Evolving Options for First-line Antiretroviral Therapy Eric S. Daar, MD Chief, Division of HIV Medicine Harbor-UCLA Medical Center Professor of Medicine David Geffen School of Medicine at UCLA Torrance, California Hello everybody, my name is Eric Daar. I’m the Chief of the Division of HIV Medicine at Harvard UCLA Medical Center and Professor of Medicine at the David Geffen School of Medicine at UCLA in Torrance, California. And we’ll be discussing today some of the evolving issues and options for first-line antiretroviral therapy in treatment-naive patients. This program is supported by an educational grant from

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Disclosures Eric S. Daar, MD, has disclosed that he has received consulting fees from Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck, and ViiV and funds for research support from Abbott, Gilead Sciences, Merck, and ViiV. My disclosures are listed upon this slide.

Factors to Consider in Choosing First-line Therapy Patient’s willingness to commit to therapy/concerns regarding adherence Baseline characteristics (eg, CD4+ cell count, HIV-1 RNA, resistance) Efficacy data Tolerability Convenience Drug–drug or drug–food interactions Comorbid conditions (eg, HBV, CV risk, renal, bone) Consequences of failure (resistance) Since the introduction of potent ARV therapy, preferred regimens all include 2 NRTIs + third drug ARV, antiretroviral; CV, cardiovascular; HBV, hepatitis B virus. So let’s go ahead and start discussing how one might select a first-line regimen for a given patient. There are a variety of factors to consider in choosing such treatment. One is patients’ willingness to commit to therapy or any concerns regarding adherence; baseline characteristics such as CD4+ viral load and drug resistance; the available efficacy or tolerability data; the overall convenience of the regimen; drug-drug or drug-food interactions; comorbid conditions such as hepatitis B coinfection, cardiovascular risk factors, and renal or bone disease; or the consequences of failure, such as what type of resistance will emerge if the patient experiences virologic failure. It’s important to note that since the introduction of potent antiretroviral therapy nearly 2 decades ago, preferred regimens all have included 2 nucleosides with a third drug.

Readiness for Therapy: A Key Decision Point Potential options PI-based therapy: lower risk of resistance at treatment failure with boosted PIs vs NNRTI- and RAL-based strategies Simple regimen (1 pill, once daily): adherence more likely Regimens to avoid Complicated regimens: frequent dosing, food requirements Regimens with more adverse events: may affect adherence Regimens with higher risk of resistance at failure RAL, raltegravir. So in thinking about the readiness for therapy, key decision points would include potential options, with PI-based therapy having some advantages with regards to the risk of resistance emerging. And this would be balanced against simplicity with 1-pill, once-a-day options being perhaps simpler and possibly associated with improved adherence.   And then we would be concerned about more complicated regimens, perhaps those that require more frequent dosing, food requirements, those that have more adverse events since we know that tolerability is related to adherence and this issue of higher risk of resistance at the time of failure.

Selection of NRTIs for First-line Therapy So let’s talk a little bit about selection of nucleosides for first-line therapy.

ACTG 5202: First-line Therapy With ABC/3TC vs TDF/FTC + EFV vs ATV/RTV Stratified by HIV-1 RNA < or ≥ 100,000 copies/mL Wk 96 TDF/FTC* 300/200 mg QD + EFV† 600 mg QD (n = 464) ABC/3TC* 600/300 mg QD + EFV† 600 mg QD (n = 465) Antiretroviral-naive patients with HIV-1 RNA ≥ 1000 copies/mL and any CD4+ cell count (N = 1857) TDF/FTC* 300/200 QD + ATV/RTV† 300/100 mg QD (n = 465) 3TC, lamivudine; ABC, abacavir; EFV, efavirenz; FTC, emtricitabine; RTV, ritonavir; QD, once daily; TDF, tenofovir. Much of this decision is informed by this ACTG study 5202, which was a large randomized control trial of over 1800 patients who were randomized to receive either blinded tenofovir/FTC or abacavir/3TC with efavirenz or atazanavir/ritonavir—all once-daily regimens. And the patients were stratified based on viral loads of less than or greater than or equal to 100,000 copies/mL, with the primary endpoint being viral suppression at Week 96 as well as safety and tolerability at 96 weeks. ABC/3TC* 600/300 mg QD + ATV/RTV† 300/100 mg QD (n = 463) *Double blind. †Open label. Sax PE, et al. N Engl J Med. 2009;361:2230-2240. Daar ES, et al. Ann Intern Med. 2011;154:445-456.

Probability of No Virologic Failure (%) Wks Since Randomization A5202: Time to Virologic Failure in Patients With HIV-1 RNA ≥ 100,000 c/mL 100 TDF/FTC (26 events) 80 ABC/3TC (57 events) 60 Probability of No Virologic Failure (%) HR: 2.33 (95% CI: 1.46-3.72; P < .001, log-rank test) 40 20 3TC, lamivudine; ABC, abacavir; FTC, emtricitabine; TDF, tenofovir. You can see that there is data demonstrating that amongst those who had viral loads of greater than 100,000, there was almost a 2 and a half times greater risk of experiencing virologic failure with the abacavir/3TC than tenofovir/FTC. And this was true regardless of whether they were receiving efavirenz as a third drug or atazanavir/ritonavir, and in fact, during the course of this study at the time of an interim review, the data safety monitoring board recommended that the patients in the high viral load group have been unblinded to their nucleosides and if they’re on abacavir/3TC, be offered to switch to tenofovir/FTC. So it’s based on this data that many guidelines have suggested at the very least, those who have high viral loads, abacavir/3TC may not be a preferred option compared to tenofovir/FTC unless there’s other reasons to not use tenofovir/FTC.   Now it’s important to note that this study only compared these nucleosides and those who received boosted atazanavir or efavirenz, which happened to be 2 of our preferred options. But we don’t know for sure that the same kind of data would be seen with alternative third drugs. 12 24 36 48 60 72 84 96 108 Wks Since Randomization Pts at Risk, n ABC/3TC 398 363 313 267 222 188 137 87 49 20 TDF/FTC 399 361 321 284 236 204 160 104 65 23 Sax PE, et al. N Engl J Med. 2009;361:2230-2240.

Patients Without VF (%) HEAT: Virologic Failure by Baseline HIV-1 RNA (A5202 Efficacy Endpoint) 100 100 90 90 87 87 15 22 80 80 4 ~ 37% 19 18 ~ 59% 60 60 Patients Without VF (%) Proportion of Subjects With VF (%) 18 40 40 63 20 20 41 3TC, lamivudine; ABC, abacavir; FTC, emtricitabine; TDF, tenofovir. And in fact, a study called the HEAT study similarly randomized patients to abacavir/3TC or tenofovir/FTC, only in this case it was with lopinavir/ritonavir. And the virologic responses in this study were no different between the 2 arms, including if you broke it down into those who had greater than or equal to 100,000 copies/mL.   Now it is noteworthy that at least amongst those people who experienced virologic failure on abacavir/3TC, it seems like it disproportionately occurred amongst those who had higher viral loads. But again, it was not clear in the overall study or in the analysis of just those with high viral loads that using this as a third drug translated into different virologic outcomes based on the nucleoside choice, although recognizing that lopinavir/ritonavir is not considered one of the preferred boosted PIs for reasons that we’ll talk about a little bit later. n = 188 205 155 140 < 100,000 ≥ 100,000 ABC/3TC TDF/FTC ABC/3TC TDF/FTC ≥ 500,000 c/mL 100,000 - < 250,000 c/mL 250,000 - < 500,000 c/mL < 100,000 c/mL Pappa K, et al. IAC 2008. Abstract THAB0304. Young B, et al. ICAAC/IDSA 2008. Abstract H-1233. 9

