Correspondence AIDS 2014, 28:1241–1246
A closer look at hepatitis C clearance in HIV controllers: a response Seaberg and Thio [1] refer to evidence that suggests that route of infection may play a role in hepatitis C virus (HCV) spontaneous clearance. We did not examine the role of the route of infection on HCV clearance in HIV controllers in our study. HCV clearance differs by HIV status, but little prospective data are available to assess clearance by transmission route. One retrospective analysis showed that presumed sexually acquired HCV had higher rates of spontaneous clearance than parenterally acquired HCV [2]. Other studies have not shown this [3,4]. In prospective studies of HCV monoinfected patients, there is no evidence that clearance differs by transmission route [5,6]. Less examined is how genetic variations and mode of transmission impact divergent HCV outcomes. Seaberg et al. [7] found a higher magnitude of association between IL28B CC and HCV clearance in men MSM with reported injected drug use (IDU) than in those without, but this analysis includes MSM with and without HIV. We examined these factors in HIV controllers, the study population examined in our study ‘Human Leukocyte Antigen (HLA) B57 Does Not Fully Explain Hepatitis C Clearance in HIV Controllers’ [8]. People with the IL28B CC (vs. CT or TT) allele are significantly more likely to spontaneously clear HCV infection [9,10]. In our study, the presumed mode of HCV acquisition did not modify the association between IL28B genotype and HCV clearance: there was no difference in the effect of IL28B CC (vs. CT/TT) on HCV clearance between those with a history of IDU [prevalence ratio 2.98; 95% confidence interval (CI) 1.57–5.64] and those without reported IDU history (prevalence ratio 2.51; 95% CI 1.52–4.16; test for heterogeneity P ¼ 0.93). Unlike the study by Seaberg et al. [7], we found no evidence that the impact of IL28B CC (vs. CT/TT) on HCV clearance was modified by IDU history among MSM (prevalence ratio in non-IDU MSM 2.13; 95% CI 1.25–3.65; prevalence ratio in IDU and MSM 1.57; 95% CI 0.36–6.86). HLA B57 has been shown to be highly enriched in people who innately control their HIV infection [11,12], prompting questions about whether this may hold true for other viral infections, including HCV. We found no evidence that HLA B57 is associated with clearance in HIV-infected patients (adjusted prevalence ratio 1.36; 95% CI 0.71–2.60, P ¼ 0.35) [8]. Although power was limited, we also found no evidence for a protective role of HLA B57 in any subgroup of interest. For example, patients with HLA B57 had similar prevalence of HCV
clearance to those without HLA B57 among both HIV controllers (31 vs. 34%, P ¼ 0.83) and noncontrollers (29 vs. 27%, P ¼ 0.79). HLA B57 does not explain the increase in HCV clearance in controllers in our cohort. We also found no association between HLA B57 and HCV clearance in those with and without an IDU history (prevalence ratio 1.18; 95% CI 0.56–2.51 vs. prevalence ratio 1.19; 95% CI 0.62–2.28) and in MSM vs. nonMSM exposure groups (prevalence ratio 0.98; 95% CI 0.49–1.99 vs. prevalence ratio 1.36; 95% CI 0.68–2.70). The table presenting the multivariate analysis in the original article was mis-printed and omitted the significance of IL28B CC on clearance. An erratum will correct this. Seaberg and Thio [1] state that we did not discuss the finding that HIV controllers were more likely to clear HCV when negative for HLA B57. The original publication states that HLA B57 cannot explain the increased prevalence of HCV clearance in HIV controllers in our cohort. We agree with our colleagues that this is perhaps the most important novel finding from our study. It suggests that other unmeasured factors associated with HIV control must also contribute to HCV clearance in this setting. Future host genetic studies of HIV/HCV-coinfected controllers and noncontrollers may help shed light on these factors, potentially identifying novel genetic factors that contribute to the clearance and/or control of multiple viral pathogens. Nevertheless, as pointed out, HLA B57 has been associated with HCV clearance in other studies [13,14]. Our study does not discount those studies, as a larger sample size might have revealed a more significant effect of HLA B57. However, our study does suggest that there are factors other than HLA B57 that contribute to HCV clearance in HIV controllers. The evidence of differential outcome of HCV in association with route of exposure is inconclusive; further research is necessary to improve our understanding of this potential effect and putative mechanisms involved. We agree that further research is needed to understand why HIV controllers are more likely to clear HCV, as this cannot be entirely explained by enrichment for HLA B57.
Acknowledgements This work was supported by U.S. National Institutes for Health (NIH) TL1 RR024129. Additional support was received from NIH grants: T32 NR07081 (Ms A. K.
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Asher), T32 MH-19105–21 (Dr E. K. Dokubo) and 2 R01 DA016017-03A1 (Dr K. Page).
Conflicts of interest There are no conflicts of interest. Alice K. Ashera,b, Glenn-Milo Santosc, Jennifer Evansb, E. Kainne Dokubob, Tzong-Hae Leed, Jeffrey N. Martinb, Steven G. Deeksc, Leslie H. Toblerd, Michael Buschd, Peter W. Huntc and Kimbely Pageb, aDepartment of Community Health Systems, School of Nursing, bDepartment of Epidemiology & Biostatistics, c Department of Medicine, University of California San Francisco, and dBlood Systems Research Institute, San Francisco, California. USA. Correspondence to Alice K. Asher, RN, MS, University of California San Francisco, 50 Beale Street, Ste 1200, San Francisco, CA 94105, USA. E-mail: [email protected] Received: 23 December 2013; revised: 7 January 2014; accepted: 8 January 2014.
