We estimated MQ + AS efficacy to treat patients with uncomplicated P. falciparum
malaria to be 98.9% in the Peruvian Amazon four years after the implementation of this drug combination as first-line antimalarial treatment. Effectiveness was also evaluated and estimated to be 100%, and there was no statistically significant difference with efficacy. This evidence shows that efficacy and effectiveness are high and indicates a good treatment response to this regimen whether patients are instructed to take it by themselves or as part of a DOT strategy. In addition, all patients were negative for asexual parasites on day 3, which is indicative of high parasite's sensitivity to this regimen and artemisinin derivatives.13
Our results are consistent with evaluations of MQ + AS in the study region conducted in the past few years. A 28-day in vivo
efficacy study of MQ + AS in Iquitos, Peru in 2000 included 98 patients who randomly received either MQ alone or MQ + AS.2
Mefloquine as monotherapy and MQ + AS combination efficacies were estimated to be 100%. A more recent MQ + AS evaluation in the same region evaluated efficacy and pharmacokinetics of three commercial brands of MQ (Lariam®
, and Mefloquina-AC®
Farma) given in combination with AS against P. falciparum
over a 56-day follow-up period in 2004–2005.14
Efficacy for all three arms was 100%. Similar to our findings, all patients had cleared parasitemia by day 3, except one patient in the Mefloquina-AC®
Farma study, who cleared parasitemia on day 4 only.
In addition to fast parasite clearance, artemisinin-based combination therapy is recommended to slow the emergence and spread of drug resistance. This effect is achieved by the use of antimalarial drugs with different mechanisms of action and the use of a fast-acting highly effective antimalarial drug, such as AS, in combination with a long-lasting antimalarial drug, such as MQ. This combination has been associated with reduced selection of drug-resistant parasites, especially to MQ.15,16
Currently, WHO recommends the use of combination therapies based on artemisinin derivatives to counter the threat of drug resistance of P. falciparum
to monotherapies and to improve compliance to treatment regimens by decreasing the total number of treatment days.
A change in national antimalarial policy is often a complex matter. In the case of Peru, this process started when healthcare workers began to notice increasing rates of treatment failures with chloroquine (CQ) in the early 1990s, increasing the possibility of drug resistance.3
In 1996, SP became the interim first-line antimalarial policy in the Peruvian Amazon Basin until more data on efficacy could be obtained. The antimalarial policy was then changed in 2001, when MQ + AS was adopted as first-line treatment of this region in Peru, although this policy was fully implemented only in 2003. Several factors were taken into account during this process and were, to some extent, responsible for the success of this move. These factors included a collaborative effort by local, national, and international partners; inclusion of district-level healthcare workers and directors throughout the process; and use of standardized protocols to obtain data on antimalarial efficacy. In summary, the new policy in Peru was chosen and adopted taking into consideration not only information on antimalarial efficacy, but also political and other influential factors.
Compared with other studies that evaluated MQ + AS in Peru, side effects were more commonly reported in our evaluation.2,14
The most common side effects reported were similar to those reported for MQ + AS, i.e., those related to the gastrointestinal tract.17–19
Malaria infection and MQ use can cause neurologic and gastrointestinal symptoms. Thus, the precise role of MQ in producing the effects observed is unclear. However, in our study, side effects dissuaded only three patients from completing treatment as prescribed. Even in patients who delayed the completion of treatment, there was a sharp decrease in parasitemia and improvement in clinical symptoms.
Although Peru recommends malaria treatment to be provided as DOT, in this evaluation, by having a nonobserved group, we aimed to determine if MQ + AS would have high effectiveness when patients receive only the first dose as DOT and are instructed to complete treatment on their own. Our findings are of special interest in the Amazon region, where the population is widely dispersed and access to the healthcare facilities by patients is exacerbated by distance and geography.20,21
In addition, weekend staffing of healthcare facilities and emergency care is low, making it difficult for patients to receive DOT after hours and on weekends. Our findings demonstrate that MQ + AS can be highly effective even when not given as DOT. Patients and their caretakers reported high adherence to the drug regimen, and fever and parasitemia clearance was comparable in both study arms.