A5202: Time to Virologic Failure in Patients With HIV-1 RNA < 100,000 c/mL 1.0 0.8 0.6 Probability (Remaining Free of Virologic Failure) 0.4 EFV + TDF/FTC (33 events) EFV + ABC/3TC (39 events) ATV/RTV + TDF/FTC (29 events) ATV/RTV + ABC/3TC (35 events) 0.2 3TC, lamivudine; ABC, abacavir; EFV, efavirenz; FTC, emtricitabine; RTV, ritonavir; TDF, tenofovir. The other thing worth noting is that in ACTG 5202, the observation of a difference based on the nucleosides was only seen on those who had viral loads of greater than 100,000 at screening. Amongst the population who had a viral load of less than 100,000, there was actually no difference in the risk of virologic failure between the nucleosides, regardless of whether they were given with efavirenz or atazanavir/ritonavir. And this was the first situation in which there seemed to be very good evidence based on a large randomized control trial that the choice of preferred options may depend upon whether people come into the study with a high viral load or a low viral load. So again, in the patient described here, the viral load was over 100,000, and this would certainly favor tenofovir/FTC over abacavir, at least with efavirenz and atazanavir/ritonavir. 24 48 72 96 120 144 168 192 216 Pts at Risk, n Wks From Randomization 265 266 265 264 EFV + TDF/FTC EFV + ABC/3TC ATV/RTV + TDF/FTC ATV/RTV + ABC/3TC 246 247 245 242 229 223 233 223 220 211 220 214 205 195 212 205 163 151 164 158 120 104 123 110 78 65 80 69 26 21 26 22 Sax PE, et al. J Infect Dis. 2011:204;1191-1201.

HIV-1 RNA < 50 c/mL at Wk 48 (%) SINGLE Study: First-line Therapy With Dolutegravir/ABC/3TC vs EFV/TDF/FTC Difference (%): +7.4 (+2.5, +12.3; P = .003) DTG noninferior and superior to EFV at Wk 48 primary efficacy endpoint Time to HIV-1 RNA < 50 copies/mL 28 days with DTG vs 84 days with EFV (P < .0001) CD4+ cell change +267 with DTG vs +208 with EFV (P < .001) 100 88 81 80 60 HIV-1 RNA < 50 c/mL at Wk 48 (%) 40 3TC, lamivudine; ABC, abacavir; DTG, dolutegravir; FTC, emtricitabine; QD, once daily; TDF, tenofovir. Now there is other data that suggest that the third drug that’s used with the nucleosides may also be an important factor, so this is the SINGLE study. This was looking at first-line therapy with the investigational integrase inhibitor dolutegravir, given with abacavir/3TC, compared with one of the preferred options of tenofovir/FTC and efavirenz. This study, actually for the first time in any randomized control trial, didn’t just demonstrate noninferiority of the new drug with the standard of care of tenofovir/FTC, efavirenz, but actually showed superiority as you can see here in these figures, both with very high rates of virologic response—88 and 81—but favoring the dolutegravir arm.   It is important to note that when broken down, based upon how many of these failures were true virologic failures vs the need to switch therapy, which was one of the parts of the composite endpoint, that the difference was really driven by the need to switch therapy, that pure virologic failure was not obviously different between these options. 20 DTG 50 mg + ABC/3TC QD (n = 414) EFV/TDF/ FTC QD (n = 419) Walmsley S, et al. ICAAC 2012. Abstract H-556b.

SINGLE Study: Wk 48 Safety and Tolerability Outcome, % DTG 50 mg + ABC/3TC QD (n = 414) EFV/TDF/FTC QD (n = 419) Treatment-emergent adverse events Dizziness Headache Somnolence Insomnia Abnormal dreams 9 13 2 15† 7 35* 5 10 17* Serious adverse events < 1 Withdrawals due to adverse events Liver changes ALT > 3 x ULN Total bilirubin > 1.5 ULN Alkaline phosphatase > 1.5 x ULN 1 4 3TC, lamivudine; ABC, abacavir; ALT, alanine aminotransferase; DTG, dolutegravir; EFV, efavirenz; FTC, emtricitabine; RTV, ritonavir; TDF, tenofovir; ULN, upper limit of normal. And this is just the data demonstrating the adverse events. Not surprisingly, those who received efavirenz-based therapy were more likely to have things like dizziness and abnormal dreams. And the withdrawal due to adverse events is very typically between 5% and 10% on efavirenz-based regimens for things like central nervous system (CNS) toxicity and rash. And the withdrawal rate, while 10% in that group, was only 2% in the dolutegravir arm, again illustrating what primarily drove the difference in the overall efficacy of these combinations. *P < .001 †P = .029 Walmsley S, et al. ICAAC 2012. Abstract H-556b.

Dolutegravir Effective With ABC/3TC or TDF/FTC, Regardless of BL HIV-1 RNA HIV-1 RNA < 50 c/mL at Wk 48 by Subgroup (FDA Snapshot Analysis), % SPRING-2 SINGLE DTG + NRTIs RAL + NRTIs DTG + ABC/3TC EFV/TDF/ FTC BL HIV-1 RNA ≤ 100,000 c/mL ABC/3TC TDF/FTC 87 92 88 91 90 -- 83 BL HIV-1 RNA > 100,000 c/mL 81 82 71 76 DTG well tolerated with similar renal safety with either ABC/3TC or TDF/FTC 3TC, lamivudine; ABC, abacavir; BL, baseline; DTG, dolutegravir; EFV, efavirenz; FDA, US Food and Drug Administration; FTC, emtricitabine; RAL, raltegravir; TDF, tenofovir. An important question people asked is, “Well, but abacavir/3TC with dolutegravir, is that going to be an issue for those who have high viral loads as it has been seen in ACTG 5202 with other third drugs?” And in fact, if you look at the single study on the right side of this table, and the SPRING-2 study on the left, you can see that there was a decrease in virologic response between those with viral loads of greater than 100,000 vs less than or equal to 100,000. But the virologic response was very high regardless of study arm, and the drop off was really no different for dolutegravir with abacavir/3TC from 90% to 83%, with tenofovir/FTC and efavirenz from 83% to 76%. And similarly, even in SPRING-2, there was no apparent difference in virologic response between the high and low viral load group and those who received dolutegravir with the abacavir/3TC, further emphasizing the fact that it may be what the third drug is that’s important to consider, as to whether abacavir/3TC can be used in those patients with high viral loads. Eron J, et al. Glasgow 2012. Abstract P204.

