THE IMPORTANCE OF EARLY DETECTION IN THE DIAGNOSIS AND PREVENTION OF HIV INFECTIONS DR. GUILLEMO M. RUIZ-PALACIOS PROFESSOR AND HEAD DEPARTMENT OF INFECTIOUS DISAEASES NATIONAL INSTITUTE OF MEDICAL SCIENCES & NUTRITION MEXICO

Case Presentation Reasons for consultation: 17 y/o male - 3 wks with fever and malaise Skin rash and symmetrical lymphadenopathy Persistent fever despite multiple previous antibiotic treatments

Case Presentation History High school student Uncle diagnosed with TB 3 years ago Alcohol abuse during weekends Denies drug abuse Initiates unprotected sex at 14 years 3 heterosexual partners, not sex workers Hx of gonorrhea 1 year before

Case Presentation Physical exam on admission BP 120/70 mm Hg, R 90 beats/min, R 20 breaths/min, Temp. 39ºC cervical lymphadenopathy, no rash Laboratory CXR normal Lymph biopsy: reactive hyperplasia Blood cultures: Negative 3x

Case Presentation Serology HIV 3th Generation EIA: NEGATIVE Brucella Total Ig: NEGATIVE Epstein Barr: EBNA Ig (+), VCA IgG (+), VCA IgM (-), CMV: IgG(+) IgM(-)

HIV Serology 27.3 P -- 3.30 15 may 33.7 P 2.65 9 may 0.74 N 4 may 1.80 0.41 2 may Ab Ag Date 3th Gen. P.C. = 1.0 4th Gen. P.C.=0.25

Acute Infection Seroconversion by Western Blot GP160 ► GP110/120 ► Acute Infection Seroconversion by Western Blot 1st sample (May 2) taken 3wks after initiation of symptoms POL68 ► GAG55 ► POLP52 ► GP41 ► GAG40 ► POL34 ► GAG25 ► GAG18 ►

anti-HIV Ab by Western – Blot HIV markers of Acute infection 11-12 14-15 20-21 28-29 Time (days) Viral RNA Ab Level of detection P24 antigenemia HIV RNA anti-HIV Ab by EIA Window anti-HIV Ab by Western – Blot Acute Infection P 24

Serologic Diagnosis of HIV

Detection delay in recognition of HIV infection relative to NAT (days) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23

Detection of Acute Infections during HIV Testing in North Carolina Pilcher C et al. N Engl J Med 2005;352:1873-1883

Prevalence of HIV Infection in a General Testing Population , According to Disease Stage Prevalence of HIV ( no. /1000) No. at Risk Acute Recent Ab Established HIV All Subjects 109,250 0.2 1.0 5.3 Man who has sex with men 3,777 1.9 9.8 45.0 Victim of sexual assault 0.7 0.7 1.4 Presence of STD 21,968 0.3 0.5 3.3 Has a sex partner at risk 19,975 0.1 1.2 7.1 Heterosexual contact 35,647 0.03 0.5 2.9 Does not have an acknowledged sex partner 12,715 0 0.4 1.6

Frequency of Newly Diagnosed HIV Infections According to Type of Testing Site and Stage of Disease Pilcher, C. et al. N Engl J Med 2005;352:1873-1883 Pilcher C et al. N Engl J Med 2005;352:1873-1883

Flow chart of the study population of the Malawi Acute HIV Infection Study J Infect Dis 2007;195:416-24

Prevalence of Established and Acute HIV Infection in a STD Clinic in Malawi Population Established HIV Infection Acute HIV Infection 1450 588 ( 40.5 %) 21 (1.45 %)

Sensitivity and specificity of rapid tests and p24 antigen assays for the detection of acute HIV infection True Positive, no. True negative, no. False Positive, no. False negative, no. Sensitivity, % (95 % CI) Sensitivity, % (95 % CI) Test Discordant rapid 7 827 14 14 33 (15-57) 98 (97-99) Standard p24 antigen 12 682 3 4 75 (48-93) 99.6 (97-100) Up24 antigen 15 82 0 2 88 (64-99) 98 (96-100) Note: CI, confidence interval; Up24, ultrasenitive p24

