IAS–USA Topics in Antiviral Medicine

Case Report From the Field Negatively Influences the Response to Hepatitis C Treatment in an HIV-Infected Patient

Ellen H. Nagami, BA, Arthur Y. Kim, MD, Rachel P. Baden, MD, and Barbara H. McGovern, MD

Syphilis is a chronic inflammatory dis- Case Presentation During his course of HCV therapy, ease caused by the sexually transmit- Patient J presented with a maculopapu- ted pathogen, Treponema pallidum.1 In 2007, Patient J, a 46-year-old HIV- lar rash at week 17 and acknowledged Concomitant HIV and syphilis infec- infected white man with HCV geno- that he had had unprotected anal inter- tions are prevalent among men who type 1b , underwent a liver course. An RPR test was reactive with have sex with men (MSM).2 Syphilis biopsy that demonstrated moderately a titer of 1 to 64 and a confirmatory negatively impacts disease manage- active chronic hepatitis with evolving test was reactive for Treponema pal- ment in the HIV-infected host by caus- cirrhosis and moderate steatosis. Prior lidum antibody (TPA). Cerebrospinal ing substantial immune activation, as to HCV treatment, Patient J’s baseline fluid analysis after a lumbar puncture evidenced by precipitous declines of HCV viral load was 1.5 million IU/mL was unremarkable. Patient J was treat- CD4+ cells and by increased levels of and his plasma HIV RNA level was un- ed with three doses of intramuscular HIV RNA.3,4 Syphilis has also been re- detectable on antiretroviral therapy. injections of benzathine penicillin over ported as a risk factor for hepatitis C A baseline (RPR) a 3-week period with an appropriate virus (HCV) acquisition among MSM.5 test was nonreactive for treponemal titer decline to 1 to 16 after 6 weeks Whether intercurrent syphilis has any infection 6 weeks before starting HCV of follow-up. negative impact on HCV treatment re- treatment. At week 28 of HCV therapy, Patient sponse is unknown. Patient J was started on peginter- J was hospitalized because of acute on- We report a case of an HIV/HCV- feron alfa-2a (180 mcg subcutane- set of a transient febrile episode with coinfected man who was treated with ously weekly) and weight-based riba- hypotension and was started on broad- peginterferon alfa and ribavirin. He virin (1000 mg daily for a weight of spectrum antibiotics. At this time, his had a very slow attainment of HCV more than 75 kg). During treatment, HCV treatment was discontinued. All RNA suppression and a dramatic fall the patient reported excellent adher- cultures were negative and his of CD4+ cell count in excess of what ence to both his antiretroviral and antibiotics were stopped when no ob- would be expected in response to HCV HCV medications. His major adverse vious source of infection was found. therapy. During HCV treatment, the effect related to HCV treatment was Patient J subsequently admitted to use patient was diagnosed with intercur- anemia requiring darbepoetin alfa of intravenous crystal methamphet- rent syphilis and admitted to the use supplementation; ribavirin dose was amine a few days prior to his hospital- of methamphetamines; HCV treat- not reduced. At weeks 4 and 12 of ization. His clinicians surmised that his ment was subsequently discontinued treatment, Patient J’s HCV viral load acute and transient febrile event with at week 28. After drug rehabilitation was 147,000 IU/mL and 3,208 IU/mL, hypotension may have been related and administration of benzathine respectively. HCV RNA suppression to endotoxemia since no infectious penicillin for syphilis, the patient un- was not achieved until 21 weeks into etiology was identified. derwent retreatment for HCV with re- treatment, consistent with a slow viro- At the end of 2008, 2 months after markably improved viral kinetics and logic response. Although HIV RNA re- completion of benzathine penicillin a modest decline in CD4+ cell count. mained suppressed, his pre-treatment therapy for syphilis, Patient J requested We propose that active syphilis infec- CD4+ cell count dropped from 834/µL retreatment for his HCV infection be- tion may have been a key contributor to 311/µL at the time of discontinua- cause he felt that he was in stable sub- to the patient’s slow virologic response tion of HCV therapy and his CD4+ cell stance abuse recovery. At the time of his to his initial course of HCV treatment. percentages remained fairly constant presentation to our clinic (1 month af- Within this report we discuss the pub- at 26% and 29%, respectively (normal ter discontinuation of HCV therapy), Pa- lic health implications of this case. range, 29%-62%). tient J’s HCV RNA level had rebounded

