1
Q
Phases of clinical trials
A
- Phase 1: drug given to small number to test safety
- Phase II: Given to more people, work out dosing, also some efficacy and safety
- Phase III: given to large groups to confirm effectiveness, side effects, compare to standard treatment
- Phase IV: after approved and made available, to track safety and provide more information on benefits and optimal use
2
Q
Treatment as prevention trials
A
- HPTN052: phase 3 RCT, 880 serodiscordant mostly heterosexual couples, 1 arm started ART CD4 250-500, other <250, there was a 96% reduction in HIV transmissions in early group
- PARTNER 1: serodifferent couples (heterosexual and MSM), where HIV VL<200 no linked transmissions in 58000 sex episodes
- PARTNER 2: continuation but just in MSM, 783 couples had sex without condoms 77,000 times, no transmitted virus
- Opposites attract, serodifferent MSM, 0 transmissions in UD
3
Q
When to start ART trials:
A
- START: 4685 HIV+ve randomised to start ART immediate or when CD4<350 or developed AIDS- primary endpoint AIDS, serious non AIDS event or death. Absolute risk reduction 1.8 Vs 4.1%
- Primarily saw reduction in TB ,KS, lymphomas and non-AIDS cancers. Benefitted even those with CD4 greater than 500 indicating it’s modification of other markers than just CD4 which make a difference
- TEMPRANO: CD4<500 randomised to either immediate ART or deferred, and with or without isoniazid. Risk of death/AIDs death/non AIDs deaths/malignancies etc. was lower in the immediate arm
4
Q
SWITCHMARK 1 and 2
A
- Virally suppressed on Lop/r randomised to stay on this or switch to RAL
- Stopped early at week 24 because of greater rates of virological failure in RAL group (IF there was history of prior VF), despite better tolerability and lipids
- Ie. non inferiority NOT demonstrated
- If no Hx previous resistance, RAL non inferior\
- ODIS showed similar, SPIRAL opposite
Guidelines: recommend against switching someone on a PI with previous NRTI resistance to an NNRTI or first generation INSTI
5
Q
COAT trial
A
- Cryptococcal patients randomised to early ART (median 8 days) or deferred (median 35 days)
- Primary out one of survival at 6 months was 55% in immediate arm Vs 70% in deferred arm
- Also found increased risk of death when acellular CSF or decreased GCS
- No difference in IRIS
- Therefore aim to start ART at 4-5 weeks, may ensure CSF sterile first
6
Q
When to start ART in Tb:
A
- STRIDE: ART was given ‘immediately’ in <2 weeks or ‘early’ at 8-12 weeks
- Primary end points all cause mortality and new AIDs defining illness
- On the whole, no difference between the two arms, except for where CD4<50 where immediate ART saw less AIDS and deaths
- Therefore, CD4<50 -> start ART asap
- SAPIT found the same
- CAMELIA found starting ART at 2 weeks did better than at 8 weeks (did see more IRIS in the earlier ART group)
7
Q
STARTMRK
A
- Treatment naive
- Randomised to TDF/FTC then either RAL or EFV
- Non inferiority in terms of virological suppression, RAL 71% and 61% EFV
- Better lipid and fewer neuropsychologist SE in RAL group
8
Q
ONCE MRK
A
- 1200mg OD RAL non inferior to 400mg BD RAL in treatment naive
(QDMRK showed that RAL 800mg OD was inferior virological efficacy than RAL 400mg BD, failure especially more common where VL>100k)
9
Q
ACTG 5257
A
- Phase 3, randomised, treatment naive
- Truvada plus one of 3 below
- All equivalent virological efficacy
- Composite end point of virological efficacy and side effects
- RAL>DAR/r>Atzanavir/r
10
Q
SWORD 1 and 2
A
- Non inferiority switch study comparing current ART to juluca (DTG/RPV)
- Patients on 1st or 2nd ART with VL controlled for >6 months
- Non inferiority was shown, hence it’s a reasonable switch option, however no trials of Juluca in treatment naive so not recommended in that setting
