OTHER. Keywords Obesity. Sleeve gastrectomy. HIV. OBES SURG DOI /s # Springer Science+Business Media New York 2014

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1 DOI /s OTHER Sleeve Gastrectomy Is a Safe and Efficient Procedure in HIV Patients with Morbid Obesity: a Case Series with Results in Weight Loss, Comorbidity Evolution, CD4 Count, and Viral Load Marinos Fysekidis & Régis Cohen & Mohamed Bekheit & Joseph Chebib & Abdelghani Boussairi & Hélène Bihan & Marie Aude Khuong & Laurent Finkielsztejn & Gabriela Mendoza & Sophie Abgrall & Djiba Condé & Jean Marc Catheline # Springer Science+Business Media New York 2014 Abstract Background The efficacy and safety of bariatric surgery have been poorly studied in patients affected with HIV. Although sleeve gastrectomy (SG) is the most widely used procedure in many countries, most of the published literature reported results with the gastric bypass (GBP) procedure on morbidly obese HIV patients. Methods We have evaluated retrospectively, in eight consecutive patients who underwent a SG, its effect in weight loss and its impact on the treatment and on the markers of HIV infection. Results Seven out of eight patients were females. The mean age was 46 years, with a median preoperative BMI of 42 kg/ m 2. The mean duration of HIV infection and CD4 cell count were 13.4 years and 457 cells/mm 3,respectively.Themean weight loss was 37 kg in 20 months, the excess BMI loss was 80.8±30.9 %, and the excess weight loss is 81.5±28.9 % with one minor complication. CD4 counts were unchanged. Three patients had therapy modifications that were unrelated to bariatric surgery. Two patients had a therapeutic drug monitoring before and after the intervention. Plasma concentrations remained in therapeutic levels after the SG. Most comorbidities disappeared postoperatively, decreasing the cardiovascular risk. Conclusions The sleeve gastrectomy was safe and effective with no consequences on CD4 counts and viral load in HIVaffected obese patients. It should be considered as a part of the treatment in morbidly obese HIV patients. Keywords Obesity. Sleeve gastrectomy. HIV M. Fysekidis: H. Bihan : D. Condé Service d Endocrinologie, Diabétologie et Maladies Métaboliques, Hôpital Avicenne, Paris XIII, Bobigny, France R. Cohen (*) Service d Endocrinologie, Centre hospitalier de Saint-Denis, regis.cohen@ch-stdenis.fr M. Bekheit: J. Chebib : J. M. Catheline Service de Chirurgie Digestive, Centre hospitalier de Saint-Denis, M. Bekheit Department of Surgery, El Kabbary General Hospital, Alexandria, Egypt A. Boussairi Laboratoire de Pharmacotoxicologie, Centre hospitalier de Saint-Denis, M. A. Khuong Service de maladies infectieuses, Centre hospitalier de Saint-Denis, L. Finkielsztejn Hôpital Cochin Maladies infectieuses, 27 rue du faubourg Saint-Jacques, Saint-Jacques, France G. Mendoza Médecine Interne CHU André Grégoire Montreuil sous bois, 56 Boulevard de la Boissière, Montreuil, France S. Abgrall Service de maladies infectieuses, Hôpital Avicenne, 125 Rue de Stalingrad, Bobigny, France

2 Introduction It has been estimated by the World Health Organization that 35.3 million persons were affected with HIV/AIDS worldwide, in HIV infection weakens the immune system, and patients are highly susceptible to opportunistic infections and certain types of cancers. With the anti-retroviral regimen appearance in 1996, the spectrum of this disease changed from the wasting syndrome to a chronic condition with increased obesity rates and metabolic consequences [1]. HIV-infected patients are becoming increasingly overweight and obese at diagnosis and during HIV treatment. The prevalence of overweightness is around %, and obesity affects 6 34 % of men and % of women [2]. Weight gain seems to be secondary to improved health status and can be a consequence of HIV therapy. Weight management programs may be important components of HIV care [3]. Bariatric procedures, including gastroplasty, lapbanding surgery, sleeve gastrectomy (SG), gastric bypass (GBP), and jejunoileal bypass, represent the more successful approaches to weight loss compared to other methods in morbid obesity, decreasing morbidity and mortality [4, 5]. Few studies to date have provided data on the weight changes and consequences on the therapy among HIVinfected patients