1. HIV Alert: Updating Your Practice Based on New Guideline Recommendations
These slides include notes based on commentary provided by Eric S. Daar, MD.
This program is supported by independent educational grants from Gilead Sciences and ViiV Healthcare.

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3. Faculty
Eric S. Daar, MD Chief, Division of HIV Medicine Harbor-UCLA Medical Center Professor of Medicine David Geffen School of Medicine at UCLA Los Angeles, California
Paul E. Sax, MD Clinical Director, HIV Program and Division of Infectious Diseases Brigham and Women’s Hospital Professor of Medicine Harvard Medical School Boston, Massachusetts

4. Faculty Disclosure Information
Eric S. Daar, MD, has disclosed that he has received consulting fees from Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck, Teva, and ViiV and funds for research support from Gilead Sciences, Merck, and ViiV. Paul E. Sax, MD, has disclosed that he has received consulting fees from AbbVie, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Janssen, Merck, and ViiV and funds for research support from Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, and ViiV.

5. Program Overview Updated Initial Therapy Recommendations
Recommendations on Switching ART in Virologically Suppressed Patients
Expert Perspective
Applying the Guidelines in Clinical Practice
Other Key Guideline Updates
ART, antiretroviral therapy.
So what we’re going to do today is we’ll talk a little bit about the updated initial therapy recommendations; recommendations on switching therapy in virologically suppressed patients, a scenario that seems to be occurring with increased frequency in light of the various new drugs; an expert perspective on applying the guidelines in clinical practice and a few other key guidelines updates; and then finally, we’ll have some time at the end for questions and answers.
Slide credit: clinicaloptions.com

6. Updated Initial Therapy Recommendations

7. Updated DHHS Guidelines: Recommendations for Initial ART
Class
First-line ART Regimens
Recommended
Alternative
INSTI
DTG/ABC/3TC
DTG + FTC/TDF or FTC/TAF
EVG/COBI/FTC/TDF
EVG/COBI/FTC/TAF
RAL + FTC/TDF or FTC/TAF
Boosted PI
DRV + RTV + FTC/TDF or FTC/TAF
ATV/(COBI or RTV) + FTC/TDF or FTC/TAF
DRV/(COBI or RTV) + ABC/3TC
DRV/COBI + FTC/TDF or FTC/TAF
NNRTI
EFV/FTC/TDF
EFV + FTC/TAF
RPV/FTC/TDF or RPV/FTC/TAF
3TC, lamivudine; ABC, abacavir; ART, antiretroviral therapy; ATV, atazanavir; COBI, cobicistat; CrCl, creatinine clearance; DHHS, US Department of Health and Human Services; DRV, darunavir; DTG, dolutegravir; EFV, efavirenz; eGFR, estimated glomerular filtration rate; EVG, elvitegravir; FTC, emtricitabine; HBsAg, hepatitis B surface antigen; RAL, raltegravir; RPV, rilpivirine; RTV, ritonavir; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate.
So as far as initial therapy recommendations, this is a summary of the most recent DHHS guidelines, updated in July of 2016, very similar to the previous guidelines. Most of the recommended regimens are now integrase based. The big difference from these guidelines and the previous version is the inclusion of tenofovir alafenamide as a nucleoside backbone option. So it used to be that that was true for the elvitegravir/cobicistat/FTC regimen, either with disoproxil fumarate or alafenamide, but now they also have that as an option with dolutegravir or with raltegravir.
And similarly, the other drug that’s listed as recommended, other class, is a boosted PI. It’s darunavir/ritonavir, and again it was expanded to include not just FTC/TDF, but also FTC/TAF. And there are a variety of alternative regimens, notably lopinavir/ritonavir was removed as an alternative option because it has shown to be less tolerable than atazanavir and darunavir. And then we have these other NNRTI-based alternative regimens.
And it’s important to note in bold we have those that are single-tablet regimens, so there’s an increasing number of options for those people who really want that single-tablet option. And that we also individualize therapy. The recommendations may differ based on things like baseline viral load, CD4, creatinine clearance, HLA-B*5701 status, whether the person has chronic hepatitis B or osteopenia or osteoporosis.
Bolding indicates single-tablet regimen.
Recommendations may differ based on baseline HIV-1 RNA, CD4+ count, CrCl, eGFR, HLA-B*5701 status, HBsAg status, and osteoporosis status
Slide credit: clinicaloptions.com
DHHS Guidelines. July 2016.

