JAC Advance Access originally published online on December 11, 2007
Journal of Antimicrobial Chemotherapy 2008 61(2):466-467; doi:10.1093/jac/dkm478
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Letters to the Editor |
Comment on: Efficacy of liposomal amphotericin B for secondary prophylaxis of visceral leishmaniasis in HIV-infected patients
Section of Infectious Diseases, Hospital de Galdácano—Usánsolo, 48960 Vizcaya, Spain
* Tel: +34-94-4007005; Fax: +34-94-4007133; E-mail: julio.collazosgonzalez{at}osakidetza.net
Keywords: AmB , leishmania , antiprotozoals
Molina et al.1 analyse the efficacy of liposomal amphotericin B (AmB) for secondary prophylaxis of visceral leishmaniasis in HIV-infected patients and conclude that AmB is useful for this purpose. However, I believe that there are some shortcomings in the study that limit the validity of the results reported.
A major drawback is the small sample size, as pointed out by the authors, owing to the low incidence of leishmaniasis as a consequence of highly active antiretroviral therapy (HAART). The authors analyse 21 episodes of leishmaniasis as individual cases, although there were only 15 patients studied. Therefore, some patients had two or more episodes of leishmaniasis. I believe that it would have been better to analyse only the patients (n = 15) instead of the episodes (n = 21) for two main reasons. Firstly, continued exposure to AmB in the patients who relapsed could contribute to a decrease susceptibility of the parasite to the drug,2,3 and further relapses are not unexpected in these circumstances (parasite causes). Secondly, those patients who experienced a first relapse are probably more prone to develop further relapses than those who had never relapsed4 (host causes). If the two small groups to be compared (relapse, n = 9 and non-relapse, n = 12) were unbalanced for these important aspects, then the comparisons between them might be difficult.
Not unexpectedly, the main factor that differentiates between relapsers and non-relapsers was the increase in CD4 counts (Figure 2 of the authors’ article). As in other opportunistic infections, immunological recovery is the best preventive factor regardless of the drugs used for primary or secondary prophylaxis. Therefore, I believe that the main efficacy for the prevention of relapses in visceral leishmaniasis in this study corresponded to the host immune response rather than to the use of AmB.
The authors also compare the 1 year relapse rate using AmB (79.1%) with a historical control study from the same authors using pentavalent antimonials (93%)4 and depict the combined results in their Figure 1. This comparison is also difficult because that study was carried out many years ago, before the introduction of HAART, and the immunological recovery, the most important factor in the prevention of relapses of opportunistic infections including leishmaniasis, was expectedly lower with the earlier antiretroviral regimens. However, if any cautious conclusion is to be extracted from this difficult comparison it is that pentavalent antimonials seem to be somewhat superior to AmB, because the former patients had somewhat lower rates of relapse despite their presumably poorer immunological recovery.
Also, it is not clear to what comparison the P = 0.037 reported both in Figure 2 and in the text corresponds with. While in the figure it seems to represent the comparison of CD4 counts in relapsers and non-relapsers at a non-specified time point (which should have been indicated), in the text it seems to represent the comparison of CD4 at 12 and 24 months only in non-relapsing patients. In the latter case, a paired test should have been used instead of the Mann–Whitney test, because the variables are not independent but related.
On the other hand, the use of statistical comparisons in such a small study is of questionable utility because the statistical power is so limited that significant differences are very difficult to obtain. In fact, Table 1 shows that there were no significant differences between the two groups in the frequency of treatment with HAART despite differences so marked as 88.8% and 41.6%, indicating that clinical significance is different from statistical significance, and that absence of evidence is not evidence of absence.5 In addition, the Mann–Whitney test was used for the comparison of continuous variables, despite the fact that the P value obtained from this test is inaccurate for groups with 
15 observations. Moreover, 3 of the 15 patients died or were lost to follow-up, all of them well before the median time to relapse. Therefore, the statistical power of the study was further reduced.
Likewise, as pointed out by the authors, parasitological cure by bone marrow aspiration was not evaluated in nearly half of the patients, opening the possibility that the patients had treatment failures rather than relapses. In fact, the median time to relapse in these patients (8 months) was considerably shorter than in patients who had evidence of a parasitological cure (15.5 months, not 14 months as reported), although I agree that these episodes may represent true relapses rather than acute treatment failures.
I believe that AmB, like other drugs, might be of some utility for the prevention of recurrences of visceral leishmaniasis while awaiting for immunological recovery. However, its efficacy does not seem to be very high1,6 and, according to the authors’ previous study,4 it could be lower than pentavalent antimonials.
The key question to elucidate is the efficacy of AmB compared with other drugs and, currently, it can only be answered by means of multicentre studies with considerably larger sample sizes.
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1 Molina I, Falcó V, Crespo M, et al. Efficacy of liposomal amphotericin B for secondary prophylaxis of visceral leishmaniasis in HIV-infected patients. J Antimicrob Chemother (2007) 60:837–42.
2
Croft SL, Sundar S, Fairlamb AH. Drug resistance in leishmaniasis. Clin Microbio Rev (2006) 19:111–26.
3
Di Giorgio C, Faraut-Gambarelli F, Imbert A, et al. Flow cytometric assessment of amphotericin B susceptibility in Leishmania infantum isolates from patients with visceral leishmaniasis. J Antimicrob Chemother (1999) 44:71–6.
4 Ribera E, Ocaña I, de Otero J, et al. Prophylaxis of visceral leishmaniasis in human immunodeficiency virus infected patients. Am J Med (1996) 100:496–501.[CrossRef][Web of Science][Medline]
5
Collazos J. Statistics in medicine: some considerations from a clinician’s point of view. Postgrad Med J (1998) 74:577–8.
6
López-Vélez R, Videla S, Márquez M, et al. Amphotericin B lipid complex versus no treatment in the secondary prophylaxis of visceral leishmaniasis in HIV-infected patients. J Antimicrob Chemother (2004) 53:540–3.
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