The non-nucleoside reverse transcriptase inhibitor doravirine (DOR), was approved by the TGA in 2020 as a single drug or as a fixed dose combination with TDF and lamivudine (3TC). DOR/TDF/3TC is NOT reimbursed under the PBS in Australia.
Table 8a. Characteristics of Nucleoside Reverse Transcriptase Inhibitor Options Recommended for Antiretroviral Therapy-Naive Patients
|Dosing Frequency||Once daily||Once daily||Once daily||Once daily||Once daily|
|Adverse Effects||ABC:||See below||TDF:||TAF:||TDF:
|3TC: No significant adverse effects||FTC: Skin discoloration|
|FTC should not be used as sole treatment for HBV due to development of resistance. Discontinuation may precipitate HBV flare if no other agents active against HBV are present.|
|3TC or ABC/3TC should not be used as treatment for HBV due to development of resistance. Discontinuation may precipitate HBV flare if no other agents active against HBV are present.||
|a 3TC is recommended for use with DTG in ART-naive persons and with DRV/r if ABC, TDF, and TAF are not optimal. Otherwise, dual-NRTI backbones are recommended.
Key: 3TC = lamivudine; ABC = abacavir; ART = antiretroviral therapy; BIC = bictegravir; BMD = bone mineral density; CV = cardiovascular; DOR = doravirine; DRV = darunavir; DRV/c = darunavir/cobicistat; DRV/r = darunavir/ritonavir; DTG = dolutegravir; EFV = efavirenz; EVG = elvitegravir; EVG/c = elvitegravir/cobicistat; FTC = emtricitabine; HBV = hepatitis B virus; HLA = human leukocyte antigen; HSR = hypersensitivity reaction; NRTI = nucleoside reverse transcriptase inhibitor; RPV = rilpivirine; TAF = tenofovir alafenamide; TDF = tenofovir disoproxil fumarate
SummaryThe Food and Drug Administration (FDA)-approved nucleos(t)ide reverse transcriptase inhibitors (NRTIs) include zidovudine (ZDV), stavudine (d4T), didanosine (ddI), abacavir (ABC), tenofovir disoproxil fumarate (TDF), tenofovir alafenamide (TAF), lamivudine (3TC), and emtricitabine (FTC). Older NRTIs (ZDV, d4T, ddI) are no longer recommended for use in clinical practice in the United States because of high rates of serious toxicities, including peripheral neuropathy and mitochondrial toxicity that may lead to myopathy, hepatic steatosis, lactic acidosis, lipoatrophy, and bone marrow suppression from ZDV use. The incidence of these complications is much lower with 3TC, FTC, ABC, TDF, and TAF than with older NRTIs.1, 2 ABC/3TC, TAF/FTC, TDF/3TC, and TDF/FTC are NRTI combinations that are recommended as components of initial therapy. In addition, 3TC may be used as a single NRTI with dolutegravir (DTG), or, in select circumstances, with boosted darunavir (DRV). Table 6 provides recommendations and ratings for the individual regimens. These recommendations are based on the virologic potency and durability, short- and long-term toxicity, and dosing convenience of these drugs. TDF has been associated with bone and kidney toxicities, especially when used with a pharmacologic booster.3 TAF is less likely to cause kidney and bone toxicities than TDF. TDF is associated with lower lipid levels than TAF. Although there are insufficient data on teratogenicity in humans, TAF is now recommended as an alternative drug in pregnancy because of reassuring data from The Antiretroviral Pregnancy Registry that show no evidence of teratogenicity. Please refer to the Perinatal Guidelines. Safety, cost, and access are among the factors to consider when choosing between these drugs. ABC/3TC, TDF/3TC, TDF/FTC, and 3TC are available as generic formulations.
Clinical Trials Comparing Nucleoside Reverse Transcriptase Inhibitors
Abacavir/Lamivudine Compared to Tenofovir Disoproxil Fumarate/EmtricitabineSeveral randomized controlled trials in antiretroviral therapy (ART)-naive participants compared ABC/3TC to TDF/FTC, each administered in combination with a third ARV drug4-6 (see the Integrase Strand Transfer Inhibitor-Based Regimen section).7
- The ACTG 5202 study, a randomized controlled trial in >1,800 participants, evaluated the efficacy and safety of ABC/3TC and TDF/FTC when each combination was used with either efavirenz (EFV) or atazanavir/ritonavir (ATV/r). In patients with baseline HIV RNA ≥100,000 copies/mL, the time to virologic failure was significantly shorter with ABC/3TC than with TDF/FTC, regardless of whether the third active drug was EFV or ATV/r.4 In the HEAT study, 688 participants received ABC/3TC or TDF/FTC with once-daily lopinavir/ritonavir. Virologic efficacy was similar in the two study arms, including in a subgroup of participants with HIV RNA ≥100,000 copies/mL.6
- The ASSERT study compared open-label ABC/3TC with TDF/FTC in 385 HLA-B*5701-negative, ART-naive patients; all participants also received EFV. The primary study endpoint was renal safety of the regimens. At Week 48, the proportion of participants with HIV RNA <50 copies/mL was lower among ABC/3TC-treated participants (59%) than among TDF/FTC-treated participants (71%).5
Lamivudine Compared to Tenofovir Disoproxil Fumarate/EmtricitabineA single-tablet regimen (STR) of DTG/3TC has now been approved as an initial ARV regimen. Please refer to the Integrase Strand Transfer Inhibitor-Based Regimens section for a full discussion. GEMINI 1 and GEMINI 2 were identically designed randomized, double-blind clinical trials that found DTG plus 3TC noninferior to DTG plus TDF/FTC in ART-naive adults with HIV RNA <500,000 copies/mL and estimated glomerular filtration rate (eGFR) ≥50 mL/min.8, 9
Tenofovir Alafenamide Compared to Tenofovir Disoproxil Fumarate
- Two randomized double-blind Phase 3 clinical trials compared the safety and efficacy of elvitegravir/cobicistat (EVG/c)/TDF/FTC and EVG/c/TAF/FTC in 1,733 ART-naive adults with eGFR ≥50 mL/min.
