Adequate nutritional status supports immunity and physical performance . Weight loss, caused by low dietary intake, malabsorption and altered metabolism, is common in HIV infection. Addressing poor nutritional status may, therefore, improve clinical outcomes in HIV-infected individuals by reducing the incidence of HIV-associated complications and attenuating progression of HIV disease, thereby improving quality of life and ultimately reducing disease-related mortality .
We demonstrate that nutritional supplementation taken concurrently with ART for 6 months resulted in an increase in BMI, CD4 count, hemoglobin, red blood cell and white blood cell count and improvement in physical activity when compared to Controls. In addition, serum ferritin was the only biochemical marker that was significantly different between the two arms. Patients in the NS arm showed an increase in FFM, TBW, ICW, ECW and BMR when compared to Controls. Phase angle α was also higher in patients in the NS arm (26% vs. -1.5%; p = 0.063) which may suggest improved health in these patients which may result in improved treatment outcomes. By 12 months after ART initiation, patients in the NS arm continued to show a significant increase in BMI but not CD4 count when compared to the Control arm. The greatest gain in CD4 count and improvement in physical activity was observed in patients in the NS arm with a CD4 count < 100 cells/mm3 at study entry.
Baseline characteristics between the NS and the Control arm were similar although patients in the NS arm were slightly older with a lower CD4 count and hemoglobin. These patients also had a lower viral load, higher BMI and a greater improvement in physical activity level compared to those in the Control arm. These differences are likely due to chance and not the incorrect randomization of sicker or thinner patients to the NS arm.
We observed an improvement in various parameters in the intervention arm. Patients in the NS arm demonstrated an increase in body weight, BMI, CD4 count and hemoglobin. These results suggest that nutritional supplementation for 6 months led to an improved recovery of the immune system and an improvement in the body’s ability to fight infections. This also supports reports that adequate nutrition promotes and maintains optimal immune function . Fawzi and co-workers (2004) reported an increase in CD4 (48 x 106 cells/L IQR 10 - 85) in their study using a multivitamin supplementation [27, 31, 32] whereas Sattler and co-workers (2008) and Swaminathan and co-workers (2010) observed a slowing decline in immune function. A possible explanation for the difference observed may be that the improvement in CD4 count is related to regression-to–the-mean since the baseline counts were lower in the NS arm, albeit not statistically significant. Regardless, there are potential benefits of supplementation in immune status for patients with active weight loss and severe immunosuppression. Unlike the study by de Luis and colleagues (2001) we did not continue to observe a significant difference in percentage CD4 cell count between the 2 arms after the completion of the study .
Studies have reported that ART improves BMI while nutritional supplementation further increases BMI [15, 27, 34, 35]. We continued to observe a difference in BMI between the 2 arms 6 months after the completion of the study or 12 months after ART initiation. Regaining weight, particularly muscle mass, requires ART, treatment of opportunistic infections, consumption of a balanced diet, physical activity and mitigation of side effects . Studies have also shown an association between early weight gain when receiving ART and improved treatment outcomes . Reports suggest that there may be an optimal pre-treatment BMI range for immune recovery on ART. Patients with lower BMI with a weight change of < 10% during follow-up show markedly reduced CD4 count recovery, suggesting that a failure to gain needed weight may be a marker of incomplete virologic suppression, an intercurrent illness or may preclude an optimal response to ART . We did not find a significant increase in body fat between the two arms. Treatments that induce an increase in body fat, without affecting lean mass, do little to improve nutrition-related outcomes, such as functional status, quality of life and disease progression but may contribute to increased cardiovascular disease risk or hypertension .
The effect of a specific micronutrient will depend not only on the background intake of the micronutrient given, but also on the intake of other interacting micronutrients. To assume that all study participants are initially deficient with respect to one or more micronutrients would be incorrect . Serum ferritin was the only parameter that showed a statistical decrease in the NS arm compared to the Control arm - studies have shown a high serum ferritin concentration in patients with anemia . A significant increase in hemoglobin and red blood cells and a significant decrease in serum ferritin may suggest a decrease in the severity of anemia in the NS arm. Serum ferritin can be influenced by other factors other than iron status so another possibility is that supplementation reduces generalized inflammation. Serum ferritin, accompanied by normal or even decreased transferrin saturation, is elevated by inflammation and tissue damage. Dunn-Lewis and colleagues showed that a multi-nutrient supplement effectively reduced inflammatory status in both men and women . It has been suggested that decreasing inflammation directly in the gut may result in an immunologic benefit, possibly by promoting growth of indigenous microflora or “good” bacteria .
Significant increases in FFM, TBW, ICW and ECW were observed in the supplement arm compared to the Control arm, findings similar to those reported by Swaminathan and colleagues (2010) and Schwenk and colleagues (1999) [27, 39]. The number of patients on the NS arm with a low phase angle α (< 5.3) reduced from 6 at ART initiation to zero (0) at 6 months. This may result in better clinical outcomes since a low phase angle α has been correlated with the disease progression in HIV-infection and increased risk of morbidity or mortality [21, 22].