References 1. Seaberg EC, Thio CL. A closer look at hepatitis C clearance in HIV controllers. AIDS 2014; 28:1242–1243. 2. Shores NJ, Maida I, Soriano V, Nunez M. Sexual transmission is associated with spontaneous HCV clearance in HIV-infected patients. J Hepatol 2008; 49:323–328. 3. Dominguez S, Ghosn J, Valantin MA, Schruniger A, Simon A, Bonnard P, et al. Efficacy of early treatment of acute hepatitis C infection with pegylated interferon and ribavirin in HIVinfected patients. AIDS 2006; 20:1157–1161. 4. Thomson EC, Nastouli E, Main J, Karayiannis P, Eliahoo J, Muir D, et al. Delayed anti-HCV antibody response in HIV-positive men acutely infected with HCV. AIDS 2009; 23:89–93.
5. Wang CC, Krantz E, Klarquist J, Krows M, McBride L, Scott EP, et al. Acute hepatitis C in a contemporary US cohort: modes of acquisition and factors influencing viral clearance. J Infect Dis 2007; 196:1474–1482. 6. Micallef JM, Kaldor JM, Dore GJ. Spontaneous viral clearance following acute hepatitis C infection: a systematic review of longitudinal studies. J Viral Hepatitis 2006; 13:34–41. 7. Seaberg E, Witt M, Jacobson L, Detels R, Rinaldo C, Young S, et al. Differences in hepatitis C virus prevalence and clearance by mode of acquisition among men who have sex with men. J Viral Hepatitis 2013; ; E-pub ahead of print. doi: 10.1111/jvh. 12198. 8. Asher AK, Santos GM, Evans J, Dokubo EK, Lee TH, Martin JN, et al. Human leukocyte antigen BM57 does not fully explain hepatitis C clearance in HIV controllers. AIDS 2013; 27:2691– 2696. 9. Rauch A, Kutalik Z, Descombes P, Cai T, Di Iulio J, Mueller T, et al. Genetic variation in IL28B is associated with chronic hepatitis C and treatment failure: a genome-wide association study. Gastroenterology 2010; 138:1338–1345. 10. Grebely J, Page K, Sacks-Davis R, Schim van der Loeff M, Rice TM, Bruneau J, et al. The effects of female sex, viral genotype, and IL28B genotype on spontaneous clearance of acute hepatitis C virus infection. Hepatology 2014; 59:109– 120. 11. Kloverpris HN, Stryhn A, Harndahl M, van der Stok M, Payne RP, Matthews PC, et al. HLA-BM57 Micropolymorphism shapes HLA allele-specific epitope immunogenicity, selection pressure, and HIV immune control. J Virol 2012; 86:919– 929. 12. Migueles SA, Sabbaghian MS, Shupert WL, Bettinotti MP, Marincola 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 2000; 97:2709–2714. 13. Kim AY, Kuntzen T, Timm J, Nolan BE, Baca MA, Reyor LL, et al. Spontaneous control of HCV is associated with expression of HLA-B 57 and preservation of targeted epitopes. Gastroenterology 2011; 140:686–696; e1. 14. Ruiz-Mateos E, Machmach K, Romero-Sanchez M, FerrandoMartinez S, Viciana P, Del Val M, et al. Hepatitis C virus replication in Caucasian HIV controllers. J Viral Hepat 2011; 18:e350–e357.
DOI:10.1097/QAD.0000000000000208
A closer look at hepatitis C clearance in HIV controllers It is with great interest that we read the paper titled ‘Human leukocyte antigen B57 does not fully explain hepatitis C clearance in HIV controllers’ that was recently published in AIDS [1]. The authors of this very interesting cross-sectional study reported that several genetic markers including HLA B57, HLA Cw04 and IL28B do not explain the association between HIV controller status and hepatitis C virus (HCV) clearance that they observed in the Study of the Consequences of Protease Inhibitor Era (SCOPE) cohort. In light of the results from our recently published study of HCV prevalence and clearance in a cohort of nearly 7000 MSM enrolled in the Multicenter AIDS Cohort Study (MACS) [2], there are several aspects of the study by Asher et al. [1] that deserve further consideration.
[2]. For example, we found that the magnitude of the association between the IL28B (rs12979860) C/C genotype and HCV clearance was significantly higher among MSM with a history of IDU than among MSM who most likely acquired HCV via sexual exposure (clearance ratios 4.16 and 1.71, respectively; P ¼ 0.03). Given this difference by IDU history, one wonders whether the effects of HLA B57, HLA Cw04, IL28B and/or HIV controller status might differ between those with versus without a history of IDU in the SCOPE cohort. On the basis of the numbers reported by Asher et al. [1] in Table 1, their study cohort included nearly equal numbers of individuals with (n ¼ 137) and without (n ¼ 142) a history of IDU, which provides a sufficiently large sample for testing this hypothesis.