- TAF/FTC was virologically noninferior to TDF/FTC at Week 48 (92% vs. 90% of participants had plasma HIV RNA <50 copies/mL, respectively),10 but TAF/FTC was superior to TDF/FTC at Week 144 (84.2% vs. 80% of participants with plasma HIV RNA <50 copies/mL), largely driven by a higher rate of treatment discontinuation in the TDF arm.11
- Participants in the TAF arm had significantly smaller reductions in bone mineral density (BMD) at the spine and hip than those in the TDF arm through 144 weeks.11 Those receiving TAF also had less pronounced changes in eGFR and renal biomarkers and fewer clinically significant renal events through Week 96.12 Conversely, levels of fasting low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides increased more in the TAF group than in the TDF group at Week 96, with no change in total cholesterol to HDL ratio.13
- Two randomized studies have compared the safety and efficacy of TAF/FTC to TDF/FTC, with each combination administered with boosted DRV in ART-naive participants:
- A Phase 2 study of coformulated darunavir/cobicistat (DRV/c) plus TAF/FTC versus DRV/c plus TDF/FTC in treatment-naive patients demonstrated similar virologic suppression rates in both arms (75% vs. 74%).14 In the TAF arm, fewer participants developed proteinuria. Changes in BMD were also less pronounced among participants in the TAF group.
- The AMBER study randomized ART-naive participants to receive either coformulated DRV/c/TAF/FTC or DRV/c plus TDF/FTC. At Week 48, HIV RNA <50 copies/mL was achieved in 91% of the DRV/c/TAF/FTC participants versus 88% of the DRV/c plus TDF/FTC participants. Participants in the TAF/FTC arm showed less decline in hip and spine BMD and eGFR than participants in the TDF/FTC arm.15
- One analysis evaluated data from 14 randomized trials that compared the virologic efficacy, frequency of renal events, and bone density changes associated with the use of TDF and TAF when either drug was taken with or without pharmacokinetic (PK) boosters (RTV or COBI). No significant differences appeared between unboosted TDF and TAF in terms of virologic efficacy. TAF resulted in a clinically small but statistically significant greater virologic efficacy than TDF when used with PK boosters (94% vs. 92%; P = 0.0004). No difference was seen in bone-related toxicities and clinical or laboratory adverse events between TAF and TDF, regardless of boosting. There was a small but statistically significant difference in higher rate of discontinuation due to renal adverse events in the boosted TDF subgroup compared with the boosted TAF subgroup.16
- To assess the ability of TAF to maintain HIV and hepatitis B virus (HBV) suppression, 72 patients with HIV/HBV coinfection who had HIV RNA <50 copies/mL and HBV DNA <9 log10 IU/mL on a stable regimen were switched to EVG/c/TAF/FTC.17 In this study, 96% of participants were on a TDF/FTC-containing regimen before the switch. Key results of the study showed the following:
- Among those who switched to EVG/c/TAF/FTC, HIV suppression was maintained in 91.7% of participants at Week 48, and 91.7% of participants had HBV DNA <29 log10 IU/mL.
- Markers of proximal tubular proteinuria and biomarkers of bone turnover decreased in those who switched to EVG/c/TAF/FTC.17
- Although conducted in people without HIV for pre-exposure prophylaxis, the DISCOVER trial, with 5,387 treated participants, was the largest trial to directly compare the adverse effects of TAF/FTC with those of TDF/FTC.18
- TAF/FTC was noninferior to TDF/FTC for the primary endpoint of preventing HIV acquisition, and the groups did not differ statistically in overall, Grade 3–4, or serious adverse events, or in discontinuation due to adverse events.
- Changes in renal biomarkers and bone density significantly favored the TAF arm over TDF. One case of proximal tubular disease occurred in the TDF arm.
- LDL, HDL, and total cholesterol were significantly higher in the TAF arm than in the TDF arm, without significant difference in the total cholesterol to HDL ratio.
- Participants in the TAF arm gained 1.1 kg more than those in the TDF arm.
Nucleoside Reverse Transcriptase Inhibitor Options for Initial TherapyIn alphabetical order.
Abacavir/Lamivudine (ABC/3TC)ABC plus 3TC has been studied in combination with EFV, several protease inhibitors (PIs), and DTG in ART-naive patients.7, 19-21
- Clinically suspected hypersensitivity reactions (HSRs) were observed in 5% to 8% of individuals who started ABC in clinical trials conducted before the use of HLA-B*5701 testing. The risk of HSRs is highly associated with the presence of the HLA-B*5701 allele; approximately 50% of HLA-B*5701-positive patients who are given ABC will have a related HSR.22, 23 HLA-B*5701 testing should be done if the use of ABC is being considered. A patient who tests positive for HLA-B*5701 should not be given ABC, and ABC hypersensitivity should be noted on the patient’s allergy list. Patients who are HLA-B*5701 negative are far less likely to experience an HSR, but they should be counseled about the symptoms of the reaction. Patients who discontinue ABC because of a suspected HSR should never be rechallenged, regardless of their HLA-B*5701 status.
