Chronic Chagas Patients 3 Years After Nifurtimox Treatment
Chronic Chagas Patients 3 Years After Nifurtimox Treatment
This study shows that none of two ELISAs and a rapid immunochromatographic test (Stat-Pak®) reverted to negativity three years after nifurtimox treatment in a cohort of adults at the chronic stage of Chagas disease living in an area without vectorial transmission. One patient was found positive by Real-Time PCR. Therefore, 97.3% participants could not be adequately informed about their current clinical status, with a single patient conclusively found to be still infected. The positive serological test results could either indicate treatment failure or simply reflect the window period of persistent humoral response despite potential treatment efficacy. Moreover, we found low agreement between the two ELISAs in regards to decreasing OD values post treatment. Whereas the main limitation of the study is the sample size of 37 participants, it is the largest serological follow-up study of adults treated with nifurtimox published to date and the first study carried out in a non-endemic country.
To date, there is no early marker of treatment efficacy in adults. Currently, the criterion of treatment success is the return to negativity of a previously positive serological test and it is recommended to undergo a 10- to 20-year long serological follow-up to assess treatment efficacy in adults. These recommendations are more appropriate for the management of children, whose serology usually return to negativity within months. Our findings highlight the lack of utility of these recommendations for adults in clinical settings as all qualitative serological results remained unchanged 3 years after treatment with nifurtimox.
These results, in patients with no risk of vectorial reinfection following treatment, confirm the long lasting anti-T. cruzi humoral response after treatment, which can persist for more than 20 years. In addition to showing this long window period, these studies in adults treated with benznidazole and nifurtimox found overall low (<50%) seronegativation rates. There is evidence that a seronegative response following benznidazole treatment is correlated with a reduced risk of cardiac damage and possibly of mortality. Few studies have specifically evaluated serological response following nifurtimox treatment in adults. Fabbro and colleagues followed a cohort of 27 adults over 21 years in Argentina. They found a trend towards a higher rate of seronegativation in those treated with nifurtimox (40.5%) than with benznidazole (33.3%). Coura et al., found no serological change in 19 Brazilian patients, one year after nifurtimox treatment. In our cohort, there was no way to reliably discriminate between treatment failure and latency before seronegativation, except for the single patient with a positive PCR indicating treatment failure. Moreover, the low agreement between tests regarding OD kinetic tends to demonstrate the lack of utility of this potential criterion of cure. We observed a significant decrease in optical density levels in both ELISAs tests in 75.7% patients. The exact significance of this finding is difficult to assess, but a non-randomized study performed following treatment with benznidazole showed a positive correlation between declining antibody titers and a reduction in the risk of cardiac damage. In Argentina, Fabbro et al. showed that changes in antibody titers occurred 7 years or later after nifurtimox treatment. The ongoing BENEFIT cohort study will provide additional information on the serological kinetic and the protective effect of benznidazole - but not nifurtimox - in adults.
No follow-up study has addressed the evolution of rapid diagnostic test results after treatment. In our study population, the Stat-Pak® rapid immunochromatogaphic test has proved reliable at the diagnostic stage. However, after three years, all rapid tests remained positive, which is consistent with ELISA results. Therefore, the Stat-Pak® cannot be recommended as a test of cure, at least in the three year post-treatment period.
Different PCR techniques and primers are used to detect circulating T.cruzi. Overall, they are not appropriate to diagnose the chronic stage of infection due to limited (60-90%) sensitivity, technical challenges and lack of standardization. However, PCR is useful in verifying infection where there are contradictory serological results, and to confirm treatment failure where there are persistent seropositive results following treatment. Real-time PCR is considered more sensitive for parasite detection than conventional methods and therefore may be a better tool to assess treatment failure. In this study, we used two PCR techniques and found a discordant result in one (2.7%) patient and concordant negative results in all others. In the absence of pre-treatment PCR measurements, we were not able to identify changes. PCR is constantly evolving and efforts are underway to standardize methods. Further studies are needed to assess their exact role as a test of cure.
The limited efficacy of currently available treatments and the lack of rapidly responsive tests of cure have a significant impact on the clinical management of adults and on public health. In our experience, the inability of clinicians to propose rapid and appropriate information on the treatment outcome soon after its completion may create some resistance in patients during the pre-treatment information session. Some of our patients have been reluctant to start a long and potentially poorly tolerated treatment in absence of a rapidly measurable outcome. Moreover, clinicians are unable to adequately inform treated patients on their subsequent risk of cardiopathy as long as the tests remain positive. This hampers personalized counseling on follow-up and forces patients to undergo serial serological tests over years. Today's patients are highly mobile and Chagas disease has become a global health problem. International migrants with Chagas disease, amounting to half a million at least, may receive treatment in one country and subsequently move to another, making the currently recommended long-term serological follow-up highly impracticable. Moreover, given the frequent presence of other modifiable cardiac risk factors in adults with Chagas disease, the lack of accurate post-treatment evaluation strategies hamper clinicians in differentiating between possible causes of subsequent cardiac damage. The reliance on the return to negativity of serologies as a proof of treatment success means that treated patients are denied the opportunity to donate blood and organs for many years until tests may eventually become negative. This is unfortunate as Latino American migrants are more willing to donate blood than local residents in Switzerland. Finally, new treatment evaluation is made difficult in absence of early marker of cure.