Concerns Regarding NRTIs ABC Decreased potency compared with TDF in those with high HIV-1 RNA levels (> 100,000 copies/mL) when combined with EFV and ATV + RTV Variable results regarding relationship with CV events Avoid in patients with positive HLA-B*5701 test TDF Associated with greater decline in bone mineral density than ABC Associated with variable decline in renal function compared with other NRTIs ABC, abacavir; ATV, atazanavir; CV, cardiovascular; EFV, efavirenz; RTV, ritonavir; TDF, tenofovir. So, in summary, some of the concerns regarding nucleosides, for abacavir, there is decreased potency compared to tenofovir in those with high HIV viral loads when combined with efavirenz or boost atazanavir. I didn’t talk about this here, but there is variable results regarding the relationship between abacavir and cardiovascular events, some studies suggesting that the current or recent use of abacavir is associated with an increased risk of cardiovascular events particularly amongst those with other cardiovascular risk factors, while other studies have not made this observation.   And then it’s important to remember that HLA-B*5701 testing should be performed prior to giving abacavir because those who have HLA-B*5701 are at increased risk for abacavir-associated hypersensitivity reaction, and it should not be given in that subset of patients. The trade-off is tenofovir; while showing better efficacy in the high viral load group with certain third drugs, it has been seen in many studies to be associated with greater decline in bone mineral density than abacavir and variable declines in renal function compared to other nucleosides.

Selecting the Third Drug in a First-line Regimen What about the third drug in a first-line regimen?

What’s Available as Fixed-Dose Combinations, and What’s Coming? Available Now Efavirenz/tenofovir DF/ emtricitabine Rilpivirine/tenofovir DF/ emtricitabine Elvitegravir/cobicistat/ tenofovir DF/emtricitabine Future Options Darunavir/cobicistat Darunavir/cobicistat/ emtricitabine/tenofovir alafenamide (GS-7340) Atazanavir/cobicistat Dolutegravir/abacavir/ lamivudine Dolutegravir will be initially available as single tablet, not fixed-dose combination So when we talk about currently available, fixed-dose combinations, as mentioned, efavirenz/tenofovir/emtricitabine would be one, rilpivirine/tenofovir/emtricitabine, and the 4-drug elvitegravir/cobicistat combination. There are also other fixed‑dose combinations available or coming, not all as 1-pill complete regimens, but we know lopinavir and ritonavir was a fixed-dose combination, although no longer a preferred boosted PI.   Darunavir is being developed with cobicistat as a fixed-dose combination, and even the potential to use that as a new formulation of tenofovir and emtricitabine to be perhaps the first 1-pill, once-a-day boosted protease inhibitor combination. Atazanavir is being developed with cobicistat, again as a combination pill. And then, as mentioned, although probably not initially available when dolutegravir is approved—assuming it’s approved—but eventually dolutegravir will be created as a fixed-dose combination with abacavir and lamivudine.

Efficacy Comparison of Boosted PIs ARTEMIS[1] (ITT, TLOVR) 96 Wks CASTLE[2] (ITT, NC = F) 96 Wks 100 100 79 80 80 74 71 68 60 60 HIV-1 RNA < 50 c/mL (%) HIV-1 RNA < 50 c/mL (%) 40 40 ATV, atazanavir; BID, twice daily; DRV, darunavir; ITT, intent to treat; LPV, lopinavir; NC = F, noncompleter equals failure; RTV, ritonavir; QD, once daily; TLOVR, time to loss of virologic response. So, in thinking about the preferred option where adherence is not an issue, it’s again convenience, which we’ve talked about, and tolerability and efficacy. For the preferred PIs, it’s darunavir/ritonavir or atazanavir/ritonavir, both of which have been compared head-to-head with lopinavir/ritonavir and demonstrated at least equal efficacy but improved tolerability, particularly with regards to lipids and gastrointestinal. And that’s why they are currently considered the preferred boosted PIs. 20 20 346 343 443 440 LPV/RTV 800/200 QD or BID DRV/RTV 800/100 QD LPV/RTV 400/100 BID ATV/RTV 300/100 QD 1. Mills A, et al. AIDS. 2009;23:1679-1688. 2. Molina JM, et al. J Acquir Immune Defic Syndr. 2010;53:323-332. 17 17

A5202: Efficacy With ATV/RTV vs EFV 1.0 0.8 0.6 Probability (Remaining Free of Virologic Failure) 0.4 EFV + TDF/FTC (57 events) EFV + ABC/3TC (72 events) ATV/RTV + TDF/FTC (57 events) ATV/RTV + ABC/3TC (83 events) 0.2 3TC, lamivudine; ABC, abacavir; ATV, atazanavir; EFV, efavirenz; FTC, emtricitabine; RTV, ritonavir; TDF, tenofovir. We don’t yet have data head-to-head comparison of darunavir and atazanavir, although there is a recently completed ACTG study 5257 that actually does directly compare these boosted PIs, and data from that will likely be coming out in the not-too-distant future. We have data from the ACTG 5202. We already talked about the nucleoside comparisons, but it also compared atazanavir/ritonavir with efavirenz, so a boosted PI vs a first-line NNRTI, and showed very similar overall efficacy. 4 8 16 24 36 48 60 72 84 96 108 120 132 144 156 168 180 192 204 216 Pts at Risk, n Wks From Randomization 464 465 465 463 EFV + TDF/FTC EFV + ABC/3TC ATV/RTV + TDF/FTC ATV/RTV + ABC/3TC 448 447 450 449 435 420 427 430 419 393 415 398 406 373 403 381 397 361 390 367 392 353 380 355 379 345 370 347 367 331 364 338 332 291 322 303 287 264 285 260 254 225 252 226 206 191 214 185 166 159 178 154 127 114 126 109 91 77 87 74 41 38 45 32 9 5 5 6 Daar ES, et al. Ann Intern Med. 2011;154:445-456. Sax PE, et al. J Infect Dis. 2011;204:1191-1201.

STARTMRK: Efficacy of RAL vs EFV (MK-###) (PN###) "CONFIDENTIAL - LIMITED ACCESS", Interim Deck-Expires when CSR Deck is Available 7/22/2018 7:24 PM STARTMRK: Efficacy of RAL vs EFV RAL is BID vs QD (EFV) but fewer adverse events (52% vs 80%) 100 86 82 81 79 75 69 76 67 71 61 CD4+ gain: +374 +312 80 60 ITT, NC = F HIV-1 RNA < 50 c/mL (%) 40 20 BID, twice daily; EFV, efavirenz; ITT, intent to treat; NC = F, noncompleter equals failure; QD, once daily; QHS, at bedtime; RAL, raltegravir. And then the STARTMRK study was the first study to compare a first-line integrase inhibitor—in this case, twice-daily raltegravir—with one of the gold standards—tenofovir/FTC/efavirenz—demonstrating out here now to 240 weeks very good efficacy; in fact, over time, better virologic response rates in the raltegravir arm than the efavirenz arm. And one of the big differences in this particular study was one regimen needed to be given twice a day but was associated with substantially less toxicity—raltegravir being less toxic than the efavirenz-based regimen, although obviously both were highly effective and generally well tolerated. And when they stratify these based on viral load with the boosted PIs and the integrase inhibitor, the response rates were similarly good whether they had a high viral load—greater than 100,000—or less than 100,000 at entry. 12 24 48 72 96 120 144 168 192 216 240 Wks Pts at Risk, n 281 278 279 280 277 282 RAL 400 mg BID EFV 600 mg QHS Rockstroh JK, et al. J Acquir Immune Dis Syndr. 2013;63:77-85. White Template MASTER 120710.ppt