Ms Nagami is an HIV and hepatitis C clinical coordinator at Harvard University Center for AIDS Research in Boston, Massachusetts. Dr Kim is As- sistant Professor of Medicine at Harvard Medical School in Boston and Dr Baden is Assistant Professor of Medicine at Harvard Medical School. Dr McGovern is Associate Professor of Medicine at Tufts University School of Medicine in Boston. Send correspondence to Barbara McGovern, MD, Lemuel Shattuck Hospital, 170 Morton Street, Jamaica Plain, Massachusetts 02130, or e-mail [email protected]. Re- ceived April 3, 2012; accepted September 27, 2012.

134 Syphilis in HCV and HIV Coinfection Case Report Volume 20 Issue 4 October/November 2012

to 1,590,000 IU/mL, consistent with include high baseline HCV viremia, During the first course of treatment, his pretreatment baseline viral load HCV genotype 1 infection, male sex, the patient described herein did not level. His CD4+ cell count had risen African American race, older age, un- achieve an undetectable viral load while off of peginterferon alfa-2a and favorable IL-28 genotype, insulin resis- until week 21 of HCV therapy. In con- ribavirin treatment to 861/µL (CD4+ tance, and advanced fibrosis stage.9-14 trast, during retreatment our patient percentage: 41%) and his HIV RNA Regardless of HIV serostatus, the attained a 4 log10 decline in viremia by level remained suppressed on antiret- most powerful predictor of attaining week 4 (to 121 IU/mL) and achieved roviral therapy. Etiologies for his ini- SVR to HCV treatment is rapid viral complete viral suppression at 7 weeks, tial slow HCV viral suppression were clearance.9,15 In studies of dual HCV when he was next tested. explored, including insulin resistance, therapy in HIV seronegative patients Several factors were explored to ex- which was negative. with HCV genotype 1 infection, a rapid plain the dramatic differences in viral The patient continued to abstain virologic response (RVR) is associated clearance. Patient J had no evidence of from any illicit drug use and was re- with SVR rates ranging from 75% insulin resistance or hyperglycemia.14 started on peginterferon alfa-2a and to 8 9%. 16,17 In studies of HIV/HCV There were no changes in the inter- ribavirin. The dosing of ribavirin was coinfection, the same principles apply. feron alfa formulation that he received decreased to 400 mg twice daily based In a posthoc analysis of 323 HIV/HCV- between the first and second courses on his current weight. By week 4, his coinfected patients in the RIBAVIC of therapy and his ribavirin dose was HCV RNA level was 121 IU/mL. At re- treatment trial, RVR at week 4 had lower during retreatment (800 mg ver- peat HCV RNA testing at week 7, his a positive predictive value of 97% sus 1000 mg). Furthermore, during his HCV RNA level was below 5 IU/mL for sustained virologic clearance.18,19 first course of treatment, the patient by HCV RNA quantitative polymerase However, the proportion of coinfected had excellent adherence to both HCV chain reaction. Patient J attained a sus- patients who achieve rapid virologic and HIV therapies, evidenced by the tained virologic response (SVR) after clearance on dual therapy is low. development of anemia on ribavirin completing 48 weeks of HCV treat- Even with the recent introduction and maintenance of HIV RNA sup- ment. Of note, the patient did not of HCV