) of 67 participants, resolution of fever and parasitemia had occurred by day 7, and, through day 28, no clinical or parasitologic relapse had occurred in them. CONCLUSIONS Resolution of parasitemia was inadequate with monotherapy with either azithromycin or chloroquine, but combination therapy provided substantially improved clinical and parasitologic outcomes. The combination of azithromycin and chloroquine may be an effective alternative treatment for falciparum malaria and deserves further study.

Antimalarial drug resistance of Plasmodium falciparum in India: changes over time and space

After the launch of the National Malaria Control Programme in 1953, the number of malaria cases reported in India fell to an all-time low of 0·1 million in 1965. However, the initial success could not be maintained and a resurgence of malaria began in the late 1960s. Resistance of Plasmodium falciparum to chloroquine was first reported in 1973 and increases in antimalarial resistance, along with rapid urbanisation and labour migration, complicated the challenge that Indias large geographical area and population size already pose for malaria control. Although several institutions have done drug-resistance monitoring in India, a complete analysis of countrywide data across institutions does not exist. We did a systematic review of P falciparum malaria drug-efficacy studies in India to summarise drug-resistance data and describe changes over the past 30 years to inform future policy. Continued use of chloroquine for treatment of P falciparum malaria in India will likely be ineffective. Resistance to sulfa-pyrimethamine should be closely monitored to protect the effectiveness of treatment with artesunate plus sulfadoxine-pyrimethamine, which is the new first-line treatment for P falciparum malaria. Strategies to reduce the emergence and spread of future drug resistance need to be proactive and supported by intensive monitoring.

Malaria in India: The Center for the Study of Complex Malaria in India

Malaria is a major public health problem in India and one which contributes significantly to the overall malaria burden in Southeast Asia. The National Vector Borne Disease Control Program of India reported ∼1.6 million cases and ∼1100 malaria deaths in 2009. Some experts argue that this is a serious underestimation and that the actual number of malaria cases per year is likely between 9 and 50 times greater, with an approximate 13-fold underestimation of malaria-related mortality. The difficulty in making these estimations is further exacerbated by (i) highly variable malaria eco-epidemiological profiles, (ii) the transmission and overlap of multiple Plasmodium species and Anopheles vectors, (iii) increasing antimalarial drug resistance and insecticide resistance, and (iv) the impact of climate change on each of these variables. Simply stated, the burden of malaria in India is complex. Here we describe plans for a Center for the Study of Complex Malaria in India (CSCMi), one of ten International Centers of Excellence in Malaria Research (ICEMRs) located in malarious regions of the world recently funded by the National Institute of Allergy and Infectious Diseases, National Institutes of Health. The CSCMi is a close partnership between Indian and United States scientists, and aims to address major gaps in our understanding of the complexity of malaria in India, including changing patterns of epidemiology, vector biology and control, drug resistance, and parasite genomics. We hope that such a multidisciplinary approach that integrates clinical and field studies with laboratory, molecular, and genomic methods will provide a powerful combination for malaria control and prevention in India.

Histopathology of fatal respiratory distress caused by Plasmodium vivax malaria.

An otherwise healthy 20-year-old woman in Goa, India, received antibiotics after a diagnosis of upper respiratory tract infection. One week later, vivax malaria was diagnosed at a health center, but the patient developed respiratory distress and lost consciousness. She arrived at emergency department in shock, breathless, and comatose. She died within minutes. Two independent laboratories later confirmed Plasmodium vivax by microscopy (140,000/microL) and by nested and real-time polymerase chain reaction methods. Post-mortem examination showed congestion of alveolar capillaries by heavy monocytic infiltrates, along with diffuse damage to alveolar membranes consistent with acute respiratory distress syndrome. Parasites seen in lung tissue were roughly proportionate to both peripheral hyperparasitemia and those seen in other organs without lesions. In this patient, vivax malaria caused a rapidly fatal respiratory distress.

Genetic deletion of HRP2 and HRP3 in Indian Plasmodium falciparum population and false negative malaria rapid diagnostic test.

Genetic polymorphisms in diagnostic antigens are important factors responsible for variable performance of rapid diagnostic tests. Additionally, the failure of antigen expression due to gene deletion may also contribute to variable performance. We report Indian Plasmodium falciparum field isolates lacking both Pfhrp2 and Pfhrp3 genes leading to false negative results of rapid diagnostic tests. The study highlights need to determine the prevalence of P. falciparum isolates lacking these genes in larger field populations in India.

Pyronaridine-Artesunate versus Chloroquine in Patients with Acute Plasmodium vivax Malaria: A Randomized, Double-Blind, Non-Inferiority Trial