ECHO and THRIVE: HIV-1 RNA < 50 c/mL With EFV vs RPV Favors EFV Favors RPV ECHO Wk 48 Wk 96 THRIVE Pooled -0.4% P < .0001 -3.2% P = .0055 3.5% P < .0001 2.4% P < .0001 EFV, efavirenz; ITT, intent to treat; NC = F, noncompleter equals failure; RPV, rilpivirine; TDF, tenofovir; TLOVR, time to loss of virologic response. Now this is the data from the pivotal trials that led to the approval of rilpivirine—the so-called ECHO and THRIVE studies. These were large, phase III randomized control trials that compared first-line therapy with rilpivirine vs efavirenz to NNRTIs. The expectation based upon the phase IIb studies is that rilpivirine would be efficacious and perhaps better tolerated than efavirenz. If you look at the overall data from both of these studies, as well as the pooled data—96 weeks at the bottom of this figure—you can see very similar virologic efficacy comparing these 2 NNRTIs.   However, it was noteworthy that there was a higher rate of discontinuation because of adverse events amongst those who received efavirenz, and that was balanced out by a somewhat higher rate of virologic failure in those who received rilpivirine vs efavirenz, in particular those who came into the study with viral loads of greater than 100,000. -0.4% P < .0001 -12 -10 -8 -6 -4 -2 0 2 4 6 8 10 12 Percent Difference (Noninferiority at 12% Margin) ITT-TLOVR. All patients received TDF/FTC. Cohen CJ, et al. AIDS. 2013;27:939-950. Molina JM, et al. Lancet. 2011;378:238-246. Cohen CJ, et al. Lancet. 2011;378:229-237.

Pooled ECHO/THRIVE Analysis: Wk 96 Safety Adverse Event, % Rilpivirine (n = 686) Efavirenz (n = 682) Most common adverse events of interest Any neurologic Dizziness Any psychiatric Abnormal dreams/nightmares Rash (any type) 17 8 16 8 4 38* 27* 24* 13† 15* Grade 2-4 laboratory abnormality Total cholesterol LDL-C AST ALT 7 6 22* 18* 10 11 ALT, alanine aminotransferase; AST, aspartate aminotransferase; LDL-C, low density lipoprotein cholesterol. So this shows the adverse events demonstrating efavirenz was associated with considerably more neurologic side effects, as we might expect, as well as rash. And rilpivirine had considerably less effect on lipids, particularly cholesterol, than efavirenz.   So these were clear advantages of rilpivirine over efavirenz. *P < .0001 vs rilpivirine. †P = .0039 vs rilpivirine. Cohen CJ, et al. AIDS. 2013;27:939-950

ECHO/THRIVE Post Hoc Analysis: Wk 96 Efficacy by Baseline VL and CD4+ Count Rilpivirine Efavirenz Rilpivirine Efavirenz 100 100 84 85 80 81 79 79 80 75 80 75 70 71 69 60 60 56 HIV-1 RNA < 50 copies/mL (%) 40 40 VL, viral load. However, you can see that if you look at the virologic response amongst those who had viral loads of less than or equal to 100,000, it was very high and similar. But if you look at the drop off within the arms, when you go from less than or equal to 100,000 to greater than 100,000, for efavirenz it went from only 80% to 75% response rates, whereas with rilpivirine it dropped from 84% to 70%. And similarly, there was a drop off in response amongst those who received rilpivirine as baseline CD4s declined, going from 85% to 81%, down to 71% in those who had CD4s less than 200, and 56% in those of CD4s less than 50.   And it’s based on this data that we’ve come to understand that rilpivirine, while very effective and very well tolerated, is not as active virologically in those who have the higher viral loads. 20 20 n = 368 329 n = 318 353 n = 34 36 194 175 313 307 144 164 ≤ 100K > 100K < 50 50 - < 200 200 - < 350 ≥ 350 By Baseline HIV-1 RNA (copies/mL) By Baseline CD4+ Count (cells/mm3) Cohen CJ, et al. AIDS. 2013;27:939-950.

RPV/TDF/FTC Indications [1] DHHS guidelines 2013[2] RPV is not recommended in patients with pretreatment HIV-1 RNA > 100,000 copies/mL Higher rate of virologic failures reported in patients with pre-ART CD4+ count < 200 cells/mm3 who were treated with RPV + 2 NRTIs ART, antiretroviral therapy; DHHS, US Department of Health and Human Services; FTC, emtricitabine; RPV, rilpivirine; TDF, tenofovir. And both the package insert—the actual indication for usage—now specifically says that this should not be used in people who have viral loads of over 100,000 and that the population that it’s indicated for are those with less than this number. And the DHHS guidelines sort of echo these recommendations and also discuss the higher rate of virologic failure reported amongst those with CD4s of less than 200 who are treated with this regimen. 1. RPV/TDF/FTC [package insert]. June 2013. 2. DHHS Guidelines. February 2013.

Efficacy of EVG/COBI/TDF/FTC vs EFV/TDF/FTC 100 Diff: 3.6%, 95% CI (-1.6% to +8.8%) EVG/COBI/TDF/FTC 88 84 EFV/TDF/FTC 80 60 CD4+ change: +239 vs +206 cells/mm3 (P = .009) No difference by baseline characteristics HIV-1 RNA < 50 copies/mL (%) 40 COBI, cobicistat; EFV, efavirenz; EVG, elvitegravir; FTC, emtricitabine; TDF, tenofovir What about some of the other options, including other fixed-dose combination, 4-drug elvitegravir/cobicistat combination pill, studied in comparison with tenofovir/FTC and efavirenz? It demonstrates very high virologic response rates—88% and 84% between the groups—which was clearly noninferior. The rate of virologic nonsuppression was the same and very, very low, and the CD4+ responses were very good with both, although favoring the 4-drug combination over the efavirenz- based regimen. At least statistically, the clinical relevance of this difference is not completely clear. 20 9 7 7 5 Virologic Success Virologic Nonsuppression No Wk 48 Data Sax P, et al. Lancet. 2012;379:2439-2448. Sax P, et al. IAS 2012. Abstract TUPE028. 24

EVG/COBI/TDF/FTC vs EFV/TDF/FTC: Common Adverse Events Treatment Emergent Adverse Events in ≥ 10% of Subjects, % EVG/COBI/TDF/FTC (n = 348) EFV/TDF/FTC (n = 352) Diarrhea 23 19 Nausea* 21 14 Abnormal dreams† 15 27 Upper respiratory infection 11 Headache 10 Fatigue 13 Insomnia* 9 Depression Dizziness† 7 24 Rash‡ 6 12 COBI, cobicistat; EFV, efavirenz; EVG, elvitegravir; FTC, emtricitabine; TDF, tenofovir From a tolerability perspective, the efavirenz-based regimen was, as expected, associated with more abnormal dreams, insomnia, dizziness, and rash, where those who received the 4-drug combination pill had a somewhat higher risk for nausea, most of which was relatively mild nausea. *P < .05 †P < .001 ‡P = .009 Sax P, et al. Lancet. 2012;379:2439-2448.