Rates of Positivity for HIV-1 for HIV Among Blood Donors RNA-Positive Donations Blood Donors Total No. Rate per 106 Donation (95% CI) Ratio of First-Time Donors To repeat Donors (95% CI) HIV-1 Total 37,164,054 12 0.32 ( 0.17 – 0.56 ) Otherwise tranfusable 36,792,000† 10 0.27 ( 0.13 – 0.50 ) First-time 8,178,000‡ 6 0.73 ( 0.24 - 1.81 ) 4.1 (1.0-17.0)§ Repeat 27,692,000‡ 5 0.18 ( 0.06 - 0.43 ) † Ninety-nine percent of donations were assumed to be transfusable (nonreactive on all screening tests and suitable for transfusion) ‡ A total of 22.8 percent of donations were assumed to be from first-time donors and 77.3 percent from repeat donors. § If calculations were restricted to RNA-positive donations that were nonreactive to HIV-1 p24 antigen, the rates were 0.49 per million first-time donors (95 percent confidence interval, 0.12 to 1.41) and 0.18 per million repeat donors(95 percent confidence interval, 0.6 to 0.43), resulting in ratio of 2.7 (95 percent confidence interval, 0.5 to 12.7).

Residual risk of tansfusion-tansmitted viral infections by period of time, France, 1992-2003

Residual risk of tansfusion-tansmitted viral infections by period of time, France, 1992-2003

Effect of Early Identification of HIV Infection on Life Expectancy Figure 1. Effect of Early Identification of HIV Infection on Life Expectancy. The solid line represents the effect on life expectancy of identifying asymptomatic HIV infection, as compared with symptom-based case finding. The dashed line represents the effect on quality-adjusted life expectancy. Sanders G et al. N Engl J Med 2005;352:570-585

Cost-effectivness of screening for HIV Sensitivity Analysis of the Effect of the Prevalence of Unidentified HIV on the Incremental Cost-Effectiveness of One-Time Screening, as Compared with Current Practice (Panel A) Effect of Screening Frequency on the Incremental Cost-Effectiveness of Screening at Various HIV Incidence Rates (Panel B) Sanders G et al. N Engl J Med 2005;352:570-585

Cost-Effectiveness in HIV Screening of Blood Donation in Ghana ICER= Incremental cost-effectivness ratio Van Hulst M et al. Value in Health, 2008 on line

Cost-Effectiveness of HIVCTR Strategies in the High-Risk Population Scenario Figure 1. Cost-Effectiveness of HIVCTR Strategies in the High-Risk Population Scenario. Net program costs are depicted on the horizontal axis and health benefits, measured in quality-adjusted life-months, on the vertical axis. The stand-alone diamond ({diamondsuit}) in the lower left represents the result of current practices for the detection of HIV by means of either background testing of patients or testing of patients who present with an opportunistic infection. The points depict cost and benefit outcomes for enzyme-linked immunosorbent assay (ELISA) and rapid testing at various frequencies: one time (denoted with an X) and every five years, three years, and one year. The slopes of the lines connecting these points represent incremental ratios of effectiveness to cost. The flattening of these lines illustrates the diminishing marginal returns with increased investment in higher-frequency testing. Paltiel A et al. N Engl J Med 2005;352:586-595

Conclusions Early diagnosis of HIV infection is beneficial for the patient’s health. Early diagnosis can be achieved through: -Expanded screening programs in the general population - The use of new diagnostic methods including: (1) nucleic acid testing (NAT) or (2) the dual ultrasensitive antibody-antigen assays. Early diagnosis of acute infection plays an important role in transmission control and is a cost-effective intervention.

CONFIDENTIAL - to be presented at ICAAC, New-Orleans, Sept 21-24 2005 In the next few years, we may see some light on the control of HIV transmission with the new strategies for the diagnosis of early infection CONFIDENTIAL - to be presented at ICAAC, New-Orleans, Sept 21-24 2005