Drug trials in HIV & future practice in Sri Lanka

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Drug Trials in HIV and Future Practice in Sri Lanka

Dr Thilani Ratnayake Consultant Venereologist STD Clinic Gampaha

Clinical Trials ď‚—

Research in volunteers to find answers to specific health questions.

ď‚—

Determine the safety and efficacy of a medical intervention (Drug, diagnostic test, treatment protocol)

Clinical Trials (cont’d) 

Best evidence for clinical practice

But the evidence always depend on ◦ Trial design ◦ Inclusion and exclusion criteria ◦ End points

Types of Clinical Trials Preventive trials  Treatment trials to test new treatment or existing treatment  Diagnostic trials  Screening trials  Quality of life trials  Compassionate use trials 

Randomized Clinical Trials(RCT) ď‚—

Considered as the gold standard for a clinical trial to test the efficacy and effectiveness of a drug in a patient population

Types of RCT 

By the study design ◦ ◦ ◦ ◦

Parallel (Most common) Cross over Cluster Factorial

By the Outcome ◦ Explanatory - (Test efficacy) in research levels, more controlled and in highly selected ◦ Pragmatic - Effectiveness more flexible, in everyday practice

By Hypothesis ◦ Superiority trials ◦ Non inferiority trials ◦ Equivalence trials

Superiority Trials ď‚—

Demonstrate that new treatment is more effective than a current treatment.

ď‚—

By establishing a statically significant difference in efficacy between arms.

Non Inferiority Trials 

Demonstrates that there is no important loss of efficacy by replacing a established treatment with a new treatment

Use full in introducing new drugs with ◦ less toxicity ◦ less cost ◦ Simple regimens

Without loosing the effectiveness by predefined percentage

Non inferiority margin Non inferiority margin is what is considered to be clinically unimportant difference in efficacy(or how much loss in efficacy is tolerated)  It’s important to decide the non inferiority margin at design level.  Smaller the margin better or strict hurdle for the new treatment 

RCT in ART 

Usually parallel, superiority or inferiority trials

Most ART trials are carried out by leading pharmaceutical companies.

Main aim is to obtain license

Are these trials ideal, for getting information necessary in real clinical practice?

Missing something? Why?

Common Limitations in ART Trials Short duration ◦ 24wks, 48wks  

Could be related to end points. most trials use biochemical end points. If clinical end points are not considered, may be missing important clinical out comes.

In real clinical practice to decide on which drugs to start with or switch need longer time trials looking at clinical out comes.

End Points in ART trials 

Virological/immunological/clinical

Most ART trials use viral load measurements

Defined as number, achieved viral suppression(<50 RNA copies/ml) in pre determined time(24wks, 48wks)

Cont… 

Some consider whether virological failure has occurred by certain time point. (i.e. Two consecutive values above 50 RNA copies)

Time to Loss of Virological Response (TLOVR)

TLOVR can be fulfilled early (Before 48wks) but then can achieve less than 50 RNA copies at 48 wks.

Lack of Data on outcome in people who changed from the original regimen ď‚—

Effects of some drugs could be long time after it has been stopped

ď‚—

Can be wrongly interpreted as due to new drug (e.g. viral resistance, Toxicities

Drop Outs ď‚—

If certain number of patients drop out ,it can be a source of bias for the outcome.

ď‚—

Reasons for drop out could be related to drug efficacy, toxicity, pill burden, length of follow up etc.

How to Overcome the Problems ď‚—

To have several end points. Combination of biochemical and clinical end points

ď‚—

Use of different approaches to handle missing data in the design and in analysis

Cont…. 

including all enrolled patients in the analysis according to the treatment arms they enrolled even if they did not complete the treatment called the Intent To Treat principle

Assign all pts with missing out come as achieved <50 RNA copies, called Missing Equals Failure MEF (NC=F)approach

Trials that do not consider data outcome failures and ignore their outcomes in the analysis phase, do not provide the type information necessary for everyday clinical practice.

ART for future use in Sri Lanka ď‚—

Need new drugs -for treatment experienced patients who are failing on current regimen.

ď‚—

Replace drugs with side effects to less side effects

What are the Options? 

Raltigravir

New PIs (Atazanavir, Darunavir)

Efavirence in different dose

Why Raltigravir? 

Is a integrase inhibitor

Raltegravir administered as one 400-mg pill BID without regard to food  No effect on lipids  Raltegravir metabolized by glucuronidation ◦ May have fewer interactions with drugs metabolized by cytochrome P450 

1. Raltegravir package insert. 2. Wenning LA, et al. ICAAC 2006. Abstract A-0374.

What are evidence from clinical trials?

Use in a failing regimen

BENCHMRK-1 and BENCHMRK-2

studies ď‚—

To evaluate safety, efficacy of Raltegravir with OBR(Optimum Back bone Regimen) in treatment experienced patients with triple class resistance.

ď‚—

Double blind placebo controlled parallel trials

Study Design

*Investigator-selected OBR based on baseline resistance data and history; inclusion of darunavir and tipranavir permitted; etravirine and maraviroc not available at time of study. Steigbigel RT, et al. N Engl J Med. 2008;359:339-354. Cooper DA, et al N Engl J Med. 2008;359:355-365.

