Multimodality imaging in aortic stenosis 357subgroups, the mortality with medical therapy was higher in LF/LG followed by, LF/HG, NF/HG and NF/LG (LF/LG 26.4% vs. LF/HG 25% vs. NF/HG 21.4% vs. NF/LG 18.7%; Log Rank Test, P=0.003).Patients with HG had a higher chance of getting surgical or transcatheter AVR than those with LG (20.7% NF/HG vs. 10.6%LF/HG vs. 4.7% LF/LG and 3.6% NF/LG; P=0.01).Patients treated surgically had better survival compared to those treated medically in all subgroups except NF/LG [LF/HG (12.5% vs. 26.6%,Log Rank Test, P=0.03); NF/HG (14.7% vs. 21.6%,Log Rank Test, P=0.04); LF/LG (15.3% vs. 26.6%,Log Rank Test, P=0.02) and NF/LG (16.6% vs. 18.8%,Log Rank Test, P=0.23)].Similarly patients treated with TAVR had better survival compared to those treated medically in all subgroups except NF/LG [LF/HG (16.5% vs. 26.6%,Log Rank Test, P=0.03); NF/HG (15.7% vs. 21.6%,Log Rank Test, P=0.04); LF/LG (16.3% vs. 26.6%,Log Rank Test, P=0.02) and NF/LG (16.9% vs. 18.8%,Log Rank Test, P=0.23)].Conclusion: Patients with LF/LG represent an under-recognized high-risk group with similar prognosis to those with HG.Although these patients may benefit tremendously from surgical or transcatheter AVR, they are less likely to undergo AVR when compared to HG patients.
To the Editor: Tenofovir disoproxil fumarate (TDF) is a nucleotide analogue of adenosine-5′-monophosphate that has proven efficacy in treating antiretroviral-naive and -experienced HIV-infected patients.1,2 It offers several advantages, including a once-daily formulation with single-tablet administration, a low level of cross-resistance, and a low risk of dyslipidemia and thymidine analogue-related toxicity. As with other nucleotide analogues, cases of proximal tubular dysfunction with urinary loss of phosphorus have been reported, including severe toxicity such as Fanconi syndrome.3-5 For these reasons, it is recommended to monitor phosphatemia and creatinine clearance every 3 months to detect renal toxicity. The pharmaceutic laboratory recommends assessment for proximal dysfunction in cases in which phosphatemia is less than 0.48 mmol/L and/or creatinine clearance is less than 50 mL/min per 1.73 m2. Interestingly, the ratio of the maximal tubular reabsorption rate of phosphate and the glomerular filtration rate (TmPO4/GFR) that corresponds to the value of phosphatemia greater than which phosphate is excreted in the urine is normally higher than 0.8 mmol/L. We hypothesized that in case of TDF renal toxicity, bone phosphate stock could initially compensate renal loss, thus preventing the early detection of toxicity through the monitoring of phosphatemia. To test this hypothesis, we proposed to monitor the capacity of the kidney to reabsorb phosphate through an ambulatory screening for the TmPO4/GFR and to compare these results with the concomitant phosphatemia. The study population included HIV-infected patients receiving TDF as part as their ongoing antiretroviral therapy in the Department of Infectious Diseases. The TmPO4/GFR was estimated as described by Bijvoet,6 using measurement of phosphate and creatinine in fasting blood samples and urine collected in the morning. In patients for whom ambulatory estimates of the TmPO4/GFR were lower than <0.8 mmol/L, we checked this estimate against a complete evaluation of phosphate and calcium homeostasis in the Department of Physiology to confirm urinary phosphate loss and to look for another cause of renal loss. Bone mineral density evaluation by dual-energy x-ray absorptiometry (DEXA) was performed in patients with a confirmed decrease in the TmPO4/GFR. Ninety patients receiving TDF for a mean interval of 15 months were evaluated. At the time of the screening, 60 patients had undetectable HIV plasma RNA (<50 copies/mL). None had phosphatemia less than 0.48 mmol/L or creatinine clearance less than 50 mL/min per 1.73 m2. An estimated TmPO4/GFR less than 0.8 mmol/L, suggesting an impairment of renal phosphate transport, was found in 29 (32%) patients. Among those, only 8 had phosphatemia between 0.5 and 0.8 mmol/L (Fig. 1).FIGURE 1: TmPO4/GFR estimation and phosphatemia in 90 patients receiving tenofovir (▪, patients with a decreased TmPO4/GFR and hypophosphatemia; ░, patients with a decreased TmPO4/GFR with normal phosphatemia; □, patients with a normal TmPO4/GFR and phosphatemia).Eighteen of the 29 patients with a TmPO4/GFR less than 0.8 mmol/L underwent a complete evaluation of phosphate and calcium homeostasis. Decreased proximal reabsorption of phosphate was confirmed in 11 (61%) of 18 patients, whereas all had a normal GFR (mean of 97 ± 5 mL/min per 1.73 m2) and plasmatic ionized calcium (mean of 1.21 ± 0.02 mmol/L). Among these 11 patients, 7 had phosphatemia greater than 0.8 mmol/L. Secondary hyperparathyroidism (parathormone [PTH] values greater than 60 pg/mL and 25(OH)-vitamin D level less than 25 ng/mL) was detected in 3 of 11 patients and could explain the observed decrease in proximal phosphate reabsorption. In the 8 other patients, no other cause was detected, suggesting possible renal proximal toxicity of TDF. Eight of the 11 patients had a DEXA scan to monitor bone mineralization. Osteopenia (T-score <−1) was observed in 6 patients at the lumbar spine or the hip. Among them, 4 had phosphatemia less than 0.8 mmol/L. Since the introduction of TDF, the rate of TDF renal toxicity and the methods to detect it have been a subject of debate.7-9 Symptomatic severe acute proximal toxicity leading to an interruption in the prescription of TDF has been reported with a