- An association between ABC use and myocardial infarction (MI) was first reported in the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study. This large, multinational, observational study group found that recent (i.e., within 6 months) or current use of ABC was associated with an increased risk of an MI, particularly in participants with preexisting cardiac risk factors.24, 25
- Since the D:A:D report, several studies have evaluated the relationship between ABC therapy and cardiovascular events. Some studies have found an association.26-32 Others, including an FDA meta-analysis of 26 randomized clinical trials that evaluated ABC, have not.33-37
- An analysis of data from the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) found that use of ABC in the previous 6 months was associated with an increased risk of both type 1 and type 2 MIs after adjusting for cardiovascular disease risk factors.38
- No consensus has been reached on the association between ABC use and MI risk or the mechanism for such an association.
Other Factors and Considerations
- ABC/3TC is available as a coformulated tablet and as a coformulated STR with DTG.
- ABC and 3TC are available separately and as a coformulated tablet in generic tablet formulations.
- ABC does not cause renal dysfunction and can be used instead of TDF in patients with underlying renal dysfunction or in those who are at high risk for renal effects. No dose adjustment is required in patients with renal dysfunction.
The Panel’s Recommendations
- ABC should be prescribed only for patients who are HLA-B*5701 negative.
- On the basis of clinical trial safety and efficacy data, experience in clinical practice, and the availability of DTG/ABC/3TC as a STR, the Panel classifies DTG/ABC/3TC as a Recommended Initial Regimen for Most People with HIV (AI) (see Characteristics of Integrase Strand Transfer Inhibitors for discussion regarding the clinical efficacy data for ABC/3TC plus DTG).
- ABC/3TC use with EFV, ATV/r, atazanavir/cobicistat (ATV/c), DRV/c, darunavir/ritonavir (DRV/r), or RAL is recommended only for patients with pretreatment HIV RNA levels <100,000 copies/mL. See Table 6 for more detailed recommendations on the use of ABC/3TC with these drugs.
- ABC should be used with caution or avoided in patients with known high cardiovascular risk.
Emtricitabine (FTC) and lamivudine (3TC)FTC and 3TC generally are used interchangeably in combination with other ARVs. In a randomized open-label comparison of FTC and 3TC in 440 patients with virologic suppression on a 3TC-containing regimen and who substituted FTC 200 mg daily for 3TC 150 mg twice daily, FTC and 3TC were equivalent for virologic suppression and similar in rates of adverse events.39 A meta-analysis of 12 trials found no significant difference in treatment success between 3TC and FTC.40 In the ATHENA cohort, virologic efficacy of TDF/FTC was compared to TDF/3TC when either was combined with a non-nucleoside reverse transcriptase inhibitor (NNRTI)—EFV or nevirapine (NVP)41 —or with a boosted PI.42 TDF/3TC was associated with higher rates of virologic failure than TDF/FTC in the NNRTI analysis. However, it is noteworthy that the participants in the NNRTI cohort who were taking 3TC generally had higher viral loads and lower CD4 T lymphocyte cell counts and were more likely to be using injection drugs at the start of the study than those taking FTC.41 No difference was reported in the rates of virologic failure in people who were taking TDF/FTC and people who were taking TDF/3TC when these drug combinations were used with a boosted PI.42 A retrospective analysis of an Italian national database found that viral resistance was more common with TDF/3TC than with TDF/FTC, but this was not observed in clinical trials.43
- Both FTC and 3TC have been well tolerated with no significant treatment-limiting adverse effects.
- In early clinical trials, FTC was infrequently associated with mild hyperpigmentation of palms and soles.
Other Factors and Considerations
- 3TC is now generic in the United States and can be coformulated with other drugs, as has occurred with DOR/TDF/3TC.
- Both 3TC and FTC have activity against hepatitis B but are insufficient for HBV treatment when used alone due to the emergence of resistance. Discontinuation of FTC or 3TC can precipitate a flare in HBV if no other HBV-active drugs are in the regimen.
- The dose of FTC or 3TC should be adjusted in patients with creatinine clearance (CrCl) <50 mL/min.
- No significant drug interactions have been identified with FTC. Sorbitol-containing drugs can decrease 3TC concentration, and coadministration should be avoided.
- Both FTC and 3TC select for the M184V mutation when viral suppression is suboptimal.
The Panel’s Recommendation
- FTC and 3TC are considered interchangeable in combination with other ARV drugs (AI).
Lamivudine (3TC) as Single NRTIBased on the GEMINI-1 and GEMINI-2 studies9 that found DTG plus 3TC noninferior to DTG plus TDF/FTC in ART-naive patients with HIV RNA <500,000 copies/mL, 3TC may be used as a single NRTI with DTG (see Drug Interactions Between Integrase Strand Transfer Inhibitors and Other Drugs for more information). In addition, based on the ANDES trial, if ABC, TDF, and TAF cannot be used, 3TC can also be used as a single NRTI with DRV/r.44 (See Other Antiretroviral Regimens for Initial Therapy When Abacavir, Tenofovir Alafenamide, and Tenofovir Disoproxil Fumarate Cannot Be Used or Are Not Optimal.)
Other Factors and Considerations
- 3TC is available as an STR with DTG.
- 3TC has activity against HBV but is insufficient for HBV treatment when used alone due to the emergence of resistance. Discontinuation of 3TC can precipitate a flare in HBV if no other HBV-active drugs are in the regimen.
- 3TC is available in two brand-name formulations (one for HIV and the other for HBV), but the doses are different. The dose for HIV treatment is 3TC 300 mg daily.
- The dose of 3TC should be adjusted in patients with CrCl <50 mL/min.
- Sorbitol-containing drugs can decrease 3TC concentration, and coadministration should be avoided.
The Panel’s Recommendations
- The Panel recommends the use of DTG/3TC (AI) as a Recommended Initial Regimen for Most People with HIV with three exceptions. DTG/3TC is not recommended for—
- Individuals with HIV RNA >500,000 copies/mL,
- Individuals with HBV coinfection or whose HBV status is unknown, or
- Individuals starting ART before the results of genotypic resistance testing for reverse transcriptase are available.
