Three HIV Drugs Versus 2: What Should Patient X Do?

Case scenario

Mr. X, a 64-year male with a long-standing history of HIV-1 infection, presents for a routine follow-up visit. He has a history of HIV diagnosed in 1994 and has been on ART since 1996.  In addition to HIV, Mr. X’s medical history includes coronary artery disease (CAD), for which he takes aspirin 81 mg daily. His CAD was treated with percutaneous angioplasty and coronary artery stent placement 5 years ago. He also has hyperlipidemia, for which he takes atorvastatin. Additionally, Mr. X’s medical history includes hypertension, along with impaired glucose tolerance; he takes enalapril and metformin for these conditions. 

Before he started his first ART regimen of zidovudine (ZDV, or azidothymidine (AZT)), lamivudine (3TC), and saquinavir in 1996, lab testing revealed that he had a CD4 count of 150 cells/ml³ and an HIV viral load of 90,000 copies/ml³. He did well with this regimen, despite the high pill burden and side effects, and achieved an undetectable HIV viral load. Over the years, his CD4 count has hovered between 400 and 600 cells/ml³. 

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Over the next 2 years on his original ART regimen, Mr. X developed glucose intolerance, along with buffalo hump lipohypertrophy. Accordingly, his provider changed his ART regimen to AZT+3TC (combination tablet; Combivir^®) plus efavirenz in 1988.  Mr. X did well on this treatment until 2001, when worsening facial lipoatrophy, his AZT + 3TC was discontinued and he was started on tenofovir disoproxil fumarate (TDF) + 3TC with efavirenz.

In 2003, the patient’s HIV viral load unexpectedly increased from undetectable to 10,000 copies/ml³.  Genotypic resistance testing revealed a K103N mutation conferring high-level efavirenz resistance. Therefore, his provider changed his treatment to TDF plus ritonavir-boosted atazanavir.  This regimen effectively suppressed his viremia.

Mr. X subsequently developed gastroesophageal reflux disease, for which he was prescribed a proton pump inhibitor (PPI), necessitating an ART change to TDF + emtricitabine (FTC; Truvada^®) + raltegravir. To further improve his regimen, Mr. X then changed to tenofovir alafenamide fumarate (TAF) + FTC (Descovy^®) + dolutegravir (DTG); and in 2018 to his first single-tablet regimen, bictegravir + FTC + TAF (Biktarvy®). Mr. X tolerated this regimen relatively well.

Despite ongoing statin therapy, Mr. X. continued to have hypercholesterolemia and hypertriglyceridemia. He was unable to reduce his body mass index (BMI) to a normal range. His renal function has been mostly normal through the years, outside of the increase in serum creatinine attributed to contrast dye-related nephropathy following his angioplasty.

A screening dual-energy X-ray absorptiometry (DEXA) scan performed in 2017 revealed osteopenia of the hip.  Considering this osteopenia, an ART regimen change was contemplated.

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Two-Drug Regimens

Two-drug ART options backed by data supporting stable switching include DTG + rilpivirine (RPV; Juluca) and DTG + 3TC (Dovato). In the SWORD-1 (ClinicalTrials.gov Identifier:NCT02429791) and SWORD-2 (ClinicalTrials.gov Identifier:NCT02422797) trials, investigators enrolled adult patients who were on their first or second ART with stable plasma HIV-1 RNA (viral load <50 copies/mL) for 6 months or longer. Key exclusion criteria included virologic failure of first-line therapy and major resistance-associated mutations.

Patients who switched to DTG + RPV maintained virologic suppression through both 48 weeks and 148 weeks — regardless of the class of their initial regimen’s third drug (ie protease inhibitor, non-nucleoside reverse transcriptase inhibitor/NNRTI, or integrase strand transfer inhibitor/INSTI).^1,2 In pooled analysis at 48 weeks, 95% of participants had viral loads <50 copies/mL (486 of 513 in the DTG + RPV group versus 485 of 511 in the current ART regimen [CAR] group), with an adjusted treatment difference of -0.2% (95% confidence interval/CI, -3.0% to 2.5%). DTG + RPV demonstrated non-inferiority with a predefined margin of -8%.