As expected, and consistent with other reports, patients with a CD4 count < 100 cells/mm3 have lower median values for bioelectrical impedance at ART initiation . Reports show that absolute gains in weight, BMI, CD4 cell count, FFM and BCM are higher among patients with severe immunodeficiency, indicating that demonstrable improvements are most likely to be seen among the most immunosuppressed [3, 21]. However, we demonstrate that gains in FFM, ICW, ECW and BMR were greater in patients with CD4 cell counts ≥ 100cells/mm3. Swaminathan and colleagues (2010) found that gains were greater in patients with CD4 cell counts < 200cells/mm3. A possible explanation for the lack of effect seen in severely immunosuppressed patients (CD4 < 100 cells/mm3) may be that ART needs to be established first before malnutrition can be treated or before protein synthesis and immune-related enzyme systems can resume their functions . As previously mentioned, regaining weight requires ART and treatment of opportunistic infections, consumption of a balanced diet, physical activity and mitigation of side effects . Interestingly, severely immunosuppressed patients (CD4 < 100 cells/mm3) in the intervention arm showed the greatest improvement in physical activity.
This is one of a few studies investigating a nutritional supplement intervention that compares attrition across 2 groups of HIV-positive patients. Long term follow-up provided the opportunity to comment on patient outcomes 6 months after the completion of the study (12 months after ART initiation). Very few studies have assessed the impact of food supplements or reported on mortality, morbidity or disease progression [15, 23]. Only 2 deaths were recorded, both on the nutritional supplement arm, which was not surprising considering the late stage in presentation of the disease. One patient died after being admitted to hospital with suspected gastric carcinoma less than 4 months after initiating ART. Patients with gastrointestinal symptoms have been found to have severe intestinal damage and nutrient malabsorption. This may account for the further deterioration in BMI to 14 kg/m2. Our results suggest that patients in the NS arm are more likely to be in care by 6 months after ART initiation compared to the Control arm, who were provided standard of care (Hazard ratio 1.26 95% CI 0.65 – 2.42), however this was not statistically significant and our study had insufficient statistical power to demonstrate this difference. Of concern, are the high rates of loss to initiation and LTFU, both common problems in resource limited settings.
The supplement was well tolerated, as evidenced by the absence of gastrointestinal symptoms and adverse side effects in the nutritional supplement arm. This may have provided an incentive for regular clinic attendance. An adequate diet is an important factor influencing adherence to ART . Studies have reported improved ART adherence among food-insecure patients provided with macronutrients . A recent study in Zambia showed that after 6 months patients receiving food assistance had higher ART adherence compared to those not receiving food assistance (n = 147, 98.3% versus 88.8%, respectively; p < 0.01) . The provision of food assistance to HIV-infected adults on ART may have an incentivizing effect which can improve medication adherence, particularly among patients recently initiated on treatment and those with poor nutrition or advanced disease . We did not observe a significant difference in adherence between the two arms. Both groups were provided excellent medical care and counselling which could have led to changes in patient behaviour (and diet) that reduced the difference between the 2 groups at 6 months. This difference may be more evident in resource-limited settings where the level of care is not the same as a clinical trial setting.
Strengths and limitations
Our finding should be considered in light of the study limitations. First, our results may also be biased by the number of patients who were excluded in the first days and weeks of the study mainly lost to initiation, sicker patients who required hospitalization, disinterest in the intervention or patients that transferred out or withdrew due to work commitments. Both arms presented equally with self-reported weight-loss and advanced HIV disease. Our findings are not only applicable to malnourished HIV-positive patients (less than 30% of our patients had a BMI < 18.5 kg/m2) but also HIV-positive patients that present at ART initiation with self-reported weight loss. Second, as Sattler and colleagues (2009) highlighted, it is important to obtain weight and dietary history and quantification of total energy and macronutrient intakes (by food diaries, food frequency, or 24 h dietary recall questionnaires) before prescribing nutritional supplements for patients with HIV . While we do not report on the protein or caloric intake, the serving sizes of starch, meat or vegetables that patients normally consume, the calorie expenditure (kcal) and calculated daily estimated energy expenditure were similar between the two arms, at ART initiation and at 6 months after ART initiation (results not shown) . Third, bioelectrical impedance measurements were made by different examiners at the same clinic which may have resulted in inter-observer variation. We limited this by training experienced nurses and study coordinators to administer questionnaires, measure height, weight, wrist circumference and to record the BIA. Study staff were trained using standardized procedures and measurements were repeated twice and the average used for analysis. Fourth, a limitation of the study was the relatively small sample size. Consistent with other pilot studies, wider investigation with a larger sample size, increased duration of intervention and longer follow-up to determine the impact on patient treatment outcomes such as mortality is recommended . Lastly, we report an improvement in physical activity – this study was performed in patients with inadequate nutritional intake, on-going weight loss and pre-existing malnutrition so the increased intake may lead to a net increase in energy intake on the NS arm with subsequent improvement in physical activity.
Despite these limitations, our work contributes to the discourse on use of macronutrients in HIV-infected populations. Despite the availability, the uptake, quality and effectiveness of nutritional support services and their impact on patient and program outcomes still needs to be determined .