Cost-effectiveness of DTG + ABC/3TC versus EFV/TDF/FTC for first-line treatment of HIV-1 in the United States

Figures & data

Figure 1. Model flow diagram. AE, Adverse event; Tx, Treatment.

Table 1. Clinical inputs.

	EFV/TDF/FTC	DTG + ABC/3TC	Source
First-line therapy
Virologic response
% with viral suppression (assessed at 32 weeks)	81%	88%	48-week data from the SINGLE trial9
% failing to achieve viral suppression at 48 weeks	20%	12.3%
% failing to achieve viral suppression  from week 48 to week 96	9.7%	8.7%	96-week results from the SINGLE study10
% failing to achieve viral suppression  beyond 96 weeks	7.1%	7.1%	Rockstroh et al.16 STARTMRK 5-year study
CD4 count (for patients who achieve  virologic suppression)  Change in CD4 count within  96-week trial period	Sample CD4 at suppression time and trial end times based on the mean and SE of reported adjusted change from baseline CD4 count	Sample CD4 at suppression time and trial end times based on the mean and SE of reported adjusted change from baseline CD4 count	SINGLE trial10
Annual CD4 increase (beyond 96 weeks)	24 cells/µL	24 cells/µL	Rockstroh et al.16 STARTMRK 5-year study
CD4 count (for patients who do not achieve  virologic suppression)  CD4 count	No change from baseline	No change from baseline
Probability of treatment failure/treatment switch
Within trial period (48-week):
Due to reasons other than AEs or virologic failure	6.9%	6.5%	48-week data from the SINGLE trial9
Due to AEs	10.0%	2.4%
Due to virologic failure	3.1%	3.4%
Second-line therapy	Boosted PI + 2NRTIs
Annual probability of treatment switch	17.6%		Jansen et al.17; Svedhem-Johansson et al.18; Arasteh et al.19; Banhegyi et al.20
Annual CD4 count increase while on treatment	57.4 cells/µL		Jansen et al.17; Svedhem-Johansson et al.18; Arasteh et al.19; Banhegyi et al.20
Third-line therapy	INSTI (raltegravir) + NNRTI (etravirine) + boosted PI + 2NRTIs
Annual probability of treatment switch	15.2%		Beck et al.21
Annual CD4 count increase while on treatment	41 cells/µL		ANRS 139 TRIO trial presentation (Fagard et al.22)
Non-suppressive therapy	INSTI (raltegravir) + NNRTI (etravirine) + boosted PI + 2NRTIs
Annual CD4 count decrease	−22 cells/µL		Ledergerber et al.23

AE, Adverse event; NRTI, Nucleoside/nucleotide reverse transcriptase inhibitor; NNRTI, Non-nucleoside reverse-transcriptase inhibitors; INSTI, integrase strand transfer inhibitors; NRTI, Nucleoside/nucleotide reverse transcriptase inhibitors; PI, Protease inhibitor; SE, Standard error; µL, Microliter.

Figure 2. Time to virologic suppression on first-line treatment7.

Table 2. Risks of clinical, adverse, and mortality events.