Efficacy of EVG/COBI/TDF/FTC vs ATV/RTV + TDF/FTC 100 92% 80 88% Diff: 3.5% (95% CI: -1.0 to 8.0) 60 HIV-1 RNA < 50 c/mL (ITT, M = F) (%) COBI/EVG/TDF/FTC ATV/RTV + TDF/FTC 40 20 ATV, atazanavir; COBI, cobicistat; EVG, elvitegravir; FTC, emtricitabine; ITT, intent to treat; M = F, missing equals failure; RTV, ritonavir; TDF, tenofovir. This 4-drug combination was also compared to a preferred, boosted PI regimen—in this case, atazanivir/ritonavir—at 48 weeks, demonstrating excellent virologic responses, and the 4-drug combination in both of these studies demonstrated good efficacy regardless of baseline viral load and CD4+ counts. The CD4+ responses here were the same essentially at 48 weeks. BL 2 4 8 12 16 24 32 40 48 Wk Changes in CD4+ count: EVG/COBI/TDF/FTC +207 vs ATV/RTV +211 cells/mm3 (P = .61). No difference by baseline characteristics DeJesus E, et al. Lancet . 2012;379:2429-2438.

Adverse Events With EVG/COBI/TDF/FTC vs ATV/RTV + TDF/FTC Adverse Events > 10% in Either Group Overall Discontinuation Rate EVG/COBI/ TDF/FTC (n = 353) ATV/RTV + TDF/FTC (n = 355) Diarrhea 22 27 Nausea 20 19 Upper respiratory infection 15 16 Headache 12 Fatigue 14 13 Ocular icterus 1 EVG/COBI/ TDF/FTC (n = 353) ATV/RTV + TDF/FTC (n = 355) Overall 4 5 Diarrhea 1 < 1 Nausea Vomiting Ocular icterus Jaundice Drug eruption ATV, atazanavir; COBI, cobicistat; EVG, elvitegravir; FTC, emtricitabine; RTV, ritonavir; TDF, tenofovir. Here’s the tolerability data—again, a major factor in deciding which regimen to use. And it shows that overall, the tolerability and safety profile were quite similar, with the one difference really being the ocular icterus, which occurred substantially more often and not surprisingly in those who received boosted atazanavir in the 4-drug combination. Discontinuation rates due to renal adverse events were identical in both arms (0.3%) DeJesus E, et al. Lancet. 2012;379:2429-2438.

DHHS and IAS-USA Guidelines: What to Start DHHS Preferred Regimens[1] IAS-USA Recommended Regimens[2] NNRTI EFV/TDF/FTC EFV/TDF/FTC or EFV + ABC/3TC* Boosted PI ATV/RTV + TDF/FTC DRV/RTV + TDF/FTC ATV/RTV + (TDF/FTC or ABC/3TC*) INSTI RAL + TDF/FTC DHHS Alternative Regimens[1] IAS-USA Alternative Regimens[2] NNRTI EFV + ABC/3TC* RPV/TDF/FTC or RPV + ABC/3TC* NVP + (TDF/FTC or ABC/3TC*) RPV/TDF/FTC or RPV + ABC/3TC* Boosted PI based ATV/RTV + ABC/3TC DRV/RTV + ABC/3TC FPV/RTV + (TDF/FTC or ABC/3TC) LPV/RTV‡ + (TDF/FTC or ABC/3TC) LPV/RTV‡ + (TDF/FTC or ABC/3TC*) INSTI based RAL + ABC/3TC* EVG/COBI/TDF/FTC§ EVG/COBI/TDF/FTC 3TC, lamivudine; ABC, abacavir; ATV, atazanavir; COBI, cobicistat; DTG, dolutegravir; DRV, darunavir; EFV, efavirenz; EVG, elvitegravir; FTC, emtricitabine; LPV, lopinavir; RAL, raltegravir; RPV, rilpivirine; RTV, ritonavir; TDF, tenofovir. So based upon all of this data, in a setting in which all things are essentially equal, no concerns about adherence, not a lot in the way of comorbid conditions, and where the decision is primarily based on safety, efficacy data as well as things like convenience, the DHHS and the International AIDS Society-USA (IAS-USA) have made specific recommendations for preferred and alternative options.   For DHHS, the preferred options have been tenofovir/FTC with efavirenz, atazanavir/ritonavir, darunavir/ritonavir, or raltegravir. ISA-USA guidelines are exactly the same, although the major change that occurred in the most recent version of the guidelines is that they also acknowledge that in those who have viral loads of less than 100,000, abacavir and lamivudine may be viable, preferred alternative nucleosides if used in combination with efavirenz and atazanavir/ritonavir where there are data demonstrating equal efficacy in the subset of people with low viral loads and then a list of alternative regimens below that. *In HLA-B*5701–negative patients with baseline HIV-1 RNA < 100,000 copies/mL. †Avoiding the use of ABC or LPV/RTV might be considered for patients with or at high risk of cardiovascular disease. 1. DHHS Guidelines. February 2013. 2. Thompson MA, et al. JAMA. 2012;308:387-402.

Considerations for Patients Without Other Medical Concerns Adherence Patient preference (ie, simple regimen) Efficacy Baseline HIV-1 RNA > 100,000 copies/mL Use abacavir with caution Rilpivirine not recommended Concerns about specific adverse events And so in consideration of patients without other medical concerns, it really comes down to adherence, patient preference, which will usually be the simplest regimen available, and obviously one that’s very well tolerated; the efficacy data—we know that baseline viral load of greater than 100,000 may be relevant in using abacavir, particularly with atazanavir, ritonavir, and efavirenz and to be better characterized in other combinations, and is an issue with rilpivirine, where rilpivirine is not actually recommended in this setting; and then there are concerns about specific side effects that may influence the decision in one patient more than another.   So, in reality, for the patient in which there are not a lot of comorbid conditions, these are the main factors that drive the decision, but a lot of our patients do have other comorbid issues or other situations that might further impact the choice of therapy.

Switching From EFV/TDF/FTC to RPV/TDF/FTC in Suppressed Patients Single-arm study of 50 patients virologically suppressed on EFV/TDF/FTC as first regimen for ≥ 3 mos No known resistance mutations to study meds Desiring to switch for intolerance of regimen 100% maintained HIV-1 RNA < 50 c/mL at Wk 12 after switch to RPV/TDF/FTC (primary endpoint) No events leading to discontinuation after switch RPV mean Ctrough within target range by 2 wks Plasma Concentrations of RPV (Ctrough) or EFV (Any Time) 2000 1600 EFV concentration RPV Ctrough RPV mean Ctrough in ECHO/THRIVE 1200 800 EFV, efavirenz; FTC, emtricitabine; RPV, rilpivirine; TDF, tenofovir. So, there is some data in addition to just our clinical experience in making switches. There was a switch study that took people on tenofovir/FTC and efavirenz and put them onto tenofovir/FTC/rilpivirine. And I think the reason this study was important is because it allowed somebody to go from one simple fixed-dose combination to another; that we know rilpivirine is not associated with the kinds of CNS toxicities efavirenz is, or if it is, certainly much less frequent; and it gave us the opportunity to address whether there are real concerns about switching from efavirenz to rilpivirine because of the effect efavirenz has on the induction of cytochrome P450.   So, this was a single-arm study of 50 patients, who were virologically suppressed for at least 3 months, and in actuality the median time for suppression was well over a year. They had no known resistance mutations—and this is extremely important—and were interested in a switch for intolerance of the regimen. And what they found after 12 weeks is that all of the patients remained suppressed on rilpivirine. And they did an intensive PK study showing that, yes, there was a delay in getting the rilpivirine levels in orange up to what was thought to be therapeutic levels that are seen in this grey bar. But this didn’t translate into virologic failure either because these people had been suppressed for so long that there was plenty of time to get the levels up before they were going to rebound or perhaps that the efavirenz levels are around for so long, in this blue line, continuing to provide some virologic suppression while the rilpivirine levels were sort of increasing. So we do have some data showing that you can make this kind of a switch. It is important to note that this data was derived from a population of people who had been suppressed for a prolonged period of time, unlike the patient described here, who was on their way down virologically and had only been on therapy for 8 weeks. So we have much less data in that setting, but at least it’s suggestive that we may be able to get away with this type of a strategy. 400 Mean Concentration (ng/mL) 120 80 40 2 4 6 8 10 12 Wks After Switch Mills A, et al. ICAAC 2011. Abstract H2-794c.