protease inhibitors, the best pression.9,11,25 Finally, there were no require darbepoetin alfa during this on-treatment predictor of virologic changes in his background antiretro- second course of therapy. Despite re- clearance remains rapid viral viral regimen during this time frame, ceiving the same dose of peginterferon suppression.20 Patients who attained which could have potentially played a alfa during his second course of HCV an undetectable viral load at week 4 role in these differential treatment out- therapy, the decline in his CD4+ cell on telapravir, peginterferon alfa-2a, comes.26 count was less dramatic (861/µL to and ribavirin had an SVR rate of 88%.20 Unfortunately, we do not have the 529/µL) and his CD4+ cell percentage In contrast, those who had a greater original viral isolate and thus cannot remained relatively stable, 41% and than 1 log10 IU/mL decline in HCV RNA rule out the possibility of HCV rein- 36%, respectively. level after the 4 weeks of treatment fection. However, it is unlikely that an had an SVR rate of 64%.20,21 Similar HIV-infected patient with HCV geno- Discussion trends were seen in the clinical trial type 1 infection and a high HCV RNA evaluating boceprevir, peginterferon level would have achieved virologic End-stage liver disease is a leading alfa, and ribavirin in treatment-naive eradication after only 28 weeks of cause of death among HIV-infected patients.22 treatment, especially since he attained patients taking antiretroviral therapy.6,7 In this case report, we demon- late virologic suppression. In addition, HIV/HCV-coinfected patients have strate that viral kinetics dramatically after discontinuing the first course of higher rates of liver-related and over- improved during the second course treatment the patient’s HCV RNA level all mortality than patients with HCV of HCV therapy after treatment of in- returned to his pretreatment level. This alone.8 However, successful treatment tercurrent syphilis infection. Such is consistent with rebound viremia of HCV infection is associated with de- changes in viral kinetics have not back to the viral setpoint. creased liver-related disease and im- been reported among patients under- Patient J’s remarkable change in vi- proved survival.9 Therefore, treatment going retreatment for HCV with dual ral kinetics led us to question whether of HCV infection in the setting of HIV therapy.23,24 In fact, retreatment with intercurrent syphilis may have modi- is of paramount importance. a different formulation of peginterfer- fied the cytokine environment and Unfortunately, response rates to on alfa (switching from peginterferon negatively impacted his first course of HCV treatment are generally lower alfa-2a to peginterferon alfa-2b or vice treatment. Modulators of response to among HIV/HCV-coinfected patients, versa) has been largely unsuccessful. interferon alfa-based therapies include although this finding has not been di- In a large study of patients with chron- cytokines such as inducible protein-10 rectly linked to immunosuppression.9 ic HCV infection, only 9% achieved (IP-10) and interleukin 10 (IL-10).27-31 In Pretreatment predictors of virologic SVR after retreatment with peginter- a study of 19 HIV/HCV-coinfected pa- failure in HIV/HCV-coinfected patients feron alfa and ribavirin for 48 weeks.23 tients, pretreatment IP-10 levels were

