- Email: [email protected]
Antiretroviral treatment
CORRESPONDENCE
normal, impaired, or diabetic, particular attention should be paid to the carbohydrate content of their last meal. Even more attention, however, should be paid to the fat content of that meal. In fact, the impaired glucose tolerance found by Kaneko and colleagues among those patients whose last meal contained 10% carbohydrate, 25% protein, and 65% fat may actually reflect a too high fat content, not a low carbohydrate meal. High fat diets deteriorate carbohydrate metabolism,2,3 because human beings have been metabolically shaped by a low fat nutritional environment.4 Diets containing more than 10–15% fat were virtually impossible for millions of years, because game was very lean and oils, butter, and dairy products did not exist.4 Before concluding that a low carbohydrate dinner is responsible for subsequent impairment of glucose tolerance, Kaneko and co-workers should also have investigated the effects of a third possible meal, namely a high protein dinner containing, say, 10% carbohydrate, 80% protein, and 10% fat. A similar diet has been reported to improve dramatically both the carbohydrate and the lipid metabolism of diabetic patients,5 which further supports the view that the impaired glucose tolerance observed by Kaneko and colleagues mirrors an unnaturally high fat dinner, not a low carbohydrate one. Riccardo Baschetti Via Savonarola 144, 35137 Padua, Italy 1
2
3
4 5
Kaneko T, Wang P-Y, Tawata M, Sato A. Low carbohydrate intake before oral glucose-tolerance tests. Lancet 1998; 352: 289. Swinburn BA, Boyce VL, Bergman RN, Howard BV, Bogardus C. Deterioration in carbohydrate metabolism and lipoprotein changes induced by modern, high fat diet in Pima Indians and caucasians. J Clin Endocrinol Metab 1991; 73: 156–65. Marshall JA, Hoag S, Shetterly S, Hamman RF. Dietary fat predicts conversion from impaired glucose tolerance to NIDDM. The San Luis Valley Diabetes Study. Diabetes Care 1994; 17: 50–56. Baschetti R. Low-fat diets and HDL cholesterol. Am J Clin Nutr 1998 (in press). O’Dea K. Marked improvement in carbohydrate and lipid metabolism in diabetic Australian Aborigines after temporary reversion to traditional lifestyle. Diabetes 1984; 33: 596–603.
Authors’ reply Sir—Keiji Yoshioka and co-workers make important comments on our report. The impairment of glucose tolerance after a restricted carbohydrate intake was invariably accompanied by an increase in the fasting plasma concentration of free
1224
fatty acids, suggesting that the impairment is associated with the Randle effect. It is possible that the effects of fatty acids on glucose metabolism may be involved in the impairment of glucose tolerance after a low carbohydrate intake. In our study, the insulinogenic index decreased after restricted carbohydrate intake, which indicates that after carbohydrate restriction proportionally less insulin is released in response to the glycaemic stimulus. Over 60 years ago, Himsworth1 showed, with a state-of-the-art approach, that the glucose tolerance in non-diabetic men is adversely affected by a lowered carbohydrate intake (not by an increased fat intake) before an OGTT. He found that the glucose tolerance and insulin sensitivity improved as a result of the change from a low-carbohydrate/high-fat diet to a high-carbohydrate/low-fat diet, and that the improvement was solely due to the amount of carbohydrate in the diet. We agree with the view that a high carbohydrate intake increases the insulin sensitivity. We agree with Yoshioka that an OGTT is not necessarily inferior to a fasting plasma glucose test. The scientific reason why an OGTT is judged inferior to a fasting plasma glucose test is that the OGTT is more subject to within-individual variation. In the study by Mooy and colleagues,2 in which OGTTs were repeated pver 2–6 weeks, the within-individual coefficients of variation were 6·4% for the fasting plasma glucose concentrations and 16·7% for the 2-h postload plasma glucose concentrations. However, Mooy and co-workers mentioned that “participants were instructed to abstain from alcohol from 17:00 hours and to fast (except for drinking water) from 22:00 hours the previous day”. As we showed in our study, one of the factors that contributed to the withinindividual variation in OGTTs is the carbohydrate intake before a test. In response to Richard Baschetti, when we prepare isocaloric diets containing a fixed amount of protein, we change the contents of fat and carbohydrate simultaneously. Therefore, a high-carbohydrate diet is nothing but a low-fat diet, and conversely, a low-carbohydrate diet inevitably contains excessive amounts of fat. Thus is is difficult to differentiate the effect of a low-carbohydrate diet from that of excessive amounts of fat. The works of Swinburn and coworkers3 and Marshall and colleagues4 do not necessarily support the idea that high-fat diets deteriorate carbohydrate
metabolism. The transition from a high-carbohydrate diet to a lowcarbohydrate diet may partly explain the dramatic increase in the prevalence of non-insulin-dependent diabetes mellitus among Pima Indians over the past century. The main findings of the study by O’Dea5 was the improvement in glucose tolerance in ten diabetic Aborigines after a 7-week reversion to traditional hunter-gatherer lifestyle. The lifestyle change (an increase in protein intake and decrease in energy intake) accompanied substantial weight loss. Perhaps the decreased energy intake rather than the increased protein intake improved the glucose tolerance of the diabetic Aborigines. Takashi Kaneko, Pei-Yu Wang, *Masato Tawata, Akio Sato Departments of Environmental Health and *Third Department of Internal Medicine, Medical University of Yamanashi, Tamaho, Yamanashi, 409-3898 Japan (e-mail: [email protected]) 1
2
3
4
5
Himsworth HP. Dietetic factor determining glucose tolerance and sensitivity to insulin of healthy men. Clin Sci 1935; 2: 67–94. Mooy JM, Gootenhuis PA, de Vries H, et al. Intra-individual variation of glucose, specific insulin and proinsulin concentrations measured by two oral glucose tolerance tests in general Caucasian population: the Hoorn Study. Diabetologia 1996; 39: 298–305. Swinburn BA, Boyce VL, Bergman RN, Howard BV, Bogardus C. Deterioration in carbohydrate metabolism and lipoprotein changes induced by modern, high fat diet in Pima Indians and Caucasians. J Clin Endocrinol Metab 1991; 73: 156–65. Marshall JA, Hoag S, Shetterly S, Hamman RF. Dietary fat predicts conversion from impaired glucose tolerance to NIDDM. The San Luis Valley Diabetes Study. Diabetes Care 1994; 17: 50–56. O’Dea K. Marked improvement in carbohydrate and lipid metabolism in diabetic Australian Aborigines after temporary reversion to traditional lifestyle. Diabetes 1984; 33: 596–603.
Antiretroviral treatment Sir—As your June 20 editorial1 makes clear, there is an urgent need for less expensive antiretroviral therapies for use in the developing world. One such combination might be that of the very cheap drugs chloroquine and hydroxyurea with didanosine. These three drugs have different sites of antiretroviral action: hydroxyurea inhibits ribonucleotide reductase; didanosine is a nucleoside reversetranscriptase (RT) inhibitor; and chloroquine interferes with the The production of gp120.2 combination of hydroxyurea and didanosine has a potent and longlasting antiretroviral effect. The antimalarial chloroquine is widely available in developing countries and it
THE LANCET • Vol 352 • October 10, 1998
CORRESPONDENCE
Treatment
Untreated HU HU+ddI CQ HU+ddI+CQ
H-9 cells
U-937 cells 3
3
p24 Ag (ng/mL)
RT activity (cpm⫻10 /mL)
p24 Ag (ng/mL)
RT activity (cpm⫻10 /mL)
31 (2·3) 9·8 (1·3) 4·3 (1·0) 7·3 (1·8) 1·3 (0·5)
456 (104) 124 (45) 23 (1·6) 132 (51) 14 (11)
24 (2·3) 7·5 (1·0) 2·3 (0·5) 8·2 (1·1) 0·8 (0·1)
546 (123) 176 (56) 13 (0·4) 185 (59) 0·2 (0·1)
All values are means (SE). HU=hydroxyurea; ddI=didanosine; CQ=chloroquine. After treatment cells were infected with HIV-1IIIB. Infection was assessed by measurement of RT and p24 antigen (Ag) in the culture supernatant 4 days after infection.