Tenofovir Alafenamide/Emtricitabine (TAF/FTC)TAF, an oral prodrug of tenofovir (TFV), is hydrolyzed to TFV in plasma and then converted to TFV-diphosphate (TFV-DP) intracellularly, where it exerts its activity as an NRTI. Unlike TDF, which readily converts to TFV in plasma after oral absorption, TAF remains relatively stable in plasma, resulting in lower plasma and higher intracellular TFV concentrations. After oral administration, TAF 25 mg resulted in plasma TFV concentrations that were 90% lower than those seen with TDF 300 mg. Intracellular TFV-DP concentrations, however, were substantially higher with TAF.
Renal and Bone Effects
- The potential for adverse kidney and bone effects is lower with TAF than with TDF. In randomized controlled trials that compared TAF and TDF in treatment-naive or virologically suppressed patients, TAF had more favorable effects on renal biomarkers and bone density than TDF.
- In randomized controlled trials in ART-naive patients, in switch studies and in a large study of preexposure prophylaxis, levels of LDL and HDL cholesterol and triglycerides were higher in patients receiving TAF than in patients receiving TDF. However, total cholesterol to HDL ratios did not differ between patients receiving TAF and those receiving TDF. The clinical significance of this finding is not clear.10, 45, 46
- Initiation of TAF in ART-naive individuals and in people without HIV has been associated with greater weight gain than initiation of TDF47, 48 and ABC.48 Significant weight gain initially was reported in a cohort of patients switching from TDF- to TAF-containing regimens.49 In ADVANCE, an open-label trial conducted in South Africa that compared EFV/TDF/FTC versus DTG plus TDF/FTC versus DTG plus TAF/FTC in ART-naive patients, a greater increase in body weight was reported with initiation of TAF than with TDF.47 Weight gain was most pronounced in Black women (10 kg over 96 weeks). This area is under intense investigation, and the clinical significance of the effect is still uncertain. It is also unclear whether change of therapy results in reversal of weight gain.
Other Factors and Considerations
- TAF/FTC is available in FDCs with bictegravir (BIC), DRV/c, EVG/c, or rilpivirine (RPV), allowing the regimens to be administered as a single pill taken once daily with food.
- In Phase 3 randomized trials, BIC/TAF/FTC was comparable to DTG/ABC/3TC and to DTG plus TAF/FTC (see Drug Interactions Between Integrase Strand Transfer Inhibitors and Other Drugs).
- TAF-containing regimens are approved for patients with eGFR ≥30 mL/min. Renal function, urine glucose, and urine protein should be assessed before initiating treatment with TAF, and these assessments should be repeated periodically during treatment. EVG/c/FTC/TAF was safe and effective in a single-arm switch study that was conducted in patients on hemodialysis with eGFR <15 mL/min.50
- Both TAF and FTC are active against HBV. In patients with HIV/HBV coinfection, TAF/FTC may be used as the NRTI pair in an ARV regimen because these drugs have activity against both viruses (see Hepatitis B Virus/HIV Coinfection).17
- Although there are insufficient data on teratogenicity in humans, TAF is now recommended as an alternative drug in pregnancy because of reassuring data from The Antiretroviral Pregnancy Registry that show no evidence of teratogenicity.
The Panel’s Recommendation
- On the basis of clinical trial safety and efficacy data, supportive bioequivalence data,51 and its availability as a component of various FDCs, the Panel considers TAF/FTC a recommended NRTI combination for initial ART in most people with HIV when prescribed with BIC, DTG, and RAL, and as part of Recommended Regimens in Certain Clinical Situations.
Tenofovir Disoproxil Fumarate/Emtricitabine (TDF/FTC) and Tenofovir Disoproxil Fumarate/Lamivudine (TDF/3TC)TDF, with either 3TC or FTC, has been studied in combination with DOR, EFV, RPV, several boosted PIs, EVG/c, RAL, and DTG in randomized clinical trials.52-61
- New onset or worsening renal impairment has been associated with TDF use.62, 63 Risk factors may include advanced HIV disease, longer treatment history, low body weight (especially in women),64 and preexisting renal impairment.65 Concomitant use of a PK-enhanced regimen (with a PI or EVG) can increase TDF concentrations; studies have suggested that the risk of renal dysfunction is greater when TDF is used in these regimens. As previously noted, adverse effects on renal biomarkers, such as proteinuria, especially tubular proteinuria, were more frequent with TDF than with TAF.66
- Adverse renal outcomes are more likely when TDF/FTC is coadministered with PK boosters (RTV or COBI). A meta-analysis of randomized trials found that discontinuation due to renal adverse events is more frequent in people who take TDF/FTC than TAF/FTC with PK boosting.16
- Although initiation of all NRTI-containing regimens has been associated with a decrease in BMD, the loss of BMD is greater with TDF-containing regimens. For example, in two randomized studies that compared TDF/FTC with ABC/3TC, participants who received TDF/FTC experienced a significantly greater decline in BMD than ABC/3TC-treated participants.67, 68 BMD generally stabilizes following an early decline after ART initiation. Loss of BMD with TDF is also greater than with TAF.
- Cases of osteomalacia associated with proximal renal tubulopathy have been reported with the use of TDF.69 Adverse bone outcomes have been found to be more likely when TDF/FTC is coadministered with PK boosters.(Arribas, Thompson et al. 2017; Hill, Hughes et al. 2018) However, a recent meta-analysis found no difference in bone-related toxicities between TAF and TDF, regardless of boosting.16
Other Factors and Considerations
- TDF/FTC is available in FDCs with EFV, EVG/c, and RPV, allowing the regimens to be administered as a single pill taken once daily.
- TDF/3TC is available in FDCs with DOR 100 mg, EFV 600 mg, and EFV 400 mg.
