Journal ClubAUGUST 2015

Dr Prageeth Premadasa

IntroductionSTART – Strategic timing of ART

•The immune compromise caused by HIV is characterized by a loss of CD4 T cells.

•It has been the general practice to defer the initiation of ART in asymptomatic patients with a CD4 count above a certain threshold.

•The CD4 threshold has changed over time and recommendations remain inconsistent across various guidelines

• Over the years most of the RCTs assessed the benefits and risks of initiating ART enrolling patients with a CD4 count of less than 500 cells/mm3.

•Therefore evidences for initiating ART in patients with higher CD4 counts were limited.

•Furthermore most studies have focused only on the risks of the AIDS and death and have not fully addressed the risks and benefits of initiating antiretroviral therapy in patients with a high CD4+ count, in whom complications and death are largely attributed to non–AIDS-related events.

•It is important to establish whether it is safe and beneficial to initiate ART in asymptomatic patients who have a CD4+ count that is much higher than 350 cells per cubic millimeter

Objective•To determine the risks and benefits of the immediate initiation of antiretroviral therapy in asymptomatic HIV-positive patients who have a CD4+ count of more than 500 cells/mm3, as compared with deferring initiation until the CD4+ count is 350 cells/mm3.

•Initiation of ART - (experiment/intervention)

•Immediate vs late - (Random allocation)

•Determine the risks and benefits

Suitable study design

•Interventional

•Experimental

•Random allocation

Randomized control trial

Methods

•A multi continental randomized study.

•35 countries

•215 sites

•Sample : 4685 patients

START Clinical sites and enrolment by continent

Randomized controlled trial

Methods – Study population

Eligibility criteria:

Inclusion criteria◦ >18years◦ ART Naïve◦ No history of AIDS◦ Generally good health ◦ Two CD4 cell counts > 500

cells/mm3 (at least 2 weeks apart within 60 days )

Exclusion criteria• Pregnant and breast

feeding women

Methods – Study design

4685 HIV +ve adults with CD4 cell count >500 cells/mm3

Randomization

Immediate ART group (n=2326)

Deferred group (n=2359) till cd4 declined to 350cells/mm3 or

development of an AIDS related event or another condition that

dictated the use of ART

Methods – Study end points

4685 HIV +ve adults with CD4 cell count >500

cells/mm3Randomization

Immediate ART group (n=2326)

Deferred group (n=2359)

Primary end pointsTwo major components1. Any serious AIDS-related

event, which included death from AIDS or Any AIDS-defining event (except non fatal HSV or esophageal candidiasis )

2. Any serious non–AIDS-related event, including death from causes other than AIDS (CVS events ,ESRD, liver disease etc.) or non AIDS defining cancer and any death not attributable to AIDS

Follow up

Methods – Study end points

Secondary end points• Serious AIDS related events, • Serious non–AIDS-related events,• Death from any cause, grade 4 events, and• Unscheduled hospitalizations for reasons other than AIDS(Grade 4 events were defined as potentially life-threatening symptomatic events not attributable to AIDS that required a medical intervention)

Clinical end points ?

•In a clinical research trial, a clinical endpoint generally refers to occurrence of a disease, symptom, sign or laboratory abnormality that constitutes one of the target outcomes of the trial, but may also refer to any such disease or sign that strongly motivates the withdrawal of that individual or entity from the trial, then often termed humane (clinical) endpoint.

•The primary endpoint of a clinical trial is the endpoint for which subjects are randomized and for which the trial is powered.

•Composite primary end points -used to overcome the difficulties associated with designing a study around a single event of interest (e.g. death)

•Secondary endpoints are endpoints that are analyzed post hoc, for which the trial may not be powered nor randomized. These are additional events of interest, but which the study is not specifically powered to assess

Methods – Statistical analysis•Compared the two study groups according to the intention-to-treat principle

•Used time-to event methods, including Kaplan–Meier survival curves and Cox proportional-hazards models, to compare the two groups for the primary end point, its two major components, death from any cause, and other serious clinical events.