8. Updated IAS-USA Guidelines: Recommendations for Initial ART
Key difference from DHHS: recommended regimens include only INSTIs + FTC/TAF or ABC/3TC (ie, no TDF)
Panel notes that if FTC/TAF is unavailable, TDF + FTC or 3TC remains effective and in general well tolerated
Class
First-line ART Regimens
Recommended
Alternative (If INSTI Not an Option)
INSTI
DTG/ABC/3TC
DTG + FTC/TAF
EVG/COBI/FTC/TAF
RAL + FTC/TAF
Boosted PI
DRV/(COBI or RTV) + ABC/3TC
DRV/(COBI or RTV) + FTC/TDF or FTC/TAF
NNRTI
EFV/FTC/TDF
RPV/FTC/TDF or RPV/FTC/TAF
3TC, lamivudine; ABC, abacavir; ART, antiretroviral therapy; COBI, cobicistat; CrCl, creatinine clearance; DHHS, US Department of Health and Human Services; DRV, darunavir; DTG, dolutegravir; EFV, efavirenz; eGFR, estimated glomerular filtration rate; EVG, elvitegravir; FTC, emtricitabine; HBsAg, hepatitis B surface antigen; IAS-USA, International Antiviral Society-USA; RAL, raltegravir; RPV, rilpivirine; RTV, ritonavir; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate.
And here are the new IAS-USA guidelines. Now these are only updated every 2 years, so this represents more of a dramatic shift from when they were last updated in the summer of And here they have of the recommended options only integrase-based regimens. So there is not a boosted PI as a recommended option. They’re listed as alternatives, and that represents one major shift from previous guidelines and a difference from the DHHS guidelines. The other thing that’s notable is if you look at the recommended options, all of the FTC/tenofovir-based regimens recommend alafenamide as opposed to tenofovir disoproxil fumarate. Now there’s an important caveat in that they have a footnote that says that if FTC/TAF is unavailable, TDF plus FTC or 3TC would be an effective option and is generally well tolerated. So this represents one of the main differences from previous guidelines as well as from DHHS. Otherwise, things are very similar with the same caveats that we individualize therapy based on a variety of baseline factors and comorbid conditions.
Recommendations may differ based on baseline HIV-1 RNA, CD4+ count, CrCl, eGFR, HLA-B*5701 status, HBsAg status, and osteoporosis status
Slide credit: clinicaloptions.com
Günthard HF, et al. JAMA. 2016;316:

9. Clinical Trials Supporting FTC/TAF Use
TAF noninferior to TDF as initial therapy in GS-104/111
Wk 48 virologic success: 92% with EVG/COBI/FTC/TAF vs 90% with EVG/COBI/FTC/TDF (difference: 2%; 95% CI:-0.7% to 4.7)
Study
Pt Population
Treatment
GS-104/111[1]
Treatment naive (N = 1733)
EVG/COBI/FTC/TAF vs EVG/COBI/FTC/TDF
GS-109[2]
Virologically suppressed on TDF-based regimen (N = 1436)
Switch to EVG/COBI/FTC/TAF vs remain on TDF-based regimen
GS-1089[3]
Virologically suppressed on FTC/TDF + third ARV (N = 663)
Switch to FTC/TAF + continue third ARV vs remain on FTC/TDF + third ARV
GS-112[4]
Virologically suppressed on varied regimens; stable eGFRCG mL/min (N = 242)
Switch to EVG/COBI/FTC/TAF
ARV, antiretroviral; COBI, cobicistat; EVG, elvitegravir; FTC, emtricitabine; eGFRCG, estimated glomerular filtration rate by Cockcroft-Gault formula; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate.
So what about the data that support TAF/FTC since this represents one of the big changes from previous guidelines? Well, so there’s quite a bit. But interestingly enough, there are a variety of TAF-based regimens, included in the preferred options, but really only one that was compared in a head-to-head trial in treatment-naive patients. And that was the Trials 104 and 111, which enrolled over 1700 treatment-naive patients and randomized them to elvitegravir/cobicistat/FTC with either TAF or TDF and showed very high rates of virologic suppression at 48 weeks—90% and 92%—and clearly met noninferiority.
The other regimens that are TAF based and approved for first-line therapy are not based on head-to-head comparisons in this patient population, but based upon switch data, and 2 of the big switch studies were 109 and The 109 study included 1400 patients who were suppressed on a TDF-based regimen, and then switched to elvitegravir/cobicistat/FTC and TAF vs remaining on their regimen and again showed noninferiority with good tolerability. And we’ll come back to the tolerability issue in a moment because that’s really the factor that’s driving some of the recommendations to use TAF over TDF.
The 1089 study enrolled people who were FTC/TDF plus a third drug and randomized them to switch to FTC/TAF, continuing their third drug or remain on their FTC/TDF and their third drug. And again, also showed noninferiority with some safety advantages.
And then finally the study at the bottom, Study 112, with a single-arm open-label study of virologically suppressed patients on a variety of regimens, who had stable estimated glomerular infiltration rates between 30 and 69, to address the safety of a TAF-based regimen, in this case elvitegravir/cobicistat/FTC/TAF in people with significant kidney disease. It’s actually this study—and we’ll talk about the data in a moment—that led to the current recommendations and the package insert for all TAF-based regimens allowing them to be used for people with creatinine clearances of 30 mL/min or above.
1. Sax PE, et al. Lancet. 2015;385: Mills A, et al. Lancet Infect Dis. 2016;16: Gallant JE, et al. Lancet HIV. 2016;3:e158-e Pozniak A, et al. J Acquir Immune Defic Syndr. 2016;71:
Slide credit: clinicaloptions.com