Effect of adding chloroquine to hydroxyurea and didanosine
has, together with its hydroxyderivative, beneficial anti-HIV-1 effects. These antimalarials are active against HIV-1 in vitro2,3 and in HIV-1infected patients, with an activity similar to that of zidovudine.4 Chloroquine may also exhibit antimicrobial properties against different pathogens that cause opportunistic infections in AIDS, such as Mycobacterium tuberculosis, Cryptococcus neoformans, and Histoplasma capsulatum.5 Another potential benefit of chloroquine is a decrease in iron accumulation in the reticulo-endothelial system, which reduces the effect of excess iron in HIV-1 infection.5 We examined in vitro whether the addition of chloroquine to the combination of hydroxyurea plus didanosine has any additive anti-HIV-1 activity in T cell and monocytic cell lines (table). Treatment with hydroxyurea (0·2 mmol) or chloroquine (0·1 mmol) alone reduces p24 antigen (Ag) and RT activity by 70% 4 days after infection of the H-9 and the U-937 cells, compared with the untreated cells. There is a further two-fold reduction in p24 Ag and RT activity in both cell types when hydroxyurea is combined with didanosine (1 mol). Addition of chloroquine to hydroxyurea plus didanosine results in an additional fall in p24 Ag and RT activity, compared with hydroxyurea plus didanosine. There were no increased toxic effects to H-9 or U-937 cells after the addition of chloroquine to hydroxyurea plus didanosine. Taken together, our preliminary findings in vitro suggest that the combination of hydroxyurea, didanosine, and chloroquine merits clinical testing. If found to be effective, this less expensive antiretroviral combination may help to bridge the gap,1 particularly among HIV-1infected people in developing countries. *Johan R Boelaert, Kirk Sperber *Unit of Renal and Infectious Diseases, Algemeen Ziekenhuis St-Jan, 8000-Brugge, Belgium; and Clinical Immunology, Mount Sinai School of Medicine, New York, NY, USA 1
Editorial. AIDS, the unbridgable gap. Lancet 1998; 351: 1825.
THE LANCET • Vol 352 • October 10, 1998
2
3
4
5
Sperber K, Kalb TH, Stecher VJ, Banerjee R, Mayer L. Inhibition of human HIV-1 replication by hydroxychloroquine in T cells and monocytes. AIDS Res Hum Retroviruses 1993; 9: 91–98. Tsai W-P, Nara PL, Kung HF, Oroszlan S. Inhibition of human immunodeficiency virus infectivity by chloroquine. AIDS Res Hum Retroviruses 1990; 6: 481–89. Sperber K, Chiang G, Chen H, et al. Comparison of hydroxychloroquine with zidovudine in asymptomatic patients infected with HIV-1. Clin Ther 1997; 19: 913–23. Boelaert JR, Weinberg GA, Weinberg ED. Altered iron metabolism in HIV infection, possible consequences and proposals for management. Infect Agents Dis 1996; 5: 36–46.
Bread fortification with folic acid, vitamin B12, and vitamin B6 in Hungary Sir—The recent recommendation of the US National Academy of Sciences on the daily intake of folate and folic acid, reported in Therese Droste’s April 11 news item, 1 reinforced the Hungarian efforts for prevention of neural-tube defects and other congenital abnormalities by periconceptional folic acid/multivitamin supplementation. However, only 45% of women plan their pregnancies and a 1996 country-wide campaign found that only 12% of women used periconceptional care. A new curriculum subject, entitled “preparing for family life”, was introduced in 1997 for pupils aged 14–16, but it will be many years before educational measures have the desired impact. Food fortification seems to be the medium-term solution. In Hungary, the national basic food is bread, and the average daily intake is 200 g, thus it can deliver the necessary supplements of folic acid, vitamin B12, and B6 to the target population. Another purpose of bread fortification with these three vitamins is to attempt the reduction of vascular diseases.2 The role of folic acid does not need explanation. Vitamin B12 is an independent risk factor for neural-tube defects and may be appropriate to neutralise the possible adverse effect of pharmacological dose (>1000 g) of folic acid in people affected with pernicious anaemia.
