The "Base Score" roughly represents HIV-ASSIST recommendations for Naive patients and no modifying factors.
- Lower numbers represent preferred regimens
- When no modifying factors are entered, our algorithm ranks ARV regimens according to this 'base-score', which are analagous to the DHHS groupings for "Recommended in Most Circumstances" (ranked 1), and "Recommended in Certain Clinical Situations (ranked 2-3)".
- For regimens not specifically listed, we provide a ranking for regimens on the basis of classes of drugs used as well.
- Regimens ranked 3-6 are those for which there is some clinical trial evidence, but are not formally considered by the current IAS or DHHS guidelines. In many cases, NRTI-sparing regimens are listed here.
| Rank | Sample Regimens (not exhaustive list) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| 1 |
Our top ranked regimens when there are no other considerations: click for clinical trial data to support | INSTI based regimens |
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INSTI containing regimens: Consistent with IAS-USA guidelines, we have prioritized INSTI based regimens paired with 2 NRTI’s. Regimens consisting of 2 NRTIs and 1 INSTI are also consistent with DHHS recommendations for preferred treatment options. Please note that as of May 2018, DHHS guidelines have not yet been updated to include TAF/FTC/BIC. However, based on available data, we have included it as a top ranked regimen consistent with IAS guidance (2018). INSTI vs PI: We prioritized INSTIs over PIs. In head to head studies of PK boosted PI versus INSTI containing regimens, the INSTI was better tolerated with fewer treatment discontinuations.
There is limited data directly comparing the 3 INSTIs (DTG, RAL, EVG), and as such we do not distinguish them in our base-rankings. However, our algorithm adds a mathematical penalty based on pill burden, which impacts the final weighted score of INSTI containing regimens. In the Phase III SPRING-2 trial, TDF/FTC or ABC/3TC was paired with either once daily DTG or twice-daily RAL, and found DTG was non-inferior in week 48 primary efficacy analysis (88% vs 85% viral suppression), which was maintained at 96 weeks ((81% vs 76%) [bib]121[/bib] [bib]122[/bib]. INSTI vs NNRTI: While NNRTI based regimens also have a strong track record of durable virologic efficacy, we have prioritized it lower on the basis of lower barrier to resistance and side effect profile, consistent with IAS and DHHS recommendations.
NRTI backbone: Currently preferred NRTI combinations consist of either ABC/3TC, TAF/FTC, or TDF/FTC. While DHHS recommendations suggest either TDF or TAF as part of the NRTI backbone, consistent with IAS-USA guidance, we have prioritized TAF over TDF on the basis of studies suggesting it is likely to be as effective as TDF in terms of achievement of virologic suppression, with fewer renal and bone effects. TDF usage may be associated with declines in kidney function or development of proximal renal tubular nephropathy, and reduced bone mineral density. As such, we have ranked TDF containing regimens slightly lower in all of our algorithms, compared to TAF containing regimens. NOTE: To avoid too many potential regimen choices appearing on our Results page, we have 'pre-checked' TDF to be 'excluded' on the 'Input' page. If you would like to include TDF in the potential options, please uncheck this box. TAF vs TDF: TAF was approved by FDA in 2015 coformulated with TAF/FTC/EVG/c. It is also available coformulated as TAF/FTC/RPV or TAF/FTC. TAF reaches cells as TAF and is metabolized intracellulalry to Tenofovir and phosphorylated to the active Tenofovir diphosphate; by contrast TDF is converted to tenofovir in the blood. Consequently, there are lower plasma levels of tenofovir with TAF than with TDF, and higher intracellular concentrations of the active form, allowing lower dosing which theoretically leads to lower tenofovir-related toxicity. 2 studies compared TAF/FTC/EVG/c and TDF/FTC/EVG/c, with pooled data showing noninferiority at 48 weeks with respect to viral suppression[bib]123[/bib][bib]189[/bib]. Safety analysis demonstrated lower increases in Cr, less proteinuria, and lesser bone effects with TAF than with TDF (though TAF had higher rise in lipids). Recently 144 week data has become available. In the GS 104/111 studies (parallel randomized double-blind phase III studies) (866 and 867 patients in each arm), TAF/FTC/EVG/c was superior with regards to virologic success (84% vs 80%, p=.02) compared to TDF/FTC/EVG/c, with greater disscontinuations for AE's with TDF (3.3 vs 1.3) than with TAF; psine and hip BMD were greater for TDF than TAF. Lipd increases on the other hand were greater with TAF than TDF, but not difference in TC:HDL ratio, and rates of lipid modifying therapy were similar [bib]189[/bib]. Additional support for TAF comes from the WAVES study, evaluating TAF/FTC/EVG/c in women[bib]126[/bib][bib]190[/bib]. This study evaluated TDF/FTC+ATV/r with TDF/FTC/EVG/c in 575 treatment naive patients, with primary endpoint at 48 weeks. 212 women that met viral suppression then either continued ATV/r or switched to TAF/FTC/EVG/c. An additional 48 weeks later, 94% were suppressed in the TAF/FTC/EVG/c arm compared to those that stayed on the PI[bib][190[/bib] Switching led to improvements in spina and hip bone mineral density, but did also have greater lipid increased compraed to the TDF/FTC+ATV/r regimen.