The most commonly reported adverse events (AEs) in the DTG + RPV and CAR cohorts included nasopharyngitis (10% each) and headache (8% and 5%, respectively). More participants taking DTG + RPV (3%) reported AEs leading to withdrawal than did participants taking CAR (<1%).¹

At week 148, 432 of 513 (84%) early-switch SWORD 1/2 participants (148 weeks of DTG + RPV exposure) and 428 of 477 (90%) of late-switch participants (96 weeks of exposure) maintained viral suppression. Eleven participants (1%) on DTG + RPV, including 8 from the early-switch group, met the criteria for confirmed virologic withdrawal through week 148, with no integrase resistance identified. Investigators observed NNRTI resistance-associated mutations in 6 participants (<1%).

Drug-related AEs (primarily grades 2-4, with nasopharyngitis and headache again among the most common) occurred in 6% of early-switch patients and 3% of late-switch patients. Significant improvements in bone biomarkers over baseline in SWORD-1/2, and in a bone-mineral density (BMD) sub-study, stemmed largely from patients who had switched from TDF-based regimens. TDF is known to lead to nonprogressive BMD declines which have been linked, although not causally, with fractures in longitudinal cohort studies.^3,4 As most 3DRs now include TAF, which does not negatively impact BMD, instead of TDF, it is unclear whether switching from a TAF-based 3DR to DTG + RPV would confer the same BMD benefits seen in the SWORD patients.^2,5

Significant improvements in renal biomarkers occurred only in SWORD participants taking tenofovir disoproxil fumarate (TDF) pre‐switch.^6,7 These patients exhibited improvement in markers of tubular proteinuria and creatinine clearance.^2,3 Based on patient-reported outcomes through week 148, patients who switched to DTG + RPV tolerated this regimen well, although not necessarily better than their prior 3DR.⁸ Altogether, the investigators concluded that switching to DTG + RPV maintained virologic suppression for a high proportion of participants for 3 years, with low rates of virologic failure and a high degree of safety.

The TANGO trial (ClinicalTrials.gov Identifier:NCT03446573) evaluated patients with previously suppressed HIV viral loads (no VLs > 200 copies in 12 months prior to screening) on a first-line 3- or 4-drug TAF-based regimen. Investigators randomized 372 patients to remain on their TAF-based regimen and 371 patients to switch to a fixed-dose combination agent containing DTG + 3TC.

At 48 weeks, 93% of patients in both arms maintained virologic suppression.⁹ AEs, most commonly nasopharyngitis, upper respiratory tract infection, and diarrhea, occurred in 79.9% of patients in both groups. 

Using a homeostasis model of assessment for insulin resistance (HOMA-IR; scores ≥2 defined as insulin resistance), TANGO participants showed slightly decreased levels of insulin resistance among patients who switched to DTG+3TC. Specifically, 69% and 68% in the DTG + 3TC and TAF-based cohorts, respectively, had HOMA-IR ≥2 at baseline. At week 48, the corresponding proportions were 65% and 74%, respectively (odds ratio, 0.59; 95% CI, 0.40 to 0.87; P =.008).

Additionally, patients who switched to DTG + 3TC exhibited slightly improved cholesterol parameters; namely, percentage changes in total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides (all P <.001) and total cholesterol to HDL cholesterol ratio (P =.017). Though patients on the DTG + 3TC regimen experienced decreases from baseline in high-density lipoprotein (HDL), while HDL rose in the TAF group, this difference did not reach statistical significance (P =.059).

Adjusted mean weight increase from baseline to week 48 was 0.8 kg in both treatment groups. Similarly, adjusted mean BMI increase was 0.25 kg/m² in the DTG + 3TC group and 0.26 kg/m² in the TAF group.

Based on standardized quality-of-life measures, no significant changes in quality of life were observed for those who switched versus those who did not. The TANGO study did not report on BMD changes or other markers of bone turnover. 