10. TAF Associated With More Favorable Renal and Bone Marker Changes vs TDF
In both initial therapy and switch studies, TAF-based ART associated with the following (vs TDF-based ART) at Wk 48:
Higher eGFRCG
Less proteinuria (urinary protein, albumin, RBP, and β2-M to urine Cr ratio)
No proximal renal tubulopathy or Fanconi syndrome has been observed with TAF-based treatment
In initial therapy studies: smaller declines in spine and hip BMD with TAF-based ART vs TDF-based ART at Wk 48 (P < .001)
In switch studies: TAF-based treatment improved spine and hip BMD vs remaining on TDF-based treatment at Wk 48
TAF lipid neutral, lacks lipid lowering effects observed with TDF
ART, antiretroviral therapy; β2-M, β2-microglobulin; BMD, bone mineral density; Cr, creatinine; eGFRCG, estimated glomerular filtration rate by Cockcroft-Gault formula; RBP, renal-binding protein; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate.
So this slide describes some of the advantages of TAF. So in general in most of these trials, whether it was the head-to-head comparison in naives or switch studies, demonstrate similar virologic efficacy. But the advantages were in the safety profile in that, in both initial and switch studies, the TAF-based regimens were associated with higher GFRs and less proteinuria, urinary protein as well as tubular proteins. There were no cases of proximal renal tubulopathy or Fanconi syndrome observed in these TAF-based treatment studies. And the initial therapy studies showed smaller declines in spine and hip bone mineral density with TAF when compared to TDF. And similarly, in the switch studies, those who received TAF experienced improvement in their spine and their hip BMDs.
Finally, from a lipid perspective as you’re all aware, TDF actually has a lipid-lowering effect, and with TAF, you have lower systemic levels and presumably less of an effect on lipids. And this is what’s seen in that lipid profile with TAF doesn’t demonstrate the benefits. You tend to see in these studies—higher lipids in those who receive TAF vs TDF.
Sax PE, et al. Lancet. 2015;385: Mills A, et al. Lancet Infect Dis. 2016;16: Gallant JE, et al. Lancet HIV. 2016;3:e158-e165. Wohl D, et al. J Acquir Immune Defic Syndr. 2016;72:58-64.
Slide credit: clinicaloptions.com