Endpoints ◦ HIV-1 RNA < 50 copies/ mL at 16 and 48 wks ◦ HIV-1 RNA < 400 copies/mL at 16 and 48 wks ◦ Change in CD4+ cell count from baseline to 48 wks ◦ Change in HIV-1 RNA from baseline to 48 wks

Findings

*NC = F analysis. Steigbigel RT, et al. N Engl J Med. 2008;359:339-354. Cooper DA,et al N Engl J Med. 2008;359:355-365.

Main Findings (cont’d)

Steigbigel RT, et al. N Engl J Med. 2008;359:339-354. Cooper DA, et al N Engl J Med. 2008;359:355-365.

Main Findings (cont’d)

Steigbigel RT, et al. N Engl J Med. 2008;359:339-354. Cooper DA, et al N Engl J Med. 2008;359:355-365.

Main Findings (cont’d)

Conclusions ď‚—

Treatment experienced patients with triple class resistance , raltegravir associated with significantly grater efficacy than placebo

ď‚—

Greater virological and immunological response with raltegravir vs placebo (analyses across patient subgroups stratified by baseline RNA,CD4 cell count and predicted OBR activity (darunavir and enfuvirtide)

Conclusions (cont’d) 

Similar rates of adverse events in both arms

Virological failure due to integrase resistance mutations Q148,N155,Y143

Most had >2 raltegravir resistance mutations.

As a replacement with less side effects?

SWITCHMRK-1 and SWITCHMRK-2

Basis  Lopinavir/r is a potent ART but resulting lipid abnormalities as a side effect. 

Raltegravir not known to associate with dyslipidaemia

Switching from LPV/r to raltegravir may reduce lipid related side effects

Study Design

*All patients continued background regimen including ≼ 2 NRTIs.

Eron JJ, et al. Lancet. 2010;375:396-407.

Primary endpoint ◦ Mean percentage change in serum lipid concentrations from baseline to wk 12 ◦ Proportion of patients with HIV-1 RNA < 50 copies/mL at wk 24 ◦ Frequency of adverse events up to wk 24

Eron JJ, et al. Lancet. 2010;375:396-407.

Main Findings ď‚—

Raltegravir did not meet non inferiority criteria for efficacy vs continued Lopinavir/ritonavir at 24Wk ; study terminated

Eron JJ, et al. Lancet. 2010;375:396-407.

Main Findings ď‚—

Raltegravir associated with more favorable lipid effects vs continued LPV/RTV at 12 Wk in both studies

. Eron JJ, et al. Lancet. 2010;375:396-407.

Conclusions ď‚—

In patients with undetectable HIV-1 RNA on Lopinavir/ r based regimen, switching to raltegravir-based regimen associated with inferior virologic efficacy vs continuing lopinavir/r

ď‚—

Switching to raltegravir based regimen associated with significant reductions in lipids after 12 wks

Eron JJ, et al. Lancet. 2010;375:396-407.

3. Drug for ART na誰ve patients

Positive points to use in treatmentnaive Patients (cont’d) 

Potent

Does not require ritonavir boosting

Can be used as basis for NNRTI- and PI-sparing regimens

Neutral effect on lipids

STARTMRK Phase III: RAL vs EFV in Treatment-Naive Patients

◦ Primary endpoint: HIV-1 RNA < 50 copies/mL at Week 48 ◦ 53% of patients had HIV-1 RNA > 105 copies/mL; 47% of patients had CD4+ cell counts < 200 cells/mm3 at baseline ◦ Secondary endpoints: CD4+ cell count, safety, and tolerability Lennox J, et al. ICAAC/IDSA 2008. Abstract 896a.

Findings 

At 48 wks both drugs showed similar virological and immunological efficacy among all sub groups according to ◦ Baseline RNA levels ◦ CD4 counts ◦ Viral sub types ◦ Demographic characteristics(age, race,sex) ◦ Coinfection with hepatitis B or C Moderate/severe drug-related clinical adverse events more frequent in EFV vs RAL arm (32% vs 16%; P < .001)

Virologic and Immunologic Efficacy at 48Wk

Significantly shorter time to virologic response with RAL vs EFV (P < .001)

Significantly greater CD4+ cell count increase with RAL vs EFV ◦ +189 vs +163 cells/mm3; Δ: 26 cells/mm3 (95% CI: 4-47)

Lennox J, et al. ICAAC/IDSA 2008. Abstract 896a.

Efavirenz- dose 

600mg once daily standard dose

Widely used drug both in developed and resource poor countries.

CNS side effects common in most patients on EFV

If used in lower dose but without loosing the same effect  Less side effects, less cost 

ENCORE1: 400-mg EFV Noninferior to 600-mg EFV With TDF/FTC for Initial ART Randomized, double-blind, placebo-controlled, noninferiority phase III trial  Part of ongoing effort to identify ARVs effective at lower doses (and cost) 

No significant difference in SAEs between treatment arms  More pts with study drug–related AEs for EFV 600 mg vs EFV 400 mg (47.2% vs 36.8%; P = .008)  More pts discontinued EFV 600 mg due to AE vs EFV 400 mg (1.9% vs 5.8%; P = .010) 

Puls R, et al. IAS 2013. Abstract WELBB01.

*EFV administered as 200-mg tablets.

Findings ď‚—

Lower dose of EFV was non inferior to current dose 600mg

ď‚—

Less number of patients with drug related adverse effects with 400 mg of EFV than 600mg.

Decision Scientific evidence ď‚— Experience ď‚—

Thank You

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