Prioritizing HIV comparative effectiveness trials based on value of information: generic versus brand-name ART in the US

Figures & data

Table 1 Model outcomes of interest.

Outcome of interest	Definition/methodology
		Result	Supplementary materials
Pre-trial outcomes
Pre-trial expected QALY and expected cost for all strategy options	Average QALY/cost across the entire set of simulation runs performed per strategy	Table 3	Appendix A
Post-trial outcomes
Distribution of post-trial optimal strategies	The proportion of trial simulations for which a strategy has the highest NMB	Fig. 1	Appendix A and B
Post-trial expected QALY and expected cost	Average QALY/cost conditional on the trial result (assuming the post-trial optimal strategy is selected for each trial result)	Table 4	Appendix A and B
VOI outcomes
Probability of changing treatment decision with new trial information	The proportion of PSA runs of which the pre-trial default strategy (i.e. single-pill branded) does not have the highest NMB post-trial (after ascertaining perfect information of the target parameters from the trial)	Fig. 1, Table 4	Appendix B
Expected change in QALYs and cost associated with these treatment decision changes	Difference between post-trial optimal and pre-trial default (i.e. single-pill branded) QALYs and cost	Table 4	Appendix B
Value of information per person associated with these treatment decision changes	Expected change in QALYs (due to treatment changes) multiplied by WTP minus expected change in cost (due to treatment changes)	Fig. 2, Table 4	Appendix B and C
Optimal trial design	The trial design which highest VOI per person for a given WTP	Fig. 2	Appendix C

NMB: net monetary benefit; PSA: probabilistic sensitivity analysis; QALY: quality-adjusted life year; VOI: value of information; WTP: willingness to pay.

Table 2 Model inputs

Target parameters (inputs with information to be gained from the trial)
	Distribution	Mean	SD	Reference
Patients with HIV RNA suppression after 24 weeks on first line ART
Three-pill generic (generic EFV+generic 3TC+TDF)	Hyper-beta^¥	Uniform (78%, 85%)	2.40%	^Citation16,Citation19
Two-Pill generic (generic EFV+ TDF/FTC)	Hyper-beta^¥	Uniform (84%, 85%)	2.18%	^Citation17,Citation19
Single-pill branded (TDF/FTC/EFV)	Beta	85%	1.90%	^Citation19
Monthly probability of failure after 24 weeks on first line ART^Δ
Three-pill generic (generic EFV+generic 3TC+TDF)	Hyper-adjusted log-normal (bounded above by 1)^¥	Uniform (0.21%, 0.45%)	0.44%	^Citation16,Citation19
Two-pill generic (Generic EFV+TDF/FTC)	Hyper-adjusted log-normal (bounded above by 1)^¥	Uniform (0.21%, 0.43%)	0.43%	^Citation17,Citation19
Single-pill branded (TDF/FTC/EFV)	Adjusted log-normal (bounded above by 1)	0.21%	0.27%	^Citation19
Complementary parameters (other inputs to be varied in PSA)
Cohort's initial mean CD4	Lognormal	400	80	^Citation20,Citation21
Annual cost of generic EFV+3TC (part of three-pill generic first line ART)	Lognormal	$6330	$3160	^Citation22
Annual cost of generic EFV (part of two-pill generic first line ART)	Lognormal	$2360	$1180	^Citation22
Monthly probability of loss to follow-up	Beta	0.62%	0.05%	^a
Monthly probability of returning to care	Beta	1.38%	0.11%	^a
Other baseline inputs
		Mean	SD¶	Reference
Cohort characteristics
Age, years		43	12	^Citation20
Male		84%	–	^Citation20
Distribution of Initial HVL
HVL 100 000+copies/mL		25%	–	^Citation23
HVL 30 001–100 000 copies/mL		42%	–
HVL 10 001–30 000 copies/mL		21%	–
HVL 3001–10 000 copies/mL		6%	–
HVL 501–3000 copies/mL		6%	–
HVL 0–500 copies/mL		0%	–
Other non-PSA efficacy parameters of ART
Patients with HIV RNA suppression after 24 weeks on second line ART (ATV/RTV+TDF/FTC)		73%	–	^Citation24,Citation25
Monthly probability of failure after 24 weeks on second line ART (ATV/RTV+TDF/FTC)^Δ		1.71%	–
CD4 increase at 48 week, × 10^9 cells/L‡
First line 3-pill generic (generic EFV+generic 3TC+TDF)		0.206	0.045	^Citation19
First line two-pill generic (Generic EFV+TDF/FTC)		0.206	0.045
First line single-pill branded (TDF/FTC/EFV)		0.206	0.045
Second line (ATV/RTV+TDF/FTC)		0.110	0.028	^Citation24,Citation25
Annual costs, 2013 U.S. $
First line, branded TDF (part of 3-pill generic ART)		$8950	–	^Citation22
First Line, branded FTC/TDF (part of 2-pill generic ART)		$13 560	–
First line, single-pill branded EFV/TDF/FTC		$20 830	–
Second line, two-pill branded ART, ATV/RTV+TDF/FTC		$28 490	–

3TC: lamivudine; ART: antiretroviral therapy; ATV: atazanavir; CD4: cluster of differentiation 4; EFV: efavirenz; FTC: emtricitabine; HVL: human immunodeficiency virus viral load; mL: milliliters; PSA: probabilistic sensitivity analysis; QALY: quality-adjusted life year; RTV: ritonavir; SD: standard deviation; TDF: tenofovir

a Source: Personal communication with Dr. John Fleishman and the HIV Research Network on 20 June 2014

