Presented by: Daniel Poe Sana Safeer March 24, 2016 Initiation of Antiretroviral Therapy for Early Asymptomatic HIV Infection Presented by: Daniel Poe Sana Safeer March 24, 2016

HIV Infection/AIDS Epidemiology Global pandemic - cases almost every country Estimated 39 million people have died thus far from AIDS-related illness Estimated 35 million individuals living w/ HIV infection (2013) 95% people living with HIV/AIDS reside in low/middle income countries Approx 50% female, 3.2 million children <15 yo Has been 38% decrease in HIV infection incidence since 2001: prevention efforts and increased ART: less likely to transmit person → person Beginning of pandemic - early 1990’s low/middle income countries - Sub-Saharan Africa, Ukraine, Brazil etc. Fauci A, Lane C. Harrisons Principles of Internal Medicine. 19e. 2015; 226(14):1223-1224

HIV Infection/AIDS Etiology Immune compromise caused by the Human Immunodeficiency Virus (HIV) characterized by loss of CD4+ T cells Rates of HIV-associated complications and death increase as CD4+ T cells in peripheral blood decline Longo DL, et al: Harrison’s Principles of Internal Medicine, 18th Ed: www.accessmedicine.com

Other Clinical Trials - Temprano The TEMPRANO Trial was a trial of early antiretrovirals and Isoniazid preventive therapy in Africa Assessed the benefits of early ART, 6 mos of preventative isoniazid or both in high CD4+ count pts 2056 pts (41% with CD4+ > 500) treated immediately, delayed with or without isoniazid Results of immediate initiation with isoniazid: 44% reduction in risk of severe complications 35% reduction in risk of all cause death Temprano ANRS 12136 Study Group. N Engl J Med. 2015;373:808-22

Initiation of Antiretroviral Therapy in Early Asymptomatic HIV Infection (INSIGHT START) Clinical Question: Is it more beneficial in reducing risk of serious events/death for asymptomatic HIV-positive patients by initiating antiretroviral therapy (ART) when CD4+ count is >500 cells/mm3 or deferring initiation of ART until CD4+ count is ≤ 350 cells/mm3? Objective: Establish the safety and benefit of initiating ART in asymptomatic pts when CD4+ counts are >350 cells/mm3 Note: ART has known benefits in preventing further HIV outbreak by reducing risk of pt infectivity.

Current Recommendations... General practice: Defer ART in asymptomatic pts with a CD4+ count above a certain threshold level. recommended threshold has changed over time recommendations remain inconsistent across various guidelines Current randomized studies assess benefit/risk of treating pts with CD4+ count <500 cells/mm3 CD4+ counts of 200 or 250 cells/mm3 Observational studies determined CD4+ counts of 350 cells/mm3 *RECOMMENDATIONS ARE NONSPECIFIC AND CAN BE IMPROVED!!! INSIGHT START Study Group. N Engl J Med. 2015;373(9):795-807

INSIGHT START Design Multicenter, international, randomized controlled trial n=4,685 treatment-naive HIV-infected patients Immediate initiation of ART (n=2,326) Deferred initiation of ART (n=2,359) Setting: 215 centers across 35 countries Enrollment period: 2009-2013 Mean follow-up: 3.0 years Funding: National Institute of Allergy and Infectious Diseases and others ART meds donated by: AbbVie, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline/ViiV Healthcare, Janssen Scientific Affairs, and Merck. INSIGHT START Study Group. N Engl J Med. 2015;373(9):795-807

Study Design Flowchart 2 study branches: Immediate initiation occured when CD4+ count >500 cells/mm^3 Deferred initiation occured when CD4+ count (<or=) 350 cells/mm^3 Q: Why don’t numbers add up? 2287 + 93 = 2380 patients (54 extra patients!) 1134 + 119 = 1253 (missing 1,106 patients!) In immediate - people may have been added who were initially in deferred therapy because they developed seriousAIDS-related event or other condition (ex: pregnancy) that req’d ART initiation bove 350 cells/mm^3 In deferred - the study had to be cut short on May 26,2015 b/c primary findings had been answered and the board recommended offering ART to pts in deferred branch at that time INSIGHT START Study Group. N Engl J Med. 2015;373(9):795-807