Drug-Drug Interactions

DTG, which is included in both FDA-approved 2DRs, has a key drug-drug interaction with metformin, which Mr. X takes for glucose intolerance.  Specifically, DTG slows the metabolism of metformin, increasing metformin levels significantly.¹⁰ The integrase inhibitor bictegravir has a similar drug-drug interaction. It is important to be aware that while prescribing information for both DTG-containing regimens and for bictegravir + TAF + FTC note this interaction, these agents can still be safely co-administered due to metformin’s relatively wide therapeutic window.^10-13 

Weight Gain

Integrase inhibitor-based regimens, such as those that include DTG, bictegravir, or cobicistat-boosted elvitegravir, have been shown to lead to weight gain, as do ART regimens that contain TAF.^14-16

In the ADVANCE trial (ClinicalTrials.gov Identifier:NCT03122262), investigators compared 3 ART regimens in treatment-naïve patients:

• TDF + emtricitabine + efavirenz (local standard of care)
• DTG + emtricitabine + TAF
• DTG + emtricitabine + TDF

Although treatment with DTG combined with either of the 2 tenofovir prodrugs showed noninferior efficacy to standard care, patients on the DTG-containing regimens experienced significantly more weight gain, especially those whose regimens combined DTG with TAF.¹⁴

Case Discussion

The foregoing case illustrates key challenges and considerations associated with switching a patient with stable viral control on a commonly used 3DR to a more user-friendly 2DR. Three-drug regimens have long represented state-of-the-art ART, and they have a lengthy track record of successfully suppressing HIV viremia and reducing mortality for PLWH.¹⁷ The efficacy of 3DRs, combined with the chronic nature of HIV itself, means that patients typically take multiple medications for decades, some of which carry side effects that can range from mild to severe. This situation has generated interest in reducing the medication burden and simplifying treatment for PLWH.

In appropriately selected cases, the United States Department of Health and Human Services (HHS) Panel on Antiretroviral Guidelines for Adults and Adolescents HIV treatment guidelines supports the switching of stable viral-load patients to either DTG + RPV or DTG + 3TC, both with level A1 recommendations.¹⁸

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When switching ART, the guidelines say, the focus should be on maintaining virologic suppression, which includes maintaining control of the hepatitis B virus (HBV) for HIV/HBV co-infected patients. Because coverage with either lamivudine or FTC may not provide sufficient HBV control, guideline authors advise caution with respect to switching to a 2DR regimen without TDF or TAF, either of which would provide additional HBV control. Therefore, switching HBV co-infected patients to DTG + RPV or DTG + lamivudine should be done very cautiously, if at all.

Conversely, HHS guideline authors say, DTG + RPV is a reasonable option when a nucleoside reverse transcriptase inhibitor (NRTI) is undesirable, but only in patients who meet the following conditions (A1 recommendation):

• No HBV infection;
• No evidence of resistance to either DTG or RPV; and
• No significant drug-drug interaction that might reduce the concentration of either drug.

As HHS guidelines give the switch to DTG + RPV an A1 recommendation in patients without HBV co-infection, this option may be considered for Mr. X, with the previously noted caveats. In fact, his lipoatrophy, which is likely mediated by his past exposure to NRTIs, makes the NRTI-free DTG + RPV 2DR a particularly attractive option in this case. Similarly, the guidelines say that, switching to a DTG + 3TC regimen can be an effective option for people with no HBV co-infection or evidence of resistance to either drug.

Based on TANGO findings related to metabolic parameters, Mr. X, who has some baseline pre-diabetes or insulin resistance, may benefit from a switch to DTG+3TC. A crucial caveat is that the TANGO study did not enroll patients with extensive treatment experience such as Mr. X. Although he has no known anti-retroviral resistance to DTG+3TC based on genotypic resistance testing, caution is recommended due to the limited availability of switch data for patients who have a long ART history, as he does. 

Conversely, Mr. X should likely avoid DTG + RPV. Data from SWORD-1/2 do not necessarily apply to patients like him. Patients enrolled in this trial had to be on their first or second ART regimen, and Mr. X’s medical history included several preceding ART regimens. The SWORD trials moreover excluded patients who had changed ART regimens due to prior virologic failure — as Mr. X had in 2003.