after bariatric surgery [6]. This study had as a primary objective to demonstrate the efficacy and safety of the SG in HIV patients with morbid obesity from a single center and as a secondary objective to evaluate the absence of side effects on HIV treatment or viral load or on HIV plasma drug levels. The resolution of comorbidities underlines the importance of the SG as a part of therapy in HIV patients with severe obesity. Patients and Methods We reviewed retrospectively the records of patients that underwent bariatric surgery in the tertiary center of Saint- Denis from January 2011 to December The study included seven females and one male, with a mean age of 46 years (range 40 50) and a mean preoperative body mass index of 42 kg/m 2 (range 35 50). All patients that were candidates for bariatric surgery fulfilled the French criteria for bariatric surgery, that is, body mass index (BMI) of more than 35 kg/m 2 with at least one comorbidity (hypertension, diabetes, sleep apnea,, severe rheumatologic disease) or a BMI >40 kg/m 2 and at least 6 months of follow-up by a dietician or nutritionist and no underlying active psychiatric disorder [7]. The decision for the operation was taken from a multi-disciplinary team that included a bariatric surgeon, endocrinologist, anesthesiologist, clinical psychologist, and a clinical dietician. Preoperative comorbidities were assessed by personal medical history and prescribed treatment. These comorbidities included two patients with type 2 diabetes mellitus/impaired glucose tolerance, five with hypertension, two with, two with sleep apnea, one with asthma, and three with arthritis. There were no major psychiatric disorders, coronary artery disease/chronic heart failure, or compulsive eating behavior. Postoperatively, the presence of comorbidities was assessed as follows: for type 2 diabetes, improvement was considered if medication was no longer needed and HbA1c was equal to or less than 6.0 %; impaired glucose tolerance was estimated with an oral glucose tolerance test; and in the case of hypertension and, we examined the need for medication and for sleep apnea if the use of a continuous positive airway pressure was no longer necessary after a polysomnographic control. The mean duration of HIV infection was 13.4 years, and all patients except one (patient 4) were receiving highly active anti-retroviral therapy (HAART) at the time of surgery. The average CD4 cell count was 457 cells/mm 3 ( ). One patient had viral hepatitis B and C coinfection with undetectable viral load. The most common anti-retroviral class used was nucleoside reverse transcriptase inhibitors (Table 1). For the surgical procedure that has been previously described, we have used a 34-French bougie [8]. HIV Drug Assay Protease inhibitor (PI; darunavir, atazanavir, lopinavir, ritonavir, saquinavir), non-nucleoside reverse transcriptase inhibitor (NNRTIs; nevirapine, efavirenz, etravirine), and integrase inhibitor (raltegravir (RAL)) concentrations in a stored plasma at 20 C were determined using high-performance liquid chromatography coupled with photodiode array detection (Spectra System, Thermo Fischer, France). Chromatographic separation of PIs and NNRTIs was performed by a 5-μmC18 column LiCrospher 60 RP select B ( mm ID; Agilent, France). Chromatographic separation of RAL was performed by a 3-μm Altima C18 column (150 3-mm ID; Agilent, France). The run was monitored in the range of nm by the PDA detector, and the selected wavelength to quantify PIs, NNRTIs, and RAL is 210 nm. Quantification limits of PIs and RAL are 0.05 mg/l and 35 μg/l. Results All patients had SG and one of them did not reveal his HIV status before surgery (patient 7). All patients were operated by laparoscopy. There was no conversion to laparotomy and no postoperative mortality. No early complications (less than 1 month) occurred in these patients. One patient (case 7) had persistent vomiting, food intolerance for more than 2 years after surgery, and asthenia