One important finding from our study was that several participant characteristics were differentially associated with HCV clearance by presumed mode of acquisition
Asher et al. [1] also reported that HCV clearance was similar among men and women and concluded that ‘there is no clear explanation for why men were equally likely to
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Correspondence
clear their HCV infection as women in this cohort’. Our study in the MACS might provide an insight into this observation. We found that HCV clearance was significantly higher among non-IDU MSM (34.5%) than among IDU MSM (11.5%) (P < 0.001) [2]. Consequently, mode of HCV acquisition might confound the comparison of HCV clearance between men and women in the SCOPE cohort if, for instance, women were more likely to have been infected with HCV via IDU while men were more likely to have been infected via sexual contact. This possibility is supported by the authors’ statement that HIV-positive MSM is ‘a group well represented within the SCOPE cohort’[1]. Our final two comments about the study by Asher et al. [1] concern their multivariable analysis. First, in the last paragraph of the Results section, the authors report that HIV controller status and IL28B genotype were the only two factors found to be independently associated with HCV clearance. IL28B genotype, however, was not reported in Table 4; thus, it is not clear whether Table 4 accurately portrays the results from their final multiple regression model. Second, the authors note that HIV controller status was not associated with HCV clearance in their univariate analysis even though this association was found to be statistically significant in the multiple regression analysis. Assuming that the results in Table 4 are accurate, the reason for these apparently discrepant findings is clear. An interaction term for HIV controller status by HLA B57 was forced into the model even though it was not statistically significant (P ¼ 0.21). With this interaction term in the model, the HCV clearance difference between HIV controllers and noncontrollers [adjusted clearance ratio (ACR) 1.78] that the authors highlight in their discussion represents this comparison restricted to individuals without HLA B57. In contrast, the interaction term demonstrates that HIV controllers with HLA B57 were less likely to clear HCV (ACR 0.52). The univariate analysis effectively combined these two ACRs, resulting in the nonsignificant association between HIV controller status and HCV clearance. It is indeed intriguing that the HIV controller effect was qualitatively different between those with versus without HLA B57. Unfortunately, the authors provided no discussion about the cause or implication of their finding that HIV controllers were more likely to clear HCV only if they were HLA B57 negative.
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In summary, there is mounting evidence that the factors associated with spontaneous HCV clearance may differ by mode of acquisition, and these differences suggest that the mechanisms involved with spontaneous HCV clearance might also differ by mode of acquisition. Future research should examine whether any association observed between HIV controller status and HCV clearance differs by IDU status.
Acknowledgements Financial support was provided by the National Institute of Allergy and Infectious Diseases with supplemental funding from the National Cancer Institute [grant numbers UO1 AI35042 and UM1 AI35043].
Conflicts of interest We have no conflicts to disclose. Eric C. Seaberga and Chloe L. Thiob, aDepartment of Epidemiology, Bloomberg School of Public Health, and b Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA. Correspondence to Eric C. Seaberg, PhD, MPH, Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, 615 North Wolfe Street, Room E-7634, Baltimore, MD 21205, USA. Tel: +1 410 955 4320; fax: +1 410 955 7587; e-mail: [email protected] Received: 18 November 2013; revised: 8 January 2014; accepted: 8 January 2014.
References 1. Asher AK, Santos GM, Evans J, Dokubo EK, Lee TH, Martin JN, et al. Human leukocyte antigen BM57 does not fully explain hepatitis C clearance in HIV controllers. AIDS 2013; 27:2691– 2696. 2. Seaberg EC, Witt MD, Jacobson LP, Detels R, Rinaldo CR, Young S, et al. Differences in hepatitis C virus prevalence and clearance by mode of acquisition among men who have sex with men. J Viral Hepat 2013; [Epub ahead of print] doi:10.1111/jvh.12198.
DOI:10.1097/QAD.0000000000000207
Biomarkers for sexual behaviour change: a role for nonpaternity studies? The HIV pandemic, especially the devastating epidemics in sub-Saharan Africa (SSA) and the subsequent recent rapid declines in prevalence/incidence in several countries, has raised many questions. Among these are
(i) why major HIV epidemics appear to have occurred only in SSA and (ii) to what extent are these marked declines in HIV transmission attributable to sexual behavior changes? Both questions have generated intense
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debates, often focusing on aspects of sexual behaviour; for example, whether the difference between SSA and the rest of the world can be explained by the higher levels of concurrency, that is having multiple sex partners simultaneously [1].
evidence [12]. Nonpaternity studies may provide insights about female sexuality that are of relevance not only for the epidemiology of sexually transmitted infections, but well beyond in fields as far as evolutionary anthropology [12].
Definitive answers to these questions require accurate data on sexual behaviour. However, although impressive amounts of data on sexual behaviour have been collected, they all tend to be self-reported [2]. The sensitive nature of sexual behaviour, and nonrandom social desirability and recall biases, can introduce inaccuracy in these data [3–6]. Several studies have also shown that such data can be unreliable; biomarker studies have shown underreporting of recent unprotected intercourse by women [7,8].
Admittedly, limitations may affect the interpretation of nonpaternity data. Birth control methods and fertility differentials may introduce bias. Nonpaternity could be also due to covert adoptions, misidentified stepchildren or sperm donations [10,13]. There are also complex ethical challenges in the conduct of such studies.