The advantages of TAF and TDF over ABC are their activity against Hepatitis B, lack of needing HLA-B5701 testing, and some observations of ABC and cardiovascular risk (seen in some but not all observational studies). ABC has not been compared head to head with TAF. ABC/3TC: ABC/3TC has been compared to TDF/FTC in several randomized controlled trials (ACTG 5202 [with EFV or ATV/r], ASSERT [with EFV], HEAT [with LPV/r]). Some prior studies (ACTG 5202 and ASSERT) have suggested efficacy advantage of TDF/FTC over ABC/3TC, but this advantage has not been substantiated in studies that use DTG.
As such, we considered ABC/3TC as similar to TDF/FTC in our rankings in the absence of comorbidities, when paired with DTG. However, when paired with other agents, we incorporate a mathematical penalty for the weighted score relative to tenofovir containing regimens. We note that the listed cobicistat containing regimens (i.e. when paired with Elvitegravir) have the benefit of fixed dosed combinations and lower pill burden, but may have greter numbers of drug interactions, when compared to regimens without cobicistat. Cobicistat may also increase serum measurements of creatinine, which can make it more challenging to monitor creatinine clearance in some patients. |
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| 1-2 |
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Consistent with IAS guidelines (2018)[bib]315[/bib], we have given lower priority to regimens containing EVG/c or RAL, compared to BIC or DTG. We note that the listed cobicistat containing regimens (i.e. when paired with Elvitegravir) have the benefit of fixed dosed combinations and lower pill burden, but may have greter numbers of drug interactions, when compared to regimens without cobicistat. Cobicistat may also increase serum measurements of creatinine, which can make it more challenging to monitor creatinine clearance in some patients. Additionally, given lower barrier to resistance, we have ranked EVG/c anchored regimens slightly lower than those regimens utilizing DTG or BIC, Given lower barrier to resistance and BID dosing, we have also given lower preference to RAL based regimens despite the fact that they appear alongside other INSTI regimens in current DHHS guidelines. Other combinations of 2 NRTIs + 1 INSTI have less data. As such, we rank such combinations lower than the specific regimens listed above. |
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| 1.5-2.5 |
Alternative Regimens in some clinical situations | PI based Regimens |
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Some 2 NRTI’s plus 1 boosted protease inhibitor (DRV) are considered "Recommended initial regimen in some circumstances' in the DHHS guidelines, and an alternative if the IAS-USA guidelines (to be considered if INSTI cannot be used). Given that INSTIs outperformed DRV in the FLAMINGO study (DTG vs DRV/r,[bib]120[/bib]) and the WAVES study (EVG/c vs ATV/r[bib]126[/bib].), and ACTG 5257 (RAL vs ATV/r or DRV/r[bib]162[/bib]), we have considered PI based regimens slightly lower in our rankings than INSTI based regimens. We considered PK boosted DRV regimens to be ranked slightly higher than NNRTI based regimens, which have somewhat lower genetic barriers to resistance. While EFV containing regimens have strong virologic efficacy (and was non-inferior to INSTI in the GS Study 102[bib]164[/bib], including in patients with high HIV RNA), it is ranked lower also due to high rates of CNS related side effects. We note, however, that when compared to older PI's, time to virologic failure was similar between EFV and ATV/r in ACTG 5202[bib]112[/bib][bib]168[/bib]; and was superior to LPV/r[bib]169[/bib] When comparing PI’s, in a large randomized trial (from DHHS) comparing DRV/r, ATV/r, and RAL (all in combination with TDF/FTC), all three regimens achieved similar rates of virologic suppression, but there was a higher rate of adverse effects leading to drug discontinuation in the ATV arm. As such we ranked ATV based regimens lower.