Background New antimalarials are needed for P. vivax and P. falciparum malaria. This study compared the efficacy and safety of pyronaridine-artesunate with that of chloroquine for the treatment of uncomplicated P. vivax malaria. Methods and Findings This phase III randomized, double-blind, non-inferiority trial included five centers across Cambodia, Thailand, India, and Indonesia. In a double-dummy design, patients (aged >3–≤60 years) with microscopically confirmed P. vivax mono-infection were randomized (1∶1) to receive pyronaridine-artesunate (target dose 7.2∶2.4 mg/kg to 13.8∶4.6 mg/kg) or chloroquine (standard dose) once daily for three days. Each treatment group included 228 randomized patients. Outcomes for the primary endpoint, Day-14 cure rate in the per-protocol population, were 99.5%, (217/218; 95%CI 97.5, 100) with pyronaridine-artesunate and 100% (209/209; 95%CI 98.3, 100) with chloroquine. Pyronaridine was non-inferior to chloroquine: treatment difference −0.5% (95%CI −2.6, 1.4), i.e., the lower limit of the 2-sided 95%CI for the treatment difference was greater than −10%. Pyronaridine-artesunate cure rates were non-inferior to chloroquine for Days 21, 28, 35 and 42. Parasite clearance time was shorter with pyronaridine-artesunate (median 23.0 h) versus chloroquine (32.0 h; p<0.0001), as was fever clearance time (median 15.9 h and 23.8 h, respectively; p = 0.0017). Kaplan-Meier estimates of post-baseline P. falciparum infection incidence until Day 42 were 2.5% with pyronaridine-artesunate, 6.1% with chloroquine (p = 0.048, log-rank test). Post-baseline P. vivax or P. falciparum infection incidence until Day 42 was 6.8% and 12.4%, respectively (p = 0.022, log rank test). There were no deaths. Adverse events occurred in 92/228 (40.4%) patients with pyronaridine-artesunate and 72/228 (31.6%) with chloroquine. Mild and transient increases in hepatic enzymes were observed for pyronaridine-artesunate. Conclusion Pyronaridine-artesunate efficacy in acute uncomplicated P. vivax malaria was at least that of chloroquine. As pyronaridine-artesunate is also efficacious against P. falciparum malaria, this combination has potential utility as a global antimalarial drug. Trial registration Clinicaltrials.gov NCT00440999

Field evaluation of the ICT Malaria P.f/P.v immunochromatographic test for diagnosis of Plasmodium falciparum and P.vivax infection in forest villages of Chhindwara, central India

Summary A rapid new immunochromatographic test (ICT malaria P.f/P.v) for diagnosis of Plasmodium falciparum and P.vivax was evaluated against thick blood smears in forest villages of Chhindwara, Madhya Pradesh, where both Plasmodium falciparum and P.vivax are prevalent. 344 symptomatic patients (Gond ethnic tribe) in five villages were screened by field staff of the Malaria Research Centre in October 1999. For P.falciparum, the ICT was 97.5% sensitive and 88% specific, with a positive predictive value (PPV) of 87.6% and a negative predictive value (NPV) of 97.6%. For P.vivax the sensitivity was only 72%, the specificity 99%, with a PPV of 92% and an NPV of 96%. Although a negative test result was inadequate to exclude parasitaemia ≤ 300/μl for P.falciparum and ≤ 1500/μl for P.vivax, the test is potentially useful in remote areas.

An Open-Label, Randomised Study of Dihydroartemisinin-Piperaquine Versus Artesunate-Mefloquine for Falciparum Malaria in Asia

Background The artemisinin-based combination treatment (ACT) of dihydroartemisinin (DHA) and piperaquine (PQP) is a promising novel anti-malarial drug effective against multi-drug resistant falciparum malaria. The aim of this study was to show non-inferiority of DHA/PQP vs. artesunate-mefloquine (AS+MQ) in Asia. Methods and Findings This was an open-label, randomised, non-inferiority, 63-day follow-up study conducted in Thailand, Laos and India. Patients aged 3 months to 65 years with Plasmodium falciparum mono-infection or mixed infection were randomised with an allocation ratio of 2∶1 to a fixed-dose DHA/PQP combination tablet (adults: 40 mg/160 mg; children: 20 mg/320 mg; n = 769) or loose combination of AS+MQ (AS: 50 mg, MQ: 250 mg; n = 381). The cumulative doses of study treatment over the 3 days were of about 6.75 mg/kg of DHA and 54 mg/kg of PQP and about 12 mg/kg of AS and 25 mg/kg of MQ. Doses were rounded up to the nearest half tablet. The primary endpoint was day-63 polymerase chain reaction (PCR) genotype-corrected cure rate. Results were 87.9% for DHA/PQP and 86.6% for AS+MQ in the intention-to-treat (ITT; 97.5% one-sided confidence interval, CI: >−2.87%), and 98.7% and 97.0%, respectively, in the per protocol population (97.5% CI: >−0.39%). No country effect was observed. Kaplan-Meier estimates of proportions of patients with new infections on day 63 (secondary endpoint) were significantly lower for DHA/PQP than AS+MQ: 22.7% versus 30.3% (p = 0.0042; ITT). Overall gametocyte prevalence (days 7 to 63; secondary endpoint), measured as person-gametocyte-weeks, was significantly higher for DHA/PQP than AS+MQ (10.15% versus 4.88%; p = 0.003; ITT). Fifteen serious adverse events were reported, 12 (1.6%) in DHA/PQP and three (0.8%) in AS+MQ, among which six (0.8%) were considered related to DHA/PQP and three (0.8%) to AS+MQ. Conclusions DHA/PQP was a highly efficacious drug for P. falciparum malaria in areas where multidrug parasites are prevalent. The DHA/PQP combination can play an important role in the first-line treatment of uncomplicated falciparum malaria. Trial Registration Controlled-Trials.com ISRCTN81306618