The foregoing factors aside, some providers may be tempted to apply SWORD findings to patients such as Mr. X.  While Mr. X. had some documented ART resistance, including an NNRTI mutation (specifically a K103N mutation, which confers resistance to the NNRTI efavirenz), his virus probably remains susceptible to DTG + RPV. However, SWORD subjects who switched to this therapy did not really report fewer drug-related AEs despite being on 1 or 2 fewer medications. Additionally, the renal and/or BMD benefits attributable to the switch to DTG + RPV apply largely to those switching from a TDF-based regimen, which Mr. X has not been on for some time.  Available data therefore do not suggest that Mr. X would definitively benefit significantly from switching from bictegravir + FTC + TAF to DTG + RPV.  

The issue of weight gain is also pertinent to the 2DR versus 3DR conversation. Compared to TDF-based regimens, TAF-based regimens are safer from a renal and BMD standpoint. However, TAF-based regimens seem to lead to more weight gain. Therefore, regimens that do not include TAF but are still effective, such as DTG + RPV or DTG + 3TC, may offer an option for patients in whom minimizing weight gain is a priority. Note that data to support these 2DRs for limiting weight gain do not currently exist — the SWORD studies did not demonstrate a benefit for the 2DR regarding weight gain. Moreover, in the ADVANCE trial, DTG was associated with significant weight gain.  So, while 2DRs may be associated with less weight gain, DTG-containing 2DRs, which are the most-studied 2DRs to date, likely offer little benefit with respect to minimizing this side effect. 

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Conclusion

Given Mr. X’s current condition and lengthy experience with numerous ART regimens, he may benefit from a switch to DTG + 3TC under the rationale of simplifying and enhancing the tolerability of his ART. As the pivotal study of this regimen excluded patients with extensive ART experience, Mr. X’s provider must continue to monitor his case carefully.

References

1. Llibre JM, Hung CC, Brinson C, et al. Efficacy, safety, and tolerability of dolutegravir-rilpivirine for the maintenance of virological suppression in adults with HIV-1: phase 3, randomised, non-inferiority SWORD-1 and SWORD-2 studies. Lancet. 2018;391(10123):839-849. doi:10.1016/S0140-6736(17)33095-7

2. van Wyk J, Orkin C, Rubio R, et al. Brief report: durable suppression and low rate of virologic failure 3 years after switch to dolutegravir + rilpivirine 2-drug regimen: 148-week results from the SWORD-1 and SWORD-2 randomized clinical trials. J Acquir Immune Defic Syndr. 2020;85(3):325-330. doi:10.1097/QAI.0000000000002449

3. Komatsu A, Ikeda A, Kikuchi A, Minami C, Tan M, Matsushita S. Osteoporosis-related fractures in HIV-infected patients receiving long-term tenofovir disoproxil fumarate: an observational cohort study. Drug Saf. 2018;41(9):843-848. doi:10.1007/s40264-018-0665-z

4. Borges ÁH, Hoy J, Florence E, et al. Antiretrovirals, fractures, and osteonecrosis in a large international HIV cohort. Clin Infect Dis. 2017;64(10):1413-1421. doi:10.1093/cid/cix167

5. McComsey GA, Lupo S, Parks D, et al. Switch from tenofovir disoproxil fumarate combination to dolutegravir with rilpivirine improves parameters of bone health. AIDS. 2018;32(4):477-485. doi:10.1097/QAD.0000000000001725

6. Llibre JM, Voronin E, Rubio R, et al.  SWORD 1 & 2: Maintenance or improvement in renal function in PLWH through 148 weeks after switch to the dolutegravir + rilpivirine 2-drug regimen. 17^th European AIDS Conference; November 6-9, 2019; Basel, Switzerland.  https://d201nm4szfwn7c.cloudfront.net/5f95dbd7-245e-4e65-9f36-1a99e28e5bba/9f7e2ea8-75ba-4e97-be4b-f5f1c1ceaceb/9f7e2ea8-75ba-4e97-be4b-f5f1c1ceaceb_viewable_rendition__v.pdf?medcommid=REF–ALL-002439. Accessed February 23, 2021.