11. GS-112: Switching to EVG/COBI/FTC/TAF in Pts With Renal Impairment
Multicenter, single-arm, open-label phase III trial in which virologically suppressed pts with stable eGFRCG mL/min switched to EVG/COBI/FTC/TAF (N = 242)
Varied preswitch regimens: 65% received TDF
Measured GFR by Iohexol Clearance
Clinically Relevant Proteinuria
Proteinuria (UPCR)
≤ 200 mg/g
> 200 mg/g
100
BL < 50 mL/min
BL ≥ 50 mL/min
100 9 25 80 80 35 65 65 67 56 60 60
mGFR (mL/min) 47
Pts (%) 43 44 91
BL, baseline; COBI, cobicistat; eGFRCG, estimated glomerular filtration rate by Cockcroft-Gault formula; EVG, elvitegravir; FTC, emtricitabine; mGFR, measured glomerular filtration rate; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate; UPCR, urine protein to creatinine ratio.
In the 112 study, remember this was a single-arm open-label study of people with significant chronic kidney disease with creatinine clearances estimated between 30 and 69. And they were switched to elvitegravir/cobicistat/FTC/TAF and then monitored over time. And you can see in the panel on the left, it’s actually measured GFR by iohexol clearance, showing that there was no change regardless of whether they started out with a baseline creatinine clearance < 50 or
And when you looked at relevant proteinuria in these panels, baseline and Week 48, yellow is bad, so more yellow is bad, more green is good. And you can see that that’s exactly what was seen in these people, both in the < 50 and the group, that the proteinuria profile improved with the switch, and about two thirds or so of these people were on a TDF-based regimen at the time they were switched. And it’s based on these data—and these data really alone—that all of the package inserts for all TAF-based regimens and the guidelines recommend that TAF can be used in people with creatinine clearances of 30 mL/min or above. 40 40 75 65 20 20 44 BL
Wk 2/4/8
Wk 24 BL
Wk 2/4/8
Wk 24 BL
Wk 48 BL
Wk 48
BL < 50 mL/min
BL ≥ 50 mL/min
Slide credit: clinicaloptions.com
Pozniak A, et al. J Acquir Immune Defic Syndr. 2016;71:

12. Recommendations on Switching ART in Virologically Suppressed Patients
ART, antiretroviral therapy.

13. Reasons to Consider Regimen Switching in Virologically Suppressed Pts
Simplification
Avoid toxicity
Improve tolerability or convenience
Manage drug–drug or drug–food interactions
Pregnancy
Cost
The reasons to consider a switch would be for simplification, and I would say that this is probably the most common reason I’m seeing people switching in my clinic; to avoid toxicity, for people either experiencing or concerned about it; improved tolerability or convenience; manage drug–drug or drug–food interactions; in the setting of pregnancy; and perhaps in some cases, to save money or reduce cost.
Slide credit: clinicaloptions.com
DHHS Guidelines. July 2016.

14. Principles of Regimen Switching in Virologically Suppressed Pts
Review ART history for intolerance or virologic failure
Review resistance testing results
If prior resistance uncertain, consider switch only if new regimen likely to maintain suppression of resistant virus
Care needed when switching from pharmacologically-boosted PI to another class if full treatment or resistance history is unknown
Consult an expert when switching a pt with resistance to ≥ 1 class
Within-class switches usually maintain virologic suppression if no resistance to drugs in that class
Increase monitoring during first 3 mos after switch
Don’t forget about HBV
ART, antiretroviral therapy; HBV, hepatitis B virus.
There are some key principles that have not changed in the guidelines for some time, and that is if you’re going to switch, the goal is to maintain virologic suppression and hopefully achieve some benefit, as described on the previous slide. And I think that’s an important thing to remind our patients that there’s always some risk associated with switching and that there should be a good reason to do it. Inconvenience, simplification, those are all good reasons, but there should be some reason to do it, not just because there’s some new drug out.
And in order to do it safely, you need to review the treatment history, looking at tolerance or virologic failures to see if there are certain drugs you may need to avoid or for which resistance may have been selected for. You need to review as much of the resistance data as possible. Sometimes it’s not all available, but what you can access in the past is helpful. And if prior resistance is uncertain, you really need to consider switch only in a new regimen where there’s likely to maintain good viral suppression. And this is particularly important in somebody who’s stably suppressed on a boosted protease inhibitor where we know that it doesn’t necessarily need 2 other fully active drugs to have suppression, and that some people on a boosted PI, even with resistant NRTIs in the background, can be suppressed.
In contrast, for most non–PI-based regimens, you really do need more active drugs in the background. And this is the setting where we’ve seen people go wrong, where they switch in the regimen like this without noticing their resistance may have been selected for in the past and put them on an NNRTI- or an INSTI-based regimen, and they end up experiencing viral rebound and perhaps selection of new resistance for the new drug.
The comment of consult an expert when switching a patient with resistance ≥ 1 class illustrates just how hard this can be when things start to get tricky. In contrast to someone who’s been suppressed on their first regimen forever who’s looking to switch, where there’s unlikely to be any resistance in the background, within-class switches usually maintain viral suppression if there’s no resistance to the drugs in the class. And generally, we recommend increased monitoring the first few months, both for tolerability and to make sure there’s no viral rebound.
And that important caveat at the bottom of the slide that we sometimes forget is remember if they’ve got chronic hepatitis B infection, they need to be on 2 drugs that are active against hep B in most cases. So you need to be aware of that if you’re thinking about making a switch to a regimen perhaps that only has 1 active drug against hepatitis B.
Slide credit: clinicaloptions.com
DHHS Guidelines. July 2016.