Vitamin B6 is also important in the prevention of homocysteine-related vascular diseases.3 We made two proposals for bread fortification in June, 1997. The minimum requirement was 160 g folic acid, 0·80 g vitamin B12, and 880 g vitamin B6 for 100 g of flour. The proportion of flour is 75% in the bread and there is a 20% loss of these vitamins during production, therefore, the daily intake of folic acid, vitamin B12, and B6 is about 200 g, 1 g, and 1080 g, respectively, in 200 g of bread. Daily intake of 200 g folic acid results in a 41% estimated reduction in risk of neural-tube defects. 4 The optimum requirement would include 330 g folic acid, 20 g vitamin B12, and 3000 g vitamin B6 for 100 g of flour. Thus, in 200 g of bread, there is 400 g folic acid, 25 g vitamin B12, and 3600 g vitamin B6. With the fortification of bread with 330 g of folic acid 1–2% of the Hungarian population would exceed the tolerable upper intake level (1000 g), however, 25 g of vitamin B12 can protect the so-called masking effect of folic acid in patient with pernicious anaemia. 5 About 1% of oral dose of vitamin B12 can be absorbed via nonphysiological mass action in these patients. Thus, vitamin B12 has no toxic effect under 1000 g . The tolerable upper intake level of vitamin B6 is 100 mg. In April 1998, the minimum requirement proposal was accepted by the authorities and the initial production of fortified bread began in August, 1998. However, we will attempt to get support from the scientific authorities to introduce at a later date the optimum requirements of the three vitamin B groups. *Andrew E Czeizel, Zoltan Merhala WHO Collaborating Centre for the Community Control of Hereditary Diseases, Bolgárkerék u.3, Budapest H-1148, Hungary 1
2
3
4
5
Droste TM. US study recommends daily amounts of vitamins. Lancet 1998; 351: 1113. Boushey CJ, Beresford SAA, Omenn GS, Motulsky AG. A quantitative assessment of plasma homocysteine as a risk factor for vascular diseases. JAMA 1995; 274: 1049–57. Rimm EB, Willett WC, Hu FB, et al. Folate and vitamin B6 from diet and supplements in relation to risk of coronary heart disease among women. JAMA 1998; 279: 392–93. Daly S, Mills JL, Molloy AM, et al. Minimum effective dose of folic acid for food fortification to prevent neural-tube defects. Lancet 1997; 350: 1666–69. Herbert V, Bigaouette J. Call for endorsement of petition to the Food and Drug Administration to always add vitamin B-12 to any folate fortification or supplement. Am J Clin Nutr 1997; 65: 572–73.
1225
normal, impaired, or diabetic, particular attention should be paid to the carbohydrate content of their last meal. Even more attention, however, should be paid to the fat content of that meal. In fact, the impaired glucose tolerance found by Kaneko and colleagues among those patients whose last meal contained 10% carbohydrate, 25% protein, and 65% fat may actually reflect a too high fat content, not a low carbohydrate meal. High fat diets deteriorate carbohydrate metabolism,2,3 because human beings have been metabolically shaped by a low fat nutritional environment.4 Diets containing more than 10–15% fat were virtually impossible for millions of years, because game was very lean and oils, butter, and dairy products did not exist.4 Before concluding that a low carbohydrate dinner is responsible for subsequent impairment of glucose tolerance, Kaneko and co-workers should also have investigated the effects of a third possible meal, namely a high protein dinner containing, say, 10% carbohydrate, 80% protein, and 10% fat. A similar diet has been reported to improve dramatically both the carbohydrate and the lipid metabolism of diabetic patients,5 which further supports the view that the impaired glucose tolerance observed by Kaneko and colleagues mirrors an unnaturally high fat dinner, not a low carbohydrate one. Riccardo Baschetti Via Savonarola 144, 35137 Padua, Italy 1
2
3
4 5
Kaneko T, Wang P-Y, Tawata M, Sato A. Low carbohydrate intake before oral glucose-tolerance tests. Lancet 1998; 352: 289. Swinburn BA, Boyce VL, Bergman RN, Howard BV, Bogardus C. Deterioration in carbohydrate metabolism and lipoprotein changes induced by modern, high fat diet in Pima Indians and caucasians. J Clin Endocrinol Metab 1991; 73: 156–65. Marshall JA, Hoag S, Shetterly S, Hamman RF. Dietary fat predicts conversion from impaired glucose tolerance to NIDDM. The San Luis Valley Diabetes Study. Diabetes Care 1994; 17: 50–56. Baschetti R. Low-fat diets and HDL cholesterol. Am J Clin Nutr 1998 (in press). O’Dea K. Marked improvement in carbohydrate and lipid metabolism in diabetic Australian Aborigines after temporary reversion to traditional lifestyle. Diabetes 1984; 33: 596–603.