•Follow-up was censored on May 26, 2015, or the date of last study contact.

•For the primary end point, hazard ratios and 95% confidence intervals were estimated from a Cox model stratified according to six geographic regions (Africa, Europe and Israel, North America, South America and Mexico, Australia, and Asia) with a single binary indicator (immediate vs. deferred therapy).

Intention to treat analysis•Randomized controlled trials often suffer from two major complications• noncompliance

• missing outcomes.

• One potential solution to this problem is a statistical concept called intention-to-treat (ITT) analysis. ITT analysis includes every subject who is randomized according to randomized treatment assignment. It ignores noncompliance, protocol deviations, withdrawal, and anything that happens after randomization. ITT analysis maintains prognostic balance generated from the original random treatment allocation.

•ITT analysis avoids overoptimistic estimates of the efficacy of an intervention resulting from the removal of non-compliers by accepting that noncompliance and protocol deviations are likely to occur in actual clinical practice

Time-to event methods, Kaplan–Meier survival curves and Cox proportional-hazards models.

•They are known generically used to express survival data in statistics

Time – to event methods

•Survival analysis is generally defined as a set of methods for analyzing data where the outcome variable is the time until the occurrence of an event of interest. The event can be death, occurrence of a disease, marriage, divorce, etc. The time to event or survival time can be measured in days, weeks, years, etc. For example, if the event of interest is heart attack, then the survival time can be the time in years until a person develops a heart attack.

Kaplan–Meier survival curves

•Kaplan-Meier estimate is one of the best options to be used to measure the fraction of subjects living for a certain amount of time after treatment. In clinical trials or community trials, the effect of an intervention is assessed by measuring the number of subjects survived or saved after that intervention over a period of time. The time starting from a defined point to the occurrence of a given event, for example death is called as survival time and the analysis of group data as survival analysis.

Cox proportional-hazards models.

•A popular model used in survival analysis that can be used to assess the importance of various covariates in the survival times of individuals or objects through the hazard function. In addition, the quantitative impact of these variables on important lifetime variables of interest (such as median survival) can be described.

Hazard ratio•In survival analysis, the hazard ratio (HR) is the ratio of the hazard rates corresponding to the conditions described by two levels of an explanatory variable.

•For example, in a drug study, the treated population may die at twice the rate per unit time as the control population. • The hazard ratio would be 2, indicating higher hazard of death from the treatment.

•Or in another study, men receiving the same treatment may suffer a certain complication ten times more frequently per unit time than women, giving a hazard ratio of 10.

Results – Study patients•The median age was 36 years, and 27% of the patients were women.

•The median CD4+ count was 651 cells per cubic millimeter.

•The median HIV RNA viral load was 12,759 copies per milliliter.

Results – Follow up

•The mean follow-up time was 3.0 years, and the median was 2.8 years (interquartile range, 2.1 to 3.9); 23% of the patients were followed for more than 4 years.

•On May 26, 2015, the status with regard to the primary end point was unknown (which was defined as a lack of contact for at least 10 months) for 93 patients (4.0%) in the immediate-initiation group and 119 (5.0%) in the deferred-initiation group

•Patients received antiretroviral therapy for 94% of the total follow-up time accrued in the immediate- initiation group and for 28% in the deferred-initiation group.

•The median time until the initiation of antiretroviral therapy in the deferred-initiation group was 3 years

Kaplan–Meier survival curves

Results •A total of 4685 patients were followed for a mean of 3.0 years.

•At study entry, the median HIV viral load was 12,759 copies per milliliter, and the median CD4+count was 651 cells per cubic millimeter.

• On May 15, 2015, on the basis of an interim analysis, the data and safety monitoring board determined that the study question had been answered and recommended that patients in the deferred-initiation group be offered antiretroviral therapy.

• The primary end point occurred in 42 patients in the immediate-initiation group (1.8%; 0.60 events per 100 personyears),as compared with 96 patients in the deferred-initiation group (4.1%; 1.38events per 100 person-years), for a hazard ratio of 0.43 (95% confidence interval [CI], 0.30 to 0.62; P<0.001).