Self-reported data should therefore preferably neither be dependent upon comparing differences in behaviour between populations nor on monitoring changes in behaviour over time to evaluate the impact of behavioural interventions. Nonetheless, such self-reported data are still widely collected and analysed. We believe that there should be more emphasis on developing biomarkers that can reliably detect differences and trends in behaviour patterns. Recently, viral genetic linkage has been used to distinguish transmission within discordant couples from transmission from outside partners. Its finding, that a large fraction of infections acquired from outside the partnership occurred in individuals who reported no extramarital sex, has provided insight into the ongoing HIV epidemic and how misleading reliance on self-reported data may be [9]. Yet, as a measure of sexual behaviour in the population, this biomarker is not appropriate. It is complex to carry out and interpret and is restricted to HIVaffected couples. An easier type of biomarker, one that seems never to have been carried out in SSA, is nonpaternity [10], the percentage of children whose biological father differs from the official or presumed father, usually the husband or regular male partner of the mother. In addition to providing a direct biomarker of extramarital sex, nonpaternity can capture not only current behaviour but also past trends. With adequately powered studies, it is possible to derive a time-series of the rate of extra-marital sex from the nonpaternity age-stratified prevalence, and accordingly trends in sexual risk behaviour over decades, including the decades that witnessed the rise of the HIV epidemic. Although nonpaternity probes sexual behaviour only in women, the main challenges in self-reported data relate to women’s sexual behaviour [11]. Although multiple mating in human males is believed to be well characterized, the nature of multiple mating in human females is subject to intense debate and conflicting
Despite these caveats, some limitations can be overcome, and others may be an issue in some settings but not others. These limitations may not also hinder the ability of nonpaternity studies to provide at least a lower-bound estimate for extra-marital sex, which is in its own of greatest interest. Nonpaternity studies could be conducted as secondary data analyses on already collected samples for other studies or routine data, or ideally could be nested, with appropriate ethical prudence, within broader population-based surveys such as the Demographic and Health Surveys. In sum, nonpaternity studies can provide a trove of data on sexual behaviour and trends that are not prone to the extensive limitations of self-reported data. The potential for enhancing our knowledge with such data is immense. Not only they can facilitate a better understanding of HIV epidemics and their evolution, but also provide critical data to inform concept and design of interventions. This in turn would help optimize the impact of programmes by better targeting the drivers of HIV transmission.
Acknowledgements This publication was made possible by NPRP grant number 5-752-3-177 from the Qatar National Research Fund (a member of Qatar Foundation). The statements made herein are solely the responsibility of the authors.
Conflicts of interest There are no conflicts of interest. Laith J. Abu-Raddada,b,c and Nico Nagelkerked,e, a Infectious Disease Epidemiology Group, Weill Cornell Medical College - Qatar, Cornell University, Qatar Foundation - Education City, Doha, Qatar, bDepartment of Healthcare Policy and Research, Weill Cornell Medical College, Cornell University, New York, New York, cVaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Centre, Seattle, Washington, USA, dDepartment of Public Health, United Arab
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Correspondence Emirates University, Al Ain, United Arab Emirates, and e Department of Public Health, Erasmus Medical Center, Rotterdam, The Netherlands. Correspondence to Dr Laith Abu-Raddad, Infectious Disease Epidemiology Group, Weill Cornell Medical College – Qatar, Qatar Foundation – Education City, PO Box 24144, Doha, Qatar. Tel: +974 4492 8321; fax: +974 4492 8333; e-mail: [email protected] Received: 9 January 2014; revised: 20 January 2014; accepted: 20 January 2014.
References 1. Epstein H. The invisible cure: why we are losing the fight against AIDS in Africa.New York, NY: Picador; 2008. 2. Obasi A, Mosha F, Quigley M, Sekirassa Z, Gibbs T, Munguti K, et al. Antibody to herpes simplex virus type 2 as a marker of sexual risk behavior in rural Tanzania. J Infect Dis 1999; 179:16–24. 3. Caldwell JC, Caldwell P, Quiggin P. The social context of AIDS in Sub-Saharan Africa. Populat Develop Rev 1989, 15:185– 234.
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4. Lee RM, Renzetti CM. The problems of researching sensitive topics. Am Behav Sci 1990; 33:510–528. 5. Wadsworth J, Field J, Johnson AM, Bradshaw S, Wellings K. Methodology of the National Survey of Sexual Attitudes and Lifestyles. J R Stat Soc Ser A Stat Soc 1993; 156:407–421. 6. Morris M. Telling tails explain the discrepancy in sexual partner reports. Nature 1993; 365:437–440. 7. Gallo MF, Behets FM, Steiner MJ, Hobbs MM, Hoke TH, Van Damme K, et al. Prostate-specific antigen to ascertain reliability of self-reported coital exposure to semen. Sex Transm Dis 2006; 33:476–479. 8. Minnis AM, Steiner MJ, Gallo MF, Warner L, Hobbs MM, van der Straten A, et al. Biomarker validation of reports of recent sexual activity: results of a randomized controlled study in Zimbabwe. Am J Epidemiol 2009; 170:918–924. 9. Ndase P, Celum C, Thomas K, Donnell D, Fife KH, Bukusi E, et al. Outside sexual partnerships and risk of HIV acquisition for HIV uninfected partners in African HIV serodiscordant partnerships. J Acquir Immune Defic Syndr 2012; 59:65–71. 10. Anderson K. How well does paternity confidence match actual paternity? Curr Anthropol 2006; 47:513–520. 11. Catania JA, Gibson DR, Chitwood DD, Coates TJ. Methodological problems in AIDS behavioral research: influences on measurement error and participation bias in studies of sexual behavior. Psychol Bull 1990; 108:339–362. 12. Scelza BA. Choosy but not chaste: multiple mating in human females. Evol Anthropol 2013; 22:259–269. 13. Bellis MA, Hughes K, Hughes S, Ashton JR. Measuring paternal discrepancy and its public health consequences. J Epidemiol Community Health 2005; 59:749–754.