Inclusion/Exclusion Criteria Inclusion Criteria HIV-infected patients Age ≥18 years Antiretroviral treatment-naïve No progression to AIDS Two CD4+ counts >500 cells/mm3, at least 2 weeks apart Exclusion Criteria Pregnant or breastfeeding Diagnosis of AIDS Cardiovascular event within 6 months Dialysis within 6 months History of malignancy History of decompensated liver disease Current imprisonment or compulsory detention for physical or psychiatric disorder Is there anything more from supplemental that we need? INSIGHT START Study Group. N Engl J Med. 2015;373(9):795-807

Initial START treatment therapy options (2009) Next two slides: can explain that the initial therapy for ART was modified over the time period of which this study was conducted, however did not affect study b/c evidence prompting the changes was limited. INSIGHT START Study Group. N Engl J Med. 2015;373(9):795-807

Updated treatment therapy options (2014)

INSIGHT TRIAL Endpoints Primary outcome: composite outcome → combination of: serious AIDS-related events death from AIDS or any other serious AIDS related event such as Hodgkin's Lymphoma serious non–AIDS-related events complications of external diseases such as CV disease, ESRD, liver disease, non-AIDS defining cancer, or death from any of the above and any death not attributable to AIDS. Secondary outcomes: other serious AIDS related or non-AIDS-related events death from any cause grade 4 events unscheduled hospitalizations for reasons other than AIDS. Grade 4 events: potentially life-threatening symptomatic events not attributable to AIDS that required a medical intervention

Follow-up Follow up study visits: Each visit: Each annual visit: At month 1, month 4, then every 4 months thereafter. Each visit: Targeted health history and examination conducted, ART changes and adherence (if relevant) assessed, and CD4+ cell count and HIV RNA levels obtained. Each annual visit: Lipids, liver function tests, glucose and creatinine measured, non-AIDS risk factors assessed, and 12-lead ECG obtained. Mean follow-up time: 3.0 years INSIGHT START Study Group. N Engl J Med. 2015;373(9):795-807

Statistical Analysis Time-to-event methods used: Kaplan-Meier survival curves & Cox proportional-hazards model Primary analysis: Intention-to-treat (ITT) using Cox proportional hazards model with single indicator for tx group Primary Endpoint comparisons: Hazard Ratios & 95% confidence intervals w/ Cox model in all 6 geographic regions Primary endpoint also summarized for subgroups categorized via 8 predefined baseline characteristics Interpret w/ caution b/c no adjustment made for type I error & statistical power limited for subgroup analyses* Intention to treat (ITT) analysis means all patients who were enrolled and randomly allocated to treatment are included in the analysis and are analysed in the groups to which they were randomized Type I error: Incorrect rejection of true null hypothesis Statistical power low: Type II error chance increases (saying no effect of tx group when there is one) INSIGHT START Study Group. N Engl J Med. 2015;373(9):795-807

Statistical Analysis cont... Kaplan Meier curves: used to describe time until initiation of ART Longitudinal mixed models: used to compare changes in both arms from start to follow-up All P values were two-sided Statistical analyses were performed with the use of SAS software version 9.3 (an online program)

Results: Patient Demographics Only 26% patients female when approx 50% of the HIV cases are female IQR = Interquartile range

Results: Primary Endpoint Overall composite primary endpoint: Occurred in 42 pts in immediate-initiation group Occurred in 96 pts in the deferred-initiation group Q: Based on results, primary composite endpoint significant? *Majority of primary events occurred when CD4+ count >500 cells/mm^3 37/42 & 57/96 Hazard Ratio: The hazard ratio is an expression of the hazard or chance of events occurring in the treatment arm as a ratio of the hazard of the events occurring in the control arm. Therefore if it is below 1, more likely to happen in the control arm, if above 1, more likely to happen in the treatment arm

INSIGHT START Study Group. N Engl J Med. 2015;373(9):795-807

Results: Primary Endpoint Components Significant primary endpoint components contributing to the primary composite endpoint were as follows: Serious AIDS-related event 0.28 (95% CI 0.15-0.50, p= <0.001) Serious non-AIDS related event 0.61 (0.38-0.97), p= 0.04

Results: Secondary Endpoints Significant secondary endpoints were as follows: Tuberculosis 0.29 (0.12-0.73, p= 0.008) Kaposi’s Sarcoma 0.09 (0.01-0.71, p=0.02) Bacterial infectious disorder 0.38 (0.20-0.70, p= 0.002) Grade 4 event, unscheduled hospitalization, or primary endpoint 0.82 (0.71-0.96), p= 0.01

