Determination of a major histocompatibility complex class I restricting simian immunodeficiency virusGag241–249 epitopeSeveral major histocompatibility complex class I (MHC-I) carboxyl terminus. Comparison of amino acid sequences alleles such as HLA-BÃ57 have been shown to be associated of antigenic peptide-binding domains (a1 and a2 with lower viral loads and better prognosis in HIV-1 domains) in Mamu-AÃ90120-5 with those in HLA- infections, and MHC-I-restricted epitope-specific effec- BÃ5701 revealed limited similarities (154/182 ¼ 84.6%) tive cytotoxic T lymphocyte (CTL) responses are found to between these two (Fig. 1b). This might be compatible play an important role in this reduction of viral loads [1–3].
with previous reports indicating that human and macaque Characterization of these effective CTLs could contribute MHC-I molecules with divergent peptide-binding to the development of an effective AIDS vaccine.
grooves can bind similar or identical peptides [10,11].
MHC-I molecules form a peptide-binding groove We have developed a prophylactic vaccine using a Sendai including B-pocket and F-pocket that play a key role virus vector expressing simian immunodeficiency virus in determination of the binding peptide motif for its mac239 (SIVmac239) Gag (SeV-Gag) and have shown its specific binding to the MHC-I. Mamu-AÃ90120-5 and protective efficacy against SIVmac239 challenge in a HLA-BÃ5701 showed similarity in eight of 11 residues at group of Burmese rhesus macaques (Macaca mulatta) 7, 9, 24, 25, 34, 45, 63, 66, 67, 70, and 99, which are sharing an MHC-I haplotype 90-120-Ia [4]. Involvement considered to be anchor residues involved in B-pocket of SIVmac239 Gag241–249 (SSVDEQIQW) epitope- binding and in seven of eight residues at 77, 80, 81, 116, specific CTL responses in this viral control have been 123, 143, 146, and 147 involved in F-pocket binding indicated [5]. Interestingly, the SIVmac239 Gag241–249 epitope is located in a region corresponding to the HLA-BÃ57-restricted HIV-1 Gag240–249 epitope, TW10 In addition, TW10 epitope-specific CTLs, HLA-BÃ57- (TSTLQEQIAW), and TW10-specific CTL responses restricted HIV-1 Gag147–155 [ISW9 (ISPRTLNAW)] have also been indicated to exert strong suppressive epitope-specific CTLs have also been indicated to exert pressure on HIV-1 replication resulting in lower viral loads strong selective pressure on HIV-1 [14]. The SIVmac239 [6,7]. An SIVmac239 Gag241–249-specific CTL escape Gag149–157 amino acid sequence corresponding to the mutation has been shown to result in a loss of viral fitness HIV-1 Gag147–155 epitope region is LSPRTLNAW, similarly with a TW10-specific CTL escape mutation [5].
showing a difference at the amino terminus, and CTL In the present study, for further analysis of SIVmac239 responses specific for a peptide including the SIVmac239 Gag241–249-specific CTL function, we have tried to Gag149–157 amino acid sequence were not induced by determine the MHC-I that restricts this CTL epitope.
SeV-Gag vaccination in Mamu-AÃ90120-5-positivemacaques (data not shown). Interestingly, the SIVmac239 Among eight MHC-I alleles consisting of MHC-I Gag 148th proline (P) and 149th leucine (L) correspond haplotype 90-120-Ia [4,8], expression of three alleles, to the HIV-1 Gag 146th P and the 147th L, respectively that have been indicated to be selected in HIV-1-infected BÃ90120-6, was predominant at RNA levels. We cloned humans possessing HLA-BÃ57. Selection of the former cDNAs of these three alleles and established HLA-A/B/ 146th P has been shown to result in escape from ISW9- C-negative human 721.221 cell lines [9] expressing these specific CTL recognition by disturbance in antigen cDNAs, respectively. These cells were pulsed with processing [14]. Thus, it is speculated that the SIVmac239 10 nmol/l of Gag241–249 peptide and used as target cells Gag149–157-derived peptide may not be presented by for the CTL assay using an SIVmac239 Gag241–249- Mamu-AÃ90120-5 even if it has an ability to bind this specific CTL clone as the effector. Measurement of cytotoxicity in standard 51Cr release assay [5] revealedspecific killing of Gag241–249-pulsed cells expressing Both SIVmac239 Gag241-249-specific CTLs and HIV-1 Mamu-AÃ90120-5, indicating restriction of this CTL TW10-specific CTLs have been indicated to exert strong epitope by the Mamu-AÃ90120-5 molecule (Fig. 1a).