15. Updated DHHS Guidelines: Switching ART in Virologically Suppressed Pts
Switch Strategies With Good Supporting Evidence
Switch Strategies under Evaluation
(Not Yet Recommended)
Switch Strategies Not Recommended
Within-class switch
EFV to RPV
TDF to TAF
RAL to DTG or EVG/COBI
PI/RTV to PI/COBI
Between-class switch, provided no resistance to other regimen components
Boosted PI to RPV
NNRTI to INSTI
Boosted PI to INSTI
PI/RTV + 3TC, if no baseline resistance and pt has had sustained virologic suppression
Switch to PI/RTV + INSTI
Switch to EVG/COBI/FTC/TDF + DRV
Switch to DTG + 3TC or FTC
Switch to RTV-boosted PI monotherapy
Switching 1 component to MVC
3TC, lamivudine; COBI, cobicistat; DHHS, US Department of Health and Human Services; DTG, dolutegravir; EFV, efavirenz; EVG, elvitegravir; FTC, emtricitabine; MCV, maraviroc; RAL, raltegravir; RPV, rilpivirine; RTV, ritonavir; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate.
With increasing numbers of options, there have been more and more studies of switching to assess safety and efficacy. So there are a variety of switch studies that have demonstrated strong evidence that switch is going to happen within classes, such as one NNRTI to another, efavirenz to rilpivirine; TDF to TAF; integrase inhibitors or raltegravir to dolutegravir or elvitegravir/cobicistat; and then within boosted protease inhibitors, such as a PI with ritonavir to a PI with cobicistat. A lot of data and every reason to believe these kinds of switches can occur safely.
Between class switches, there’s data looking at boosted PIs to NNRTI such as rilpivirine, again, though, being cautious that there’s fully active NRTIs in the backbone that you’re going to then be including with the rilpivirine. An NNRTI to an INSTI and boosted PI to an INSTI, again, with the same caveat. And then there are some data looking at a boosted PI with just 3TC where 3TC is predicted to be a fully active drug based on treatment history, where this too has proven to be effective in maintaining viral suppression.
There are variety of switch studies under investigation, such as switching a boosted PI to a boosted PI plus an INSTI, switching people who have underlying resistance who perhaps are on NRTIs, a boosted PI and an INSTI, to a simplified regimen of elvitegravir/cobicistat/FTC and TDF plus darunavir. A 2-pill regimen for a highly treatment–experienced population. Or perhaps switching to dolutegravir plus 3TC or FTC, again, where there’s some early data showing that this may be adequate to maintain suppression. But these 3 groups, there’s less data.
And then it’s not recommended that we switch to ritonavir-boosted PI monotherapies or switch one component to maraviroc based on some studies that have shown less than optimal outcomes.
Slide credit: clinicaloptions.com
DHHS Guidelines. July 2016.