frequency of 0.39%.7 The occurrence of mild asymptomatic toxicity has been estimated through phosphatemia monitoring and measurement of creatinine level. It was estimated to be <1% for hypophosphatemia less than 1 mg/L and 7% for a 5-μmol/L increase in serum creatinine.8 These rates have to be compared with those of the 30% of patients with a decrease in phosphate reabsorption in our study and that of Badiou et al.9 The detection of a mild alteration of renal proximal function is difficult, because renal loss of phosphate can be compensated by bone loss to maintain normal phosphatemia. This probably explains why phosphatemia remained normal in 60% of the patients with proven renal loss of phosphate in our study. This result showed that monitoring phosphatemia lacks the sensitivity to detect renal toxicity; thus, we propose the use of TmPO4/GFR estimation for the assessment of TDF toxicity. TmPO4/GFR estimation is practical to perform and more sensitive than phosphatemia in the detection of renal loss of phosphate. We acknowledge that the positive and negative predictive values of this test could not be estimated here, because a complete exploration of phosphate and calcium metabolism was not performed in patients with a normal estimated TmPO4/GFR. The complete evaluation of calcium and phosphate metabolism in 18 patients revealed the frequency of other disturbed parameters involved in the decrease in renal phosphate reabsorption, such as the modification of vitamin D and PTH metabolism observed in 27% of the patients. TDF remained the only identified cause of tubular toxicity in 72% of the patients. Modification of vitamin D metabolism has recently been demonstrated in HIV-infected patients with a decrease in 25- or 1-α-hydroxylation and 1,25(OH)2 vitamin D degradation.10,11 Vitamin D is the major known regulator of intestinal phosphate absorption, and, through its regulation of PTH, it also affects renal phosphate reabsorption. Our results suggest that vitamin D and PTH concentrations should be checked before imputing renal phosphate loss to TDF toxicity. Our patients showed neither other alterations of proximal function nor glomerular filtration alteration. Because no follow-up monitoring was conducted, however, we cannot rule out the possibility of a decrease in renal function during the course of TDF chronic toxicity. In conclusion, using an estimated TmPO4/GFR, we demonstrated a urinary loss of phosphate despite normal phosphatemia in 23% of patients receiving TDF. Because long-term consequences of this mild toxicity are currently not known, a pragmatic approach might be to monitor renal tubular function on a regular basis. In case of worsening function, the interruption of TDF should be weighed against the potential benefit of this nucleotide in the therapeutic strategy for each patient. Marie Essig, MD, PhD* Xavier Duval, MD, PhD† Firas Al Kaied, MD‡ Laura Iordache, MD‡ Anne Gervais, MD‡ Pascale Longuet, MD‡ Francoise Blanchet, PharmD§ Gilles Peytavin, PharmD∥ Catherine Leport, MD, PhD‡ *Assistance Publique-Hôpitaux de Paris (AP-HP) Hôpital Bichat Service de Néphrologie Paris, France †AP-HP, Hôpital Bichat Centre d'Investigations Cliniques Paris, France ‡Laboratoire de recherche en Pathologie Infectieuse, Université Paris 7, AP-HP, Hôpital Bichat Services de Maladies Infectieuses et Tropicales, Paris, France §AP-HP, Hôpital Bichat Claude Bernard, Physiologie-Explorations-Fonctionnelles, Paris, France ∥AP-HP, Hôpital Bichat, Pharmacologie, Paris, France
There is currently no medical therapy that can prevent the progression of aortic valve stenosis (AS). Recent data highlight a possible relationship between bone metabolism and AS progression but prospective data are lacking.Serum levels of calcium, phosphorus, creatinine, 25-OH vitamin D, intact parathyroid hormon (iPTH), C-terminal-telopeptide of type-1-collagen (CTX) and osteocalcin were assessed at baseline in 110 elderly patients (age ≥70 years) with at least mild AS. CTX/osteocalcin ratio was calculated as a marker of bone remodelling balance. AS severity was assessed at baseline and 1-year based on the mean gradient. Two-thirds of patients had low 25-OH vitamin D and 20% had secondary hyperparathyroidism. AS progression was not associated with age, glomerular filtration rate (GFR), calcium and phosphorus levels, calcium-phosphorus product, but significantly with iPTH, CTX/osteocalcin and vitamin D status (all P < 0.01). There was no correlation between iPTH and CTX/osteocalcin (R = 0.04, P = 0.70) and AS progression was associated with CTX/osteocalcin (R = 0.42, P = 0.009), but not with iPTH (R = 0.10, P = 0.55) in patients with normal vitamin D levels, whereas it was associated with iPTH (R = 0.47, P < 0.001) and not with CTX/osteocalcin (R = 0.04, P = 0.73) in those with low vitamin D levels, especially if mild renal insufficiency was present (R = 0.61, P < 0.001).In elderly patients with AS, we observed an association between AS progression and vitamin D, iPTH and CTX/osteocalcin ratio and their respective influence varied according to the vitamin D status. In patients with normal vitamin D levels, AS progression was associated with a bone resorptive balance, whereas in patients with low vitamin D levels, AS progression was associated with iPTH and secondary hyperparathyroidism, especially if mild renal insufficiency was present. These findings may have important prognostic and therapeutic implications. Trial registration information: Clinicaltrials.gov identifier number: NCT00338676, funded by AP-HP, the COFRASA study.
