1. The Effect of Syphilis Co-infection on Clinical Outcomes in HIV-Infected Persons The Effect of Syphilis Co-infection on Clinical Outcomes in HIV-Infected Persons Weintrob A 1, Gu W 2, Robertson J 1, Qin J 2, Ganesan A 1, Crum-Cianflone N 1, Wegner S 1, Follmann D 2, Agan B 1 1 Infectious Disease Clinical Research Program of the Uniformed Services University of the Health Sciences, Bethesda, MD, 2 National Institute of Allergy and Infectious Disease, Rockville, MD Background: Syphilis co-infection transiently decreases CD4 count and increases viral load (VL) in HIV-infected persons. With the continued increase in syphilis cases among those with HIV, understanding whether these changes affect time to AIDS or death is important. Methods: 2239 HIV seroconverters from a longitudinal US military cohort followed from 1986 – 2006 were analyzed to determine the effect of syphilis on time to AIDS and/or death. Confirmed syphilis was a positive RPR and treponemal test after HIV infection. Probable syphilis was a clinical diagnosis and treatment for syphilis. Subjects were compared using chi-square and Wilcoxon tests. Cox regression models were used to analyze survival data right censoring at HAART/last visit/1996 (Model A) or last visit (Model B, treating HAART as time-dependent variable). Results: Of the 2239, 205 (9%) had confirmed syphilis and 66 (3%) had probable syphilis. Those acquiring syphilis were more likely to be older, African American, male, and co-infected with hepatitis B/C or other STDs. There was no difference in time from imputed seroconversion to HIV diagnosis or in CD4 or VL at HIV diagnosis between those with and without syphilis. The rate of acquiring syphilis was lower in the pre-HAART era (HR 0.49, p<0.0001). In multivariate models of time to AIDS or death or time to death alone (Model A) adjusting for CD4, age, race, gender, and hepatitis B/C status, syphilis (confirmed + probable) was not associated with increased hazard (HR 0.99, 95% CI 0.73-1.33, and 1.57, 95% CI 0.84-2.9, respectively). Likewise, in Model B, syphilis was not associated with increased hazard of time to AIDS or death (HR 0.95, 95%CI 0.72-1.25) or time to death alone (HR 1.53, 95%CI 0.84-2.78). Results of all analyses were similar when syphilis was limited to confirmed cases. Conclusions: In a large, prospectively followed cohort of HIV seroconverters with equal access to free healthcare, syphilis co-infection did not affect time to AIDS or death. 2239 HIV-infected subjects enrolled in the TACC NHS, an ongoing, prospective multicenter observational study which began in 1986, were analyzed. All subjects had negative HIV tests prior to their first positive HIV test allowing for an estimation of seroconversion date. Syphilis definitions: Confirmed = positive non-treponemal and treponemal assays Probable = received treatment for clinical diagnosis of syphilis Possible = positive non-treponemal assay only, no treatment Cox regression models were used to analyze time to death or AIDS (1993 CDC definition) right censoring at either: time of HAART initiation, last visit, or Jan 1, 1996 (model A) time of last visit, treating HAART as a time-dependent variable (model B) In the TACC HIV NHS, syphilis was more common in African Americans than in other ethnicities and more common amongst males than females. Those with syphilis were more likely to be infected with other sexually transmitted diseases including hepatitis B and C. Syphilis co-infection at least transiently decreases CD4 counts and increases HIV viral loads. The effects of syphilis on CD4 count and viral load however do not translate into faster progression to AIDS or death. Abstract Materials & Methods Results Results Conclusions 1 Palacios R, Jimenez-Onate F, Aguilar M, et al. Impact of syphilis infection on HIV viral load and CD4 cell counts in HIV-infected patients. J Acquir Immune Defic Syndr 2007;44:356-9. 2 Buchacz K, Patel P, Taylor M, et al. Syphilis increases HIV viral load and decreases CD4 cell counts in HIV-infected patients with new syphilis infections. AIDS 2004;18:2075-9. 