135 IAS–USA Topics in Antiviral Medicine

statistically significantly lower among lower among HIV/HCV-coinfected pa- from 7% to 64%.43 Furthermore, the virologic responders (217 pg/mL; inter- tients than among those who have HCV current syphilis epidemic among MSM quartile range [IQR], 181 pg/mL–301 infection alone.38,39 Although this lower has disproportionately affected those pg/mL) than among nonresponders response rate has been attributed with HIV infection.46 Many factors (900 pg/mL; IQR, 628 pg/mL–2048 to HIV-associated immunosuppres- may have contributed to the resur- pg/mL).32 A similar inverse relation- sion, an additional hypothesis is that gence of syphilis among HIV-infected ship has been described for IL-10. In undiagnosed intercurrent syphilis re- MSM, including serosorting of sexual a study of 79 patients with HCV gen- duces treatment efficacy in a subset of partners, initiation of higher-risk sex- otype 1 infection, low baseline levels patients. ual activity due to a sense of security of IL-10 were strongly associated with We also suspect that our patient’s created by effective HIV therapeutics, high rates of virologic eradication.31 dramatic decline in CD4+ cells during and a longer lifespan of HIV-infected Other factors predictive of HCV clear- the first course of HCV therapy was individuals.46 Other risk factors asso- ance include hepatic interferon-stim- related to several factors, including pe- ciated with syphilis infection include ulated gene (ISG) expression levels. ginterferon alfa exposure and active underlying HIV infection and use of Patients who achieve rapid HCV clear- syphilis. Treatment of HCV in HIV-in- methamphetamines.46 ance have strong up-regulation of ISGs fected patients is associated with sub- A major obstacle to the diagnosis of in response to peginterferon alfa treat- stantial declines in the absolute CD4+ syphilis is that many infected individu- ment. In contrast, HCV patients who cell count, which resolve with discon- als are asymptomatic. In a cohort of do not respond have high levels of tinuation of peginterferon alfa therapy. 218 HIV-infected patients with newly ISGs before therapy and are refractory In APRICOT (AIDS Pegasys Ribavirin detected and untreated syphilis, 60% to further stimulation.33,34 International Coinfection Trial), which were asymptomatic and, most likely, The role of cytokines in HCV treat- examined HCV treatment in the set- would have gone undiagnosed if not ment outcomes is pertinent when con- ting of HIV, the mean CD4+ cell de- for annual screening.2 A recent study sidering the possible negative impact cline was 157/µL.9 However, Patient J in an Australian HIV clinic compared of syphilis during our patient’s first had a dramatic drop of 523 cells/µL, syphilis diagnoses in HIV-infected MSM course of HCV therapy. T pallidum infec- which is much greater than would before and after the implementation tion alters the balance of T helper cell be expected with peginterferon alfa of syphilis serologic testing with every 47 1 (TH1) and T helper cell 2 (TH2) CD4+ alone. This profound drop in CD4+ cell routine blood sample. The proportion cell profiles of the host. Initially, T pal- count is consistent with reports of im- of asymptomatic HIV-infected MSM lidum elicits vigorous munologic changes seen in HIV-infect- who tested positive for syphilis rose characterized by a predominant TH1 ed patients with primary or second- from 21% to 85% percent with the im- (cellular) response. This is followed by ary syphilis, which may be attributed plementation of this routine screening 47 activation of TH2 (humoral) responses to increased cell turnover, apoptosis, intervention. The Centers for Disease that are thought to contribute to spiro- and changes in T-cell homeostasis.3,4,40 Control and Prevention and the United chete evasion of the host immune sys- Generalized immune activation is as- Kingdom National Screening and Test- tem and to the development of chronic sociated with increased expression ing Guidelines now recommend annu- infection, if left untreated. This switch of CC chemokine receptor 5 (CCR5) al serologic testing for HIV and syphilis 48,49 to a TH2 response is characterized by and dendritic cell-specific intercellular for sexually active MSM. profound increases in IL-10 level, which adhesion molecule-3-grabbing non- The alteration of viral kinetics and may facilitate the persistence of various integrin (DC-SIGN) receptors on hu- the immunologic changes observed in pathogens through interference with man monocytes and dendritic cells, Patient J support the possibility that innate and adaptive immunity.35-37 In a which enhances the cells’ susceptibil- intercurrent syphilis is a modulator of novel study of cytokine responses dur- ity to HIV infection.1,3,41 Of note, syphi- HCV treatment outcome. This would ing syphilis infection in 36 HIV-infected lis has also been associated with in- indicate that it is important to screen patients, IL-10 levels increased substan- creased HIV RNA levels in patients not patients who are at risk for syphilis tially during primary and secondary on antiretroviral therapy.3,4,40 infection prior to initiating HCV antivi- stage syphilis, only to decline with peni- Overall incidence rates of primary ral therapy as well as counsel patients cillin therapy.35 An attractive hypothesis and secondary syphilis have been on about the importance of safe sex. is that early syphilis led to marked in- the rise since 2001, after decreasing Syphilis screening may also be war- creases in IL-10 levels, which interfered throughout the 1990s.42,43 Recent re- ranted among HCV-infected patients with our patient’s initial response to ports have shown an increasing inci- who demonstrate slow virologic clear- interferon alfa. Subsequent treatment dence of syphilis specifically among ance during HCV treatment, despite of syphilis may have led to declines in MSM in the United States and Eu- excellent adherence. Syphilis screening IL-10 level, which facilitated clearance rope.44,45 Between 2000 and 2004, should also be considered among of HCV RNA in response to treatment.31 the percent of cases of primary and patients with dramatic CD4+ cell de- Interestingly, treatment response rates secondary syphilis attributed to MSM clines that exceed what is normally ex- for acute HCV infection are generally in the United States rose dramatically pected with peginterferon alfa therapy.

