Incidence, Clinical Presentation and Outcome of CerebralToxoplasmosis in HIV-infected patients during the HighlyActive Antiretroviral Therapy Era: A Nationwide Cohort StudyRaquel Martin-Iguacel1, Magnus Glindvad Ahlström2, Madeleine Touma2, Frederik Neess Engsig3,Nina Breinholt Stærke4, Mette Stærkind5, Niels Obel2, Line D. Rasmussen1

1 Department of infectious Diseases, Odense University Hospital, Odense, Denmark,2 Department of Infectious Diseases, Rigshospitalet, Copenhagen, Denmark,

3 Department of infectious Diseases, Copenhagen University Hospital, Hvidovre, Denmark,4 Department of infectious Diseases, Aarhus University Hospital, Aarhus, Denmark,

5 Department of infectious Diseases, Aalborg University Hospital, Aalborg, Denmark

IntroductionCerebral toxoplasmosis (CTX) is the most common ofthe opportunistic infections (OI) in the central nervoussystem (CNS) of HIV-infected patients. Since the in-troduction of cART, the overall IR of OI and the post-OI mortality rate (MR) have declined dramatically (1-4). Still, incidence and mortality of CTX vary consid-erably between studies probably due to differences insociodemographic characteristics, access to care andpercentage of late presentation of HIV-infection of thedifferent study populations. As CTX still remains an im-portant cause of morbidity and mortality in HIV-infect-ed patients (1,5-6), it seems important to further inves-tigate the incidence, presenting symptoms, risk factorsand prognosis of HIV-associated CTX as of today.

ObjectivesWe conducted a cohort study to assess the riskof CTX and associated mortality in HIV-infected pa-tients during the pre-cART (1995-1996) and cART-era(1997-2014), and assessed the associated predictiveand prognostic factors. We further described the pre-senting characteristics and the clinical course of pa-tients with CTX.

Materials & MethodsFrom the Danish HIV Cohort Study (DHCS), we iden-tified 6,325 Danish HIV-infected individuals aged ≥16years (study period: 1995-2014). Data on CTX wereobtained through medical files review. We assessedincidence rate (IR), mortality rate (MR), predictive fac-tors, clinical presentation and prognosis of CTX dur-ing the pre-combination antiretroviral therapy (pre-cART: 1995-1996) and cART-era (1997-2014). Weused Poisson regression analysis to assess adjustedincidence rate ratios (aIRR), mortality rate ratios (aM-RR) and 95% confidence intervals (CI).

Results72 patients were diagnosed with CTX (IR: 1.17; 95%CI 0.93-1.47), of whom the majority (56.9%) were di-agnosed with HIV before 1995. All CTX patients hadadvanced HIV-disease (table 1).

Table 1. Demographics and HIV-related characteristicsof the study patients and the patients who developedcerebral toxoplasmosis (CTX) diagnosed during thestudy period

Incidence and predictive factors associated withCTX: From the pre-cART to the cART-era we observedan unchanged risk of CTX during the first year af-ter study inclusion (i.e. HIV diagnosis) (aIRR: 0.81;95%CI: 0.42-1.56). In contrast, a substantial reductionin risk of CTX was observed in the subsequent yearsduring the cART-era (aIRR: 0.06; 0.03-0.11. Higherrisk of CTX was significantly associated with a lowCD4+ cell count (< 200 cells/μL) and high VL (VL≥100.000 c/mL) (table 2).

Table 2. Predictive factors for cerebral toxoplasmosisin HIV-infected individuals

Mortality: Forty-two patients (58.3%) diagnosed withCTX died during the study period of whom thirty (71%)died within the first year and nine (25%) within 30 daysafter the CTX diagnosis (data not shown).

We observed a substantial reduction in post CTXmortality with later calendar periods (1995-1996vs. 1997-2014) during both the first (aMRR: 0.13;0.06-0.30) and subsequent years (aMMR: 0.02;0.01-0.04). And, during 1997-2014, no statistically sig-nificant difference in risk was observed between pa-tients who had survived the first year after CTX diag-nosis and in whom CTX was diagnosed before and af-ter year 1996 (aMRR: 0.36; 0.08-1.74).

When evaluating prognostic factors, age at CTX diag-nosis, injection drug use, and no exposure to cART be-fore CTX diagnosis were associated with a statisticallysignificant higher risk of mortality in univariate models(table 3).

Table 3. Prognostic factors for death in HIV-infected in-dividuals diagnosed with cerebral toxoplasmosis.

Figure 1. Kaplan-Meiercurves for overall survivalof HIV-infected individ-uals with cerebral toxo-plasmosis (CTX) by cal-endar time of CTX diag-nosis (1995-1996) (blue),1997-2014 (red).

Presenting symptoms and and neurological out-come in patients diagnosed with CTX (table 3,4)

Headache (37.5%), cognitive deficit (41.7%), limbparesis (36.1%) and fever (75.9% > 37.5°C and 31% >38.5°C) were the most common symptoms at presen-tation (table 4).

Four months after CTX, 61.2% of the patients experi-enced an improvement of their neurological symptomsand 18.4% experienced a complete resolution of theirdeficits. Three years after CTX, further improvementwas observed, with 45.5% experiencing additional im-provement of the neurological symptoms and 30% re-porting a complete resolution of symptoms (table 5).

Table 4. Neurologicalsymptoms of cerebral tox-oplasmosis in HIV-infectedindividuals at primary pre-sentation, at first follow-upvisit after 4 months, and af-ter 3 years

Table 5. Clinical data andlaboratory results at pre-sentation of HIV-infectedindividuals with cerebraltoxoplasmosis.

ConclusionsIn conclusion, CT still remains an important cause ofmorbidity and mortality among HIV-infected patientswith advanced immunosuppression. However, the in-cidence of CT and post CT mortality has declined sub-stantially during the cART-era, especially when surviv-ing the first year of HIV-infection and CT, respective-ly. As a result, individuals diagnosed with HIV or CTduring the pre-cART-era can be assured a low riskof CT or post CT mortality when compliant to cART.Hence, early diagnosis of HIV and cART initiation re-mains paramount.

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