3 Table 1 Characteristics of the patients included in the study Patient Sex Type Age BMI (kg/m 2 ) Drugs CD4 (units) before surgery VL (units) before surgery CD4** (units) after surgery VL (units) after surgery Comorbidities 1 F SG a ATV/r, TDF, and FTC 2 F SG ATV/r, 3TC, and ABC 3 F SG DRV/r, TDF, and FTC Arthritis 579 < <20 Hypertension and 414 < <20 Arthritis and 4 F SG a No drugs , Hypertension, SAS, and diabetes 5 F SG ATV/r, 3TC, and 459 < <20 Hypertension ABC, 6 F SG DRV/r, ETV, ABC, 3TC, and ddl 7 M SG RAL, FTC, and TDF 8 F SG DRV/r, TDF, and ABC 375 < <37 Hypertension and 527 < <20 Hypertension and asthma 510 < <20 SAS, arthritis, and hyperglycemia There was a tendency of increase in mean CD4 after surgery 565±167 vs before surgery 457±77 F female, M male, VL viral load, 3TC lamivudine, ddl didanosine, TDF tenofovir, ABC abacavir, FTC emtricitabine, RTV ritonavir, ATVatazanavir, DRV darunavir, ETV etravirine, RAL raltegravir, RPV rilpivirine **p=0.058 (non-parametric test, Wilcoxon s test for two related samples) a Patients had a lapbanding before sleeve gastrectomy with no vitamin deficits. Upper GI series with barium swallow, gastroscopy, and esophageal PH measurements were normal. The mean follow-up was 20 months (range 5 42). The mean weight loss was 37 kg (range 28 47). The percentage of excess BMI loss was 80.8±30.9 %, and the percentage of excess weight loss was 81.5±28.9 %. Postoperatively, there was improvement of the comorbidities: in two out of two cases of type 2 diabetes mellitus/impaired glucose tolerance, in three out of five cases of hypertension, in two out of two cases of, and in two out of two cases of sleep apnea. HIV Disease Follow-Up During the follow-up, there was no progression of the HIV infection. Average CD4 cell count and viral load remained unchanged, except in patient 4 that was treated with HAART (Table 1). Three patients had either therapy initiation or modifications. Patient 2 received a rilpivirine (RPV)/emtricitabine (FTC)/tenofovir (TDF) combination in order to decrease the number of daily tablets; in patient 4, therapy was started with abacavir and lamivudine (ABC + 3TC) and etravirine; and for patient 6, didanosine was stopped and was replaced by raltegravir 1 year after the surgery in relation to side effects in a patient with multi-hiv mutations. Two patients (5 and 6) had preoperative and postoperative assay of anti-retroviral drugs (Table 2). This assay was done as part of their regular follow-up. Efficiency and adherence to treatment for all patients were estimated by viral load since drug levels are not part of the guidelines. In patient 5, there was a decrease in the concentration of ritonavir (RTV) and atazanavir (ATV) after SG. The concentration of the ATV remained in therapeutic levels because it was greater than the half maximal inhibitory concentration (IC 50). Plasma concentrations were considered suboptimal if they were lower than 0.15 mg/l. It is noteworthy that RTV is given as a booster and its half-life is short. At a low concentration, RTV can inhibit cytochrome P450 isoenzyme 3A4 and exert its therapeutic action by increasing the activity of associated drugs. For patient 6, the concentration of anti-retroviral (ARV) drugs remained in therapeutic range after SG despite a decrease in the concentration of etravirine (ETV). Despite suboptimal adherence and a slight drop in the plasma concentrations of some ARVs, there was no change in the control of the disease, as evidenced by a viral load that remained undetectable and the tendency of increase in mean CD4 after surgery 565±167 vs before surgery 457±74 (p=0.058). Discussion The laparoscopic SG was a safe and efficient procedure for HIV-infected patients with no significant postoperative complications. It should be proposed for HIV patients as it is the case for non-infected subjects. HIV infection parameters were

4 Table 2 Measured anti-retroviral drug levels before and after sleeve gastrectomy Patient 5 (F) Drugs Concentration recommended Before C12h a After C12h a RTV (mg/l) 0.25 Traces ATV (mg/l) 1.50 at H b 0.64 b Patient 6 (F) Drugs Concentration recommended Before C10h Before C12h After C16h After unknown RTV (mg/l) ND c 0.58 DRV mg/l at H ND c 3.61 ETV (mg/l) at H RAL (μg/l) >150 at H For both patients, viral load and CD4 count were constant ND Non-detectable drug levels a C12h plasma levels 12 h after drug administration a Possible non-adherence c Undetectable RTV and DRV could be adequate because they are used as booster and have a short half-life not modified by the surgery, except for patient 4 who had therapy