Results: Subgroup Analysis Subgroups according to characteristics at study entry (demographic measures/other risk factors) were created for serious AIDS-related and serious non-AIDS related disease. Immediate initiation group favored across all subgroups. Q: From what you can see, are these the only insignificant results from this subgroup analysis? No! All of the p values are above 0.05 because no adjustment made for type I error & statistical power limited

Results: Summary Benefit of immediate initiation of ART evident compared to deferred initiation of ART in terms of serious AIDS-related (72% relative reduction) and serious non-AIDS-related (39% relative reduction) events. No increased rate of adverse effects associated with immediate ART initiation No evidence that beneficial effect of immediate ART differed according to age, sex, race, region of world, CD4+ count, viral load, or risk factors for serious non-AIDS-related diseases *Anticipated rate of non-AIDS-related events was lowered than anticipated however (52% vs expected 77%) INSIGHT START Study Group. N Engl J Med. 2015;373(9):795-807

Author’s Discussion Benefit of immediate ART over deferred ART quantified & safety assessed across various outcomes In addition to previous studies indicating ART reduces risk of sexual transmission of HIV, these results provide policymakers, clinicians and HIV positive patients with data to be informed regarding proper initiation of antiretroviral therapy. The findings possess global relevance: study conducted in 215 clinics/35 countries AIDS/non-AIDS events still a possibility even though ART improved CD4+ counts, indicating the need for better markers of impaired immune function and earlier diagnosis along with increased research for treatments to use along with ART INSIGHT START Study Group. N Engl J Med. 2015;373(9):795-807

Class Discussion: Strengths Large trial (4685 individuals) Funding: Funded by the National Institute of Allergy and Infectious Disease ART medications were donated by various companies Multiple sites on an international level Culturally very diverse Generalizable (many different races/ethnicities/countries) Success in answering the trial’s main clinical question Others?

Class Discussion: Limitations Mean follow-up of 3 years is a short period to assess risks and benefits of chronic ART ….important to assess long term therapy for chronic ART users Early termination of deferred initiation ART arm The effects of immediate initiation ART on arterial disease and serious non-AIDS related serious events were lower than anticipated Both of these factors may have contributed to a lower statistical power Lower amount of female patients in the study Could have been larger proportion of African American pts (most prevalent race for HIV) Others? Lower statistical power does not accurately quantify benefit*

Class Discussion: Statistics Primary composite outcome and primary outcome components were all valid (HR below 1, 95% CI between 0 and <1, p-values below 0.05) Many secondary outcomes were insignificant Subgroup analyses was not adjusted for error and therefore is unreliable

Author’s Conclusion In HIV infected pts (CD4+ counts >500 cells/mm3) early ART initiation reduced serious AIDS-related & non-AIDS-related complications compared to delayed ART initiation (CD4+ counts ≤ 350 cells/mm3) Clinical significance: Recommend immediate initiation of ART in patients with HIV infection regardless of CD4+ count. These results align individual patient benefit from immediate ART with general public health benefits from immediate ART (reduced risk of transmitting infection). Findings reinforce need for health systems to improve programs to diagnose HIV infection and quickly link patients to care.

Class Discussion: Learner Conclusions Statistical Impact: Statistical analysis was performed correctly Results in primary outcomes were significant This trial clearly statistically showed that immediate initiation of ART is beneficial over deferred initiation of ART Clinical Impact: This trial has the potential to change practice - AIDS-related events ranging from Hodgkin's lymphoma to death are decreased with immediate ART initiation Non-AIDS-related events ranging from liver disease complications to death due to cancer are decreased with immediate ART initiation Pts may still need to weigh multiple factors before committing to immediate lifelong ART however (religious beliefs, costs)

Class Discussion: Future Studies? Possible Future Studies? Study design with more women Longer study period to determine longer term effects for pts who will require lifelong ART Conduct a proper subgroup analysis in which adjustment for type I error is made and a greater statistical power is achieved (eliminate type II error)

QUESTIONS? ? ? ?

References 1. Fauci A, Lane C. Harrisons Principles of Internal Medicine. 19e. 2015; 226(14):1223-1224 2. Longo DL, et al: Harrison’s Principles of Internal Medicine, 18th Ed: www.accessmedicine.com 3. Temprano ANRS 12136 Study Group. N Engl J Med. 2015;373:808-22 4. INSIGHT START Study Group. N Engl J Med. 2015;373(9):795-807