Reply to I Potani et al

Dear Editor:

The purpose of the systematic review and meta-analysis published by Potani et al. (1) was to inform the WHO on the efficacy of Ready to Use Therapeutic Foods (RUTF) containing no or <50% protein from dairy products in the treatment of children with severe acute malnutrition (SAM) compared with the standard formulation as described by the WHO (2). Data from a randomized controlled trial on the amino-acid-enhanced plant-based soya, maize, sorghum(SMS)-RUTF, 1 of the 6 studies included in the Potani meta-analysis, demonstrated that the recipe was highly effective in promoting recovery according to the present WHO and Sphere criteria (3). Published data also show that the plant-based amino-acid-enhanced RUTF recipe is more effective at promoting recovery from iron deficiency and anemia than the standard WHO accepted milk-based recipe with 50% of the protein coming from dairy products (4). A subsequent operational pilot of the recipe in a government-run Community-based Management of Acute Malnutrition program in Malawi also achieved recovery rates of 88.3%, exceeding those recorded in the Bahwere 2017 trial (78%) as well as the Sphere criteria (>75%) and the Ministry of Health target (>85%) (5).

The data presented in the systematic review and meta-analysis by Potani et al. on alternative RUTF (1), do not support their conclusion that formulations containing <50% of the protein from dairy products are less effective in treating uncomplicated SAM. Pooling of data from fundamentally dissimilar RUTF recipes (as recognized in their study limitations) contravenes standard practice for meta-analyses (6). Combining the data from RUTF recipes that have been fundamentally changed because they did not prove to be efficacious with subsequent data from RUTF recipes that have proved to be successful, serves to dilute and obscure the data from the successful recipe. Such an approach means that the longer the research and development (R&D) process and the greater the number of trials required before the successful development of a new product, the larger amount of evidence that will be generated to dilute and obscure the data from any successful trials; also meaning the greater the number of successful trials on the final recipe that will be required to show benefit. This process undermines innovation and greatly increases the time and cost associated with developing new products. Given the high mortality rates associated with untreated SAM and the fact that treatment coverage is currently so low and with product cost being such a limiting factor, such delays result in needless child mortality.

Three of the 6 trials included in the Potani et al. review (3, 7, 8) were on recipes made from ingredients that can be grown in countries affected by malnutrition, and were part of a Valid Nutrition, 15 year R&D program (9) designed to create, a lower cost, non-milk RUTF. The first 2 studies found that initial formulations were inferior to standard RUTF in terms of recovery rates in children aged <24 months but superior in terms of their ability to treat iron deficiency and anemia (7, 8). Additional results also identified several important issues limiting efficacy, in particular, the protein quality. Importantly, these trials were part of a developmental process used to identify key nutritional limitations in the development of a low-cost RUTF. Consequently, data from these trials, together with animal studies on growth and recovery from malnutrition using RUTF recipes fortified with different amino acid mixes (8, 10), were used to develop a third, fundamentally different, RUTF enriched with crystalline amino acids. In a large randomized controlled 3-arm trial, this new recipe was shown not to differ from the standard RUTF with regard to the Sphere primary outcome indicators of recovery, default, mortality, and restoration of essential amino acids (3, 11).

The rate of weight gain is an inappropriate primary outcome in the Potani et al. review. Differences in the rate of weight gain between the recipes formed the basis for their conclusion that RUTF recipes with <50% of the protein from dairy products are less effective. It was also the only measure used in their cumulative and network meta-analyses. The rate of weight gain as a primary outcome for the treatment of SAM is, however, not accepted practice. The Sphere standards governing therapeutic care for SAM specify that the rate of weight gain is a secondary outcome indicator (12). This is because the rate of weight gain is not a health outcome in itself and the significance of different rates of weight gain are not known—indeed in some children, very rapid rates of weight gain are undesirable because they are associated with iron deficiency (13, 14). By contrast, iron deficiency and iron deficiency anemia, which receive only passing comment in the Potani et al. review, are life-threatening conditions that affect most children with SAM and are better prevented and treated with plant-based RUTFs within the therapeutic care package (4).

A third serious limitation of the Potani et al. study is their cursory examination of the efficacy of the different RUTF recipes in correcting iron deficiency and treating anemia. Data from 2 of the trials (3, 8) included in their meta-analysis shows that the amino-acid-enhanced plant-based SMS-RUTF recipe is superior to the standard milk-based RUTF in restoration of iron status and treatment of anemia, and that the benefit to iron status is inversely proportional to the milk content (4). The authors’ assertion that the superiority of the plant-based recipes can be explained by differences in the iron and vitamin C content of the plant-based recipes are inconsistent with the published data (15). Iron deficiency and anemia occur in most cases of SAM and in contrast to the rate of weight gain, a secondary outcome given such prominence in the Potani et al. review, their treatment is an important health outcome in its own right.

Potani et al. did not conduct a cost-effectiveness analysis. A cost-effectiveness analysis formed 1/3 of the original Terms of Reference for the WHO RUTF guideline review (16), however, no analysis was ever undertaken. The high cost of the RUTF in the face of limited budgets for its procurement, is the most important factor limiting the treatment coverage of SAM to <20%. Given that the cost of ingredients for the amino-acid-enhanced plant-based RUTF is >29% lower than those used in the milk-based recipe (17), the adoption of this new recipe could play a vital role in increasing program coverage and impact.

A comprehensive meta-analysis of RUTF is urgent because the global coverage of SAM treatment is unacceptably low and new effective lower cost RUTF recipes are urgently needed. However, as a direct consequence of the fundamental flaws and misleading conclusion of the Potani et al. review and the absence of any costs-effectiveness analysis, the WHO (18) has now reaffirmed that 50% of the protein in RUTF must come from dairy products. This is likely to prevent the use of the much cheaper amino-acid plant-based RUTFs cementing low treatment coverage of SAM for years to come. Adoption of the low-cost amino-acid-enhanced plant-based RUTF is essential if treatment coverage is to be increased, treatment integrated with prevention, and true competition introduced into the global market for RUTF. Without this, the goals of the Global Action Plan on wasting (19) will not be attained.

Notes

Author disclosures: 3 of the 6 trials included in the Potani review (Irena et al., 2015; Bahwere et al., 2016; Bahwere 2017) were on recipes made from ingredients that can be grown in countries affected by malnutrition and were part of a VALID Nutrition (an independent, Irish registered public charity), 15-y R&D program designed to create, a lower cost, nonmilk RUTF. This research was funded by Irish Aid, Japan's International Cooperation Agency (JICA), and the Global Innovation Fund; and incorporates research outputs from 3 of the authors of this letter (PB, SC, and PA).