• Hazard ratios for serious AIDS-related and serious non–AIDS-related events were 0.28 (95% CI, 0.15 to 0.50; P<0.001) and 0.61 (95% CI, 0.38 to 0.97; P = 0.04), respectively.

•More than two thirds of the primary end points (68%) occurred in patients with a CD4+ count of more than 500 cells percubic millimeter.

•The risks of a grade 4 event were similar in the two groups, as were the risks of unscheduled hospital admissions

Results

•Drugs that were primarily used for initial treatment in the immediate-initiation group and the deferred-initiation group were tenofovir (89% in the two groups), emtricitabine (89% and 88%,respectively), and efavirenz (73% and 51%, respectively)

Results •The percentage of patients who had an HIV RNA level of 200 copies per milliliter or less during follow-up mirrored the percentage who were receiving antiretroviral therapy

Results – End pointsThe composite primary end point was reported in 42 patients in the immediate-initiation group and in 96 in the deferred-initiation group

Results – End points

Conclusions•In designing this study, they hypothesized that immediate antiretroviral therapy would have a greater benefit for serious AIDS-related events than for serious non–AIDS-related events.

•The 72% relative reduction in serious AIDS-related events in the immediate-initiation group◦ Tuberculosis

◦ Kaposi’s sarcoma

◦ malignant lymphomas,

•39% relative reduction in serious non–AIDS related events was largely due to non–AIDS-defining cancers.

.

Conclusions•The initiation of antiretroviral therapy in HIV-positive adults with a CD4+ count of more than 500 cells per cubic millimeter provided net benefits over starting such therapy in patients after the CD4+ count had declined to 350 cells per cubic millimeter.

•In this study, the benefit of immediate antiretroviral therapy over deferred therapy was quantified, and safety was assessed across various outcomes, including a diverse set of non-AIDS conditions.

•Study results indicate that antiretroviral therapy should be recommended for patients in whom HIV has been diagnosed regardless of the CD4+ count.

Conclusions•The risk of AIDS was not zero among patients receiving antiretroviral therapy, even among those who had full viral suppression while receiving antiretroviral drugs. This finding indicates that damage to the immune system may occur early in the course of HIV infection

Limitations•The percentage of primary events that were attributable to serious non–AIDS-related conditions was lower than anticipated (54% vs. 77% projected), which, combined with the early termination of the deferred-therapy strategy, resulted in a low statistical power to precisely quantify benefit.

•This factor limits their understanding of the effects of immediate therapy on the risk of individual serious non-AIDS conditions such as cardiovascular disease, for which reductions might be anticipated because of reductions in coagulation and inflammatory markers.

•Finally, although they conducted a relatively long study of HIV treatment, 3 years is a rather short period for patients who will require antiretroviral therapy for the rest of their lives. It will be important to assess risks and benefits of long-term therapy

Critical appraisalCritical appraisal is the process of carefully and systematically examining research to judge its trustworthiness, and its value and relevance in a particular context. (Burls 2009)

Impact factor

0.00Ceylon medical journal

Digital object identifierDOI : Digital Object Identifier (unique character string use to identify an electronic document like URL for a specific website), All DOI numbers begin with a 10 and contain a prefix and a suffix separated by a slash.

The prefix is a unique number of four or more digits assigned to organizations; the suffix is assigned by the publisher and was designed to be flexible with publisher identification standards.

Published on July 20, 2015, at NEJM.org.DOI: 10.1056/NEJMoa1506816

•Original articles

•Review articles

•Case reports

•Commentaries

•Editorials

•Letters (to the editor)

Types of papers in a medical journal

Original article•Most important type of paper.

•It provides new information based on original research.

•Conclusions should be supported by the data provided in the results

•Should consist of the following headings: structured abstract, Introduction, Methods, Results and Discussion (IMRAD).

