1. 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

2. 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):

3. 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:

4. 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 Study Group. N Engl J Med. 2015;373:808-22

5. 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.

6. 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):

7. 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:
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):

8. 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?
= 2380 patients
(54 extra patients!)
= 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):

9. 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):

10. 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):

11. Updated treatment therapy options (2014)

12. 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

13. 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):

14. 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):

15. 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)

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

17. 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

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

19. 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 , p= <0.001)
Serious non-AIDS related event 0.61 ( ), p= 0.04

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

22. 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

23. 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):

24. 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):

25. 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?

26. 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*

27. 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

28. 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.

29. 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)

30. 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)

31. QUESTIONS? ? ? ?

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