	Probability of AIDS-related events (per 3 months)		Probability of non-AIDS-related events (per 3 months)		Reference
	First opportunistic infection	Second opportunistic infection	Cancer	Infection
CD4 category 1 (0–50)	4.24%	16.51%	0.15%	0.04%
CD4 category 2 (51–200)	3.45%	13.42%	0.15%	0.04%	Simpson et al.25
CD4 category 3 (201–350)	0.50%	1.95%	0.12%	0.03%
CD4 category 4 (351+)	0.18%	0.68%	0.09%	0.04%
		Proportion of events	Case fatality	Long-term mortality (per 3-month period)
Acute AIDS-related events
Cervical cancer		0.3%	1%	0%	Simpson et al.25
Cryptosporidiosis		2.3%	2%	0%
Coccidiosis		0.2%	2%	0%
Oral esophageal candidiasis		9.0%	12%	0%
Histoplasmosis		0.3%	1%	0%
PCP		20.1%	15%	0%
Pneumonia		13.0%	20%	0%
Salmonella sepsis		0.2%	1%	0%
Tuberculosis		4.9%	1%	0%
Chronic AIDS-related events
AIDS dementia		3.2%	39%	22%	Simpson et al.25
CMV retinitis		4.5%	7%	12%
CMV colitis/other		0.9%	7%	12%
Cryptococcal meningitis		1.2%	34%	15%
Kaposi’s sarcoma cutaneous		3.8%	1%	22%
Kaposi’s sarcoma visceral		0.9%	4%	22%
Lymphoma, central nervous system		2.4%	58%	22%
Lymphoma, other		0.6%	17%	45%
MAC		5.8%	30%	22%
PML		1.4%	21%	22%
Toxoplasmic encephalitis		1.9%	20%	31%
Wasting syndrome		23.1%	39%	15%
Cardiovascular events		EFV/TDF/FTC	DTG + ABC/3TC	Subsequent treatments
Event rate per patient per year		0.0094	0.0134	0.0093	Choi et al.26
Mortality risk due to events		Probability event is fatal	Ongoing mortality risk
Non-AIDS-related cancer		0%	12%
Non-AIDS-related infection		9%	0%		Simpson et al.25
CVD event		6%	0%
Background death		Relative risk of death in HIV patients vs general population
CD4 category 1 (0–50)		11.28
CD4 category 2 (51–200)		5.31			Rodger et al.27
CD4 category 3 (201–350)		2.34			Marin et al.28
CD4 category 4 (351+)		1.77

3TC, Lamivudine; ABC, Abacavir; CMV, Cytomegalovirus; CVD, Cardiovascular disease; DTG, Dolutegravir; EFV, Efavirenz; FTC, Emtricitabine; MAC, Mycobacterium avium cellulare; PCP, Pneumocystis carinii jiroveci pneumonia; PML, Proliferative multifocal leukoencephalopathy; TDF, Tenofovir.

Table 3. Utility inputs.

Utility decrement due to events	Utility decrement	Duration (months)	Reference
Baseline utility
Utility = 0.836 − 0.001 × age − 0.038 × female + 0.025 × CD4 >200			Kauf et al.29
Acute AIDS-related events
Cervical cancer	0.15	3.00	Simpson et al.25
Cryptosporidiosis	0.15	3.00
Coccidiosis	0.15	3.00
Oral esophageal candidiasis	0.15	3.00
Histoplasmosis	0.15	3.00
PCP	0.15	1.00
Pneumonia	0.15	1.00
Salmonella sepsis	0.15	4.00
Tuberculosis	0.15	4.00
Chronic AIDS-related events
AIDS dementia	0.39	Lifetime	Simpson et al.25
CMV retinitis	0.15	Lifetime
CMV colitis/other	0.15	Lifetime
Cryptococcal meningitis	0.15	Lifetime
Kaposi’s sarcoma cutaneous	0.15	Lifetime
Kaposi’s sarcoma visceral	0.15	Lifetime
Lymphoma, central nervous system	0.39	Lifetime
Lymphoma, other	0.15	Lifetime
MAC	0.39	Lifetime
PML	0.39	Lifetime
Toxoplasmic encephalitis	0.15	Lifetime
Wasting syndrome	0.39	Lifetime
Non-AIDS-related events
Non-AIDS-related cancer (annual)	0.39	Lifetime	Simpson et al.25
Non-AIDS-related infection (per episode)	0.39	1.00
CVD (per episode)	0.15	1.00
Adverse events
Dizziness	0.03	1st line of treatment	Kauf et al.29

CMV, Cytomegalovirus; MAC, Mycobacterium avium cellulare; PCP, Pneumocystis carinii jiroveci pneumonia; PML, Proliferative multifocal leukoencephalopathy.

Table 4. Cost inputs.