16. Expert Perspective: Applying the Guidelines in Clinical Practice
So how do we apply these to clinical practice?

17. How to Choose Among Recommended First-line Regimens: Comparison of INSTIs
Advantages
Disadvantages
DTG
QD dosing
Available as STR
Highest barrier to resistance
No food requirement
Superior to EFV and DRV/RTV
Superior to RAL in tx-exp’d pts
Superior to ATV/RTV in women
Only coformulated with ABC/3TC
Serum Cr increases (inhibits tubular secretion)
Insomnia and headache more frequent in some studies
Largest pill size of STRs
EVG
Requires PK boosting (COBI)
Only coformulated with FTC/(TDF or TAF)
Most drug-drug interactions
Serum Cr increases because cobicistat inhibits tubular secretion
Requires food with dosing
RAL
Longest safety record
Fewest drug-drug interactions
Superior to ATV/RTV and DRV/RTV
Currently BID
Not available as STR
3TC, lamivudine; ABC, abacavir; ATV, atazanavir; BID, twice daily; COBI, cobicistat; Cr, creatinine; DRV, darunavir; DTG, dolutegravir; EFV, efavirenz; EVG, elvitegravir; FTC, emtricitabine; QD, once daily; RAL, raltegravir; RTV, ritonavir; STR, single-tablet regimen; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate.
I think it’s important since integrase inhibitors are now preferred options in both guidelines that we think about some of the different factors, how they distinguish from each other. So for example, without going through all the details on this slide, dolutegravir has some clear advantages in that it’s once a day, available as a single-tablet regimen. There is growing evidence showing it has a higher barrier to resistance than the other integrase inhibitors such that the likelihood of developing resistance is much smaller. In fact, at least in treatment naive trials to date, there has been no one who’s selected for any resistance, not just to the INSTI, but even the NRTIs in the backbone.
There are several studies showing superior overall efficacy to efavirenz, darunavir/ritonavir, raltegravir, and most recently, in a study of women, with atazanavir and ritonavir. Now it only comes with abacavir/3TC, so if you didn’t want to use those NRTIs, you couldn’t use the single-tablet regimen. There is an effect of dolutegravir on increasing creatinine artifactually, but it does happen. There are maybe some CNS side effects in some people, and it’s a relatively large single-tablet regimen.
For elvitegravir, it also comes in a single-tablet regimen. It is superior to atazanavir/ritonavir in women, and there is some boosting, though, so you need to be aware of drug-drug interactions anytime you use it, much like we’re used to with our boosted PIs. It’s only coformulated with FTC and tenofovir DF or AF, so again, if you want to use abacavir/3TC, you wouldn’t be able to use it as a single-tablet regimen. And it also has the effect on renal function, needs to be taken with food.
And then raltegravir, we have the longest record of safety and efficacy, fewest drug–drug interactions, no food requirement, has been shown to be superior to atazanavir/ritonavir and darunavir. But it is currently a BID regimen, and that would be a disadvantage. It’s not available as a single-tablet regimen.
Günthard HF, et al. JAMA. 2016;316: Orrell C, et al. AIDS Abstract THAB0205LB.
Slide credit: clinicaloptions.com

18. When to Use Alternative Regimens for Initial ART: When INSTIs Not an Option
When you cannot use an INSTI
For EVG/COBI, if potential DDIs exist
Eg, in combination with rifampin or rifapentine, lovastatin, simvastatin, corticosteroids, etc.
For DTG, in combination with dofetilide or rifapentine
If pt experiences neuropsychiatric adverse events with INSTI
Previously, INSTIs avoided in absence of drug resistance testing, but latest DHHS guidance recommends the following regimens in this setting:
(DRV/RTV or DTG) + (FTC/TAF or FTC/TDF)
ART, antiretroviral therapy; COBI, cobicistat; DDI, drug-drug interaction; DHHS, US Department of Health and Human Services; DRV, darunavir; DTG, dolutegravir; EVG, elvitegravir; FTC, emtricitabine; RTV, ritonavir; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate.
What about alternatives? When do we need to use something else or need to consider using something else? When is an integrase inhibitor not an option, for example? Well, for elvitegravir/cobicistat, if there are important drug–drug interactions. And there are many, just like there are with ritonavir. This includes rifampin, the other rifamycins, some of the statins, and corticosteroids. Remember corticosteroids given with cobicistat or ritonavir results in high and more sustained levels. This has been a problem with inhaled steroids, where we generally don’t think of much in the way of systemic levels, but particularly fluticasone. In some of the others, we’ve seen people become Cushingoid or when they stop the inhalers, for example, develop adrenal crisis.
The same thing is true with some systemic steroid preparations, particularly with injections, like epidural injections, where the person may have sustained levels if they’re using corticosteroids with booster. So it needs to be used with caution with ritonavir- and cobicistat-boosted agents, whether that’s a protease inhibitor or elvitegravir.
For dolutegravir, there’s some important drug–drug interactions. In addition, metformin, which you can use, but you need to start at a lower dose and titrate up to avoid toxicity. And then if there’s patients who have experienced neuropsychiatric adverse events with an INSTI, you might want to consider an alternative option.
Traditionally, we’ve said not to use integrase inhibitors in people where you don’t have drug resistance data for fear that they may have some underlying nucleoside resistance. And this has been a setting where the guidelines have generally recommended if you’re in a rush to start treatment, to use a boosted PI where you’re not as reliant upon the NRTIs. There’s growing data that dolutegravir may be similar and that you can get away with less than 2 other fully active drugs and is now listed in the guidelines as another option for those people who you’re in a rush to start therapy, and you haven’t yet received their drug resistance data.
Slide credit: clinicaloptions.com
DHHS Guidelines. July 2016.