Discussion
This study shows that none of two ELISAs and a rapid immunochromatographic test (Stat-Pak®) reverted to negativity three years after nifurtimox treatment in a cohort of adults at the chronic stage of Chagas disease living in an area without vectorial transmission. One patient was found positive by Real-Time PCR. Therefore, 97.3% participants could not be adequately informed about their current clinical status, with a single patient conclusively found to be still infected. The positive serological test results could either indicate treatment failure or simply reflect the window period of persistent humoral response despite potential treatment efficacy. Moreover, we found low agreement between the two ELISAs in regards to decreasing OD values post treatment. Whereas the main limitation of the study is the sample size of 37 participants, it is the largest serological follow-up study of adults treated with nifurtimox published to date and the first study carried out in a non-endemic country.
To date, there is no early marker of treatment efficacy in adults. Currently, the criterion of treatment success is the return to negativity of a previously positive serological test and it is recommended to undergo a 10- to 20-year long serological follow-up to assess treatment efficacy in adults. These recommendations are more appropriate for the management of children, whose serology usually return to negativity within months. Our findings highlight the lack of utility of these recommendations for adults in clinical settings as all qualitative serological results remained unchanged 3 years after treatment with nifurtimox.
These results, in patients with no risk of vectorial reinfection following treatment, confirm the long lasting anti-T. cruzi humoral response after treatment, which can persist for more than 20 years. In addition to showing this long window period, these studies in adults treated with benznidazole and nifurtimox found overall low (<50%) seronegativation rates. There is evidence that a seronegative response following benznidazole treatment is correlated with a reduced risk of cardiac damage and possibly of mortality. Few studies have specifically evaluated serological response following nifurtimox treatment in adults. Fabbro and colleagues followed a cohort of 27 adults over 21 years in Argentina. They found a trend towards a higher rate of seronegativation in those treated with nifurtimox (40.5%) than with benznidazole (33.3%). Coura et al., found no serological change in 19 Brazilian patients, one year after nifurtimox treatment. In our cohort, there was no way to reliably discriminate between treatment failure and latency before seronegativation, except for the single patient with a positive PCR indicating treatment failure. Moreover, the low agreement between tests regarding OD kinetic tends to demonstrate the lack of utility of this potential criterion of cure. We observed a significant decrease in optical density levels in both ELISAs tests in 75.7% patients. The exact significance of this finding is difficult to assess, but a non-randomized study performed following treatment with benznidazole showed a positive correlation between declining antibody titers and a reduction in the risk of cardiac damage. In Argentina, Fabbro et al. showed that changes in antibody titers occurred 7 years or later after nifurtimox treatment. The ongoing BENEFIT cohort study will provide additional information on the serological kinetic and the protective effect of benznidazole - but not nifurtimox - in adults.
No follow-up study has addressed the evolution of rapid diagnostic test results after treatment. In our study population, the Stat-Pak® rapid immunochromatogaphic test has proved reliable at the diagnostic stage. However, after three years, all rapid tests remained positive, which is consistent with ELISA results. Therefore, the Stat-Pak® cannot be recommended as a test of cure, at least in the three year post-treatment period.
Different PCR techniques and primers are used to detect circulating T.cruzi. Overall, they are not appropriate to diagnose the chronic stage of infection due to limited (60-90%) sensitivity, technical challenges and lack of standardization. However, PCR is useful in verifying infection where there are contradictory serological results, and to confirm treatment failure where there are persistent seropositive results following treatment. Real-time PCR is considered more sensitive for parasite detection than conventional methods and therefore may be a better tool to assess treatment failure. In this study, we used two PCR techniques and found a discordant result in one (2.7%) patient and concordant negative results in all others. In the absence of pre-treatment PCR measurements, we were not able to identify changes. PCR is constantly evolving and efforts are underway to standardize methods. Further studies are needed to assess their exact role as a test of cure.
The limited efficacy of currently available treatments and the lack of rapidly responsive tests of cure have a significant impact on the clinical management of adults and on public health. In our experience, the inability of clinicians to propose rapid and appropriate information on the treatment outcome soon after its completion may create some resistance in patients during the pre-treatment information session. Some of our patients have been reluctant to start a long and potentially poorly tolerated treatment in absence of a rapidly measurable outcome. Moreover, clinicians are unable to adequately inform treated patients on their subsequent risk of cardiopathy as long as the tests remain positive. This hampers personalized counseling on follow-up and forces patients to undergo serial serological tests over years. Today's patients are highly mobile and Chagas disease has become a global health problem. International migrants with Chagas disease, amounting to half a million at least, may receive treatment in one country and subsequently move to another, making the currently recommended long-term serological follow-up highly impracticable. Moreover, given the frequent presence of other modifiable cardiac risk factors in adults with Chagas disease, the lack of accurate post-treatment evaluation strategies hamper clinicians in differentiating between possible causes of subsequent cardiac damage. The reliance on the return to negativity of serologies as a proof of treatment success means that treated patients are denied the opportunity to donate blood and organs for many years until tests may eventually become negative. This is unfortunate as Latino American migrants are more willing to donate blood than local residents in Switzerland. Finally, new treatment evaluation is made difficult in absence of early marker of cure.