DOI:10.1097/QAD.0000000000000217
Intravenous iron and vertical HIV transmission: any connection? Due to antenatal testing and preventive interventions, iron-sucrose, 200 mg) each separated by a 3-day interval. HIV transmission to infants in the UK is very low (
A closer look at hepatitis C clearance in HIV controllers: a response Seaberg and Thio [1] refer to evidence that suggests that route of infection may play a role in hepatitis C virus (HCV) spontaneous clearance. We did not examine the role of the route of infection on HCV clearance in HIV controllers in our study. HCV clearance differs by HIV status, but little prospective data are available to assess clearance by transmission route. One retrospective analysis showed that presumed sexually acquired HCV had higher rates of spontaneous clearance than parenterally acquired HCV [2]. Other studies have not shown this [3,4]. In prospective studies of HCV monoinfected patients, there is no evidence that clearance differs by transmission route [5,6]. Less examined is how genetic variations and mode of transmission impact divergent HCV outcomes. Seaberg et al. [7] found a higher magnitude of association between IL28B CC and HCV clearance in men MSM with reported injected drug use (IDU) than in those without, but this analysis includes MSM with and without HIV. We examined these factors in HIV controllers, the study population examined in our study ‘Human Leukocyte Antigen (HLA) B57 Does Not Fully Explain Hepatitis C Clearance in HIV Controllers’ [8]. People with the IL28B CC (vs. CT or TT) allele are significantly more likely to spontaneously clear HCV infection [9,10]. In our study, the presumed mode of HCV acquisition did not modify the association between IL28B genotype and HCV clearance: there was no difference in the effect of IL28B CC (vs. CT/TT) on HCV clearance between those with a history of IDU [prevalence ratio 2.98; 95% confidence interval (CI) 1.57–5.64] and those without reported IDU history (prevalence ratio 2.51; 95% CI 1.52–4.16; test for heterogeneity P ¼ 0.93). Unlike the study by Seaberg et al. [7], we found no evidence that the impact of IL28B CC (vs. CT/TT) on HCV clearance was modified by IDU history among MSM (prevalence ratio in non-IDU MSM 2.13; 95% CI 1.25–3.65; prevalence ratio in IDU and MSM 1.57; 95% CI 0.36–6.86). HLA B57 has been shown to be highly enriched in people who innately control their HIV infection [11,12], prompting questions about whether this may hold true for other viral infections, including HCV. We found no evidence that HLA B57 is associated with clearance in HIV-infected patients (adjusted prevalence ratio 1.36; 95% CI 0.71–2.60, P ¼ 0.35) [8]. Although power was limited, we also found no evidence for a protective role of HLA B57 in any subgroup of interest. For example, patients with HLA B57 had similar prevalence of HCV
clearance to those without HLA B57 among both HIV controllers (31 vs. 34%, P ¼ 0.83) and noncontrollers (29 vs. 27%, P ¼ 0.79). HLA B57 does not explain the increase in HCV clearance in controllers in our cohort. We also found no association between HLA B57 and HCV clearance in those with and without an IDU history (prevalence ratio 1.18; 95% CI 0.56–2.51 vs. prevalence ratio 1.19; 95% CI 0.62–2.28) and in MSM vs. nonMSM exposure groups (prevalence ratio 0.98; 95% CI 0.49–1.99 vs. prevalence ratio 1.36; 95% CI 0.68–2.70). The table presenting the multivariate analysis in the original article was mis-printed and omitted the significance of IL28B CC on clearance. An erratum will correct this. Seaberg and Thio [1] state that we did not discuss the finding that HIV controllers were more likely to clear HCV when negative for HLA B57. The original publication states that HLA B57 cannot explain the increased prevalence of HCV clearance in HIV controllers in our cohort. We agree with our colleagues that this is perhaps the most important novel finding from our study. It suggests that other unmeasured factors associated with HIV control must also contribute to HCV clearance in this setting. Future host genetic studies of HIV/HCV-coinfected controllers and noncontrollers may help shed light on these factors, potentially identifying novel genetic factors that contribute to the clearance and/or control of multiple viral pathogens. Nevertheless, as pointed out, HLA B57 has been associated with HCV clearance in other studies [13,14]. Our study does not discount those studies, as a larger sample size might have revealed a more significant effect of HLA B57. However, our study does suggest that there are factors other than HLA B57 that contribute to HCV clearance in HIV controllers. The evidence of differential outcome of HCV in association with route of exposure is inconclusive; further research is necessary to improve our understanding of this potential effect and putative mechanisms involved. We agree that further research is needed to understand why HIV controllers are more likely to clear HCV, as this cannot be entirely explained by enrichment for HLA B57.
Acknowledgements This work was supported by U.S. National Institutes for Health (NIH) TL1 RR024129. Additional support was received from NIH grants: T32 NR07081 (Ms A. K.
ISSN 0269-9370 Q 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
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2014, Vol 28 No 8
Asher), T32 MH-19105–21 (Dr E. K. Dokubo) and 2 R01 DA016017-03A1 (Dr K. Page).
Conflicts of interest There are no conflicts of interest. Alice K. Ashera,b, Glenn-Milo Santosc, Jennifer Evansb, E. Kainne Dokubob, Tzong-Hae Leed, Jeffrey N. Martinb, Steven G. Deeksc, Leslie H. Toblerd, Michael Buschd, Peter W. Huntc and Kimbely Pageb, aDepartment of Community Health Systems, School of Nursing, bDepartment of Epidemiology & Biostatistics, c Department of Medicine, University of California San Francisco, and dBlood Systems Research Institute, San Francisco, California. USA. Correspondence to Alice K. Asher, RN, MS, University of California San Francisco, 50 Beale Street, Ste 1200, San Francisco, CA 94105, USA. E-mail: [email protected] Received: 23 December 2013; revised: 7 January 2014; accepted: 8 January 2014.