- Renal function, urine glucose, and urine protein should be assessed before initiating treatment with TDF and periodically during treatment (see Laboratory Testing for Initial Assessment and Monitoring). In patients who have preexisting renal insufficiency (CrCl <60 mL/min),70 use of TDF generally should be avoided. If TDF is used, a dose adjustment is required if the patient’s CrCl falls below 50 mL/min (see Appendix B, Table 11 for dose recommendations).
- TDF, FTC, and 3TC are active against HBV. In patients with HBV/HIV coinfection, TDF/FTC or TDF/3TC may be used as the NRTI pair of the ARV regimen because these drugs have activity against both viruses (see Hepatitis B Virus/HIV Coinfection).
The Panel’s Recommendations
- On the basis of clinical trial safety and efficacy data, long-term experience in clinical practice, and the combination’s availability as a component of FDC drugs, the Panel considers TDF/FTC and TDF/3TC as recommended NRTI combinations for initial ART in most people with HIV when combined with DTG or RAL. See Table 6 for recommendations regarding use of TDF/FTC with other drugs.
- TDF should be used with caution or avoided in patients with renal disease and osteoporosis.
- When TDF is used, especially in conjunction with a PK booster, clinicians should monitor for renal and bone safety during therapy. Boosters should be avoided when possible in patients taking TDF.
- Birkus G, Hitchcock MJ, Cihlar T. Assessment of mitochondrial toxicity in human cells treated with tenofovir: comparison with other nucleoside reverse transcriptase inhibitors. Antimicrob Agents Chemother. 2002;46(3):716-723. Available at: https://www.ncbi.nlm.nih.gov/pubmed/11850253.
- Johnson AA, Ray AS, Hanes J, et al. Toxicity of antiviral nucleoside analogs and the human mitochondrial DNA polymerase. J Biol Chem. 2001;276(44):40847-40857. Available at: https://www.ncbi.nlm.nih.gov/pubmed/11526116.
- Hill A, Hughes SL, Gotham D, Pozniak AL. Tenofovir alafenamide versus tenofovir disoproxil fumarate: is there a true difference in efficacy and safety? J Virus Erad. 2018;4(2):72-79. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29682298.
- Sax PE, Tierney C, Collier AC, et al. Abacavir-lamivudine versus tenofovir-emtricitabine for initial HIV-1 therapy. N Engl J Med. 2009;361(23):2230-2240. Available at: https://www.ncbi.nlm.nih.gov/pubmed/19952143.
- Post FA, Moyle GJ, Stellbrink HJ, et al. Randomized comparison of renal effects, efficacy, and safety with once-daily abacavir/lamivudine versus tenofovir/emtricitabine, administered with efavirenz, in antiretroviral-naive, HIV-1-infected adults: 48-week results from the ASSERT study. J Acquir Immune Defic Syndr. 2010;55(1):49-57. Available at: https://www.ncbi.nlm.nih.gov/pubmed/20431394.
- Smith KY, Patel P, Fine D, et al. Randomized, double-blind, placebo-matched, multicenter trial of abacavir/lamivudine or tenofovir/emtricitabine with lopinavir/ritonavir for initial HIV treatment. AIDS. 2009;23(12):1547-1556. Available at: https://www.ncbi.nlm.nih.gov/pubmed/19542866.
- Walmsley SL, Antela A, Clumeck N, et al. Dolutegravir plus abacavir-lamivudine for the treatment of HIV-1 infection. N Engl J Med. 2013;369(19):1807-1818. Available at: https://www.ncbi.nlm.nih.gov/pubmed/24195548.
- Cahn P, Madero JS, Arribas JR, et al. Dolutegravir plus lamivudine versus dolutegravir plus tenofovir disoproxil fumarate and emtricitabine in antiretroviral-naive adults with HIV-1 infection (GEMINI-1 and GEMINI-2): week 48 results from two multicentre, double-blind, randomised, non-inferiority, phase 3 trials. Lancet. 2019;393(10167):143-155. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30420123.
- Cahn P, Madero JS, Arribas JR, et al. Durable Efficacy of Dolutegravir Plus Lamivudine in Antiretroviral Treatment-Naive Adults With HIV-1 Infection: 96-Week Results From the GEMINI-1 and GEMINI-2 Randomized Clinical Trials. J Acquir Immune Defic Syndr. 2019. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31834000.
- Sax PE, Wohl D, Yin MT, et al. Tenofovir alafenamide versus tenofovir disoproxil fumarate, coformulated with elvitegravir, cobicistat, and emtricitabine, for initial treatment of HIV-1 infection: two randomised, double-blind, phase 3, non-inferiority trials. Lancet. 2015;385(9987):2606-2615. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25890673.
- Arribas JR, Thompson M, Sax PE, et al. Brief report: randomized, double-blind comparison of tenofovir alafenamide (TAF) vs tenofovir disoproxil fumarate (TDF), each coformulated with elvitegravir, cobicistat, and emtricitabine (E/C/F) for initial HIV-1 treatment: week 144 results. J Acquir Immune Defic Syndr. 2017;75(2):211-218. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28282300.
- Rijnders BJ, Post FA, Rieger A, et al. Longer-term renal safety of tenofovir alafenamide vs tenofovir disoproxil fumarate. Presented at: Conference on Retroviruses and Opportunistic Infections; 2016. Boston, MA. Available at: https://www.croiconference.org/sessions/longer-term-renal-safety-tenofovir-alafenamide-vs-tenofovir-disoproxil-fumarate.
- Wohl D, Oka S, Clumeck N, et al. Brief report: a randomized, double-blind comparison of tenofovir alafenamide versus tenofovir disoproxil fumarate, each coformulated with elvitegravir, cobicistat, and emtricitabine for initial HIV-1 treatment: week 96 results. J Acquir Immune Defic Syndr. 2016;72(1):58-64. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26829661.
