drug trials in hiv & future practice in sri lanka

Drug Trials in HIV

and Future Practice in Sri Lanka

Dr Thilani Ratnayake

Consultant Venereologist

STD Clinic

Gampaha

Clinical Trials

Research in volunteers to find answers to

specific health questions.

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)

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

Demonstrate that new treatment is more

effective than a current treatment.

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.

Effects of some drugs could be long time

after it has been stopped

Can be wrongly interpreted as due to

new drug (e.g. viral resistance, Toxicities

Lack of Data on outcome in people who

changed from the original regimen

Drop Outs

If certain number of patients drop out ,it

can be a source of bias for the outcome.

Reasons for drop out could be related to

drug efficacy, toxicity, pill burden, length of

follow up etc.

How to Overcome the Problems

To have several end points. Combination

of biochemical and clinical end points

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

Need new drugs -for treatment

experienced patients who are failing on

current regimen.

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

To evaluate safety, efficacy of Raltegravir with

OBR(Optimum Back bone Regimen) in

treatment experienced patients with triple class

resistance.

Double blind placebo controlled parallel trials

Study Design

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

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

*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.

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

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

*NC = F analysis.

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

Treatment experienced patients with triple

class resistance , raltegravir associated with

significantly grater efficacy than placebo

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


Main Findings

Raltegravir did not meet non inferiority criteria for

efficacy vs continued Lopinavir/ritonavir at 24Wk ; study

terminated


Main Findings

Raltegravir associated with more favorable lipid

effects vs continued LPV/RTV at 12 Wk in both

studies

.


Conclusions

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

Switching to raltegravir based regimen

associated with significant reductions in lipids

after 12 wks


3. Drug for ART naïve patients

Positive points to use in treatment-

naive 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

Lower dose of EFV was non inferior to current

dose 600mg

Less number of patients with drug related

adverse effects with 400 mg of EFV than 600mg.

Decision

Scientific evidence

Experience

Thank You

drug trials in hiv & future practice in sri lanka

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