Authors’ reply Sir—Keiji Yoshioka and co-workers make important comments on our report. The impairment of glucose tolerance after a restricted carbohydrate intake was invariably accompanied by an increase in the fasting plasma concentration of free
1224
fatty acids, suggesting that the impairment is associated with the Randle effect. It is possible that the effects of fatty acids on glucose metabolism may be involved in the impairment of glucose tolerance after a low carbohydrate intake. In our study, the insulinogenic index decreased after restricted carbohydrate intake, which indicates that after carbohydrate restriction proportionally less insulin is released in response to the glycaemic stimulus. Over 60 years ago, Himsworth1 showed, with a state-of-the-art approach, that the glucose tolerance in non-diabetic men is adversely affected by a lowered carbohydrate intake (not by an increased fat intake) before an OGTT. He found that the glucose tolerance and insulin sensitivity improved as a result of the change from a low-carbohydrate/high-fat diet to a high-carbohydrate/low-fat diet, and that the improvement was solely due to the amount of carbohydrate in the diet. We agree with the view that a high carbohydrate intake increases the insulin sensitivity. We agree with Yoshioka that an OGTT is not necessarily inferior to a fasting plasma glucose test. The scientific reason why an OGTT is judged inferior to a fasting plasma glucose test is that the OGTT is more subject to within-individual variation. In the study by Mooy and colleagues,2 in which OGTTs were repeated pver 2–6 weeks, the within-individual coefficients of variation were 6·4% for the fasting plasma glucose concentrations and 16·7% for the 2-h postload plasma glucose concentrations. However, Mooy and co-workers mentioned that “participants were instructed to abstain from alcohol from 17:00 hours and to fast (except for drinking water) from 22:00 hours the previous day”. As we showed in our study, one of the factors that contributed to the withinindividual variation in OGTTs is the carbohydrate intake before a test. In response to Richard Baschetti, when we prepare isocaloric diets containing a fixed amount of protein, we change the contents of fat and carbohydrate simultaneously. Therefore, a high-carbohydrate diet is nothing but a low-fat diet, and conversely, a low-carbohydrate diet inevitably contains excessive amounts of fat. Thus is is difficult to differentiate the effect of a low-carbohydrate diet from that of excessive amounts of fat. The works of Swinburn and coworkers3 and Marshall and colleagues4 do not necessarily support the idea that high-fat diets deteriorate carbohydrate
metabolism. The transition from a high-carbohydrate diet to a lowcarbohydrate diet may partly explain the dramatic increase in the prevalence of non-insulin-dependent diabetes mellitus among Pima Indians over the past century. The main findings of the study by O’Dea5 was the improvement in glucose tolerance in ten diabetic Aborigines after a 7-week reversion to traditional hunter-gatherer lifestyle. The lifestyle change (an increase in protein intake and decrease in energy intake) accompanied substantial weight loss. Perhaps the decreased energy intake rather than the increased protein intake improved the glucose tolerance of the diabetic Aborigines. Takashi Kaneko, Pei-Yu Wang, *Masato Tawata, Akio Sato Departments of Environmental Health and *Third Department of Internal Medicine, Medical University of Yamanashi, Tamaho, Yamanashi, 409-3898 Japan (e-mail: [email protected]) 1
2
3
4
5
Himsworth HP. Dietetic factor determining glucose tolerance and sensitivity to insulin of healthy men. Clin Sci 1935; 2: 67–94. Mooy JM, Gootenhuis PA, de Vries H, et al. Intra-individual variation of glucose, specific insulin and proinsulin concentrations measured by two oral glucose tolerance tests in general Caucasian population: the Hoorn Study. Diabetologia 1996; 39: 298–305. Swinburn BA, Boyce VL, Bergman RN, Howard BV, Bogardus C. Deterioration in carbohydrate metabolism and lipoprotein changes induced by modern, high fat diet in Pima Indians and Caucasians. J Clin Endocrinol Metab 1991; 73: 156–65. Marshall JA, Hoag S, Shetterly S, Hamman RF. Dietary fat predicts conversion from impaired glucose tolerance to NIDDM. The San Luis Valley Diabetes Study. Diabetes Care 1994; 17: 50–56. O’Dea K. Marked improvement in carbohydrate and lipid metabolism in diabetic Australian Aborigines after temporary reversion to traditional lifestyle. Diabetes 1984; 33: 596–603.