suppressive pressure on SIV/HIV-1 replication and selectfor a mutation resulting in escape from their recognition Both of the Mamu-AÃ90120-5-restricted SIVmac239 at the cost of viral fitness. Thus, this Gag region may be a Gag241–249 epitope and the HLA-BÃ57-restricted HIV-1 promising CTL target for viral control, and SIVmac239 TW10 epitope are considered to have the same anchor infection in Mamu-AÃ90120-5-positive macaques could residues, serine (S) at position 2 and tryptophan (W) at the be a unique model for examining viral replication in the ISSN 0269-9370 Q 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Division of Viral Immunology, Center for AIDS Research, Kumamoto University, Kumamoto, and cDepartment of Molecular Pathogenesis, Medical Research Institute, Tokyo Medical and Dental Univer- Correspondence to Dr Tetsuro Matano; International Research Center for Infectious Diseases, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
ÃThese authors contributed equally to the study.
Mamu-A*90120-5 GSHSMRYFYT SMSRPGRGQP RFFAVGYVDD TQFVRFDSDA HLA-B*5701 ---------- A-------E- --I------- ---------- Mamu-A*90120-5 ESPRMEPRAP WVEQEGPEYW DQETRKAKDT AQNYRVNLRT HLA-B*5701 A----A---- -I-------- -G---NM-AS --T--E---I Mamu-A*90120-5 ALRYYNQSEA GSHTIQKMYG CDLGPDGRLL RGYDQSAYDG 1. Kaslow RA, Carrington M, Apple R, Park L, Mun˜oz A, Saah AJ, HLA-B*5701 ---------- ---I--V--- --V------- --H------- et al. Influence of combinations of human major histocompat-ibility complex genes on the course of HIV-1 infection. Nat Mamu-A*90120-5 RDYIALNEDL RSWTAADMAA QNTQRKWEAA GWTEQMRAYL 2. Migueles SA, Sabbaghian MS, Shupert WL, Bettinotti MP, Mar- HLA-B*5701 K--------- S------T-- -I-------- RVA--L---- incola FM, Martino L, et al. HLA BM5701 is highly associated with restriction of virus replication in a subgroup of HIV- infected long term nonprogressors. Proc Natl Acad Sci U S A 3. Kiepiela P, Leslie AJ, Honeyborne I, Ramduth D, Thobakgale C, Chetty S, et al. Dominant influence of HLA-B in mediating the Fig. 1. Mamu-AM90120-5 that restricts the SIV Gag241–249 potential co-evolution of HIV and HLA. Nature 2004; 432:769– epitope. (a) CTL assay using a Gag241–249-specific CTL clone on a B-lymphoblastoid cell line derived from a macaque 4. Matano T, Kobayashi M, Igarashi H, Takeda A, Nakamura H, possessing 90-120-Ia (BLCL), 721.221 cells (mock), and Kano M, et al. Cytotoxic T lymphocyte-based control of simianimmunodeficiency virus replication in a preclinical AIDS vac- 721.221 cells expressing Mamu-AÃ90120-4 (A120-4), cine trial. J Exp Med 2004; 199:1709–1718.
Mamu-AÃ90120-5 (A120-5), and Mamu-BÃ90120-6 (B120- 5. Kawada M, Igarashi H, Takeda A, Tsukamoto T, Yamamoto H, 6), respectively. (b) Amino acid sequences of the Mamu- Dohki S, et al. Involvement of multiple epitope-specific cyto- toxic T-lymphocyte responses in vaccine-based control of a1 and a2 domains in comparison with HLA- simian immunodeficiency virus replication in rhesus maca- BÃ5701. The anchor residues involved in B and F-pocket binding are indicated by à and #, respectively.
6. Leslie AJ, Pfafferott KJ, Chetty P, Draenert R, Addo MM, Feeney M, et al. HIV evolution: CTL escape mutation and reversion presence of those CTLs targeting this region like TW10- after transmission. Nat Med 2004; 10:282–289.