136 Syphilis in HCV and HIV Coinfection Case Report Volume 20 Issue 4 October/November 2012

Acknowledgements and 10. Saludes V, Bracho MA, Valero O, et al. American Association for the Study for Baseline prediction of combination ther- Liver Diseases Annual Meeting. Novem- Disclosures apy outcome in hepatitis C virus 1b in- ber 3-8, 2011; San Francisco, CA. fected patients by discriminant analysis 25. Lo Re V, III, Teal V, Localio AR, Amorosa VK, The authors extend their apprecia- using viral and host factors. PLoS One. Kaplan DE, Gross R. Relationship between tion to the patient who is the subject 2010;5(11):e14132. adherence to hepatitis C virus therapy and of this report. Work on this paper was 11. Rodriguez-Torres M, Sulkowski MS, virologic outcomes: a cohort study. Ann In- Chung RT, Hamzeh FM, Jensen DM. Fac- tern Med. 2011;155(6):353-360. supported by the National Institutes tors associated with rapid and early viro- 26. Vispo E, Barreiro P, Pineda JA, et al. 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Med. 2004;351(5):438-450. untreated subjects. [Abstract 975.] 62nd 2011;6(4):278-284. 137 IAS–USA Topics in Antiviral Medicine

39. van de Laar TJ, Matthews GV, Prins M, 43. Centers for Disease Control and Preven- the detection of early asymptomatic Danta M. Acute hepatitis C in HIV-in- tion and US Department of Health and syphilis among HIV-positive homosexual fected men who have sex with men: an Human Services. Division of STD Preven- men. JAIDS. 2010;55(2):211-216. emerging sexually transmitted infection. tion. Sexually transmitted disease sur- 48. Workowski KA, Berman SM. Sexu- AIDS. 2010;24(12):1799-1812. veillance, 2009. November 2010. http:// ally transmitted diseases treatment 40. Palacios R, Jimenez-Onate F, Aguilar M, et www.cdc.gov/std/stats09/surv2009-Com guidelines, 2006. MMWR Recomm Rep. al. Impact of syphilis infection on HIV vi- plete.pdf. Accessed September 19, 2012. 2006;55:1-94. ral load and CD4 cell counts in HIV-infect- 44. Syphilis on the rise in the USA. Lancet. 49. Screening Guidelines Steering Commit- ed patients. JAIDS. 2007;44(3):356-359. 2011;378(9791):542. tee. Sexually transmitted infections: UK 41. Sellati TJ, Wilkinson DA, Sheffield JS, 45. Peterman TA, Furness BW. The resur- national screening and testing guidelines. Koup RA, Radolf JD, Norgard MV. Viru- gence of syphilis among men who have http://www.bashh.org/documents/59/59. lent Treponema pallidum, lipoprotein, sex with men. Curr Opin Infect Dis. pdf. Accessed September 19, 2012. and synthetic lipopeptides induce CCR5 2007;20(1):54-59. on human monocytes and enhance their 46. Peterman TA, Heffelfinger JD, Swint EB, susceptibility to infection by human im- Groseclose SL. The changing epidemiolo- munodeficiency virus type 1. J Infect Dis. gy of syphilis. Sex Transm Dis. 2005;32(10 2000;181(1):283-293. Suppl):S4-10. 42. Twisselmann B. Rates of syphilis in 47. Bissessor M, Fairley CK, Leslie D, Howley England are rising. Euro Surveill. K, Chen MY. Frequent screening for syph- Top Antivir Med. 2012;20(4):134-138 2002;6(30):pii=1909. ilis as part of HIV monitoring increases ©2012, IAS–USA

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