initiation, but this was due to the timing of the operation that preceded HIV treatment as it was decided both by the patient and the infectious disease specialist. The absence of modifications was confirmed after a 20-month follow-up, a sufficient observation period for detecting modified drug kinetics and/or poor adherence. Plasma anti-retroviral level was not modified for two patients who had drug assay. Moreover, comorbidities like diabetes,, hypertension, and sleep apnea syndrome (SAS) regressed after bariatric surgery, reducing this way the existing cardiovascular risk. This is the first report on effect of SG in HIV-infected patients. Previous reports were concerned with patients treated by GBP [6, 9, 10]. The benefit to risk ratio (morbidity and mortality) has been poorly studied in HIV obese patients. In France, SG remains the most frequent bariatric procedure, with 11,000 operations in We have shown that the SG is safe in patients at risk of surgical complications like the superobese [8]. In the SG procedure, 90 % of the stomach is removed, but the rest of the gastrointestinal tract remains intact and there is a marked reduction in acid production. The current literature suggests that GBP might present more postsurgical complications and needs lifetime vitamin supplementation while being equally efficient in losing weight when compared to SG at least for the first year of the follow-up [11]. Large, multi-centric, randomized studies are lacking, and that is the main reason for the absence of enough evidence for a definitive conclusion. SG is known to produce weight loss by at least two possible mechanisms including the decrease of orexigenic hormone ghrelin and gastric volume restriction [12, 13]. In HIV-infected patients, a previous report indicated that three out of seven patients experienced postsurgical GBP complications [6]. In our report, only one patient presented a significant long-term complication affecting his quality of life. Anti-retroviral therapy has dramatically improved the health and extended the survival of patients with HIV infection, but poor adherence could interfere with the full benefits of treatment [14]. There is a large number of evidence indicating the need for improving the observance in HIV patients in order to avoid the risk of development of resistant strains. It has been suggested that adherence should be at 95 % and not 80 % as for other diseases like diabetes or hypertension. The changes in drug absorption induced by bariatric surgery have been poorly studied and may differ according to the alteration of gastrointestinal anatomy and physiology, the presence of drug interactions, and the reduction in body mass. In literature, there are few publications reporting the drug alteration after GBP surgery in non-hiv patients, notably drugs used in depression, some antibiotics, and thyroxin in hypothyroidism [15 17]. The authors concluded that these modifications were not critical in the management of their disease. The effect of bariatric surgery on drug absorption may be specific to the drug or the type of operation. The various stages of drug absorption could be modified: disintegration/ dissolution, mucous membrane exposure, transport through the gut, and transport across the intestinal epithelium. Gastric disintegration mixture could be significantly reduced after GBP and SG. Drug dissolution and solubility can potentially be affected by the increase in gastric ph in GBP and SG or by the use of anti-acid therapy. Most anti-hiv treatments are absorbed in the ileum. The absorption can be changed after GBP due to the reduced availability of bile acids to improve the solubility and reduced drug exposure to intestinal mucosa. The changes in the volume of distribution of lipophilic drugs may be increased in obese patients and decreased after surgery. Few reports suggested no modifications or small changes; after oral administration, post-gbp achieved sufficient