7. Goulder PJ, Watkins DI. HIV and SIV CTL escape: implications specific CTLs. Finally, we obtained a phycoerythrin- for vaccine design. Nat Rev Immunol 2004; 4:630–640.
conjugated Gag241–249 epitope-Mamu-AÃ90120-5 tetra- 8. Takahashi-Tanaka Y, Yasunami M, Naruse T, Hinohara K, Matano T, Mori K, et al. Reference strand-mediated conforma- tion analysis (RSCA)-based typing of multiple alleles in the This could be useful for the analysis of Gag241–249- rhesus macaque MHC class I Mamu-A and Mamu-B loci.
specific CTL responses in Mamu-AÃ90120-5-positive 9. Shimizu Y, DeMars R. Production of human cells expressing individual transferred HLA-A,-B,-C genes using an HLA-A,-B,-Cnull human cell line. J Immunol 1989; 142:3320–3328.
10. Evans DT, Knapp LA, Jing P, Piekarczyk MS, Hinshaw VS, Watkins DI. Three different MHC class I molecules bind thesame CTL epitope of the influenza virus in a primate specieswith limited MHC class I diversity. J Immunol 1999; 162:3970– The present work was supported in part by grants from the Ministry of Education, Culture, Sports, Science, and 11. Hickman-Miller HD, Bardet W, Gilb A, Luis AD, Jackson KW, Watkins DI, et al. Rhesus macaque MHC class I molecules Technology, grants from the Japan Health Sciences present HLA-B-like peptides. J Immunol 2005; 175:367–375.
Foundation, and grants from the Ministry of Health, 12. Bjorkman PJ, Saper MA, Samraoui B, Bennett WS, Strominger JL, Wiley DC. The foreign antigen binding site and T cell recogni-tion regions of class I histocompatibility antigens. Nature 1987;329:512–518.
Tetsuo Tsukamotoa, Sachi Dohki b, Takamasa Uenob, 13. Saper MA, Bjorkman PJ, Wiley DC. Refined structure of the Miki Kawadaa, Akiko Takedaa, Michio Yasunami c, human histocompatibility antigen HLA-A2 at 2.6 A˚ resolution.
Takiguchib,M and Tetsuro Matanoa,M, aInternational 14. Draenert R, Le Gall S, Pfafferott KJ, Leslie AJ, Chetty P, Brander C, et al. Immune selection for altered antigen processing leads Research Center for Infectious Diseases, The Institute to cytotoxic T lymphocyte escape in chronic HIV-1 infection.
of Medical Science, The University of Tokyo, Tokyo, Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Does tenofovir increase efavirenz hepatotoxicity? Antiretroviral drugs have the potential to cause liver and AST was 29 IU/l, respectively. The patient is on toxicity, especially in hepatitis B virus or hepatitis C virus didanosine, lamivudine and nevirapine since December coinfected patients. Tenofovir is among the few whereas efavirenz can cause liver enzyme elevations No cases of tenofovir-related hepatotoxicity have been [1,2]. We report three cases of liver enzyme elevations in reported in the literature, and the drug appears to be well persistently hepatitis B virus and hepatitis C virus- tolerated even in cirrhotic patients [1]. In contrast, negative, HIV-infected patients after the addition of numerous cases of hepatotoxicity are related to efavirenz tenofovir to an efavirenz-containing regimen.
use [2,3]. Interestingly, in individuals who are slowefavirenz metabolisers, such as those with CYP2B6 loss/diminished-function alleles, efavirenz plasma area underthe curve values are highest among patients receiving tenofovir [4], and an unexpected development ofneuropsychiatric adverse events has been reported A 58-year-old Caucasian man was on virologically following addition of tenofovir to an efavirenz-contain- successful antiretroviral therapy (zidovudine, lamivudine ing ART regimen [5]. We have not measured efavirenz and efavirenz, respectively) since July 2002. In July 2007, plasma concentrations in our three patients, and therefore zidovudine was replaced by tenofovir because of we cannot prove whether an increased efavirenz plasma lipoatrophy and bone marrow toxicity. Four weeks later, concentration is responsible for the observed rise in alanine aminotransferase (ALT, normal values <50 IU/l) aminotransferase levels. Alternatively, hepatotoxicity may was 92 IU/l and aspartate aminotransferase (AST, normal be responsible for a highly infrequent tenofovir-related values <50 IU/l) was 62 IU/l. Both enzymes had always side-effect. Analysis of large databases or pharmacokinetic been within the normal range prior to the switch. Further studies is needed to confirm, extend and explain our controls showed ALT 144 IU/l and AST 84 IU/l (after a further 1 month) and ALT 142 IU/l and AST 77 IU/l 3months after tenofovir introduction. The patient then Emanuela Lattuadaa, Massimiliano Lanzafamea, Giada stopped tenofovir and began didanosine. Three weeks Caroloa, Martina Gottardia, Ercole Conciaa and later, ALT was 48 IU/l and AST was 44 IU/l.