Considerations With Alternative Regimens and Near-Future Regimens So let me just share with you some of the data on some of the alternative regimens, as well as some near-future regimens in development that may have an impact on this type of patient.

GS102 & GS103: EVG/COBI/TDF/FTC vs EFV/TDF/FTC or ATV/RTV + TDF/FTC Randomized, double-blind, double dummy, active-controlled, international phase III studies Wk 48 Wk 192 GS 102 ~ 89% men 33% > 105 c/mL CD4+ ~ 380 c/mm3 EVG/COBI/TDF/FTC QD EFV/FTC/TDF QD Treatment naive HIV-1 RNA ≥ 5000 c/mL Any CD4+ cell count eGFR ≥ 70 mL/min ATV, atazanavir; COBI, cobicistat; EFV, efavirenz; eGFR, estimated glomerular filtration rate; EVG, elvitegravir; FTC, emtricitabine; QD, once daily; RTV, ritonavir; TDF, tenofovir. So, first the 4-drug combination, which was compared head-to-head with tenofovir/FTC/efavirenz and tenofovir/FTC and a preferred boosted PI atazanavir/ritonavir in these Studies 102 and 103. And as you can see in orange, as far as the baseline characteristics, in addition to being treatment naive, they all had an estimated glomerular filtration rate of greater than or equal to 70 mL/min. So that’s the group that’s been studied and that’s the group for which this drug is indicated. The 4-drug elvitegravir/cobicistat combination pill, studied in comparison with tenofovir/FTC and efavirenz, demonstrates very high virologic response rates—88% and 84% between the groups—which was clearly noninferior. GS 103 ~ 90% men ~ 41% > 105 c/mL CD4+ ~ 359 c/mm3 EVG/COBI/TDF/FTC QD ATV/RTV + TDF/FTC QD Sax P, et al. Lancet. 2012;379:2439-2448. DeJesus E, et al. Lancet. 2012;379:2429-2438.

EVG/COBI/TDF/FTC vs EFV or ATV/RTV: Creatinine Changes 0.35 0.28 EFV/TDF/FTC ATV/RTV + TDF/FTC 0.30 0.24 0.25 0.20 0.20 0.16 0.15 Change from BL in Serum Creatinine (mg/dL) (IQR) 0.12 0.10 0.08 0.05 0.04 -0.05 ATV, atazanavir; BL, baseline; COBI, cobicistat; EFV, efavirenz; EVG, elvitegravir; FTC, emtricitabine; RTV, ritonavir; TDF, tenofovir. And this is what you observe when you initiate therapy. With the 4-drug combination in green, you see this sudden increase in the first 2-4 weeks in creatinine, and then it levels off. So there are lots of ways you can follow someone like this—assuming they start out with a creatinine clearance of greater than 70—but perhaps one of the simplest is to look at the creatinine after 2-4 weeks and use that as a new set point. And really only consider nephrotoxicity emerging if their creatinine continues to increase after that initial period of time. And the same thing was seen when compared with atazanavir/ritonavir, although, as has been seen in other studies, there is a modest increase in the first few weeks with atazanavir/ritonavir as well. -0.10 -0.04 BL 2 4 8 12 16 24 32 40 48 BL 2 4 8 12 16 24 32 40 48 Wks Wks Cobicistat is associated with reduced active secretion of creatinine in the renal tubules leading to initial rises in creatinine levels Sax P, et al. Lancet. 2012;379:2439-2448. DeJesus E, et al. Lancet. 2012;379:2429-2438.

SPRING-2: Wk 48 Analysis of TDF/FTC or ABC/3TC + DTG vs RAL HIV-1 RNA < 50 copies/mL CD4+ Cell Change (cells/mm3) Δ 2.5% (95% CI: -2.2 to 7.1) 100 250 230 230 88 85 80 200 60 150 Patients (%) CD4+ Cell Change (cells/mm3) 40 100 20 3TC, lamivudine; ABC, abacavir; BID, twice daily; DTG, dolutegravir, FTC, emtricitabine; QD, once daily; RAL, raltegravir; TDF, tenofovir. And then we talked a little bit about dolutegravir as a drug in development—a new integrase inhibitor. This was SPRING-2, a head-to-head comparison of dolutegravir vs raltegravir. You can see that the overall virologic response rates were very high with both, and it demonstrated noninferiority. Dolutegravir is given once a day and doesn’t require any pharmacologic boosting.   There was an identical increase in CD4+ cells between the 2 arms. 50 DTG 50 mg QD (n = 411) RAL 400 mg BID (n = 411) DTG 50 mg QD (n = 411) RAL 400 mg BID (n = 411) Noninferiority criteria met. Raffi F, et al. IAC 2012. Abstract ThLBB04.

SPRING-2: Changes in Serum Creatinine and Creatinine Clearance Change in Serum Creatinine, Mean (± SD) Change in CrCl, Mean (± SD) 25 10 20 15 +12.3 Mean Change From Baseline of Creatinine (µmol/L) Mean Change From Baseline (µmol/L) 10 10 +4.7 5 DTG 50 mg QD (n = 411) RAL 400 mg BID (n = 411) -20 -5 BID, twice daily; BL, baseline; CrCl, creatinine clearance; DTG, dolutegravir; SD, standard deviation; RAL, raltegravir. And then this effect on creatinine: again, the change in serum creatinine observed in the first 2-4 weeks of dolutegravir therapy that’s not seen with raltegravir. And this translates into a reduction in calculated creatinine clearance, but this doesn’t represent real nephrotoxicity; it’s an effect of dolutegravir on the renal tubular handling of creatinine, but it does complicate monitoring therapy.   Now these studies included people who had creatinine clearances of above 50, but again, it needs to be monitored very closely. -30 2 4 8 12 16 24 32 40 48 BL 4 12 24 48 Wk Wk Baseline (µmol/L): DTG 74.7 vs RAL 75.2 Baseline (mL/min): DTG 125 vs RAL 128 Raffi F, et al. IAC 2012. Abstract ThLBB04.

SPRING-2: Wk 48 Safety and Tolerability Outcome Dolutegravir 50 mg QD (n = 411) Raltegravir 400 mg BID (n = 411) Treatment-emergent adverse events, % Nausea Headache Nasopharyngitis Diarrhea 14 12 11 13 Serious adverse events, % 7 8 Withdrawals due to adverse events, % 2 Mean change in creatinine clearance (mL/min) -15.5 -5.4 3TC, lamivudine; ABC, abacavir; BID, twice daily; FTC, emtricitabine; TDF, tenofovir. And here’s simply some data looking at the overall tolerability between dolutegravir and raltegravir. Both were extremely well tolerated—withdrawals due to adverse events only occurred in 2% in each—but there was this greater increase in creatinine translating into a greater decrease in creatinine clearance with dolutegravir vs raltegravir. All patients received either TDF/FTC or ABC/3TC. Raffi F, et al. IAC 2012. Abstract ThLBB04.