5 serum concentrations for lopinavir, whereas administration through the jejunal tube did not [18]. In a case of gastrectomy, lopinavir/ritonavir plasma levels were not affected [19]. Finally, non-pharmacokinetic parameters have to be taken into account such as the impact on fat cells on the immune system. In the study of Palermo et al., higher BMI predicted higher CD4+ T lymphocyte gains in HIV-infected men receiving anti-retroviral therapy, but there was no association between BMI and cellular immune activation [20]. The weak points of this study include its retrospective nature, its sample size, and the presence of uncontrolled pharmacokinetic factors. On the other hand, we have to notice the rarity of publications despite the popularity of this type of surgery and the rarity of randomized trials and the difficulty in perfoming this type of studies in surgical procedures. Our study suggests that measuring preoperatively and postoperatively the levels of the HIV drugs could be very useful to ensure the maintenance of therapeutic levels and for monitoring therapeutic observation. We have a positive signal from these patients in the present study but not a definitive conclusion. In conclusion, the SG procedure did not modify in a negative way the course of HIV infection in morbidly obese patients while significantly improved comorbidities, reducing this way the cardiovascular risk. Our results present certain limitations and further larger prospective studies are necessary. Conflict of Interest References All authors declare no conflict of interest. 1. UNAIDS report on the global AIDS epidemic [cited 29 October 2013]; Available from: unaids/contentassets/documents/epidemiology/2013/gr2013/ UNAIDS_Global_Report_2013_en.pdf. 2. Keithley JK, Duloy AM, Swanson B, et al. HIV infection and obesity: a review of the evidence. J Assoc Nurses in AIDS Care: JANAC. 2009;20(4): Miller M, Kahraman A, Ross B, et al. Evaluation of quantitative liver function tests in HIV-positive patients under anti-retroviral therapy. Eur J Med Res. 2009;14(9): Adams TD, Gress RE, Smith SC, et al. Long-term mortality after gastric bypass surgery. N Engl J Med. 2007;357(8): Buchwald H, Avidor Y, Braunwald E, et al. Bariatric surgery. JAMA: J Am Med Assoc. 2004;292(14): Selke H, Norris S, Osterholzer D, et al. Bariatric surgery outcomes in HIV-infected subjects: a case series. AIDS Patient Care STDS. 2010;24(9): Fried M, Yumuk V, Oppert J-M, et al. Interdisciplinary European guidelines on metabolic and bariatric surgery. Obes Facts. 2013;6(5): Catheline J-M, Cohen R, Khochtali I, et al. Traitement de la super obésité morbide par gastrectomie longitudinale. Presse Med. 2006;35(3): Fazylov R, Soto E, Merola S. Laparoscopic gastric bypass surgery in human immunodeficiency virus-infected patients. Surg Obes Relat Dis: Off J Am Soc Bariatric Surg. 2007;3(6): Flancbaum L, Drake V, Colarusso T, et al. Initial experience with bariatric surgery in asymptomatic human immunodeficiency virus-infected patients. Surg Obes Relat Dis. 2005;1(2): Keidar A, Hershkop KJ, Marko L, et al. Roux-en-Y gastric bypass vs sleeve gastrectomy for obese patients with type 2 diabetes: a randomised trial. Diabetologia. 2013: Consten EC, Gagner M, Pomp A, et al. Decreased bleeding after laparoscopic sleeve gastrectomy with or without duodenal switch for morbid obesity using a stapled buttressed absorbable polymer membrane. Obes Surg. 2004;14(10): Cohen R, Uzzan B, Bihan H, et al. Ghrelin levels and sleeve gastrectomy in super-super-obesity. Obes Surg. 2005;15(10): Leeman J, Chang YK, Lee EJ, et al. Implementation of antiretroviral therapy adherence interventions: a realist synthesis of evidence. J Adv Nurs. 2010;66(9): Sardo P, Walker JH. Bariatric surgery: impact on medication management. Hosp Pharm. 2008;43(2): Brocks DR, Ben-Eltriki M, Gabr RQ, et al. The effects of gastric bypass surgery on drug absorption and pharmacokinetics. Expert Opin Drug Metab Toxicol. 2012;8(12): Michalaki MA, Gkotsina MI, Mamali I, et al. Impaired pharmacokinetics of levothyroxine in severely obese volunteers. Thyroid: Off J Am Thyroid Assoc. 2011;21(5): Kamimura M, Watanabe K, Kobayakawa M, et al. Successful absorption of antiretroviral drugs after gastrojejunal bypass surgery following failure of therapy through a jejunal tube. Intern Med. 2009;48(12): Boffito M, Lucchini A, Maiello A, et al. Lopinavir/ritonavir absorption in a gastrectomized patient. AIDS. 2003;17(1): Palermo B, Bosch RJ, Bennett K, et al. Body mass index and CD4+ T-lymphocyte recovery in HIV-infected men with viral suppression on antiretroviral therapy. HIV Clin Trials. 2011;12(4):222 7.