Sandro Ventob, aUnit of Infectious Diseases, ‘G.B.
Rossi’ Hospital, Verona, Italy, and bUnit of InfectiousDiseases, ‘Annunziata’ Hospital, Cosenza, Italy.
Correspondence to Massimiliano Lanzafame, Unit of Infectious Diseases, ‘G.B. Rossi’ Hospital, Verona, viaStrada Romana 11, San Bonifacio (VR), CAP 37047, A 34-year-old African woman was on zidovudine, lamivudine and abacavir since September 2003. In Tel: +39 0458128256; fax: +39 0458128257; October 2006, abacavir was replaced by efavirenz because of virological failure. In August 2007, owing to anaemia,zidovudine was stopped and tenofovir was started. InSeptember 2007, ALT and AST (previously normal) were133 and 199 IU/l, respectively; liver enzyme elevation was confirmed subsequently after 3 weeks (ALT 186 IU/l, AST146 IU/l). Highly active antiretroviral therapy (HAART) 1. Gutierrez S, Guillemi S, Jahnke N, Montessori V, Harrigan PR, Montaner JSG. Tenofovir-based rescue therapy for advanced was stopped and, in the beginning of November 2007, liver disease in 6 patients coinfected with HIV and hepatitis B ALT and AST were back to normal (36 and 30 IU/l, virus and receiving lamivudine. Clin Infect Dis 2008; 46:e28– respectively). The patient is on abacavir, lamivudine and 2. Kontorinis N, Dieterich DT. Toxicity of nonnucleoside analogue lopinavir/ritonavir since December 2007.
reverse transcriptase inhibitors. Semin Liver Dis 2003; 23:173–182.
3. Rivero A, Mira JA, Pineda JA. Liver toxicity induced by nonnucleoside reverse transcriptase inhibitors. J AntimicrobChemother 2007; 59:342–346.
4. Rotger M, Colombo S, Furrer H, De´costerd L, Buclin T, Telenti A.
Does tenofovir influence efavirenz pharmacokinetics? AntivirTher 2007; 12:115–118.
A 30-year-old Caucasian man was on lamivudine, 5. Allavena C, Le Moal G, Michau C, Chiffoleau A, Raffi F. Neu- tenofovir and efavirenz since April 2007. In May 2007, ropsychiatric adverse events after switching from an antiretro-viral regimen containing efavirenz without tenofovir to an ALTand AST (previously normal) were 392 and 225 IU/l,.
efavirenz regimen containing tenofovir: a report of nine cases.
ARTwas discontinued and, 40 days later, ALTwas 23 IU/l Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Methodological issues of non-inferiority trials in HIV-infected patients: a need for consensus? We read with great interest the publication by Pulido et al.
analyses as it minimizes the difference between groups [5].
[1] who reported the results of a randomized trial Pulido and colleagues thus tested the robustness of their evaluating a lopinavir–ritonavir monotherapy for main- results by performing an as-treated analysis. The results of tenance in HIV-infected patients. On the basis of the additional sensitivity analyses would be more convincing primary endpoint, the authors concluded that mainten- by using the worst-case methodology to quantify the ance with lopinavir–ritonavir monotherapy is non- potential for bias due to missing data, that is considering inferior to a triple therapy in the studied population. The missing data to be failures in the intervention group, but authors also acknowledged the limitations of their results, successes in the comparator group and vice versa. Indeed, in particular the fact that non-inferiority was not a per-protocol (or as-treated) analysis in non-inferiority demonstrated for all secondary endpoints.
and equivalence designs might also bias the results towardsa smaller difference between groups [5–7]. The worst- The present report illustrates some of the methodological case method, by contrast, may provide a truly con- difficulties in the design and analysis of non-inferiority servative assessment of the robustness of a binary endpoint trials for HIV treatment strategies in general.
in a non-inferiority trial and its broader applicationshould be discussed for future trials.