For reasons outlined above, we considered TAF based regimens as preferred over TDF. ABC/3TC/DRV/r has only been evaluated in a small retrospective study, but was found to be effective in treatment naïve patients. We have prioritized this lower than (TAF or TDF)/FTC/DRV/r consistent with DHHS guidelines. DHHS recommendations list TAF/FTC/DRV/c as an alternative to TAF/FTC+DRV/r, while IAS-USA recommendations do not prioritize between the coformulated DRV/c versus DRV/r. A combination of DRV/c is considered bioequivalent to DRV/r in healthy volunteers. Similarly, ATV/c has been found to be noninferior to ATV/r with comparable rates of virologic success and adverse events[bib]174[/bib][bib]175[/bib] On this basis, and benefits of diminished pill burden, we have ranked DRV/c and DRV+r equivalently in our rankings. We note that DRV/c has the benefit of reduced pills, but DRV+r has smaller pill sizes We note that DHHS guidelines (May 2018) have not yet been updated to incorporate coformulated DRV/c/TAF/FTC. IAS guidance has considered this a recommended initial regimen if an INSTI cannot be used |
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| 1.8-2 | NNRTI based regimens |
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NNRTI based regimens have a demonstrated history of high virologic suppression, and are available coformulated as single pill once-daily regimens. They have a lower barrier to genetic resistance with suboptimal adherence, lowering their overall ranking in our algorithm. We note that when compared to older PI's, time to virologic failure was similar between EFV and ATV/r in ACTG 5202[bib]112[/bib][bib]168[/bib]; and was superior to LPV/r[bib]169[/bib], adn was non-inferior to INSTI in the GS Study 102[bib]164[/bib]. TDF/FTC/EFV is ranked lower on the basis of higher rates of CNS toxicity compared to regimens ranked higher. While TAF/FTC/RPV is better tolerated, TDF/FTC/RPV has been shown to have higher rates of virologic failure in individuals with viral loads of greater than 100,000, lowering it in the regimen[bib]171[/bib][bib]170[/bib]. Overall, we prioritized TAF containing regimens over TDF and ABC. |
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| 2-3 |
Other Regimens to consider, but with less evidence or other factors that make these less appealing | Other PI and NNRTI anchored regimens with NRTI backbone |
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Both DHHS and IAS guidelines suggest ABC/3TC /boosted DRV is an alternative regimen. DHHS guidelines prioritize (TAF or TDF)/FTC+DRV/r over ABC/3TC+DRV/r on the basis of lack of studies to support its use. ACTG 5202 alternatively did generally support the efficacy of ABC/3TC when combined with a PI (ATV/r). When comparing PI’s, in a large randomized trial (ACTG A5257)[bib]162[/bib] comparing DRV/r, ATV/r, and RAL (all in combination with TDF/FTC), all three regimens achieved similar rates of virologic suppression, but there was a higher rate of adverse effects leading to drug discontinuation in the ATV arm. As such we ranked ATV based regimens lower. For reasons outlined above, we considered TAF based regimens as preferred over TDF. ABC/3TC/DRV/r has only been evaluated in a small retrospective study, but was found to be effective in treatment naïve patients. We have prioritized this lower than (TAF or TDF)/FTC/DRV/r consistent with DHHS guidelines. |
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| 2.5-3 |
Regimens when TAF, TDF, or ABC cannot be used |
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Overall, we considered the data on dual therapy to be promising, but continues to be lower ranked than NRTI based regimens listed above based on available data. Per IAS guidelines, “Initial 2-drug regimens are under investigation.This strategymay offer cost or toxicity advantages over standard 3-drug regimens, but efficacy needs to be confirmed.27Darunavir/ritonavir plus raltegravirwas noninferior to darunavir/ritonavir plus2NRTIs, but the2-drug regimen had higher rates of treatment failure in patients with aCD4 cell count below 200/μL or an HIV RNA level above 100 000 copies/mL.28 Dolutegravir plus lamivudine and darunavir/ritonavir plus lamivudine are being studied.29,30 Until further data are available, initial 2-drug regimens are reserved for the rare situation when individuals cannot take abacavir, TAF, or TDF. In this situation, darunavir/ritonavir plus raltegravir (if <100 000 HIV RNA copies/mL and CD4 cell count >200/μL) or darunavir/ritonavir plus lamivudine may be used (if there is no lamivudine resistance) (evidence rating BIa). Short-term data from comparative trials may provide support for dolutegravir plus lamivudine as initial 2-drug therapy(NCT02831764). Dolutegravir plus rilpivirinehasnotyetbeen assessed for initial therapy.31” On the basis of this data DHHS suggests 3TC + LPV/r, and DRV/r + RAL as regimens to consider when NRTI cannot be used. However, given the poor tolerability of LPV/r, and the BID dosing of RAL, we have prioritized other regimens (for which efficacy is inferred, or supported only by limited experience) above these regimens. In support of 1 INSTI + 1 PI: As noted above, DTG+RAL was non-inferior to DRV+2NRTI, but had higher rates of failure in those with high baseline Vl or low CD4. Whether this data applies to DTG+boosted DRV is unclear. DTG+ DRV/r is not ranked among the regimens in the DHHS Guidelines and is not formally discussed in IAS guidelines, but has some clinical evidence in its favor. Other Evidence in support of 1 INSTI + 1 PI:
Based on relative potency and barrier to resistance, we have prioritized INSTI + PI for situations in which TAF, FTC, or ABC cannot be used. Nonetheless there is evidence in support of the strategy of 3TC + (1PI or 1 INSTI):I 1PI + 1 NRTI: limited data in experienced and naive patients
1INSTI + 1 NRTI: limited data in experienced and naive patients
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| 3.5-5 |
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There is limited data on using drugs from 3 separate classes. As a result, we have rated these regimens lower than those listed above. However, in some instances, we have prioritized inclusion of 3 active drugs in patients with high viral loads or poor adherence. There is data on 1PI + 1 INSTI, and 1NRTI+PI, and 1 NRTI+1INSTI, and we anticipate similar virologic responses with the addition of an extra active agent to such a regimen (and potential for lower rates of virologic failure in instances of suboptimal adherence when using 3 rather than 2 active drugs), recognizing that the lack of clinical trial data precludes confidence in these assumptions.