References 1. Seaberg EC, Thio CL. A closer look at hepatitis C clearance in HIV controllers. AIDS 2014; 28:1242–1243. 2. Shores NJ, Maida I, Soriano V, Nunez M. Sexual transmission is associated with spontaneous HCV clearance in HIV-infected patients. J Hepatol 2008; 49:323–328. 3. Dominguez S, Ghosn J, Valantin MA, Schruniger A, Simon A, Bonnard P, et al. Efficacy of early treatment of acute hepatitis C infection with pegylated interferon and ribavirin in HIVinfected patients. AIDS 2006; 20:1157–1161. 4. Thomson EC, Nastouli E, Main J, Karayiannis P, Eliahoo J, Muir D, et al. Delayed anti-HCV antibody response in HIV-positive men acutely infected with HCV. AIDS 2009; 23:89–93.
5. Wang CC, Krantz E, Klarquist J, Krows M, McBride L, Scott EP, et al. Acute hepatitis C in a contemporary US cohort: modes of acquisition and factors influencing viral clearance. J Infect Dis 2007; 196:1474–1482. 6. Micallef JM, Kaldor JM, Dore GJ. Spontaneous viral clearance following acute hepatitis C infection: a systematic review of longitudinal studies. J Viral Hepatitis 2006; 13:34–41. 7. Seaberg E, Witt M, Jacobson L, Detels R, Rinaldo C, Young S, et al. Differences in hepatitis C virus prevalence and clearance by mode of acquisition among men who have sex with men. J Viral Hepatitis 2013; ; E-pub ahead of print. doi: 10.1111/jvh. 12198. 8. Asher AK, Santos GM, Evans J, Dokubo EK, Lee TH, Martin JN, et al. Human leukocyte antigen BM57 does not fully explain hepatitis C clearance in HIV controllers. AIDS 2013; 27:2691– 2696. 9. Rauch A, Kutalik Z, Descombes P, Cai T, Di Iulio J, Mueller T, et al. Genetic variation in IL28B is associated with chronic hepatitis C and treatment failure: a genome-wide association study. Gastroenterology 2010; 138:1338–1345. 10. Grebely J, Page K, Sacks-Davis R, Schim van der Loeff M, Rice TM, Bruneau J, et al. The effects of female sex, viral genotype, and IL28B genotype on spontaneous clearance of acute hepatitis C virus infection. Hepatology 2014; 59:109– 120. 11. Kloverpris HN, Stryhn A, Harndahl M, van der Stok M, Payne RP, Matthews PC, et al. HLA-BM57 Micropolymorphism shapes HLA allele-specific epitope immunogenicity, selection pressure, and HIV immune control. J Virol 2012; 86:919– 929. 12. Migueles SA, Sabbaghian MS, Shupert WL, Bettinotti MP, Marincola 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 2000; 97:2709–2714. 13. Kim AY, Kuntzen T, Timm J, Nolan BE, Baca MA, Reyor LL, et al. Spontaneous control of HCV is associated with expression of HLA-B 57 and preservation of targeted epitopes. Gastroenterology 2011; 140:686–696; e1. 14. Ruiz-Mateos E, Machmach K, Romero-Sanchez M, FerrandoMartinez S, Viciana P, Del Val M, et al. Hepatitis C virus replication in Caucasian HIV controllers. J Viral Hepat 2011; 18:e350–e357.
DOI:10.1097/QAD.0000000000000208
A closer look at hepatitis C clearance in HIV controllers It is with great interest that we read the paper titled ‘Human leukocyte antigen B57 does not fully explain hepatitis C clearance in HIV controllers’ that was recently published in AIDS [1]. The authors of this very interesting cross-sectional study reported that several genetic markers including HLA B57, HLA Cw04 and IL28B do not explain the association between HIV controller status and hepatitis C virus (HCV) clearance that they observed in the Study of the Consequences of Protease Inhibitor Era (SCOPE) cohort. In light of the results from our recently published study of HCV prevalence and clearance in a cohort of nearly 7000 MSM enrolled in the Multicenter AIDS Cohort Study (MACS) [2], there are several aspects of the study by Asher et al. [1] that deserve further consideration.
[2]. For example, we found that the magnitude of the association between the IL28B (rs12979860) C/C genotype and HCV clearance was significantly higher among MSM with a history of IDU than among MSM who most likely acquired HCV via sexual exposure (clearance ratios 4.16 and 1.71, respectively; P ¼ 0.03). Given this difference by IDU history, one wonders whether the effects of HLA B57, HLA Cw04, IL28B and/or HIV controller status might differ between those with versus without a history of IDU in the SCOPE cohort. On the basis of the numbers reported by Asher et al. [1] in Table 1, their study cohort included nearly equal numbers of individuals with (n ¼ 137) and without (n ¼ 142) a history of IDU, which provides a sufficiently large sample for testing this hypothesis.