First, we are concerned by the apparent absence of aconsensus regarding the choice of the primary endpoint Third, there is a need for a large consensus regarding the in trials comparing different strategies of antiretroviral non-inferiority margin in trials evaluating maintenance treatment. Pulido et al. [1] chose a composite endpoint to strategies in treatment-experienced patients with sup- define therapeutic failure as follows: confirmed HIV pressed HIV replication. For an assumed failure rate of RNA higher than 500 copies/ml, or loss to follow-up, or 10%, Pulido et al. [1] defined a non-inferiority margin of treatment discontinuation, or change of randomized 12%, without commenting on the latter choice. The lack therapy other than reinduction. According to the of rationale for the non-inferiority margin seems indeed provided definition, cases in the monotherapy group common in HIV trials [8], and its relevance remains to be with confirmed virological failure (two measurements of properly assessed. According to the authors’ premise, a HIV RNA > 500 copies/ml separated by at least 2 weeks) failure rate of up to 22% is accepted in pretreated patients are not considered failures, if HIV RNA is resuppressed in whom viral replication is controlled prior to successfully after reindroduction of nucleosides. To our randomization. We postulate that the acceptability of knowledge, this is an uncommon choice as compared this assumption should be scrutinized [9]. A consensual, with the endpoints of other randomized trials evaluating clinically relevant non-inferiority margin should be simplification regimens in HIV-infected patients [2–4].
defined for a given response rate and be applied to all Yet, if reinduction in the monotherapy group is not non-inferiority trials in this population, as has been considered as therapeutic failure, non-inferiority of the proposed in other research areas [10].
two treatment strategies is more likely to be demon-strated. For example, one could assume that due to early In summary, some key aspects of non-inferiority trials in virological failure, a number of the patients would receive HIV-infected patients warrant thorough methodological reinduction treatment shortly after the switch to deliberation. We need an international consensus to help monotherapy. Consequently, these patients would receive design future non-inferiority trials in HIV patients, as the same treatment as the comparator group for almost these trials are more and more common, given the the entire length of the trial, which in turn would potency of current antiretroviral drugs.
downsize the difference between the two groups over thetime of the trial. Thus, we believe that the secondary Laura Richert, Vincent Bouteloup, Rodolphe Thie´bautand Genevie`ve Cheˆne, INSERM U897 & CIC-EC 7, analyses reported by the authors, in which treatment University Victor Segalen Bordeaux 2, School of Public modification was considered as failure, constitute a more cautious choice. In that case, the authors could notconclude consistently that the simplification strategy was Correspondence to Laura Richert, INSERM U897, non-inferior to a triple therapy in the studied population.
University Victor Segalen Bordeaux 2, 146, rue Le´oSaignat, 33076 Bordeaux cedex, France.
Second, we suggest that some aspects concerning the Tel: +33 557 57 48 12; fax: +33 557 57 11 72; treatment of missing data and the statistical approach in e-mail: non-inferiority trials should be further clarified. In someof the analyses reported by Pulido et al. [1], the authors considered missing data to be failures. It is noteworthythat this approach tends to equalize outcomes in the 1. Pulido F, Arribas JR, Delgado R, Cabrero E, Gonza´lez-Garcı´a J, compared groups. This effect is deliberate in superiority Pe´rez-Elias MJ, et al. Lopinavir-ritonavir monotherapy versuslopinavir-ritonavir and two nucleosides for maintenance trials, but it may be inappropriate in non-inferiority therapy of HIV. AIDS 2008; 22:F1–F9.
Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
2. Cameron W, da Silva B, Arribas J, Myers R, Bellos NC, Gilmore 5. Piaggio G, Elbourne DR, Altman DG, Pocock SJ, Evans SJ.
N, et al. A two-year randomized controlled clinical trial in CONSORT Group. Reporting of noninferiority and equivalence antiretroviral-naive subjects using lopinavir/ritonavir (LPV/r) randomized trials: an extension of the CONSORT statement.
monotherapy after initial induction treatment compared to an efavirenz (EFV) 3-drug regimen (Study M03-613). In: Program 6. Jones B, Jarvis P, Lewis JA, Ebbutt AF. Trials to assess equivalence: and abstracts of the XVI International AIDS Conference; 13–18 the importance of rigorous methods. BMJ 1996; 313:36–39.
August 2006; Toronto. Canada. Abstract THLB0201.