7. Canadian Agency for Drugs and Technologies in Health (CADTH) Common Drug Review. Clinical Review Report: Dolutegravir/Rilpivirine (Juluca): (ViiV Healthcare): Indication: As a complete regimen to replace the current antiretroviral regimen for the treatment of HIV-1 infection in adults who are virologically stable and suppressed (HIV-1 RNA less than 50 copies per mL). Ottawa (ON): June 2018. https://www.ncbi.nlm.nih.gov/books/NBK536125/.

8. Oglesby A, Angelis K, Punekar Y, et al. Patient reported outcomes after switching to a 2-drug regimen of dolutegravir + rilpivirine: week 148 results from the SWORD-1 and SWORD-2 studies. Abstract 2484.Open Forum Infect Dis. 2019;6 (Suppl):S861. doi:10.1093/ofid/ofz360.2162

9. van Wyk J, Ajana F, Bisshop F, et al. Efficacy and safety of switching to dolutegravir/lamivudine fixed-dose 2-drug regimen vs continuing a tenofovir alafenamide-based 3- or 4-drug regimen for maintenance of virologic suppression in adults living with human immunodeficiency virus type 1: phase 3, randomized, noninferiority TANGO study. Clin Infect Dis. 2020;71(8):1920-1929. doi:10.1093/cid/ciz1243

10. Song IH, Zong J, Borland J, et al. The effect of dolutegravir on the pharmacokinetics of metformin in healthy subjects. J Acquir Immune Defic Syndr. 2016;72(4):400-407. doi:10.1097/QAI.0000000000000983

11. Juluca (dolutegravir and rilpivirine tablets) [prescribing information]. Research Triangle Park, NC: Viiv HealthCare; 2017. Revised July 2020. Https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Juluca/pdf/JULUCA-PI-PIL.PDF. Revised July 2020. Accessed February 20, 2021.

12. Dovato (dolutegravir and lamivudine) [prescribing information]. Research Triangle Park, NC: Viiv HealthCare; 2019. Revised April 2019. Accessed February 19, 2021. Https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/211994s000lbl.pdf. Revised April 2019. Accessed February 19, 2021.

13. Biktarvy (bictegravir, emtricitabine, and tenofovir alafenamide) [prescribing information]. Foster City, CA: Gilead Sciences, Inc; 2018. Https://www.gilead.com/~/media/files/pdfs/medicines/hiv/biktarvy/biktarvy_pi.pdf. Revised February 2021. Accessed February 19, 2021.

14. Venter WDF, Moorhouse M, Sokhela S, et al. Dolutegravir plus two different prodrugs of tenofovir to treat HIV. N Engl J Med. 2019;381(9):803-815. doi:10.1056/NEJMoa1902824

15. Eckard AR, McComsey GA. Weight gain and integrase inhibitors. Curr Opin Infect Dis. 2020;33(1):10-19. doi:10.1097/QCO.0000000000000616

16. Sax PE, Erlandson KM, Lake JE, et al. Weight gain following initiation of antiretroviral therapy: risk factors in randomized comparative clinical trials. Clin Infect Dis. 2020;71(6):1379-1389. doi:10.1093/cid/ciz999

17. Antiretroviral Therapy Cohort Collaboration. Survival of HIV-positive patients starting antiretroviral therapy between 1996 and 2013: a collaborative analysis of cohort studies. Lancet HIV. 2017;4(8):e349-e356. doi:10.1016/S2352-3018(17)30066-8.

18. US Department of Health and Human Services Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. https://clinicalinfo.hiv.gov/sites/default/files/inline-files/AdultandAdolescentGL.pdf. Updated December 18, 2019. Accessed Feb 12, 2021. 

Posted by Haymarket’s Clinical Content Hub. The editorial staff of Infectious Disease Advisor had no role in this content’s preparation.

                                                                                                                   Reviewed March 2021