		Reference
Drug costs, mean annual
EFV/TDF/FTC	$24,983	BMS data: Truvada 43.85 + emtricitabine 24.60
DTG	$15,012	Source: RED BOOK Online Truven Health Analytics30
ABC/3TC	$13,443	Fixed-dose combination Epzicom or Kivexa
Second-line treatment	$32,980	Source: RED BOOK Online Truven Health Analytics30
Third-line treatment	$43,841
Non-suppressive treatment	$43,841
Disease monitoring costs (incurred every 3 months), mean
Long-term follow-up costs*	$2532	Simpson et al.25
Acute AIDS-related events (per event), mean
Cervical cancer	$1336	Simpson et al.25
Cryptosporidiosis	$2674
Coccidiosis	$2674
Oral esophageal candidiasis	$2938
Histoplasmosis	$20,248
PCP	$2839
Pneumonia	$6291
Salmonella sepsis	$4047
Tuberculosis	$25,209
Chronic AIDS-related events (annual), mean
AIDS dementia	$22,788	Simpson et al.25
CMV retinitis	$120,000
CMV colitis/other	$5052
Cryptococcal meningitis	$12,600
Kaposi’s sarcoma cutaneous	$6720
Kaposi’s sarcoma visceral	$48,024
Lymphoma, central nervous system	$76,380
Lymphoma, other	$19,164
MAC	$81,720
PML	$45,120
Toxoplasmic encephalitis	$16,812
Wasting syndrome	$87,768
Non-AIDS-related events, mean
Non-AIDS-related cancer (annual)	$66,516	Simpson et al.25
Non-AIDS-related infection (per episode)	$6784
CVD (per episode)	$24,227

ABC, Abacavir; CMV, Cytomegalovirus; CVD, Cardiovascular disease; DTG, Dolutegravir; MAC, Mycobacterium avium cellulare; PCP, Pneumocystis carinii jiroveci pneumonia; PML, Proliferative multifocal leukoencephalopathy.

*This includes the costs of CD4 count and HIV-1-RNA monitoring tests.

Table 5. Base-case results.

	EFV/TDF/FTC	95% CI	DTG + ABC/3TC	95% CI	DTG + TDF/FTC	95% CI	Incremental
							DTG + ABC/3TC vs EFV/TDF/FTC	DTG + TDF/FTC vs EFV/TDF/FTC
Health outcomes
LYs	18.71	18.66–18.77	18.88	18.82–18.94	18.88	18.82–18.94	0.16	0.16
Total QALYs	14.00	13.96–14.04	14.12	14.08–14.17	14.12	14.08–14.17	0.12	0.12
Cost outcomes
Total cost	$561,872		$581,025		$594,559		$19,153	$32,687
Drug cost	$495,553	$493,679–$497,427	$513,765	$512,019–$515,511	$527,300	$525,923–$529,404	$18,212	$31,278
Monitoring cost	$47,143	$47,003–$47,284	$47,550	$47,402–$47,698	$47,550	$47,402–$47,698	$407	$407
Event cost	$19,176		$19,710		$19,710		$534	$534
Incremental cost-effectiveness ratios
Incremental cost per LY gained							$112,994	$198,544
Incremental cost per QALY gained							$158,890	$272,389

3TC, Lamivudine; ABC, Abacavir; CI, Confidence interval; DTG, Dolutegravir; EFV, Efavirenz; FTC, Emtricitabine; LY, Life-year; QALY, Quality-adjusted life-year; TDF, Tenofovir.

Figure 3. Base case results presented as net monetary benefit analysis. The two lines representing EFV/TDF/FTC and DTG + ABC/3TC are nearly parallel (indicating that the efficacy benefit of the two treatments is nearly identical), with the EFV/TDF/FTC line remaining very slightly higher, indicating it is marginally more cost-effective.

Table 6. Results of one-way sensitivity scenarios (EFV/TDF/FTC vs DTG/ABC/3TC).