7. Brittain E, Lin D. A comparison of intent-to-treat and per- 3. Delfraissy JF, Flandre P, Delaugerre C, Ghosn J, Horban A, protocol results in antibiotic noninferiority trials. Stat Med Girard PM, et al. Lopinavir/ritonavir monotherapy or plus zidovudine and lamivudine in antiretroviral-naive HIV- 8. Parienti JJ, Verdon R, Massari V. Methodological standards in infected patients. AIDS 2008; 22:385–393.
noninferiority AIDS trials: moving from adherence to compli- 4. Girard PM, Cabie´ A, Michelet C, Verdon R, Katlama C, Mercie´ ance. BMC Med Res Methodol 2006; 6:46.
P, et al. TenofovirDF þ efavirenz (TDFþEFV) vs tenofovirDFþ 9. Garattini S, Bertele’ V. Noninferiority trials are unethical because efavirenz þ lamivudine (TDFþEFVþ3TC) maintenance regimen they disregard patients’ interests. Lancet 2007; 370:1875–1877.
in virologically controlled patients (pts): COOL Trial. In: Pro- 10. Committee for Proprietary Medicinal Products. Note for gram and abstracts of the 46th Interscience Conference on guidance on the evaluation of medicinal products indicated Antimicrobial Agents and Chemotherapy; 27–30 September for treatment of bacterial infections. London: EMEA; 2004.
2006; San Francisco, California. Abstract H-1383.
Incidence of pancreatitis in HIV-infected patients, and the association with antiretroviral therapy We recently reported a low incidence of pancreatitis in a Additionally, the authors highlight the lack of an European cohort of HIV-positive individuals followed association between pancreatitis and the use of stavudine prospectively from 2001 to 2006, with a rate of 1.27 cases and didanosine. Although they do not investigate per 1000 person-years [1]. Fessel and Hurley [2], in an whether this association is present in their cohort, they editorial comment in the same issue of AIDS, reported a highlight the fact that a number of other studies have much higher incidence of approximately five times that observed such an association [3,4]. The authors rightly seen in our study in the years 1996–2006 in a North highlight the fact that use of didanosine and stavudine is American cohort. The authors noted that the rate of less widespread in more recent years. Indeed, much of the pancreatitis remained constant over time. However, we stavudine and didanosine use in the EuroSIDA cohort is feel that there are important differences in the definition likely to be historical, rather than current. Awareness of of pancreatitis used in the two studies that may go some the potential link between these antiretrovirals and way to explaining the disparate incidence rates observed.
pancreatitis may have led to less use of this combinationas other nucleosides were developed, and to a reduction Fessel and Hurley use a definition of pancreatitis based on in the use in patients most susceptible to pancreatitis.
either the presence of plasma lipase greater than four times Those susceptible to this complication may have already the upper limit of normal (ULN), amylase greater than six stopped the antiretroviral(s) prior to the study period, times the ULN, or a pancreatitis diagnosis captured in the either because of the prior occurrence of pancreatitis, or electronic medical record. In contrast, the EuroSIDA study used a detailed case definition of pancreatitis, and all eventswere source verified, reviewed, and classified centrally by In addition to the helpful suggestions made by Fessel and the study physicians. Even when considering presumptive Hurley, we would also highlight the importance of pancreatitis, two of the following three events were applying consistent case definitions between studies so required: one or more characteristic symptoms or that results can be reliably compared. We have already characteristic signs of pancreatitis; raised enzymes; at least begun further work, investigating the association between one imaging investigation suggesting pancreatitis accord- pancreatitis and triglycerides [5], and strongly agree that ing to a radiologist or clinician. Furthermore, raised further research is needed in this subject area.
amylases were only considered as a pancreatitis event ifother aetiology could be excluded. Only if definitive Colette J. Smitha, Amanda Mocrofta and Jens D.
source documentation could not be obtained was a Lundgrenb for the EuroSIDA Study Group, aRoyal Free pancreatitis event assumed without further investigation.
and University College Medical School, London, UK, Thus, we suggest that the EuroSIDA study group used and bRigshospitalet and Copenhagen HIV Program, more stringent criteria to define pancreatitis events that included exclusion of other possible causes of abnormal Correspondence to Colette Smith, Research Depart- laboratory values, and required the presence of clinical ment of Infection and Population Health, Royal Free manifestation of disease in nearly all cases. Thus, a lower and University College Medical School, Hampstead incidence of pancreatitis would be expected in our study Campus, Rowland Hill Street, London, NW3 2PF, when compared with that found when using the definition Tel: +44 20 7830 2239; e-mail: Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
3. Maxson CJ, Greenfield SM, Turner JL. Acute pancreatitis as a common complication of 20,30-dideoxyinosine therapy in theacquired immunodeficiency syndrome. Am J Gastroenterol 1. Smith CJ, Olsen CH, Mocroft A, et al. The role of anti- retroviral therapy in the incidence of pancreatitis in HIV- 4. Moore RD, Keruly JC, Chaisson RE. Incidence of pancreatitis in positive individuals in the EuroSIDA study. AIDS 2008; 22: HIV-infected patients receiving nucleoside reverse transcriptase inhibitor drugs. AIDS 2001; 15:617–620.
