Table 2. Currently Available and Improved Hypothetical Combination ARVs

ARV Drug Combinations	Innovator Companies	Estimated Cost per Year (US$)^a	Comments
Current WHO-Recommended ARV Regimens for Adults
Efavirenz + TDF + lamivudine or emtricitabine (Atripla is a comparable pill marketed in the US)	NA (generic available)	$122	Preferred first-line regimen Highly effective and well tolerated Drawbacks include weak resistance barrier, potential for kidney and bone toxicity, neuropsychiatric side effects, possible interaction with contraceptive implants, and greater incidence of severe adverse birth outcomes in pregnancies receiving TDF-containing regimens compared with zidovudine-containing regimens
Lopinavir/ritonavir or atazanavir/ritonavir + zidovudine^b + lamivudine	NA (generic available)	$305–$318	Preferred second-line regimen Not available as a fixed-dose combination Resistance barrier suboptimal due to lack of second highly potent and robust agent to couple with the protease inhibitor Drug-drug interactions increased by ritonavir
Highly Effective Alternatives, Not Ideal for Resource-Limited Settings
Elvitegravir + TDF + emtricitabine + cobicistat (Stribild, the “quad” pill)	Gilead	$184	Elvitegravir's resistance barrier is less robust than dolutegravir's Cobicistat increases drug-drug interactions and cost Bone and kidney toxicity possible with TDF A second-generation “quad” with TAF is in development and should decrease side effects and cost to a degree
Dolutegravir + abacavir + lamivudine (Triumeq, the “tri” pill)	ViiV	$179	Abacavir is expensive to manufacture and is associated with a rare but potentially life-threatening hypersensitivity syndrome Has utility for pediatrics due to abacavir not affecting bone
Illustrative Improved (Hypothetical) 3-Drug Regimens
Dolutegravir + TAF + lamivudine or emtricitabine	ViiV + Gilead	$60	Higher resistance barrier and durability Reduced risk of renal and bone toxicity and manufacturing cost with TAF compared with TDF Primarily for first-line treatment, although it might have good activity as second-line for some patients
Dolutegravir + boosted protease inhibitor + TAF	ViiV + Gilead + Others	$266–$357 (or more^c)	Improved second-line regimen, with a very robust resistance barrier that could make the need for third-line regimens very rare
Dolutegravir + TAF + doravirine	ViiV + Gilead + Merck	$64	Might be effective for first- or second-line treatment as doravirine has in vitro activity against non-nucleoside reverse transcriptase–resistant isolates common in sub-Saharan Africa
Illustrative Improved (Hypothetical) 2-Drug Maintenance Combinations (for use after undetectable viral load achieved)
Dolutegravir + rilpivirine	ViiV + Janssen	<$40	Excellent tolerability with minimal side effects Both agents are already approved, allowing for expedited development Proof of concept for efficacy available from LATTE study Downsides include interactions with TB regimens, food requirement, and suboptimal efficacy for second-line treatment Currently in late stage clinical development that could lead to licensure
Cabotegravir + rilpivirine (long-acting injectable)	ViiV + Janssen	$40	Injection every 1–2 months may reduce risk of resistance due to non-adherence and increase confidentiality and quality of life If patients are lost to follow-up, risk of resistance could be much higher than an oral formulation Other advantages and disadvantages may be similar to dolutegravir/rilpivirine oral combination above Currently in phase II development
Dolutegravir + doravirine	ViiV + Merck	$50	Doravirine's different resistance profile, lack of food requirement, shorter half-life, and possibly lower potential for TB medication interactions might make it a better partner for dolutegravir than rilpivirine as part of 2-drug regimen Might have efficacy in first- and/or second-line treatment This is a hypothetical combination, not in development, and doravirine is now in early phase III development
Dolutegravir + lamivudine	ViiV	$46	Might be effective and well tolerated in first-line treatment, preserving many second-line options This is a hypothetical combination, not in development, but because one company makes both medicines, fewer obstacles might exist to develop it
Dolutegravir + TAF	ViiV + Gilead	$39	Hypothetical combination for first-line treatment, with some possible efficacy in second-line Currently not in development
Dolutegravir + boosted protease inhibitor	ViiV + Others	$252–$343 (or more^c)	Hypothetical combination, not currently in development Could provide a very robust resistance barrier for second-line treatment

Abbreviations: ARV, antiretroviral; NA, not applicable; TAF, tenofovir alafenamide fumarate; TB, tuberculosis; TDF, tenofovir disoproxil fumarate; WHO, World Health Organization.
↵a For approved and available ARVs, these costs were based upon the generic prices from the Supply Chain Management Systems E-catalog, November 2014 version.⁴ Costs do not include in-country logistic and storage costs. While these prices are more than the manufacturing cost, they are used as a proxy for the fully loaded costs, given that the generic market is competitive with a relatively low profit margin. For hypothetical ARV combinations, illustrative manufacturing costs were estimated as follows: (1) rilpivirine oral or injectable: $15, based upon expert consultation,⁶ and assuming cost of oral rilpivirine ≤ cost of injectable; (2) dolutegravir oral: $25, based upon expert consultation,⁶ and assuming cost of oral dolutegravir ≤ cost of injectable; (3) cabotegravir injectable: $25, assumed to be same cost as dolutegravir injectable and given similar structure of the 2 compounds; (4) TAF: $14 assumes TAF costs 1/3 of TDF at approximately 1/10 the dose; (5) cobicistat: $90; in the absence of other data, cost assumed to be the same as another pharmacokinetic booster, ritonavir²⁵; and (6) elvitegravir (150 mg/day) and doravirine (100 mg/day), both assumed to cost $25 per year to manufacture in the absence of other data. Note that the costs for these hypothetical ARVs are solely meant to provide a sense of the degree of savings that might be possible; actual costs may be substantially higher or lower than these estimates.
↵b WHO recommends that in cases in which zidovudine has been used in a first-line regimen, TDF should be included in the second-line regimen rather than zidovudine.
↵c Darunavir/ritonavir has the most robust resistance barrier of any boosted protease inhibitor but is not currently as widely available as a generic as lopinavir/ritonavir or atazanavir/ritonavir. Darunavir/ritonavir may be somewhat more expensive to manufacture.