Using samples obtained during this evaluation, we conducted a secondary investigation to evaluate molecular makers for parasite drug resistance to SP for which results have been published.22
Molecular analysis demonstrated that the frequency of SP-resistant alleles, the first-line treatment of P. falciparum
in the Peruvian Amazon until 2001, had decreased four years after the change in policy to MQ + AS. This molecular epidemiology evaluation showed how removal of selective drug pressure through antimalarial policy change affected the prevalence of drug-resistant parasites. Similarly, molecular surveillance demonstrated a decrease in the prevalence of the gene responsible for CQ resistance among P. falciparum
isolates in Malawi after it was removed from the national guidelines.23
A subsequent in vivo
efficacy evaluation demonstrated CQ to be highly efficacious in this country in Africa.24
Unfortunately, to date, there is no reliable molecular marker for AS resistance, and in vivo
efficacy monitoring continues to be the gold-standard method for monitoring the efficacy of this drug. Parasite clearance on day 3 has been proposed as an early indicator of in vivo
efficacy of AS.13
Molecular epidemiology, provided adequate molecular markers are available, can document the genetic basis for antimalarial resistance and be of use for drug resistance monitoring when logistics for in vivo
studies are prohibitive. With the ever-decreasing incidence of malaria in the Amazon region, the recommendation from WHO to evaluate in vivo
efficacy every three years has become more difficult to follow.10
For example, data collection for this evaluation took almost one year to reach adequate sample size. Molecular epidemiology can serve as a tool to evaluate the prevalence of drug-resistant isolates and be part of an early detection system for antimalarial resistance. However, it has its limitations: not all drugs have already identified molecular markers to track resistance, and there is still uncertainty in the exact correlation of resistant genes and in vivo
For this reason, in vivo
studies using WHO guidelines continue to be the most useful alternative for guiding antimalarial treatment policies.26
There are several limitations in our evaluation. The evaluation might have been too short in duration to detect late recrudescences because of the long half-life of MQ, which might have caused an overestimation of adequate response rates. Patients in the nonobserved arm were informed about the study at the time of consent, which might have affected their adherence to treatment and our estimate of effectiveness.27
The high treatment adherence to treatment and consequent high effectiveness observed in our study might have been influenced because this region is a setting of low malaria transmission. In such areas, patients with malaria illness seek care and are more prone to take treatment as recommended. We used an adaptation of the WHO in vivo
efficacy trials to assess effectiveness in a group of patients who were not supervised while taking their treatment. Some authors may consider other alternatives to measure effectiveness as more appropriate, especially in areas of high transmission.28
Finally, although we have interpreted the single reappearance of parasitemia observed in our study as recrudescence, one needs to be cautious about such interpretations because some recent studies suggest a high level of genetic similarity between parasite isolates obtained in the Peruvian Amazon region.29
Although this interpretation did not change substantially the final outcome of this study because of the high efficacy of this drug, it will become relevant when the efficacy of the drugs decreases. Therefore, further studies are required to develop better molecular tools that can discriminate parasite isolates in this region with a high resolution to differentiate true recrudescence from reinfection.
In summary, we provide evidence that the current drug policy (MQ + AS) for treatment of patients with malaria in Peru for the Amazon region continues to be highly efficacious and effective. Despite these findings, health authorities in Peru should continue to monitor antimalarial efficacy at regular intervals. Per WHO/Pan American Health Organization recommendations, routine surveillance should be based on conducting in vivo
efficacy trials every three years.10,26
Molecular epidemiology and parasite clearance on day 3 should be collected as complementary information to assess appropriateness of current policies based on artemisinin derivatives.13
Finally, the investigation and evaluation of adherence, effectiveness, and their impact on the development of drug resistance are critical to the decision-making process in malaria-endemic countries.