Tenofovir Alafenamide (TAF) vs Tenofovir DF in ART-Naive Patients TAF (GS-7340), investigational prodrug of tenofovir with lower plasma concentrations, increased delivery to hepatocytes, lymphoid cells Gut TFV TDF TAF Plasma TDF/TFV TAF Lymphoid Cells TAF TFV ART, antiretroviral; DP, diphosphate; MP, monophosphate; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate; TFV, tenofovir. Now there is a new form of tenofovir that’s being developed, a new prodrug called tenofovir alafenamide, or TAF, T-A-F. There is a phase IIb study comparing this to tenofovir disoproxil fumarate (TDF), the currently approved form of tenofovir that is also present in several of the fixed‑drug combinations. The rationale for developing this particular drug is that we know that tenofovir in its native form is not absorbed, but with the TDF prodrug, you do get the metabolism of active tenofovir present in plasma and accumulating in lymphoid cells in the active form.   TAF can be given at a much lower dose; it’s not metabolized into tenofovir in the plasma, so your plasma levels of tenofovir—the active drug—is very, very low. But then TAF is accumulated in the lymphoid cells where it’s actually working, metabolized into the active form of tenofovir, and then provides its antiviral activity. And the rationale is that if you have very low levels of tenofovir in the plasma, perhaps it will have less effect on some of the end organs that are adversely affected by tenofovir, such as the kidneys and perhaps the bone. Cathepsin A TFV-MP TFV-DP Zolopa A, et al. CROI 2013. Abstract 99LB.

Study 292: Wk 24 Virologic and Immunologic Outcomes HIV-1 RNA < 50 copies/mL CD4+ Cell Change 100 200 89.7 87.5 177 P = .76 175 163 80 150 125 60 Patients (%) CD4+ Cell Gain (cells/mm3) 100 40 75 COBI, cobicistat; EVG, elvitegravir; FTC, emtricitabine; TAF, tenofovir alafenamide; TDF, tenofovir. So in the phase IIb studies, they simply compared the 4-drug combination, as currently approved with tenofovir disoproxil fumarate to a similar drug with TAF. And it showed, again, in relatively small numbers of patients, excellent virologic responses in both groups with similar CD4+ changes. 50 20 25 EVG/COBI FTC/TAF (n = 112) EVG/COBI FTC/TDF (n = 58) EVG/COBI FTC/TAF (n = 112) EVG/COBI FTC/TDF (n = 58) Zolopa A, et al. CROI 2013. Abstract 99LB.

Study 292: Wk 24 Safety and Tolerability EVG/COBI/FTC/TAF (n = 112) EVG/COBI/FTC/TDF (n = 58) Treatment-emergent adverse events, % Nausea Diarrhea Fatigue Headache 18 12 10 9 Grade 3/4 creatine phosphokinase, % 5 3 Median change in eGFR (Cockcroft-Gault), mL/min -4.9 -11.8 (P = .04) Median change in lipids, mg/dL Total cholesterol LDL-C HDL-C Triglycerides +31 +17 +6 +24 +15 (P < .001) +4 (P = .001) +2 (P = .007) +21 Change in bone mineral density, % Spine Hip -0.8 -0.3 -2.5 (P = .002) -2.0 (P < .001) COBI, cobicistat; eGFR, estimated glomerular filtration rate; EVG, elvitegravir; FTC, emtricitabine; HDL-C, high density lipoprotein cholesterol; LDL-C, low density lipoprotein cholesterol; TAF, tenofovir alafenamide; TDF, tenofovir. The tolerability was extremely similar between the groups. However, if you looked at median change and estimated glomerular filtration rate (GFR), it was significantly less in those who received TAF vs tenofovir. Similarly, if you looked at change in bone mineral density, both at the spine and hip, there was highly significant differences in what happened during the first 24 weeks of therapy. This supports the fact that this new prodrug of tenofovir may be better tolerated. It also can be given at a lower dose, which may facilitate the development of fixed-dose combinations since there’s less drug mass that needs to go into the pill. And there are phase III trials underway now to definitely demonstrate the overall efficacy as well as safety of this new prodrug of tenofovir. Zolopa A, et al. CROI 2013. Abstract 99LB.

Key Considerations in Patients With Kidney Disease Tenofovir DF should generally be used with caution in patients with preexisting renal conditions Elvitegravir/cobicistat/tenofovir DF/emtricitabine CrCl of ≥ 70 mL/min Dolutegravir studied in CrCl > 50 mL/min but also associated with initial decline in CrCl Atazanavir/ritonavir has been associated with increased risk of nephrotoxicity CrCl, creatinine clearance. So key considerations in somebody with kidney disease: One is that tenofovir should generally be used with caution in those who have preexisting disease, recognizing that it can be directly nephrotoxic. The 4-drug elvitegravir/cobicistat combination is not approved for people with creatinine clearances of less than 70 mL/min. Dolutegravir has been studied in those with greater than 50 mL/min but is associated with an initial decline in creatinine clearance that does require careful monitoring. And atazanavir/ritonavir has also been associated with the increased risk of nephrotoxicity.

EVG/COBI/TDF/FTC vs EFV or ATV/RTV: Lipid Changes 20 19 P = .001 25 23 18 17 EVG/COBI/TDF/FTC EVG/COBI/TDF/FTC 16 20 EFV/TDF/FTC ATV/RTV + TDF/FTC 14 12 15 P = .92 10 10 P = .001 P = .30 10 Change From BL at Wk 48 (mg/dL) P = .44 11 11 8 10 8 7 7 10 P = .23 8 8 6 5 6 5 4 5 ATV, atazanavir; BL, baseline; COBI, cobicistat; EFV, efavirenz; EVG, elvitegravir; FTC, emtricitabine; HDL, high density lipoprotein; LDL, low density lipoprotein; RTV, ritonavir; TDF, tenofovir. With regards to the effect on lipids, the 4-drug elvitegravir/cobicistat combination compared with efavirenz, you can see there was a greater effect of efavirenz on cholesterol, with no difference on triglycerides. In contrast with atazanavir/ritonavir, the effect on cholesterol was essentially the same with the 4-drug combination, but there was a significantly greater effect on triglycerides with atazanavir/ritonavir. 2 Total Cholesterol LDL HDL Total Cholesterol Triglycerides LDL HDL Triglycerides Conclusion: Whereas some lipid fractions better with EVG/COBI/TDF/FTC than EFV or ATV/RTV, overall differences were modest and unlikely to be of clinical significance Sax P, et al. Lancet. 2012;379:2439-2448. DeJesus E, et al. Lancet. 2012;379:2429-2438. Sax P, et al. CROI 2012. Abstract 101.