19. When to Use Alternative Regimens for Initial ART: When TAF Not an Option
Do not use TAF
If CrCl < 30 mL/min
With rifabutin, rifampin, or rifapentine (rifamycins are potent P-gp inducers and TAF is P-gp substrate)
In pregnancy (pending data in this setting)
As PrEP
Do not use EVG/COBI/FTC/TAF
If severe hepatic impairment
If potential COBI DDIs
Eg, lovastatin, simvastatin, corticosteroids
ART, antiretroviral therapy; COBI, cobicistat; CrCl, creatinine clearance; DDI, drug-drug interaction; EVG, elvitegravir; FTC, emtricitabine; P-gp, P glycoprotein; PrEP, pre-exposure prophylaxis; TAF, tenofovir alafenamide.
So when would you not consider using TAF? Well, certainly those with creatinine clearances < 30. There are major drug–drug interactions with rifamycins, and in this case not just rifampin, but also rifabutin in that it reduces the level. So TAF can’t be used in these settings. In pregnancy, simply because we don’t have enough data yet. And an important caveat is it’s not supposed to be used as PrEP.
In the package insert, TAF-based preparations, it also says not to use it in people with chronic hepatitis B, as a hep B active drug. But the studies have been completed, the data presented, and the FDA is reviewing it, and there’s every indication that it works. In fact, the DHHS guidelines and IAS-USA guidelines that came out 2 months ago have both taken the leap and said that in people with chronic hepatitis B, TAF or TDF can be used with lamivudine or emtricitabine.
You wouldn’t use elvitegravir/cobicistat/FTC/TAF in people with severe hepatic impairment or because of important drug–drug interactions. Again, things like statins, and importantly those corticosteroids, which we often forget people are taking because they’re either getting them intermittently from a pain clinic or anesthesia for back pain as epidural injection or they’re using inhalers, either prescription or sometimes even over the counter. So again, we need to be really cognizant of that whenever using any boosted drug.
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20. Recommended TDF and TAF Co-formulations in Pts With Renal Impairment
CrCl (mL/min)
EVG/COBI/FTC/TAF[1]
or FTC/TAF[2]
FTC/TDF[3]
EVG/COBI/FTC/TDF[4]
≥ 70
No adjustment needed
50-70
No adjustment needed*
Initiation not recommended
30-49
Adjust dosing interval
Initiation not recommended; discontinue EVG/COBI/FTC/TDF if CrCl declines to this level during treatment
< 30
Initiation not recommended;
discontinue EVG/COBI/FTC/TDF if CrCl declines to this level during treatment
COBI, cobicistat; CrCl, creatinine clearance; EVG, elvitegravir; FTC, emtricitabine; IDSA, Infectious Diseases Society of America; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate.
As far as TDF and TAF in people with renal impairment, as you probably know, elvitegravir/cobicistat/FTC/TAF and FTC/TAF, based on that one single-arm study, can be used without dose adjustment in anybody with a creatinine clearance of 30 or above. FTC/TDF, you don’t need to dose adjust until they get to a creatinine clearance of < 50, but the IDSA guidelines generally recommend that it not be used in people who have creatinine clearances of < 60. And then finally elvitegravir/cobicistat/FTC/TDF is only recommended for people who have creatinine clearances of ≥ 70 mL/min.
*IDSA recommends against use of TDF if CrCl < 60 mL/min.[5]
1. EVG/COBI/FTC/TAF [package insert]. 2. FTC/TAF [package insert]. 3. FTC/TDF [package insert]. 4. EVG/COBI/FTC/TDF [package insert]. 5. Lucas GM, et al. Clin Infect Dis. 2014;59:e96-e138.
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21. When to Use Alternative Regimens for Initial ART: When ABC Not an Option
Do not use ABC
If patient is HLA-B* positive
If patient is HBsAg positive and the regimen does not include 2 other drugs active against HBV
Use ABC with caution
If patient has or is at high risk for cardiovascular disease
Do not use DTG/ABC/3TC
If moderate or severe hepatic impairment
If patient is also receiving dofetilide or rifapentine
If CrCl < 50 mL/min
3TC, lamivudine; ABC, abacavir; ART, antiretroviral therapy; CrCl, creatinine clearance; DTG, dolutegravir; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus.
What about using alternative initial options when abacavir isn’t appropriate? Well, we don’t use abacavir in people who are HLA-B*5701 positive because of concern of increased risk for hypersensitivity. And if the patient has hep B chronic infection, then we need to acknowledge that they have to be on 2 other hep B active drugs, unlike if they’re on tenofovir as TDF or TAF, then just 3TC or FTC is adequate. In this case, they would need to be on something else because abacavir doesn’t have activity against hepatitis B.
In addition, you need to use abacavir with caution in those who have high risk for cardiovascular disease, acknowledging that the data are conflicting. And then you wouldn’t use dolutegravir/abacavir/3TC in people with moderate or severe hepatic impairment, if the patient is also receiving drugs in which there’s important drug–drug interactions, and importantly if they have a creatinine clearance of < 50 mL/min. You are supposed to dose adjust 3TC. So you couldn’t use it as a single-tablet regimen.
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22. When to Use Alternative Regimens for Initial ART: When DRV/RTV Not an Option
Do not use DRV/RTV
If severe hepatic impairment
If potential DDIs present
Eg, lovastatin, simvastatin, rifampin, rifapentine, corticosteroids
Use DRV/RTV with caution
If patient has history of severe sulfonamide reaction
ART, antiretroviral therapy; DDI, drug-drug interaction; DRV, darunavir; RTV, ritonavir.
What about alternatives for boosted PIs, which remain one of the preferred options in the DHHS guidelines? Well, we don’t use darunavir/ritonavir or darunavir/cobicistat with severe hepatic impairment, the drug–drug interaction issue again with the statins, rifamycins, corticosteroids. And you’d use it with caution with people with severe sulfonamide reactions because there is a sulfa moiety in darunavir.
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23. Other Key Guideline Updates