¥ Hyper distribution refers to a hyper prior of a uniform distribution for the mean of the outcome. Thus, a hyper-beta is equivalent to a distribution of beta distributions; where the mean is uniformly distributed and the standard deviation of the beta distributions is kept constant. Similarly, hyper-lognormal distribution is equivalent to a distribution of log-normal distributions; the mean of the log-normal distributions is uniformly distributed and the standard deviation of the log-normal distributions is kept constant. Details of the derivation of the actual inputs can be found in Appendix D

¶ For variables not varied in the PSA and for which a SD was included (e.g. age and CD4 increase), its SD refer to the uncertainty within the population, i.e. the variation across individuals, which is different from the uncertainty around the input itself

Δ The monthly probability of failure after 24 weeks was estimated by transforming the probabilities of HIV RNA suppression at 48 and 96-weeks, assuming HIV RNA suppression would achieve its maximum at 24 weeks and that its rate of decline would be constant post 24 weeks

‡ We assumed independence between CD4 increase (among patients who were virologically suppressed) and the probability of HIV RNA suppression.²⁶

Table 3 Pre-trial outcomes: Pre-trial results from probabilistic sensitivity analysis (PSA) of the treatment comparisons included in alternative trials

	Expected QALYs
	Discounted	Undiscounted	Expected cost
Three-pill generic vs single-pill branded
Three-pill generic (generic EFV+Generic 3TC+TDF)	13.43	20.79	$318600
Single-pill branded (TDF/FTC/EFV)	13.58	21.13	$376100
Two-pill generic vs single-pill branded
Two-pill generic (generic EFV+TDF/FTC)	13.51	20.95	$340800
Single-pill branded (TDF/FTC/EFV)	13.58	21.13	$376100

3TC: lamivudine; EFV: efavirenz; FTC: emtricitabine; QALY: quality-adjusted life year; TDF: tenofovir.

Table 4 Value of Information of alternative trials: comparing “three-pill generic versus single-pill branded regimens” to “two-pill generic versus single-pill branded regimens”

	Three-pill generic vs single-pill branded	Two-Pill generic vs single-pill branded
WTP threshold ($/QALY gained)	$50 000	$100 000	$150 000	$200 000	$50 000	$100 000	$150 000	$200 000
Post-trial outcomes
Chance of being selected as most CE strategy post-trial
3-Pill generic (generic EFV+generic 3TC+TDF)	90%	84%	77%	71%	–	–	–	–
2-Pill generic (generic EFV+TDF/FTC)	–	–	–	–	83%	78%	73%	69%*
Single-pill branded* (TDF/FTC/EFV)	10%	16%	23%	29%	17%	22%	27%	31%
Post-trial expected QALY	13.48	13.51	13.53	13.55	13.58	13.59	13.60	13.61
Post-trial expected lifetime cost	$319 100	$321 000	$323 500	$326 300	$340 400	$341 300	$342 500	$343 800
VOI outcomes
Chance of changing treatment decisions post-trial	90%	84%	77%	71%	83%	78%	73%	69%
Expected change in QALY associated with treatment decision changes	0.097	0.071	0.051	0.035	0.003	0.009	0.018	0.026
Expected change in lifetime cost associated with treatment decision changes	$57 000	$55 100	$52 600	$49 800	$35 700	$34 900	$33 600	$32 280
VOI from trial ($ per person)	$52 100	$48 000	$45 000	$42 900	$35 600	$35,700	$36 400	$37 500

3TC: lamivudine; CE: cost-effective; EFV: efavirenz; FTC: emtricitabine; QALY: quality-adjusted life year; TDF: tenofovir; VOI: value of information; WTP: willingness to pay.

Numbers in brackets are negative

* Equivalent to the probability of re-selecting the pre-trial default strategy (i.e. single-pill branded) after ascertaining trial-based efficacy.

Figure 1 Distribution of post-trial optimal strategies of alternative trials. (A) depicts the distribution of post-trial optimal strategies of the head-to-head trial of three-pill generic ART versus single-pill branded ART. For a given willingness to pay (WTP) threshold (horizontal axis), the proportion of PSA runs (vertical axis) of which three-pill generic ART strategy and single-pill branded ART strategy has the highest net monetary benefit (NMB) after ascertaining perfect information on ART efficacy for both treatment arms in the trial are represented by the red and green curves, respectively. Net monetary benefit was defined as QALY times WTP, minus cost. The dotted vertical line represents the WTP threshold at baseline ($100 000/QALY). (B) depicts the distribution of post-trial optimal strategies of the head-to-head trial of two-pill generic ART versus single-pill branded ART. For a given WTP threshold (horizontal axis), the proportion of PSA runs (vertical axis) of which two-pill generic ART strategy and single-pill branded ART strategy has the highest NMB after ascertaining perfect information on ART efficacy for both treatment arms in the trial are represented by the blue and green curves, respectively. NMB was defined as QALY times WTP, minus cost. The dotted vertical line represents the WTP threshold at baseline ($100 000/QALY).

Figure 2 Direct comparison of the value of information (VOI) of alternative trials in relation to generic drug price discount and willingness to pay (WTP) per QALY. The value of ascertaining perfect information per person of ART efficacy from the three-pill trial (for both three-pill generic and single-pill branded treatment arms) and the two-pill trial (for both two-pill generic and single-pill branded treatment arms) are represented by the red and blue solid curves, respectively. The VOI per person was estimated as the difference in net monetary benefit (NMB) between single-pill branded (the pre-trial initial strategy of choice) and the post-trial optimal first line ART strategies. Net monetary benefit was defined as QALYs times WTP, minus cost. Further, the graph shows the changes in the VOI per person of a three-pill trial (red curves) and a two-pill trial (blue curves) while the generic drug discount from the AWP is varied from 60% (evenly dotted) to 90% (unevenly dotted), in comparison to the base case where generic drug discount was 75% (solid).

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