SPRING-2: Wk 48 Safety and Tolerability Outcome Dolutegravir 50 mg QD (n = 411) Raltegravir 400 mg BID (n = 411) Treatment-emergent adverse events, % Nausea Headache Nasopharyngitis Diarrhea 14 12 11 13 Serious adverse events, % 7 8 Withdrawals due to adverse events, % 2 Mean change in creatinine clearance, mL/min -15.5 -5.4 Median change in lipids, mg/dL Total cholesterol Triglycerides +4 +1 +8 +6 3TC, lamivudine; ABC, abacavir; BID, twice daily; FTC, emtricitabine; QD, once daily; TDF, tenofovir. In SPRING-2, it was a head-to-head comparison of dolutegravir and raltegravir. As mentioned, previous studies have shown that raltegravir is associated with minimal effect in total cholesterol in triglycerides and very similar—if nothing a little bit less—but very similar minimal effect with dolutegravir. All patients received either TDF/FTC or ABC/3TC. Raffi F, et al. IAC 2012. Abstract ThLBB04.

HIV-1 RNA < 50 copies/mL Cobicistat vs RTV to Boost ATV With TDF/FTC in Treatment-Naive Patients Double-blind phase III study Noninferiority (12% margin) Wk 48 primary outcome (“snapshot”) HIV-1 RNA < 50 copies/mL Stratified by baseline HIV-1 RNA and CD4+ count Wk 96 COBI 150 mg + ATV QD + TDF/FTC (n = 344) Treatment-naive patients, HIV-1 RNA ≥ 5000 copies/mL, any CD4+ cell count, CrCl ≥ 70 mL/min ATV, atazanavir; COBI, cobicistat; CrCl, creatinine clearance; FTC, emtricitabine; RTV, ritonavir; QD, once daily; TDF, tenofovir. What about cobicistat? One of the hopes was that perhaps cobicistat would have less of an effect on lipids than ritonavir. And we have a head-to-head comparison in a phase III double‑blind study of atazanavir and tenofovir/FTC combined with either cobicistat vs ritonavir. RTV 100 mg + ATV QD + TDF/FTC (n = 348) Gallant JE, et al. J Infect Dis. 2013;208:32-39.

COBI vs RTV to Boost ATV: Efficacy 100 80 Patients With HIV-1 RNA < 50 copies/mL (%) 60 40 COBI (n = 344) RTV (n = 348) ATV, atazanavir; COBI, cobicistat; RTV, ritonavir. This study demonstrated very high levels of virologic response that were virtually superimposable between the 2 study arms. So cobicistat, from an efficacy perspective, is a viable option when combined with atazanavir. 20 12 24 36 48 Wks Gallant JE, et al. J Infect Dis. 2013;208:32-39.

COBI vs RTV to Boost ATV: Adverse Events Adverse Events Occurring in ≥ 10% of Individuals Adverse Event, n (%) COBI (n = 344) RTV (n = 348) P Value Jaundice 72 (20.9) 54 (15.5) .076 Scleral icterus 61 (17.7) 64 (18.4) .84 Nausea 57 (16.4) .69 Diarrhea 53 (15.4) 71 (20.4) .093 Headache 38 (11.0) Nasopharyngitis 37 (10.8) 53 (15.2) .09 Hyperbilirubinemia 39 (11.3) 34 (9.8) .54 URTI 35 (10.2) 28 (8.0) .36 Adverse Events Leading to Discontinuations Adverse Event, n (%) COBI (n = 344) RTV (n = 348) Scleral icterus 8 (2.3) 4 (1.1) Jaundice 9 (2.6) 7 (2.0) Hyperbilirubinemia 1 (0.3) 2 (0.6) Rash Allergic dermatitis ATV, atazanavir; COBI, cobicistat; RTV, ritonavir; URTI, upper respiratory tract infection. From a tolerability perspective, there was also not much in the way of a difference for all of the side effects listed in these tables. Gallant JE, et al. J Infect Dis. 2013;208:32-39.

COBI vs RTV to Boost ATV: Changes in Fasting Lipids at Wk 48 25 25 ATV + COBI ATV + RTV 20 20 15 15 P = .081 P = .32 P = .69 Median Change at WK 48 (mg/dL) Median Change at WK 48 (mg/dL) 10 10 ATV, atazanavir; COBI, cobicistat; HDL, high density lipoprotein; LDL, low density lipoprotein; RTV, ritonavir. There were really very little in the way of differences from a lipid perspective either. You can see no significant differences in lipids overall for cholesterol and, although a trend, nonsignificant trend with a greater effect of ritonavir on triglycerides than cobicistat, although both were associated with an increase in triglycerides. 5 5 Total Cholesterol LDL HDL Triglycerides Gallant J, et al. IAC 2012. Abstract TUAB0103.

Key Metabolic and CVD Considerations Inconsistent data on CVD risk with ABC Increased lipids with LPV/RTV, FPV/RTV ATV/RTV and DRV/RTV are preferred PIs due to lower daily dose of RTV than LPV/RTV and less effect on lipids COBI and RTV effects on cholesterol similar, but trend for lower effect on triglycerides with COBI RAL and DTG have relatively neutral effect on plasma lipids EVG/COBI/TDF/FTC has somewhat less effect on cholesterol than EFV and similar effect to ATV/RTV for cholesterol, but less effect on triglycerides RPV has less effect on lipids than EFV ATV, atazanavir; COBI, cobicistat; CVD, cardiovascular disease; DTG, dolutegravir; DRV, darunavir; EFV, efavirenz; EVG, elvitegravir; FTC, emtricitabine; RPV, rilpivirine; RTV, ritonavir; TDF, tenofovir. So from a metabolic and cardiovascular disease considerations perspective, there is inconsistent data on cardiovascular disease risk with abacavir: some studies showing an increased risk, others not. We know that you see increased lipids with lopinavir/ritonavir and fosamprenavir/ritonavir, compared to the curve for third boosted PIs atazanavir, ritonavir, and darunavir. Cobicistat and ritonavir effects on cholesterol are similar, but a trend for lower effects on triglycerides with cobicistat. Both raltegravir and dolutegravir have relatively neutral effects on plasma lipids. The 4-drug elvitegravir/cobicistat combination has somewhat less effect on cholesterol than efavirenz, a similar effect to atazanavir/ritonavir for cholesterol but less effect on triglycerides. And finally, amongst the nonnucleosides, rilpivirine has less effect on lipids than efavirenz.

Conclusions and Summary Currently many simple and easy-to-administer first-line antiretroviral regimens The decision as to which regimen to select first is based upon efficacy, safety, and select characteristics Concerns regarding adherence Virologic characteristic (eg, baseline HIV-1 RNA, drug resistance) Comorbid conditions (eg, cardiovascular disease, hepatitis coinfection, renal disease) So in conclusion, and by way of summary, currently there are many simple and easy-to-administer first-line antiretroviral regimens. The decision as to which regimen to select first is based upon efficacy, safety, and a variety of specific characteristics. The concerns regarding adherence might be a first factor that would determine which regimen one might use. Virologic characteristics, such as baseline viral load and drug resistance, might influence the decision. And then, finally, comorbid conditions, such as cardiovascular disease, hepatitis coinfection, and renal disease will also have an impact on how one selects from amongst the many potential first-line options.

Go Online for More on First-line HIV Therapy! Interactive Virtual Presentation (slides and audio) on practical strategies to engage HIV patients in timely care Interactive Case Challenges: test your ability to make optimal choices in selecting first-line antiretroviral therapy Interactive Tool aimed at helping you select the best therapy for your individual patient clinicaloptions.com/firstline2013