Antiretroviral treatment Sir—As your June 20 editorial1 makes clear, there is an urgent need for less expensive antiretroviral therapies for use in the developing world. One such combination might be that of the very cheap drugs chloroquine and hydroxyurea with didanosine. These three drugs have different sites of antiretroviral action: hydroxyurea inhibits ribonucleotide reductase; didanosine is a nucleoside reversetranscriptase (RT) inhibitor; and chloroquine interferes with the The production of gp120.2 combination of hydroxyurea and didanosine has a potent and longlasting antiretroviral effect. The antimalarial chloroquine is widely available in developing countries and it
THE LANCET • Vol 352 • October 10, 1998
CORRESPONDENCE
Treatment
Untreated HU HU+ddI CQ HU+ddI+CQ
H-9 cells
U-937 cells 3
3
p24 Ag (ng/mL)
RT activity (cpm⫻10 /mL)
p24 Ag (ng/mL)
RT activity (cpm⫻10 /mL)
31 (2·3) 9·8 (1·3) 4·3 (1·0) 7·3 (1·8) 1·3 (0·5)
456 (104) 124 (45) 23 (1·6) 132 (51) 14 (11)
24 (2·3) 7·5 (1·0) 2·3 (0·5) 8·2 (1·1) 0·8 (0·1)
546 (123) 176 (56) 13 (0·4) 185 (59) 0·2 (0·1)
All values are means (SE). HU=hydroxyurea; ddI=didanosine; CQ=chloroquine. After treatment cells were infected with HIV-1IIIB. Infection was assessed by measurement of RT and p24 antigen (Ag) in the culture supernatant 4 days after infection.
Effect of adding chloroquine to hydroxyurea and didanosine
has, together with its hydroxyderivative, beneficial anti-HIV-1 effects. These antimalarials are active against HIV-1 in vitro2,3 and in HIV-1infected patients, with an activity similar to that of zidovudine.4 Chloroquine may also exhibit antimicrobial properties against different pathogens that cause opportunistic infections in AIDS, such as Mycobacterium tuberculosis, Cryptococcus neoformans, and Histoplasma capsulatum.5 Another potential benefit of chloroquine is a decrease in iron accumulation in the reticulo-endothelial system, which reduces the effect of excess iron in HIV-1 infection.5 We examined in vitro whether the addition of chloroquine to the combination of hydroxyurea plus didanosine has any additive anti-HIV-1 activity in T cell and monocytic cell lines (table). Treatment with hydroxyurea (0·2 mmol) or chloroquine (0·1 mmol) alone reduces p24 antigen (Ag) and RT activity by 70% 4 days after infection of the H-9 and the U-937 cells, compared with the untreated cells. There is a further two-fold reduction in p24 Ag and RT activity in both cell types when hydroxyurea is combined with didanosine (1 mol). Addition of chloroquine to hydroxyurea plus didanosine results in an additional fall in p24 Ag and RT activity, compared with hydroxyurea plus didanosine. There were no increased toxic effects to H-9 or U-937 cells after the addition of chloroquine to hydroxyurea plus didanosine. Taken together, our preliminary findings in vitro suggest that the combination of hydroxyurea, didanosine, and chloroquine merits clinical testing. If found to be effective, this less expensive antiretroviral combination may help to bridge the gap,1 particularly among HIV-1infected people in developing countries. *Johan R Boelaert, Kirk Sperber *Unit of Renal and Infectious Diseases, Algemeen Ziekenhuis St-Jan, 8000-Brugge, Belgium; and Clinical Immunology, Mount Sinai School of Medicine, New York, NY, USA 1
Editorial. AIDS, the unbridgable gap. Lancet 1998; 351: 1825.