24. Updated IAS-USA Guidelines: Opportunistic Infection Prophylaxis
“Primary Mycobacterium avium complex prophylaxis is not recommended if effective ART is initiated immediately and viral suppression achieved”[1]
“Primary Pneumocystis pneumonia prophylaxis is recommended for patients who meet CD4 cell count criteria, even if taking ART”[1]
CD4+ cell count threshold: < 200 cells/mm3[2]
ART, antiretroviral therapy; IAS-USA, International Antiviral Society-USA.
The IAS-USA guidelines added that primary MAC prophylaxis is not recommended if effective therapy is initiated immediately and viral suppression is achieved. So basically when you meet those people with advanced disease, you don’t necessarily need to rush to put them on MAC prophylaxis if your intention is to start them quickly on antiretrovirals and anticipate a good response.
In contrast, they continue to recommend Pneumocystis prophylaxis for patients who have CD4s of < 200, until they’ve had appropriate immune reconstitution.
1. Günthard HF, et al. JAMA. 2016;316: DHHS Adult OI Guidelines. August 2016.
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25. Updated Recommendations for HBV/HIV Coinfection
FTC/TAF now recommended as NRTI backbone in pts with HBV/HIV coinfection in both DHHS and IAS- USA guidelines even though not yet FDA approved for this indication
Both recommend TDF or TAF plus 3TC or FTC as backbone in suppressive ART regimen
3TC, lamivudine; ART, antiretroviral therapy; DHHS, US Department of Health and Human Services; FDA, US Food and Drug Administration; FTC, emtricitabine; HBV, hepatitis B virus; IAS-USA, International Antiviral Society-USA; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate.
And then for hep B, as I mentioned, FTC/TAF is now recommended as a NRTI backbone in patients who have coinfection with HBV and HIV. And this is true both under the DHHS and IAS-USA guidelines, even though not yet FDA approved, although I think it’s anticipated that it will be shortly. And both recommend that TDF or TAF be given plus 3TC or FTC as a backbone in suppressive antiretroviral regimens.
DHHS Guidelines. July 2016.
Günthard HF, et al. JAMA. 2016;316:
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26. Key Take-Home Points
Updated DHHS and IAS-USA Guidelines include INSTIs as part of all recommended first-line regimens
Exception: DRV/RTV also recommended in DHHS
FTC/TAF has been added as an NRTI pair of choice for all recommended regimens
Additional guidance provided on switching ART in patients with virologic suppression
Primary MAC prophylaxis no longer recommended if patients are to start ART promptly
ART, antiretroviral therapy; DHHS, US Department of Health and Human Services; DRV, darunavir; FTC, emtricitabine; IAS-USA, International Antiviral Society-USA; RTV, ritonavir; TAF, tenofovir alafenamide.
The key take-home points: The updated guidelines include INSTIs as part of all recommended first-line regimens with the exception of darunavir/ritonavir in the DHHS guidelines.
FTC/TAF has been added as an NRTI pair of choice in all the recommended options. And additional guidance is provided on switching therapy in patients with viral suppression. And a comment about the role of primary MAC prophylaxis in people who are about to start therapy and are expected to have a good response, where you may not need to start it initially.
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