5. Smith CJ, Mocroft A, Olsen CH, et al. Incidence of pancreatitis 2. Fessel J, Hurley LB. Incidence of pancreatitis in HIV-infected amongst HIV-positive individuals, and the association with trigly- patients: comment on findings from in EuroSIDA cohort. AIDS cerides and antiretroviral use [Abstract number P9.10/02]. In: 11th European AIDS Conference, 24–27 October, Madrid, Spain; 2007.
Immune reconstitution syndrome to Strongyloides stercoralis infection We thank McCarthy and Currie for their response [1] to syndrome and not disseminated infection secondary to our case report [2], which described a young Eritrean man with HIV and hepatitis B infections who presentedwith an inflammatory colitis, 6 weeks after startingantiretroviral therapy and had Strongyloides larvae detected in stool samples. After treatment with ivermectin, hissymptoms, and the associated intestinal dilatation, resolved. His presentation was localized to the intestinesand comprised loss of appetite, abdominal pain, vomiting Clare L. Taylor and Andrew P. Ustianowski, Monsall and weight loss. There were no respiratory symptoms and Unit, Department of Infectious Diseases and Tropical no evidence of dissemination of Strongyloides larvae or Medicine, North Manchester General Hospital, Delaunarys Road, Crumpsall, Manchester, UK.
We have seen and recognized the well established, strong association of corticosteroid treatment with Strongyloideshyperinfection syndrome [3–5] and agree that excluding 1. McCarthy JS, Currie B. Immune reconstitution syndrome to Strongyloides infection is important when considering Strongyloides stercoralis infection: authors’ response. AIDS steroid treatment in individuals who have lived in an endemic area [1]. We also concur that immune 2. Taylor CL, Subbarao V, Gayed S, Ustianowski AP. Immune reconstitution syndrome to Strongyloides stercoralis infection.
suppression due to HIV infection itself does not appear to cause hyperinfection [6]. In this case, however, 3. Davidson RA, Fletcher RH, Chapman LE. Risk factors for stron- although this patient had received steroid treatment (for gyloidiasis: a case control study. Arch Intern Med 1984; 144:321–324.
thrombocytopaenia) in the weeks preceding presentation, 4. Asdamongkol N, Pornsuriyasak P, Sungkanuparph S. Risk factors there was no evidence of dissemination of the parasite for Strongyloides hyperinfection and clinical outcomes. South- outside the gastrointestinal system, and therefore a local east Asian J Trop Med Public Health 2006; 27:875–885.
5. Ghosh K, Ghosh K. Strongyloides stercoralis septicaemia follow- inflammatory response, coinciding with rapid immuno- ing steroid therapy for eosinophilia: report of three cases. Trans logical recovery due to antiretroviral treatment, fits R Soc Trop Med Hyg 2007; 101:1163–1165.
6. Viney ME, Brown M, Omoding NE, Bailey JW, Gardner MP, much better with the clinical picture. We, therefore, Roberts E, et al. Why does HIV infection not lead to disseminated proposed that this case comprises immune reconstitution strongyloidiasis? J Infect Dis 2004; 190:2175–2180.
Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.


Microsoft word - psebm01.doc

Phytoestrogens in Soy-Based Infant Foods: Concentrations, Daily Intake and Possible Biological Effects C.H.G. Irvine, M.G. Fitzpatrick† and S.L. Alexander Animal and Veterinary Sciences Group, Lincoln University, New Zealand, and † Chemistry Department, University of Auckland, Auckland, New Zealand Corresponding author : Prof C.H.G. Irvine, Animal & Veterinary Sciences Group,

Contents of Supplement 6.5 A vertical line in the margin indicates where part of a text has been revised or corrected. A horizontal line in the margin indicates where part of a text has been deleted. It is to be emphasised that these indications, which are not necessarily exhaustive, are given for information and do not form an official part of the texts. Editorial changes are not indicate

Copyright © 2010-2019 Pdf Physician Treatment