- Mills A, Crofoot GJ, McDonald C, et al. Tenofovir alafenamide versus tenofovir disoproxil fumarate in the first protease inhibitor-based single-tablet regimen for initial HIV-1 therapy: a randomized phase 2 study. J Acquir Immune Defic Syndr. 2015;69(4):439-445. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25867913.
- Eron JJ, Orkin C, Gallant J, et al. A week-48 randomized phase-3 trial of darunavir/cobicistat/emtricitabine/tenofovir alafenamide in treatment-naive HIV-1 patients. AIDS. 2018;32(11):1431-1442. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29683855.
- Pilkington V, Hughes SL, Pepperrell T, et al. Tenofovir alafenamide vs. tenofovir disoproxil fumarate: an updated meta-analysis of 14 894 patients across 14 trials. AIDS. 2020;34(15):2259-2268. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33048869.
- Gallant J, Brunetta J, Crofoot G, et al. Efficacy and safety of switching to a single-tablet regimen of elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) in HIV-1/hepatitis B coinfected adults. J Acquir Immune Defic Syndr. 2016. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27171740.
- Mayer KH, Molina JM, Thompson MA, et al. Emtricitabine and tenofovir alafenamide vs emtricitabine and tenofovir disoproxil fumarate for HIV pre-exposure prophylaxis (DISCOVER): primary results from a randomised, double-blind, multicentre, active-controlled, phase 3, non-inferiority trial. Lancet. 2020;396(10246):239-254. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32711800.
- DeJesus E, Herrera G, Teofilo E, et al. Abacavir versus zidovudine combined with lamivudine and efavirenz, for the treatment of antiretroviral-naive HIV-infected adults. Clin Infect Dis. 2004;39(7):1038-1046. Available at: https://www.ncbi.nlm.nih.gov/pubmed/15472858.
- Rodriguez-French A, Boghossian J, Gray GE, et al. The NEAT study: a 48-week open-label study to compare the antiviral efficacy and safety of GW433908 versus nelfinavir in antiretroviral therapy-naive HIV-1-infected patients. J Acquir Immune Defic Syndr. 2004;35(1):22-32. Available at: https://www.ncbi.nlm.nih.gov/pubmed/14707788.
- Gathe JC, Jr., Ive P, Wood R, et al. SOLO: 48-week efficacy and safety comparison of once-daily fosamprenavir /ritonavir versus twice-daily nelfinavir in naive HIV-1-infected patients. AIDS. 2004;18(11):1529-1537. Available at: https://www.ncbi.nlm.nih.gov/pubmed/15238771.
- Saag M, Balu R, Phillips E, et al. High sensitivity of human leukocyte antigen-b*5701 as a marker for immunologically confirmed abacavir hypersensitivity in white and black patients. Clin Infect Dis. 2008;46(7):1111-1118. Available at: https://www.ncbi.nlm.nih.gov/pubmed/18444831.
- Mallal S, Phillips E, Carosi G, et al. HLA-B*5701 screening for hypersensitivity to abacavir. N Engl J Med. 2008;358(6):568-579. Available at: https://www.ncbi.nlm.nih.gov/pubmed/18256392.
- Sabin CA, Worm SW, Weber R, et al. Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients enrolled in the D:A:D study: a multi-cohort collaboration. Lancet. 2008;371(9622):1417-1426. Available at: https://www.ncbi.nlm.nih.gov/pubmed/18387667.
- Worm SW, Sabin C, Weber R, et al. Risk of myocardial infarction in patients with HIV infection exposed to specific individual antiretroviral drugs from the 3 major drug classes: the data collection on adverse events of anti-HIV drugs (D:A:D) study. J Infect Dis. 2010;201(3):318-330. Available at: https://www.ncbi.nlm.nih.gov/pubmed/20039804.
- The SMART/INSIGHT and the D:A:D Study Groups TSIatDADSG. Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients. AIDS. 2008;22(14):F17-24. Available at: https://www.ncbi.nlm.nih.gov/pubmed/18753925.
- Obel N, Farkas DK, Kronborg G, et al. Abacavir and risk of myocardial infarction in HIV-infected patients on highly active antiretroviral therapy: a population-based nationwide cohort study. HIV Med. 2010;11(2):130-136. Available at: https://www.ncbi.nlm.nih.gov/pubmed/19682101.
- Choi AI, Vittinghoff E, Deeks SG, Weekley CC, Li Y, Shlipak MG. Cardiovascular risks associated with abacavir and tenofovir exposure in HIV-infected persons. AIDS. 2011;25(10):1289-1298. Available at: https://www.ncbi.nlm.nih.gov/pubmed/21516027.
- Durand M, Sheehy O, Baril JG, Lelorier J, Tremblay CL. Association between HIV infection, antiretroviral therapy, and risk of acute myocardial infarction: a cohort and nested case-control study using Quebec’s public health insurance database. J Acquir Immune Defic Syndr. 2011;57(3):245-253. Available at: https://www.ncbi.nlm.nih.gov/pubmed/21499115.
- Young J, Xiao Y, Moodie EE, et al. Effect of cumulating exposure to abacavir on the risk of cardiovascular disease events in patients from the Swiss HIV Cohort Study. J Acquir Immune Defic Syndr. 2015;69(4):413-421. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25932884.
- Marcus JL, Neugebauer RS, Leyden WA, et al. Use of abacavir and risk of cardiovascular disease among HIV-infected individuals. J Acquir Immune Defic Syndr. 2016;71(4):413-419. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26536316.
- Sabin CA, Reiss P, Ryom L, et al. Is there continued evidence for an association between abacavir usage and myocardial infarction risk in individuals with HIV? A cohort collaboration. BMC Med. 2016;14:61. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27036962.