3 Kofoed K, Gerstoft J, Mathiesen LR, Benfield T. Syphilis and human immunodeficiency virus (HIV)-1 co- infection; influence on CD4 T-cell count, HIV-1 viral load, and treatment response. Sex Transm Dis 2006;33:143-8. 4 Burgi A, Crum-Cianflone NF, Pope B, et al. The negative effect of syphilis infections among HIV-infected persons on the CD4 cell count. The 44th Annual Meeting of the Infectious Disease Society of America Meeting, Toronto Canada, October 12-15, 2006 References Poster #H-2329 During syphilis co-infection, HIV viral loads increase and CD4 lymphocyte counts decrease. 1-4 The CD4 count decrease is transient; however, the viral load increase may remain after syphilis treatment. 1,2 These changes may be due to immune activation which enhances viral replication. Whether these changes affect clinical outcomes in HIV-infected persons with syphilis remains unclear. The objective of this study was to determine whether syphilis co- infection affected the time to death or AIDS diagnosis in subjects enrolled in the TriService AIDS Clinical Consortium (TACC) HIV Natural History Study (NHS). Introduction Amy.Weintrob@ amedd.army.mil (202)782-8710 phone (202)782-0551 fax Baseline Characteristics Variable No syphilis (n=1920 ) Confirmed Syphilis (n=205 ) Probable Syphilis (n=66 ) Possible Syphilis (n= 48) P-value Age at seroconversion (years ± SD) 28 ± 729 ± 7 29 ± 8<.05 Race (%) European American African American Hispanic Other 47 42 7 4 18 74 7 2 21 68 5 6 31 60 6 2 <.05 Gender (%) Male Female 93 7 99 1 94 6 96 4 <.05 Rank (%) Enlisted Officer 74 6 85 5 67 9 75 8 0.59 Time from seroconversion to HIV diagnosis (days ± SD) 319 ± 271325 ± 283318 ± 250376 ± 2870.52 Viral load at HIV diagnosis (log 10 c/ml ± SD) 4.8 ± 5.2 (n=857) 4.7 ± 4.9 (n=91) 4.9 ± 5.1 (n=17) 5.1 ± 5.3 (n=10) 0.27 CD4 count at HIV diagnosis (cells/mm 3 ± SD) 555 ± 262 (n=1709) 570 ± 237 (n=178) 523 ± 212 (n=59) 510 ± 195 (n=40) 0.43 Percent who started HAART55685658<.05 Year of HAART start19991998 19990.11 CD4 at HAART start (cells/mm 3 ±SD) 365 ± 212 (n=980) 382 ± 197 (n=135) 357 ± 211 (n=36) 319 ± 212 (n=27) 0.50 Viral load at HAART start (log 10 c/ml ± SD) 4.9 ± 5.4 (n=913) 4.7 ± 5.0 (n=130) 4.4 ± 4.7 (n=32) 5.0 ± 5.3 (n=27) 0.23 Hepatitis B co-infection (%)581210<.05 Hepatitis C co-infection (%)39 913<.05 # Other STDs (mean/person)0.71.10.91.0<.05 Length of follow up (days ± SD) 1548±11471878±12931990±13211849±1307<.05 Time to Death or AIDS (n=1338)* Multivariate Cox regression censored at HAART, last visit, or Jan. 1, 1996 VariableReferenceHazard Ratio 95% CIp-value Syphilis**Yes1.060.73 – 1.530.77 Age1 year1.010.99 – 1.020.23 EthnicityCaucasian0.860.62 – 0.900.002 GenderMale1.741.06 – 2.330.02 CD4 count100 cells0.700.66 – 0.74<0.0001 Hepatitis BYes0.770.55 – 1.060.10 Hepatitis CYes1.060.69 – 1.620.79 *VL was excluded from above model because of a significant number of subjects with missing baseline VLs. The effect of syphilis on time to death or AIDS did not change when VL was included in the model (n=410). **Syphilis = confirmed + probable cases. Results remain the same if analysis is limited to confirmed cases only. In a similar multivariate Cox regression censored at the same time points, syphilis had no significant effect on time to death alone (HR = 1.89, 95% CI 0.96 – 3.71, p=0.066). Time to Death or AIDS (n=1938)* Multivariate Cox regression censored at last visit with HAART treated as a time-dependent co-variate VariableReferenceHazard Ratio 95% CIp-value Syphilis**Yes0.980.75 – 1.300.89 Age1 year1.010.99 – 1.020.38 EthnicityCaucasian0.820.71 – 0.950.008 GenderMale1.210.89 – 1.660.22 CD4 count100 cells0.730.70 – 0.76<0.0001 Hepatitis BYes0.890.69 – 1.150.37 Hepatitis CYes1.441.05 – 1.970.02 HAARTYes0.250.19 – 0.31<0.0001 *VL was excluded from above model because of a significant number of subjects with missing baseline VLs. The effect of syphilis on time to death or AIDS did not change when VL was included in the model (n=1001). **Syphilis = confirmed + probable cases. Results remain the same if analysis is limited to confirmed cases only. Similarly, syphilis had no significant effect on time to death alone (HR = 1.54, 95% CI 0.85 – 2.78, p=0.16) in Cox regression with HAART treated as a time-dependent co-variate.