Syphilis Negatively Influences the Response to Hepatitis C Virus Treatment in an HIV-Infected Patient
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IAS–USA Topics in Antiviral Medicine
Case Report From the Field
Syphilis Negatively Influences the Response to Hepatitis C
Virus 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 infection, 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 rapid plasma reagin (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- blood 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 bmcgovern@tuftsmedicalcenter.org. Re-
ceived April 3, 2012; accepted September 27, 2012.
134Syphilis 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 89%.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-
trends were seen in the clinical trial type 1 infection and a high HCV RNA
Discussion
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
135IAS–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
1 (TH1) and T helper cell 2 (TH2) CD4+ alone. This profound drop in CD4+ cell routine blood sample.47 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 inflammation 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
activation of TH2 (humoral) responses to increased cell turnover, apoptosis, intervention.47 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
to a TH2 response is characterized by and dendritic cell-specific intercellular for sexually active MSM.48,49
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.
136Syphilis 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. Low
of Health/National Institute of Allergy logic response to peginterferon alfa-2a/ response to pegylated interferon plus
ribavirin treatment in HCV genotype 1 ribavirin in HIV-infected patients with
and Infectious Diseases (Hepatitis C patients representative of the general chronic hepatitis C treated with abacavir.
Cooperative Center U19 AI066345, chronic hepatitis C population. J Viral Antivir Ther. 2008;13(3):429-437.
Hepat. 2010;17(2):139-147.
K23 AI054379 to AYK, Harvard Uni- 27. Honda M, Sakai A, Yamashita T, et al. He-
12. European AIDS Treatment Network patic ISG expression is associated with ge-
versity Center for AIDS Research P30 (NEAT) Acute Hepatitis C Infection Con- netic variation in interleukin 28B and the
AI060354). sensus Panel. Acute hepatitis C in HIV- outcome of IFN therapy for chronic hepa-
infected individuals: recommendations titis C. Gastroenterology. 2010;139(2):499-
Financial Affiliations: Ms Nagami and Drs from the European AIDS Treatment 509.
Baden and McGovern have no relevant fi- Network (NEAT) consensus conference.
AIDS. 2011;25:399-409. 28. Dumoulin FL, Wennrich U, Nischalke HD,
nancial affiliations to disclose. Dr Kim has et al. Intrahepatic mRNA levels of inter-
13. Thomas DL, Thio CL, Martin MP, et al. feron gamma and tumor necrosis factor
served as a consultant to Vertex Pharmaceu- Genetic variation in IL28B and spontane- alpha and response to antiviral treat-
ticals, Inc. ous clearance of hepatitis C virus. Nature. ment of chronic hepatitis C. J Hum Virol.
2009;461(7265):798-801. 2001;4(4):195-199.
14. Nasta P, Gatti F, Puoti M, et al. Insulin re-
sistance impairs rapid virologic response 29. Darling JM, Aerssens J, Fanning G, et
in HIV/hepatitis C virus coinfected pa- al. Quantitation of pretreatment serum
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