One important finding from our study was that several participant characteristics were differentially associated with HCV clearance by presumed mode of acquisition
Asher et al. [1] also reported that HCV clearance was similar among men and women and concluded that ‘there is no clear explanation for why men were equally likely to
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Correspondence
clear their HCV infection as women in this cohort’. Our study in the MACS might provide an insight into this observation. We found that HCV clearance was significantly higher among non-IDU MSM (34.5%) than among IDU MSM (11.5%) (P < 0.001) [2]. Consequently, mode of HCV acquisition might confound the comparison of HCV clearance between men and women in the SCOPE cohort if, for instance, women were more likely to have been infected with HCV via IDU while men were more likely to have been infected via sexual contact. This possibility is supported by the authors’ statement that HIV-positive MSM is ‘a group well represented within the SCOPE cohort’[1]. Our final two comments about the study by Asher et al. [1] concern their multivariable analysis. First, in the last paragraph of the Results section, the authors report that HIV controller status and IL28B genotype were the only two factors found to be independently associated with HCV clearance. IL28B genotype, however, was not reported in Table 4; thus, it is not clear whether Table 4 accurately portrays the results from their final multiple regression model. Second, the authors note that HIV controller status was not associated with HCV clearance in their univariate analysis even though this association was found to be statistically significant in the multiple regression analysis. Assuming that the results in Table 4 are accurate, the reason for these apparently discrepant findings is clear. An interaction term for HIV controller status by HLA B57 was forced into the model even though it was not statistically significant (P ¼ 0.21). With this interaction term in the model, the HCV clearance difference between HIV controllers and noncontrollers [adjusted clearance ratio (ACR) 1.78] that the authors highlight in their discussion represents this comparison restricted to individuals without HLA B57. In contrast, the interaction term demonstrates that HIV controllers with HLA B57 were less likely to clear HCV (ACR 0.52). The univariate analysis effectively combined these two ACRs, resulting in the nonsignificant association between HIV controller status and HCV clearance. It is indeed intriguing that the HIV controller effect was qualitatively different between those with versus without HLA B57. Unfortunately, the authors provided no discussion about the cause or implication of their finding that HIV controllers were more likely to clear HCV only if they were HLA B57 negative.
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In summary, there is mounting evidence that the factors associated with spontaneous HCV clearance may differ by mode of acquisition, and these differences suggest that the mechanisms involved with spontaneous HCV clearance might also differ by mode of acquisition. Future research should examine whether any association observed between HIV controller status and HCV clearance differs by IDU status.
Acknowledgements Financial support was provided by the National Institute of Allergy and Infectious Diseases with supplemental funding from the National Cancer Institute [grant numbers UO1 AI35042 and UM1 AI35043].
Conflicts of interest We have no conflicts to disclose. Eric C. Seaberga and Chloe L. Thiob, aDepartment of Epidemiology, Bloomberg School of Public Health, and b Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA. Correspondence to Eric C. Seaberg, PhD, MPH, Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, 615 North Wolfe Street, Room E-7634, Baltimore, MD 21205, USA. Tel: +1 410 955 4320; fax: +1 410 955 7587; e-mail: [email protected] Received: 18 November 2013; revised: 8 January 2014; accepted: 8 January 2014.
References 1. Asher AK, Santos GM, Evans J, Dokubo EK, Lee TH, Martin JN, et al. Human leukocyte antigen BM57 does not fully explain hepatitis C clearance in HIV controllers. AIDS 2013; 27:2691– 2696. 2. Seaberg EC, Witt MD, Jacobson LP, Detels R, Rinaldo CR, Young S, et al. Differences in hepatitis C virus prevalence and clearance by mode of acquisition among men who have sex with men. J Viral Hepat 2013; [Epub ahead of print] doi:10.1111/jvh.12198.
DOI:10.1097/QAD.0000000000000207
Biomarkers for sexual behaviour change: a role for nonpaternity studies? The HIV pandemic, especially the devastating epidemics in sub-Saharan Africa (SSA) and the subsequent recent rapid declines in prevalence/incidence in several countries, has raised many questions. Among these are
(i) why major HIV epidemics appear to have occurred only in SSA and (ii) to what extent are these marked declines in HIV transmission attributable to sexual behavior changes? Both questions have generated intense
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2014, Vol 28 No 8
debates, often focusing on aspects of sexual behaviour; for example, whether the difference between SSA and the rest of the world can be explained by the higher levels of concurrency, that is having multiple sex partners simultaneously [1].
evidence [12]. Nonpaternity studies may provide insights about female sexuality that are of relevance not only for the epidemiology of sexually transmitted infections, but well beyond in fields as far as evolutionary anthropology [12].
Definitive answers to these questions require accurate data on sexual behaviour. However, although impressive amounts of data on sexual behaviour have been collected, they all tend to be self-reported [2]. The sensitive nature of sexual behaviour, and nonrandom social desirability and recall biases, can introduce inaccuracy in these data [3–6]. Several studies have also shown that such data can be unreliable; biomarker studies have shown underreporting of recent unprotected intercourse by women [7,8].
Admittedly, limitations may affect the interpretation of nonpaternity data. Birth control methods and fertility differentials may introduce bias. Nonpaternity could be also due to covert adoptions, misidentified stepchildren or sperm donations [10,13]. There are also complex ethical challenges in the conduct of such studies.