- Brothers CH, Hernandez JE, Cutrell AG, et al. Risk of myocardial infarction and abacavir therapy: no increased risk across 52 GlaxoSmithKline-sponsored clinical trials in adult subjects. J Acquir Immune Defic Syndr. 2009;51(1):20-28. Available at: https://www.ncbi.nlm.nih.gov/pubmed/19282778.
- Lang S, Mary-Krause M, Cotte L, et al. Impact of individual antiretroviral drugs on the risk of myocardial infarction in human immunodeficiency virus-infected patients: a case-control study nested within the French Hospital Database on HIV ANRS cohort CO4. Arch Intern Med. 2010;170(14):1228-1238. Available at: https://www.ncbi.nlm.nih.gov/pubmed/20660842.
- Bedimo RJ, Westfall AO, Drechsler H, Vidiella G, Tebas P. Abacavir use and risk of acute myocardial infarction and cerebrovascular events in the highly active antiretroviral therapy era. Clin Infect Dis. 2011;53(1):84-91. Available at: https://www.ncbi.nlm.nih.gov/pubmed/21653308.
- Ribaudo HJ, Benson CA, Zheng Y, et al. No risk of myocardial infarction associated with initial antiretroviral treatment containing abacavir: short and long-term results from ACTG A5001/ALLRT. Clin Infect Dis. 2011;52(7):929-940. Available at: https://www.ncbi.nlm.nih.gov/pubmed/21427402.
- Ding X, Andraca-Carrera E, Cooper C, et al. No association of abacavir use with myocardial infarction: findings of an FDA meta-analysis. J Acquir Immune Defic Syndr. 2012;61(4):441-447. Available at: https://www.ncbi.nlm.nih.gov/pubmed/22932321.
- Elion RA, Althoff KN, Zhang J, et al. Recent Abacavir Use Increases Risk of Type 1 and Type 2 Myocardial Infarctions Among Adults With HIV. J Acquir Immune Defic Syndr. 2018;78(1):62-72. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29419568.
- Benson CA, van der Horst C, Lamarca A, et al. A randomized study of emtricitabine and lamivudine in stably suppressed patients with HIV. AIDS. 2004;18(17):2269-2276. Available at: https://www.ncbi.nlm.nih.gov/pubmed/15577539.
- Ford N, Shubber Z, Hill A, et al. Comparative efficacy of Lamivudine and emtricitabine: a systematic review and meta-analysis of randomized trials. PLoS One. 2013;8(11):e79981. Available at: https://www.ncbi.nlm.nih.gov/pubmed/24244586.
- Rokx C, Fibriani A, van de Vijver DA, et al. Increased virological failure in naive HIV-1-infected patients taking lamivudine compared with emtricitabine in combination with tenofovir and efavirenz or nevirapine in the Dutch nationwide ATHENA cohort. Clin Infect Dis. 2015;60(1):143-153. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25273080.
- Rokx C, Gras L, van de Vijver D, Verbon A, Rijnders B, Study ANOC. Virological responses to lamivudine or emtricitabine when combined with tenofovir and a protease inhibitor in treatment-naive HIV-1-infected patients in the Dutch AIDS Therapy Evaluation in the Netherlands (ATHENA) cohort. HIV Med. 2016;17(8):571-580. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26842457.
- Maserati R, De Silvestri A, Uglietti A, et al. Emerging mutations at virological failure of HAART combinations containing tenofovir and lamivudine or emtricitabine. AIDS. 2010;24(7):1013-1018. Available at: https://www.ncbi.nlm.nih.gov/pubmed/20124969.
- Figueroa MI, Sued OG, Gun AM, et al. DRV/R/3TC FDC for HIV-1 treatment naive patients: week 48 results of the ANDES study. Presented at: Conference on Retroviruses and Opportunistic Infections; 2018. Boston, MA. Available at: https://www.croiconference.org/wp-content/uploads/sites/2/posters/2018/1430_Cahn_489.pdf.
- Gallant JE, Daar ES, Raffi F, et al. Efficacy and safety of tenofovir alafenamide versus tenofovir disoproxil fumarate given as fixed-dose combinations containing emtricitabine as backbones for treatment of HIV-1 infection in virologically suppressed adults: a randomised, double-blind, active-controlled phase 3 trial. Lancet HIV. 2016;3(4):e158-165. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27036991.
- Wohl D, Thalme A, Finlayson R, et al. Renal safety of tenofovir alafenamide in patients at high risk of kidney disease. Presented at: Conference on Retroviruses and Opportunistic Infections; 2016. Boston, MA. Available at: https://www.croiconference.org/sessions/renal-safety-tenofovir-alafenamide-patients-high-risk-kidney-disease.
- 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. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31339677.
- 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. 2019. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31606734.
- Gomez M, Seybold U, Roider J, Harter G, Bogner JR. A retrospective analysis of weight changes in HIV-positive patients switching from a tenofovir disoproxil fumarate (TDF)- to a tenofovir alafenamide fumarate (TAF)-containing treatment regimen in one German university hospital in 2015-2017. Infection. 2019;47(1):95-102. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30269210.
- Eron JJ, Lelievre JD, Kalayjian R, et al. Safety and efficacy of E/C/F/TAF in HIV-infected adults on chronic hemodialysis. Presented at: Conference on Retroviruses and Opportunistic Infections; 2018. Boston, MA. Available at: https://www.croiconference.org/abstract/safety-and-efficacy-ecftaf-hiv-infected-adults-chronic-hemodialysis/.
- Zack J, Chuck S, Chu H, et al. Bioequivalence of the rilpivirine/emtricitabine/tenofovir alafenamide single-tablet regimen. J Bioequiv Availab. 2016;8(2):49-54. Available at: https://www.omicsonline.org/open-access/bioequivalence-of-the-rilpivirineemtricitabinetenofovir-alafenamidesingletablet-regimen-jbb-1000266.pdf.
