Review for 10.1186/1471-230X-14-15 (2014)

Reviewer's report
Title:High dose multiple micronutrient supplementation improves villous
morphology in environmental enteropathy without HIV enteropathy: results from a
double-blind randomised placebo controlled trial in Zambian adults.
Version:1Date:17 October 2013
Reviewer: Angus Scrimgeour
Reviewer's report:
Observation: although micronutrient supplements have been shown to be
beneficial in HIV-infected persons not receiving HAART, few data are available to
support or refute the benefits of providing micronutrient supplements to
HIV-positive persons receiving HAART. Hence, this new study focusing on the
effects of a multiple micronutrient supplement on bowel-structure abnormalities in
both HIV-positive and negative subjects may help to decrease the side effects of
HIV medications, and/or improve clinical outcomes in HIV-infected persons in
both developed and developing countries.
Major compulsory revisions:
1. MM supplement – in the last sentence of Background, the authors postulate
that an MM supplement at HIGHER doses than used in a previous study (ref 12)
would be used. Comparing the composition of the MM used in that 2008 study
with the current MM composition indicates that in the new study, iron and copper
doses were actually decreased by 47% and 50%, respectively. If high
Fe-supplements are known to increase constipation [but none was reported in
your 2008 study], and to increase the risk of malaria [Richard 2006; Sazawal
2006], why were these trace elements decreased in the MM (vs. increased, as
suggested by the Background/Introduction)? MAJOR CONCERN: Column 4 of
Table 1 shows a wide discrepancy of dosing, from 0.83x RNI (for copper) up to
40x RNI (for thiamin). Considering the fact that this group of nutrition-scientists
has published manuscripts in a variety of nutrition/AIDS/gastroenterology
journals, it is a concern that these authors have not included a sound basis for
selecting an MM that does not follow any of the RNIs for British adults (see ref
27).
2. Initiation of highly active antiretroviral therapy (HAART) is generally
recommended for patients with HIV-related opportunistic infections, or a CD4
count <200 cells/µl. While Table 2 indicates that 15 subjects (or 40%) completed
the MM-trial, no mention is made of HAART therapy – were all HIV-positive
subjects taking HAART during the trial? Or, were some already being treated for
>6-months? The authors have not considered/discussed HAART interventions or
its effects on micronutrient status when considering why the MM-supplement
appears to be ineffective in their HIV-positive subjects. Micronutrient
interventions have been shown to alter the bioavailability, metabolism, and
pharmacokinetics of certain HIV medications; and randomized trials have shown
that supplementation with vitamin A (Fawzi 2004) and with a multivitamin
containing selenium (McClelland 2004) can cause increased viral shedding in
females – the MM used in this study provided 1.4-2.3x the RNI for Vitamin A, and
4.7x the RNI for selenium. If this reviewer assumes that the authors were aware
of these known side-effects of high-dose micronutrients in HIV-positive subjects,
why was this particular MM selected for the study? MAJOR CONCERN: the
discussion does not mention the known beneficial/detrimental effects of high
dose MM in HIV-positive subjects, with or without HAART; nor do they speculate
whether (or not) the high-dose MM had toxic effects in the (apparently)
non-responding HIV-positive subjects with EE. Had they determined baseline
micronutrient status, and powered the study for HIV-positive with/without HAART,
the outcomes might’ve been otherwise.
3. Roll Back Malaria (see www.rbm.who.int) reports that the entire country of
Zambia is “endemic for malaria with moderate-to-high transmission in all
districts”, and supplemental Fe does appear to increase susceptibility to malaria
as measured by a variety of malariometric indices. However, even in malarious
areas, iron appears beneficial in Fe-deficient subjects (reviewed by Prentice,
2008). So, for a malarious area like Lusaka, where iron is potentially beneficial in
Fe-deficient subjects, why did the authors not measure Fe status to screen out
Fe-replete subjects? The authors have not measured (or reported) malaria
status; hence the question: what criteria was used to DECREASE the Fe dose by
47% (vs. the dose used in 2008 study)?
In summary – clearly, multivitamin supplementation has been shown to reduce
clinical HIV disease progression in several well-designed observational studies
and randomized trials. Hence the objectives of this study – examining the
effect(s) of high dose MM supplementation and HIV status on small bowel
architecture in EE, is of considerable importance for clinicians/nutritionists
working within the HIV-community. However, the lack of baseline micronutrient
status (in both HIV negative and positive groups), the small HIV-pos. group size
receiving MM (n=6 in Fig 5), and considering that 14 subjects (=27%) were
excluded from histological analyses due to a technical problem (sample
orientation, see Fig 3), the authors do not provide sufficient evidence to conclude
that “EE, with superimposed HIV enteropathy is a distinct pathophysiological
condition”. At best, this is speculation.
Level of interest: An article whose findings are important to those with closely
related research interests
Quality of written English: Acceptable
Statistical review: No, the manuscript does not need to be seen by a statistician.
Declaration of competing interests:
I declare that I have no competing interests.