THE LANCET • Vol 352 • October 10, 1998
2
3
4
5
Sperber K, Kalb TH, Stecher VJ, Banerjee R, Mayer L. Inhibition of human HIV-1 replication by hydroxychloroquine in T cells and monocytes. AIDS Res Hum Retroviruses 1993; 9: 91–98. Tsai W-P, Nara PL, Kung HF, Oroszlan S. Inhibition of human immunodeficiency virus infectivity by chloroquine. AIDS Res Hum Retroviruses 1990; 6: 481–89. Sperber K, Chiang G, Chen H, et al. Comparison of hydroxychloroquine with zidovudine in asymptomatic patients infected with HIV-1. Clin Ther 1997; 19: 913–23. Boelaert JR, Weinberg GA, Weinberg ED. Altered iron metabolism in HIV infection, possible consequences and proposals for management. Infect Agents Dis 1996; 5: 36–46.
Bread fortification with folic acid, vitamin B12, and vitamin B6 in Hungary Sir—The recent recommendation of the US National Academy of Sciences on the daily intake of folate and folic acid, reported in Therese Droste’s April 11 news item, 1 reinforced the Hungarian efforts for prevention of neural-tube defects and other congenital abnormalities by periconceptional folic acid/multivitamin supplementation. However, only 45% of women plan their pregnancies and a 1996 country-wide campaign found that only 12% of women used periconceptional care. A new curriculum subject, entitled “preparing for family life”, was introduced in 1997 for pupils aged 14–16, but it will be many years before educational measures have the desired impact. Food fortification seems to be the medium-term solution. In Hungary, the national basic food is bread, and the average daily intake is 200 g, thus it can deliver the necessary supplements of folic acid, vitamin B12, and B6 to the target population. Another purpose of bread fortification with these three vitamins is to attempt the reduction of vascular diseases.2 The role of folic acid does not need explanation. Vitamin B12 is an independent risk factor for neural-tube defects and may be appropriate to neutralise the possible adverse effect of pharmacological dose (>1000 g) of folic acid in people affected with pernicious anaemia.
Vitamin B6 is also important in the prevention of homocysteine-related vascular diseases.3 We made two proposals for bread fortification in June, 1997. The minimum requirement was 160 g folic acid, 0·80 g vitamin B12, and 880 g vitamin B6 for 100 g of flour. The proportion of flour is 75% in the bread and there is a 20% loss of these vitamins during production, therefore, the daily intake of folic acid, vitamin B12, and B6 is about 200 g, 1 g, and 1080 g, respectively, in 200 g of bread. Daily intake of 200 g folic acid results in a 41% estimated reduction in risk of neural-tube defects. 4 The optimum requirement would include 330 g folic acid, 20 g vitamin B12, and 3000 g vitamin B6 for 100 g of flour. Thus, in 200 g of bread, there is 400 g folic acid, 25 g vitamin B12, and 3600 g vitamin B6. With the fortification of bread with 330 g of folic acid 1–2% of the Hungarian population would exceed the tolerable upper intake level (1000 g), however, 25 g of vitamin B12 can protect the so-called masking effect of folic acid in patient with pernicious anaemia. 5 About 1% of oral dose of vitamin B12 can be absorbed via nonphysiological mass action in these patients. Thus, vitamin B12 has no toxic effect under 1000 g . The tolerable upper intake level of vitamin B6 is 100 mg. In April 1998, the minimum requirement proposal was accepted by the authorities and the initial production of fortified bread began in August, 1998. However, we will attempt to get support from the scientific authorities to introduce at a later date the optimum requirements of the three vitamin B groups. *Andrew E Czeizel, Zoltan Merhala WHO Collaborating Centre for the Community Control of Hereditary Diseases, Bolgárkerék u.3, Budapest H-1148, Hungary 1
2
3
4
5
Droste TM. US study recommends daily amounts of vitamins. Lancet 1998; 351: 1113. Boushey CJ, Beresford SAA, Omenn GS, Motulsky AG. A quantitative assessment of plasma homocysteine as a risk factor for vascular diseases. JAMA 1995; 274: 1049–57. Rimm EB, Willett WC, Hu FB, et al. Folate and vitamin B6 from diet and supplements in relation to risk of coronary heart disease among women. JAMA 1998; 279: 392–93. Daly S, Mills JL, Molloy AM, et al. Minimum effective dose of folic acid for food fortification to prevent neural-tube defects. Lancet 1997; 350: 1666–69. Herbert V, Bigaouette J. Call for endorsement of petition to the Food and Drug Administration to always add vitamin B-12 to any folate fortification or supplement. Am J Clin Nutr 1997; 65: 572–73.
1225