Self-reported data should therefore preferably neither be dependent upon comparing differences in behaviour between populations nor on monitoring changes in behaviour over time to evaluate the impact of behavioural interventions. Nonetheless, such self-reported data are still widely collected and analysed. We believe that there should be more emphasis on developing biomarkers that can reliably detect differences and trends in behaviour patterns. Recently, viral genetic linkage has been used to distinguish transmission within discordant couples from transmission from outside partners. Its finding, that a large fraction of infections acquired from outside the partnership occurred in individuals who reported no extramarital sex, has provided insight into the ongoing HIV epidemic and how misleading reliance on self-reported data may be [9]. Yet, as a measure of sexual behaviour in the population, this biomarker is not appropriate. It is complex to carry out and interpret and is restricted to HIVaffected couples. An easier type of biomarker, one that seems never to have been carried out in SSA, is nonpaternity [10], the percentage of children whose biological father differs from the official or presumed father, usually the husband or regular male partner of the mother. In addition to providing a direct biomarker of extramarital sex, nonpaternity can capture not only current behaviour but also past trends. With adequately powered studies, it is possible to derive a time-series of the rate of extra-marital sex from the nonpaternity age-stratified prevalence, and accordingly trends in sexual risk behaviour over decades, including the decades that witnessed the rise of the HIV epidemic. Although nonpaternity probes sexual behaviour only in women, the main challenges in self-reported data relate to women’s sexual behaviour [11]. Although multiple mating in human males is believed to be well characterized, the nature of multiple mating in human females is subject to intense debate and conflicting
Despite these caveats, some limitations can be overcome, and others may be an issue in some settings but not others. These limitations may not also hinder the ability of nonpaternity studies to provide at least a lower-bound estimate for extra-marital sex, which is in its own of greatest interest. Nonpaternity studies could be conducted as secondary data analyses on already collected samples for other studies or routine data, or ideally could be nested, with appropriate ethical prudence, within broader population-based surveys such as the Demographic and Health Surveys. In sum, nonpaternity studies can provide a trove of data on sexual behaviour and trends that are not prone to the extensive limitations of self-reported data. The potential for enhancing our knowledge with such data is immense. Not only they can facilitate a better understanding of HIV epidemics and their evolution, but also provide critical data to inform concept and design of interventions. This in turn would help optimize the impact of programmes by better targeting the drivers of HIV transmission.
Acknowledgements This publication was made possible by NPRP grant number 5-752-3-177 from the Qatar National Research Fund (a member of Qatar Foundation). The statements made herein are solely the responsibility of the authors.
Conflicts of interest There are no conflicts of interest. Laith J. Abu-Raddada,b,c and Nico Nagelkerked,e, a Infectious Disease Epidemiology Group, Weill Cornell Medical College - Qatar, Cornell University, Qatar Foundation - Education City, Doha, Qatar, bDepartment of Healthcare Policy and Research, Weill Cornell Medical College, Cornell University, New York, New York, cVaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Centre, Seattle, Washington, USA, dDepartment of Public Health, United Arab
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Correspondence Emirates University, Al Ain, United Arab Emirates, and e Department of Public Health, Erasmus Medical Center, Rotterdam, The Netherlands. Correspondence to Dr Laith Abu-Raddad, Infectious Disease Epidemiology Group, Weill Cornell Medical College – Qatar, Qatar Foundation – Education City, PO Box 24144, Doha, Qatar. Tel: +974 4492 8321; fax: +974 4492 8333; e-mail: [email protected] Received: 9 January 2014; revised: 20 January 2014; accepted: 20 January 2014.
References 1. Epstein H. The invisible cure: why we are losing the fight against AIDS in Africa.New York, NY: Picador; 2008. 2. Obasi A, Mosha F, Quigley M, Sekirassa Z, Gibbs T, Munguti K, et al. Antibody to herpes simplex virus type 2 as a marker of sexual risk behavior in rural Tanzania. J Infect Dis 1999; 179:16–24. 3. Caldwell JC, Caldwell P, Quiggin P. The social context of AIDS in Sub-Saharan Africa. Populat Develop Rev 1989, 15:185– 234.
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4. Lee RM, Renzetti CM. The problems of researching sensitive topics. Am Behav Sci 1990; 33:510–528. 5. Wadsworth J, Field J, Johnson AM, Bradshaw S, Wellings K. Methodology of the National Survey of Sexual Attitudes and Lifestyles. J R Stat Soc Ser A Stat Soc 1993; 156:407–421. 6. Morris M. Telling tails explain the discrepancy in sexual partner reports. Nature 1993; 365:437–440. 7. Gallo MF, Behets FM, Steiner MJ, Hobbs MM, Hoke TH, Van Damme K, et al. Prostate-specific antigen to ascertain reliability of self-reported coital exposure to semen. Sex Transm Dis 2006; 33:476–479. 8. Minnis AM, Steiner MJ, Gallo MF, Warner L, Hobbs MM, van der Straten A, et al. Biomarker validation of reports of recent sexual activity: results of a randomized controlled study in Zimbabwe. Am J Epidemiol 2009; 170:918–924. 9. Ndase P, Celum C, Thomas K, Donnell D, Fife KH, Bukusi E, et al. Outside sexual partnerships and risk of HIV acquisition for HIV uninfected partners in African HIV serodiscordant partnerships. J Acquir Immune Defic Syndr 2012; 59:65–71. 10. Anderson K. How well does paternity confidence match actual paternity? Curr Anthropol 2006; 47:513–520. 11. Catania JA, Gibson DR, Chitwood DD, Coates TJ. Methodological problems in AIDS behavioral research: influences on measurement error and participation bias in studies of sexual behavior. Psychol Bull 1990; 108:339–362. 12. Scelza BA. Choosy but not chaste: multiple mating in human females. Evol Anthropol 2013; 22:259–269. 13. Bellis MA, Hughes K, Hughes S, Ashton JR. Measuring paternal discrepancy and its public health consequences. J Epidemiol Community Health 2005; 59:749–754.
DOI:10.1097/QAD.0000000000000217
Intravenous iron and vertical HIV transmission: any connection? Due to antenatal testing and preventive interventions, iron-sucrose, 200 mg) each separated by a 3-day interval. HIV transmission to infants in the UK is very low (
