Reasons why we will never forget. Andrea Antinori INMI L. Spallanzani IRCCS, Roma

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1 Reasons why we will never forget Andrea Antinori INMI L. Spallanzani IRCCS, Roma

2 SMRs according to time spent with CD4 count >500/mm3 after cart initiation in MSM 80,642 HIV-infected individuals eligible if they initiated combination anti-retroviral treatment (cart) between 1998 and Standardized mortality ratios (SMRs) compared with the general population The Collaboration of Observational HIV Epidemiological Research Europe (COHERE). Int J Epidemiol, 2012

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4 Survival Patterns of the First 500 Patients with AIDS in San Francisco Estimated survival probabilities for patients y of age in San Francisco with KS alone at initial AIDS diagnosis. Diagnosis before July 1983(- - -; n = 77) versus diagnosis from July 1983 through May 1984 (-- -; n = 95) is shown. (P =.0003 by generalized Wilcoxon test). The estimated overall median survival time was 11 mo, and the estimated one-year and three-year survival rates were 44% (95% confidence interval [Cl], 40%-48%) and 11% (95% CI, 7%-11%), respectively. Median survival time (mo): KS only=16; OI present=9 Bacchetti P, et al. J Infect Dis, 1988

5 Forgetting AIDS as clinical disease

6 Patients discharged by calendar year. INMI

7 Clinical case Male, 30 years old, heterosexual March 2011 Fever, leukopenia, LEE, hig-level LDH Positive HIV serology; CD4+ 56 cell/mm 3 ; HIV-1 RNA cp/ml. Start carv with FTC/TDF+ATV/r. CT scan documented lymphonodes at mediastinic and abdominal level, with infiltrating liver focal lesions. Liver biopsy: High grade B-cell non-hodgkin Lymphoma. April 2011 Start R-CHOP (Rituximab, Adriamicyn, Cyclofosfamide, Vincristin, Prendnisone). Development of severe myelotoxicity (WHO grade 4) despite supportive therapy by granulocyte colony stimulating factors, blood transfusion, and platelets. A new CT scan documented reduction of adenopathies and liver lesions. Rapid worsening of general conditions, fever and dysfagia. CMV DNAemia ( copies/ml) and CMV antigenemia detectable in peripheral blood. Intravenous Ganciclovir started HIV-RNA: 43 copies/ml. CD4 count 72 cells/mm3. Bone marrow aplasia. Death in June 2011.

8 Clinical case Female, 54 years old, heterosexual January 2012 Clinical onset with mild left motor deficit and leukopenia. Discharged with diagnosis of multiple ischemic brain injury by multi infarct encephalopathy March Worsening of neurologic picture. Positive HIV serology CD4+ 5 cells/mm 3 ; HIV-RNA copies/ml. MRI: confluent multifocal cerebral with matter lesions involving occipital white matter. Lumbar puncture: JCV-DNA: copies/ml, CSF HIV-1 RNA: copies/ml (PCR negative for DNA of CMV, HSV, VZV, EBV, T. pallidum, M. tuberculosis) EFV+TDF/FTC started in March Progressive worsening, left emiparesis, dysartria Death in May 2012

9 Adjusted mortality hazard associated with each type of AIDS-defining event (ADE) after initiation of (cart) Mocroft A, et al. For ART-CC, Clin Infect Dis, 2009

10 Causes of death in hospitalized patients. INMI % N. 229 (5,3%) N. 244 (5,8%) N. 191 (4,8%) N. 158 (4,7%)

11 Patients Starting ART at Higher CD4+ Cell Counts Overall, but Disparities Remain CD4+ cell count at start of ART (cells/mm 3 ), 2009 [1] Low income Middle income High income In San Francisco study, overall trends of starting ART at higher CD4+ counts, but patients initiating ART at CD4+ counts > 350 cells/mm 3 significantly more likely to be white, older, MSM, non poor, and diagnosed by private provider [2] 1. Mugglin C, et al. CROI Abstract Truong HH, et al. CROI Abstract 139.

12 Minimally invasive diagnosis of AIDS-PCNSL Antinori A, et al. J Clin Oncol, 1999

13 Early Fungicidal Activity of High-Dose Fluconazole, Voriconazole, and Flucytosine Given in Combination With Amphotericin B for the Treatment of HIV- Associated Cryptococcal Meningitis HIV-associated cryptococcal meningitis is associated with an estimated deaths worldwide per year. Current standard initial therapy consists of amphotericin B (AmB) plus flucytosine (5-FC), but 5-FC remains largely unavailable in Asia and Africa. Alternative, more widely available, and/or more effective antifungal combination treatment regimens are urgently needed. There was no statistically significant difference in EFA between AmB in combination with fluconazole and AmB plus 5-FC for the treatment of HIV-associated cryptococcal meningitis.the EFA of voriconazole in combination with AmB did not differ significantly from the EFA of highdose fluconazole or 5-FC with AmB. Overall mortality was 12% (9 of 78 patients died) at 2 weeks and 29% (22 of 75 patients died) at 10 weeks, with no statistically significant differences among groups. Loyse A, et al. Clin Infect Dis, 2012

14 Lessons from the past

15 Short term CD4 gain after dual nucleoside ART Hammer SM, et al, N Engl J Med, 1996

16 Incidence of Second Virological Failure Declining Over Time 120 RR*: N=30,000 Incidence per 100 Patient-Year REF 70.7 RR*: RR*: RR*: *Adjusted for time from HAART initiation, sex, age, AIDS, CD4+ cell count, HIV-1 RNA level at HAART initiation and switch, and type of HAART. Deeks S, et al. Clin Infect Dis, 2009

17 A syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance in patients receiving HIV protease inhibitors Carr A, et al. AIDS, 1998

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19 why we will never forget