Scenario	Base-case input	Sensitivity input	Incremental cost	Incremental QALY	ICER/QALY
Drug price source (referenced February 2014)	WAC	AWP	$30,100	0.12	$250,836
Alternative regimen	Two tablet regimen cost for DTG + ABC/3TC	Single tablet regimen cost for DTG + ABC/3TC	$8552	0.12	$70,945
	ABC/3TC backbone	TDF/FTC backbone	$32,687	0.12	$272,389
(1a) Time horizon	Lifetime	5 years	$8954	0.004	$2,282,759
(1b) Time horizon	Lifetime	20 years	$49,293	0.024	$2,071,933
(2) Annual drug costs	Listed price	20% reduction in EFV/TDF/FTC price	$47,534	0.12	$394,331
(3a) Treatment discontinuation	% discontinue due to AEs • EFV/TDF/FTC 10%	% discontinue due to AEs • EFV/TDF/FTC 5.9%	$20,205	0.08	$263,509
(3b) Treatment discontinuation	% discontinue due to AEs • EFV/TDF/FTC 10% • DTG 2.4%	% discontinue due to AEs • EFV/TDF/FTC 2.4% • DTG 2.4%	$21,608	0.03	$757,706
(3c) Treatment discontinuation	% discontinue due to other reasons • EFV/TDF/FTC 6.9% • DTG 6.5%	% discontinue due to other reasons • EFV/TDF/FTC 0% • DTG 0%	$18,761	0.10	$182,479
(3d) Treatment discontinuation	As indicated in above 2 scenarios (3b and 3c)	As indicated in above 2 scenarios (3b and 3c)	$23 993	0.01	$4,146,452
(4) Annual probability of CV events	• EFV/TDF/FTC 0.94% • DTG 1.34% • Other 0.93%	All treatments to be the same as EFV/TDF/FTC 0.94%	$18,320	0.15	$126,280
(5a) Utility estimating method	Kauf equation	Simpson utility table	$18,320	0.14	$134,863
(5b) Utility estimating method	Kauf equation	Tengs utility table	$18,320	0.18	$99,372
(6a) Annual probability of treatment  switch beyond 96 weeks	DTG and EFV/TDF/FTC 7.1%	• EFV/TDF/FTC 9.7% • DTG 8.7%	$12,821	0.15	$85,038
(6b) Annual probability of treatment  switch beyond 96 weeks	DTG and EFV/TDF/FTC 7.1%	• EFV/TDF/FTC 7.1% • DTG 6.4%	$12,220	0.15	$81,122
(7) Annual CD4 change beyond 96 weeks	DTG and EFV/TDF/FTC 24 cells/µL	• EFV/TDF/FTC 24 cells/µL • DTG 26.4 cells/µL	$18 754	0.12	$153,511
(8) Probability of treatment switch  for second line treatment	• EFV/TDF/FTC 0.176 • DTG 0.176	• EFV/TDF/FTC 0.194 • DTG 0.176	$18,722	0.16	$117,600
(9) % of virologic failure CD4 gain	0.71	0.00	$19,419	0.15	$130,899
(10) Annual probability of treatment switch between  48 and 96 weeks based on SPRING 1 trial	DTG 8.7%	DTG 0%	$18,875	0.13	$144,119

3TC, Lamivudine; ABC, Abacavir; CI, Confidence interval; CV, Cardiovascular; DTG, Dolutegravir; EFV, Efavirenz; FTC, Emtricitabine; LY, Life-year; NA, Not applicable; QALY, Quality-adjusted life-year; TDF, Tenofovir; tx, Treatment; µL, Microliter.

Figure 4. Incremental cost-effectiveness scatterplot and cost-effectiveness acceptability curves. In the scatterplot, the tight grouping of points indicates model results are robust to variations in parameter values and that EFV/TDF/FTC is consistently cost-saving with a slightly lower incremental health benefit. This is mirrored in the cost-effectiveness acceptability curve, which shows EFV/TDF/FTC to have a 100% probability of being cost-effective compared to DTG + ABC/3TC at accepted willingness-to-pay thresholds.

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