11
Q
Studies for Dovato (DTC/3TC)
A
- GEMINI I+II: Treatment naive, randomised to DTG/3TC or TDF/FTC/DTG, excluded those with VL>500,000, HB+ve and major mutations
- Non inferiority was shown, rapid and durable
- In those with CD4<200 only 68% in dual arm Vs 87% in triple arm (although primarily non treatment related reasons)
- Lower risk of drug related AE in dual group
- Renal and bone biomarkers better in dual
- Improvements in TC/HDL in both groups (slightly favoured TDF group)
- Therefore can use if no HBV, no resistance, VL<500k and CD4>200
12
Q
Switch studies to DTG/3TC
A
TANGO:
- Trial in favour of simplification to DTG/3TC
- Patients with VL<20 randomised to switch to DTG/3TC or stay on TAF based triple therapy
- Non interiority shown in terms of proportion with detectable VL and week 48
- Non resistance developed, no increased failure in present of pro-viral M184V
- Improvements in lipids
ASPIRE- switching from any 3 drug to DTG/3TC, end point of virological failure at week 48, showed non inferiority. 1 failure in dual arm but no resistance
13
Q
2 drug regimen phase 2b trials
A
- LATTE I ART naive randomised 1:1:1:1 to oral CAB and 3 diff doses or EFV plus 2NRTI, if suppressed NRTI then switched for RPV, CAB 30mg picked for ongoing studies
- LATTE 2: treatment naive, 20week induction or oral CAB plus kivexa, then randomly assigned to IM long acting CB plus RPV at 4 or 8 week intervals or continue oral, long acting was as effective at maintaining suppression through week 96
14
Q
Injectable ART studies:
A
ATLAS:
- Patients with undetectable VL for at least 6 months and no Hx VF
- IM injections of CAB+RPV every 4 weeks non inferior to daily oral ART at week 48
- Low rate of virological failure in each arm, no resistance developed in oral arm but 3 patients developed resistance in LA arm (2 of them subtype A1)
- E138 (RPV mutation) seen in a few, also INSTI mutations N155H
- Injection site reactions were common, treatment satisfaction still high in LA
ATLAS 2M:
- CAB/RPV 2 monthly Vs 1 monthly, 2m was non inferior (no direct comparison of 2m Vs oral)
- 1 in 60 VF in LA group. Common mutations RPV ones (E138A, K101), and INSTI (Q148R, N155H, E138E)
FLAIR:
- ‘recently naive’
- Triumeq Vs 20 weeks triumeq then 4/52 PO CAB/RPV then LA CAB/RPV
- IM injections of CAB+RPV every 4 weeks non inferior to daily oral triumeq at week 48 in terms of maintaining virological suppression
- Failures in subtype A1, also BMI>30
15
Q
PARTNERS PREP
A
- 4758 heterosexual couples enrolled, zero-different
- Randomised to TDF, TDF/FTC or placebo
- Relative reduction 67% in TDF group, 75% Truvada group as compared to placebo
- Demonstrating either TDF or Truvada were protective
- 8 found to have been HIV positive at baseline, of which 2 developed resistance
16
Q
PARTNER 1
A
- Large, international study between 2010-2014
- 1166 couples, heterosexual and MSM
- Zero linked transmissions where VL<200, in about 58,000 condomless sex acts
17
Q
PARTNER 2
A
- 800 MSM couples, 77,000 condoles sex cts
- Zero linked transmissions
18
Q
PIVOT study
A
- Protease monotherpy Vs continuing triple therapy
- Primary outcome was ‘loss of future drug options’ which was non inferior
- However, virological rebound in 8 patients in continuing triple therapy group Vs 95 in PI mono group
- Most did then successfully re-suppress however
Guidelines: don’t do PI mono therapy
19
Q
NEAT trial
A
DAR and RAL naive
TDF/FTC + DAR/r Vs RAL/DAR/r
RAL/DAR/r less effective if CD4<200
RAL failure often with resistance
Otherwise effective and well tolerated
20
Q
SPRING 2
A
- Treatment naive, 2 NRTI+RAL BD vs 2NRTI+DOL OD
- DOL non inferior virological suppression