In a trial of RAL+DRV/r+ETR in patients with multidrug resistant infections the regimen demonstrated 94% virological suppression at 24 weeks. No patients had adverse effects. We have thus considered this a preferred regimen over 2 drug regimens in those with resistance, or high viral loads. While there is not currently data to support DTG/DRV/r/ETR, we have inferred its efficacy. We have prioritized this 3 drug regimen, over alternative 2 drug regimens for individuals with high viral loads. The single-tablet regimen EVG/c/TDF/FTC plus DRV has shown promising results as a simplification strategy in patients with complicated rescue regimens.16 A recent study enrolled 135 virologically suppressed patients who were receiving DRV-containing ART and had resistance to ≥2 ARV drug classes, but no INSTI resistance. The patients were then switched to a regimen of EVG/c/TDF/FTC plus DRV. At week 24, 97% of the patients maintained virologic suppression. The pill burden was reduced from an average of five tablets to two tablets. Currently, however, there is insufficient evidence to support this regimen switch other than in a well-controlled clinical trial or in special circumstances. |
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| 4.5 | DTG/RPV | |||||||||||||||||||||||||||||||||||||||||||||||||||||||
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This regimen has not been well-studied in naive patients.
Given relatively lower barrier to resistance of RPV, and lesser efficacy (based on 2NRTI +RPV studies) in patients with high viral load, and data restricted to switch studies, we have ranked it lower for naïve pts or pts with detectable viremia, with consideration for switch in virologically suppressed patients. |
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| 4.5 |
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Maraviroc has been assessed in phase III rct's in treatment experienced patients[bib]316[/bib]. In MOTIVATE trial, patients with R5 tropic virus with history of resistance to three ARV classes were randomized to MVC with optimized background, vs placebo. More participants (42-47%) in the MVC arms had viral suppresion compared to placebo (16%)[bib]269[/bib] In the MERIT study, participants with R5 tropic virus received EFV vs MVC with AZT/3TC in ARV naive patients. The study was discontinued for lack of efficacy. As a result we rank this regimen low for ARV naive participants. In a salvage study[bib]181[/bib], 28 patients who received RAL+MVC+ETV demonstrated virological suppression with three adverse events. On this basis, we incorporate this three drug regimen DTG+MVC+ETR as a salvage regimen. |
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| 4 |
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| 4-5 |
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ETV+RAL is not ranked among the regimens in the DHHS Decision Guidelines, but nonetheless has clinical evidence in its favor. In virologically suppressed patients experiencing side effects from PI or NRTI based regimens switch to ETV/RAL demonstrated non-inferiority in terms of viral suppression to continuation of their original therapy at 48 weeks follow-up. Clinical experts consider DTG preferable to RAL because of its once daily dosing, however it hasn’t been studied as a regimen along with ETV. Standard RAL dosing is 400 mg BID, however 1200 mg once daily has demonstrated similar efficacy in a clinical trial. In another salvage trial, a regimen of 1 PI + 1NNRTI has been used with modest success. In a trial of patients who had failed multiple antiretroviral regimens and were given ETV either with DRV/r or RAL 62.3% of all patients achieved viral suppression. There is retrospective data on usage of 1 PI + CCR5 inhibitors. In a retrospective study of 60 patients started on MVC+DRV/r because of simplification or adverse effects 86% achieved viral suppression (HIV RNA < 50 copies/mL at 48 weeks). Only one patient discontinued therapy due to adverse effects. In a clinical trial comparing a MVC+LPV/r regimen to MVC+TDF/FTC the NRTI sparing regimen demonstrated complete virological suppression at 48 weeks and greater immunological benefit compared to the MVC/TDF/FTC regimen. |
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