This study aimed to determine the prevalence of macroscopic anal lesions and associated factors in HIV-infected outpatients during the era of highly active antiretroviral therapy.A randomly selected sample of patients with HIV-infection receiving follow-up care in the infectious diseases department of Bichat University Hospital was invited to participate in a systematic screening program consisting of anal examination with anoscopy and a standardized questionnaire.Of 516 patients, 473 (92 percent) participated. Overall, 208 patients (44 percent) had at least one anal macroscopic lesion: 108 patients (22.8 percent) had human papilloma (HPV)-related lesions (condyloma with or without dysplasia), 67 (14.2 percent) had hemorrhoidal disease, 50 (10.6 percent) had anal fissures, and 44 (9.3) percent had other anal lesions. Independent significantly associated factors for anal condyloma were history of anal condyloma (OR, 2.09) and median number of episodes of sexual intercourse per month (OR, 1.03) in men who have sex with men; history of genital condyloma (OR, 26.74), and unprotected sexual intercourse (OR, 7.47) in heterosexual men; and CD4 cell count below 200/mm3 (OR, 6.02), receptive anal intercourse (OR, 6.37), and history of anal condyloma (OR, 16.69) in women. Neither sexual behavior nor characteristics related to HIV infection were associated with hemorrhoidal disease or anal fissure.Because patients with HIV infections have a high prevalence of unreported anal lesions that may be highly contagious, involve risk of anal neoplasia, or negatively affect quality of life, systematic anal screening should be conducted in the HIV-infected population.
To assess the prevalence of and factors associated with squamous intraepithelial lesions and condyloma [human papillomavirus (HPV)-related lesions) in HIV-infected patients.A cross-sectional study in a tertiary-care university hospital conducted in 516 consecutive outpatients.A systematic examination for macroscopic HPV-related lesions through anoscopy with histological confirmation, evaluation of dysplasia and HPV typing. Sexual behaviours were assessed using a semi-directive questionnaire.Of 473 patients examined, (200 homosexual men, 123 heterosexual men, 150 women), 108 (23%) had histologically confirmed anal HPV-related lesions (36, 15 and 11% of the respective populations), including 51 (47%) with only endoanal localization. Among these 108 patients, histological dysplasia of grades I or II and grade III were noted in 59 and two patients, respectively, invasive endoanal cancer in one; three patients also had high-risk oncogenicity HPV without dysplasia. Independent identified associated factors of HPV-related condyloma were the number of incidents of sexual intercourse per month [odds ratio (OR) 1.04; 95% confidence interval (CI) 1.01-1.06], CD4 cell count below 200 x 10 cells/l (OR 3.22; 95% CI 1.37-7.60), history of anal HPV lesion (OR 4.57; 95% CI 2.13-9.81), and receptive anal intercourse (OR 2.30; 95% CI 1.11-4.77). The two latter factors remained associated with histological dysplasia (OR 2.82; 95% CI 1.38-5.76 for history of anal condyloma, and OR 4.29; 95% CI 2.18-8.44 for receptive anal intercourse).The high rate of condyloma and histological dysplasia seen argues for a systematic screening for these lesions in HIV-infected individuals.
Les patients infectes par le virus de l’immunodeficience humaine (VIH) le sont tres souvent aussi par le virus human papilloma (HPV) au niveau de l’anus puisque les 3 quarts des femmes, la moitie des heterosexuels masculins et presque tous les homosexuels masculins sont porteurs de ce virus. Cette infection est responsable de l’apparition d’une dysplasie anale severe dans 9 % a 24 %. Ceci explique en partie l’augmentation d’incidence du cancer de l’anus dans cette population (30 a 100 fois celle de la population generale). Les condylomes, qui sont les lesions macroscopiques de l’infection HPV, sont mis en evidence chez un quart des patients VIH. Par ailleurs, 20 % de ces patients sont porteurs d’une autre affection proctologique (hemorroides, fissure, suppuration, incontinence anale, autre infection sexuellement transmissible…). Pour toutes ces raisons, un depistage par examen proctologique complet, comportant une anuscopie standard, doit etre realise chez les patients a risque, infectes par le VIH (particulierement chez les homosexuels).