- At week96 if analysed by baseline VL there was a significant difference favouring DOL where VL>100,000
21
Q
FLAMINGO
A
- Treatment naive, open label
- 2 NRTII plus DOL or 2NRTI plus DAR/r
- DOL non inferior in terms of virological suppression
- In those with VL>100k, 82% suppressed at week 96 Vs 52% in DAR/r group
- No resistance either arm
- Less discontinuation DOL arm
- 1 suicide attempt in DOL arm
22
Q
SINGLE
A
- Triumeq Vs Atripla in treatment naive
- Triumeq met endpoint for superiority in terms of virological success
- Time to suppression 28 days in triumeq Vs 84 days triple
- 2% discontinued due to SE in triumeq Vs 10% in Atripla
- Rash and Neuropsych more common Atripla, insomnia more common triumeq
23
Q
DAWNING
A
- Patient failing first line ART (2NRTI + NNRTI)
- PI and INSTI naive
- Randomised to DOL or LOP/r and 2NRTI
- DOL demonstrated superiority in terms of virological suppression and faster to suppression
- Majority had M184V and many K65R
- Effective even with NRTI resistance
24
Q
NADIA
A
- Treatment experienced failing first line ART including an NNRTI
- Received either DOL or DAR/r with TDF or AZT (all with 3TC)
- Non inferiority seen between DOL and DAR/r
- TDF just as effective as AZT even in presence of NRTI resistance mutations e.g. K65R
- Around 6% in each had virological rebound, none of the DAR group had any resistance but 4 of the DOL group had DOL mutations
25
Trials of DOL mono therapy
- MONCAY and DOMONO
- Suboptimal and associated with resistance
- Don't do it
26
GS 1489
- Biktarvy Vs triumeq
- Non inferior virological success
- No resistance either arm
27
GS 1490
- Biktarvy Vs Descovy/DOL
- Non inferior
- Similar AEs between groups and low
28
GS 380-1844
- Biktarvy switch study
- BIK vs 2NRTI + PI/r
- Lipids better in BIK, mild headaches in BIK
- Non inferior virological efficacy, lipids improvements when switching from ABC based ART but not in those switching from TDF
29
DRIVE ahead
- Double blind, treatment naive
- Delstrigo (TDF/3TC/DOR) Vs Atripla
- Non inferior regardless of VL>100k
- Delstrigo had lower rates dizziness and sleep disorders and better lipids
30
DRIVE forward
- Blinded, treatment naive
- 2NRTI + DOR Vs 2NRTI + DAR/r
- Non inferior regardless of baseline VL
- Rash, neuropsych and lipids better with DOR
31
DRIVE shift
- Switch study from 2 NRTI plus elvitegravir/PI/NNRTI Vs TDF/3TC/DOR
- Non inferiority seen
- Mean reductions in LDL and non-HDL was significantly greater in the Delstrigo group
32
SPIRIT
Switching from PI maintained suppression to rilpivirine was safe, with or without K103N
33
SPARTAN
- Treatment naïve randomised to twice daily Atazanavir + Raltegravir Vs TDF/FTC/ATZ/r
- Achieved virological suppression rates but RAL resistance developed and higher rates hyperbilirubinaemia
- INSTI failure was with significant resistance
34
ACTG 5202
- Backbone of TDF/FTC vs ABC/3TC with ATZ or EFV
- Stratified by screening VL >100k or <100k
- When VL>100k virological failure more likely in ABC/3TC group
- Hypersensitivity likely part of it, no HLA testing
- No difference where VL<100
35
ASSERT (subgroup of 5202)
- Comparing safety of ABC/3TC and TDF/FTC plus EFV
- eGFR same in both but TDF/FTC associated with greater increases in tubular dysfunction and lower BMD, smaller increases in lipids
36
AMBER
- Symtuza vs TDF/FTC/DAR/c
- Non inferior in terms of virological suppresion
- Improved renal and bone in symtuza arm
37
Which studies informed guideline that if switching from PI based therapy should not switch to NNRTI or first generation PI if any history of previous NRTI resistance?
- SWITCHMARK (RAL did worse than continuing LOP/r in those with previous resistance)
- ODIS
38
DUAL
DAR/3TC switch
2NRTI + DARr Vs 3TC/DAR
Non inferior