Published on July 20, 2015, at NEJM.org.DOI: 10.1056/NEJMoa1506816

The members of the writing group (Jens D. Lundgren, M.D. [cochair], Abdel G.Babiker, Ph.D. [cochair], Fred Gordin,M.D. [cochair], Sean Emery, Ph.D., Birgit Grund, Ph.D., Shweta Sharma, M.S., Anchalee Avihingsanon, M.D., David A.Cooper, M.D., Gerd Fätkenheuer, M.D.,Josep M. Llibre, M.D., Jean-Michel Molina, M.D., Paula Munderi, M.D., Mauro Schechter, M.D., Robin Wood, M.D.,Karin L. Klingman, M.D., Simon Collins, H. Clifford Lane, M.D., Andrew N. Phillips,Ph.D., and James D. Neaton, Ph.D.[INSIGHT PI]) of the INSIGHT START Study Group assume responsibility for the overall content and integrity of this article.

Contributions to the Design, Conduct and Reporting of the START Study

• The three Co chairs : Jens D. Lundgren, M.D. , Abdel G.Babiker Ph.D. , Fred Gordin, M.D.

•Other study group members :Sean Emery, Ph.D., Birgit Grund, Ph.D., Shweta Sharma, M.S., AnchaleeAvihingsanon, M.D., David A. Cooper, M.D., Gerd Fätkenheuer, M.D.,Josep M. Llibre, M.D., Jean-Michel Molina, M.D., Paula Munderi, M.D., Mauro Schechter, M.D., Robin Wood, M.D., Karin L. Klingman, M.D., Simon Collins, H. Clifford Lane, M.D., Andrew N. Phillips, Ph.D., and James D. Neaton, Ph.D. [INSIGHT PI]) of the INSIGHT START Study Group assume responsibility for the overall content and integrity of this article.

•Sub study Chairs:

•The three unblinded START statisticians : Drs Grund, Phillips and Ms Sharma

•Central Drug Repository and Drug Distribution:

•Network Laboratory Group & Specimen Repositories :

•Data and Safety Monitoring Board:

•Members from international coordinating centers ( 35 countries): Argentina, Australia, Austria, Belgium, Brazil,Chile, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, India, Ireland, Israel, Italy,Luxembourg, Malaysia, Mali, Mexico, Morocco, Nigeria, Norway, Peru, Poland, Portugal, South Africa, Spain,Sweden, Switzerland, Thailand, Uganda, United Kingdom, United States

Co chairpersons

Title

Initiation of Antiretroviral Therapy in Early

Asymptomatic HIV Infection

What is missing ?

• Location of the study ?

• Population of the study ?

• Early Asymptomatic HIV infection ?

Initiation of Antiretroviral Therapy in EarlyAsymptomatic HIV Infection

Objective•To determine the risks and benefits of the immediate initiation of antiretroviral therapy in asymptomatic HIV-positive patients who have a CD4+ count of more than 500 cells per cubic millimeter, as compared with deferring initiation until the CD4+ count is 350 cells per cubic millimeter.

Does the study test a stated objectives?

Hypotheses •It is safe and beneficial to initiate antiretroviral therapy in asymptomatic patients who have a CD4+ count that is much higher than 350 cells per cubic millimeter

Literature evaluation

Literature evaluation

•Is the study question relevant?

•Does the study add anything new?

•What type of research question is being asked?

Is the study question relevant?Effects of Antiretroviral Therapy on HIV-Related Morbidity

HIV-associated immune deficiency, the direct effects of HIV on end organs, and the indirect effects of HIV-associated inflammation on these organs all likely contribute to HIV-related morbidity and mortality. In general, the available data demonstrate the following:

• Untreated HIV infection (ongoing viral replication) may have negative effects at all stages of infection.

• Earlier treatment may prevent the damage associated with HIV replication during early stages of infection.

• ART is beneficial even when initiated later in infection; however, later therapy may not repair damage associated with viral replication during early stages of infection.

• Sustaining viral suppression and maintaining higher CD4 count levels, mostly as a result of effective combination ART, may delay, prevent, or reverse some non-AIDS-defining complications, such as HIV-associated kidney disease, liver disease, CVD, neurologic complications, and malignancies, as discussed below.

Does the study add anything new?

CD4 > 500

What type of research question is being asked?

•Questions about the effectiveness of treatment

•Starting treatment early is better than early in terms of clinical effectiveness.

Study designStudy question

whether it is safe and beneficial to initiate antiretroviral therapy in asymptomatic patients who have a CD4+ count that is higher than 500 cells per cubic millimeter?

Selected study design mentioned:

Multicontinental randomized study

Comment:

•Due to the nature of the study (not a placebo controlled ), investigators and participants were not blinded to the treatment group assignment.

•However, endpoints were reviewed blinded to treatment group.

Methods – Study populationEligibility criteria:

Inclusion criteria◦ >18years

◦ ART Naïve

◦ No history of AIDS

◦ Generally good health

◦ Two CD4 cell counts > 500 cells/mm3 (at least 2 weeks apart within 60 days )

Exclusion criteria◦ Pregnant and breast feeding women

◦ Generally good health not defined

Sample size•It was projected that 4,600 participants would be required to reliably address the primary study question.

•This was based on estimates of the expected event rates for the composite primary outcome and its major components (Serious AIDS and Serious non-AIDS) in the immediate and deferred ART groups.

•These estimates were obtained using data from a large observational dataset (CASCADE collaboration ) and data from START on baseline CD4+ counts and pooled event rates (for both treatment groups combined) obtained at the time of sample size re-estimation, together with computer simulations that account for the distribution of CD4+ cell counts projected for START during follow-up.

•Could achieved the estimated sample size

End points

Appropriate end points designed

Ethical clearance• The study was approved by the institutional review board or ethics

committee at each participating site, and written informed consent was obtained from all patients.

Results-Sample

•A multi continental randomized study.•35 countries•215 sites•Sample : 4685 patients

•Median age 36 (29-44) – only young patients considered•Race/ethnic groups not equal•Some countries shows over representation•Non smokers – only 1496 (31%)•The median age was 36 years, and 27% of the patients were women.

Results -End points

•Secondary end points•Unscheduled hospital admissions

•Not defined•Subjective

Results

•A total of 4685 patients were followed for a mean of 3.0 years.

•Adequate ?

Results

•The primary end point occurred in 42 patients in the immediate-initiation group (1.8%; 0.60 events per 100 person years),as compared with 96 patients in the deferred-initiation group (4.1%; 1.38events per 100 person-years), for a hazard ratio of 0.43 (95% confidence interval [CI], 0.30 to 0.62; P<0.001).

• Hazard ratios for serious AIDS-related and serious non–AIDS-related events were 0.28 (95% CI, 0.15 to 0.50; P<0.001) and 0.61 (95% CI, 0.38 to 0.97; P = 0.04), respectively.

Study procedure - Analysis•Intention-to-treat principle

•Time-to event methods, Kaplan–Meier survival curves

Cox proportional-hazards models, to compare the two groups for the primary end point.

Follow up •These risk factors were used to estimate the Framingham risk of coronary heartdisease (CHD)

The Framingham Risk Score is a gender-specific algorithm used to estimate the 10-year cardiovascular risk of an individual.

• Study was conducted for 3 years

•The Framingham Risk Score predicts only future coronary heart disease (CHD) events, however, it does not predict future total cardiovascular events, meaning that it does not predict risk for stroke, transient ischemic attack (TIA), and heart failure

•The Framingham Risk Score could overestimate (or underestimate) risk in populations other than the US population

•Systematic COronary Risk Evaluation (SCORE)/Reynolds Risk Score

Follow up A 12-lead resting electrocardiogram (ECG) was also obtained by the majority of participating sites

Not all

Follow up - DrugsDrug supply

Same brand for all continents ? (not mentioned)

Recommendation•Our findings reinforce the need or health systems to improve programs to diagnose IV infection and link such patients to care.

•The results support global goals set by the World Health Organization and the Joint United Nations Programme on HIV/AIDS to expand the use of antiretroviral therapy to all HIV-positive patients in order to improve their health and as part of efforts to reduce the future spread of HIV

Thank you