- Cassetti I, Madruga JV, Suleiman JM, et al. The safety and efficacy of tenofovir DF in combination with lamivudine and efavirenz through 6 years in antiretroviral-naive HIV-1-infected patients. HIV Clin Trials. 2007;8(3):164-172. Available at: https://www.ncbi.nlm.nih.gov/pubmed/17621463.
- Molina JM, Podsadecki TJ, Johnson MA, et al. A lopinavir/ritonavir-based once-daily regimen results in better compliance and is non-inferior to a twice-daily regimen through 96 weeks. AIDS Res Hum Retroviruses. 2007;23(12):1505-1514. Available at: https://www.ncbi.nlm.nih.gov/pubmed/18160008.
- Molina JM, Andrade-Villanueva J, Echevarria J, et al. Once-daily atazanavir/ritonavir versus twice-daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine, for management of antiretroviral-naive HIV-1-infected patients: 48 week efficacy and safety results of the CASTLE study. Lancet. 2008;372(9639):646-655. Available at: https://www.ncbi.nlm.nih.gov/pubmed/18722869.
- Ortiz R, Dejesus E, Khanlou H, et al. Efficacy and safety of once-daily darunavir/ritonavir versus lopinavir/ritonavir in treatment-naive HIV-1-infected patients at week 48. AIDS. 2008;22(12):1389-1397. Available at: https://www.ncbi.nlm.nih.gov/pubmed/18614861.
- Smith KY, Weinberg WG, Dejesus E, et al. Fosamprenavir or atazanavir once daily boosted with ritonavir 100 mg, plus tenofovir/emtricitabine, for the initial treatment of HIV infection: 48-week results of ALERT. AIDS Res Ther. 2008;5:5. Available at: https://www.ncbi.nlm.nih.gov/pubmed/18373851.
- Lennox JL, DeJesus E, Lazzarin A, et al. Safety and efficacy of raltegravir-based versus efavirenz-based combination therapy in treatment-naive patients with HIV-1 infection: a multicentre, double-blind randomised controlled trial. Lancet. 2009;374(9692):796-806. Available at: https://www.ncbi.nlm.nih.gov/pubmed/19647866.
- DeJesus E, Rockstroh JK, Henry K, et al. Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate versus ritonavir-boosted atazanavir plus co-formulated emtricitabine and tenofovir disoproxil fumarate for initial treatment of HIV-1 infection: a randomised, double-blind, phase 3, non-inferiority trial. Lancet. 2012;379(9835):2429-2438. Available at: https://www.ncbi.nlm.nih.gov/pubmed/22748590.
- Sax PE, DeJesus E, Mills A, et al. Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir versus co-formulated efavirenz, emtricitabine, and tenofovir for initial treatment of HIV-1 infection: a randomised, double-blind, phase 3 trial, analysis of results after 48 weeks. Lancet. 2012;379(9835):2439-2448. Available at: https://www.ncbi.nlm.nih.gov/pubmed/22748591.
- DeJesus E, Rockstroh JK, Lennox JL, et al. Efficacy of raltegravir versus efavirenz when combined with tenofovir/emtricitabine in treatment-naive HIV-1-infected patients: week-192 overall and subgroup analyses from STARTMRK. HIV Clin Trials. 2012;13(4):228-232. Available at: https://www.ncbi.nlm.nih.gov/pubmed/22849964.
- Raffi F, Jaeger H, Quiros-Roldan E, et al. Once-daily dolutegravir versus twice-daily raltegravir in antiretroviral-naive adults with HIV-1 infection (SPRING-2 study): 96 week results from a randomised, double-blind, non-inferiority trial. Lancet Infect Dis. 2013;13(11):927-935. Available at: https://www.ncbi.nlm.nih.gov/pubmed/24074642.
- Karras A, Lafaurie M, Furco A, et al. Tenofovir-related nephrotoxicity in human immunodeficiency virus-infected patients: three cases of renal failure, Fanconi syndrome, and nephrogenic diabetes insipidus. Clin Infect Dis. 2003;36(8):1070-1073. Available at: https://www.ncbi.nlm.nih.gov/pubmed/12684922.
- Zimmermann AE, Pizzoferrato T, Bedford J, Morris A, Hoffman R, Braden G. Tenofovir-associated acute and chronic kidney disease: a case of multiple drug interactions. Clin Infect Dis. 2006;42(2):283-290. Available at: https://www.ncbi.nlm.nih.gov/pubmed/16355343.
- Gervasoni C, Meraviglia P, Landonio S, et al. Low body weight in females is a risk factor for increased tenofovir exposure and drug-related adverse events. PLoS One. 2013;8(12):e80242. Available at: https://www.ncbi.nlm.nih.gov/pubmed/24312465.
- Gallant JE, Moore RD. Renal function with use of a tenofovir-containing initial antiretroviral regimen. AIDS. 2009;23(15):1971-1975. Available at: https://www.ncbi.nlm.nih.gov/pubmed/19696652.
- GENVOYA [package insert]. Gilead. 2021. Available at: https://www.gilead.com/-/media/files/pdfs/medicines/hiv/genvoya/genvoya_pi.pdf.
- Stellbrink HJ, Orkin C, Arribas JR, et al. Comparison of changes in bone density and turnover with abacavir-lamivudine versus tenofovir-emtricitabine in HIV-infected adults: 48-week results from the ASSERT study. Clin Infect Dis. 2010;51(8):963-972. Available at: https://www.ncbi.nlm.nih.gov/pubmed/20828304.
- McComsey GA, Kitch D, Daar ES, et al. Bone mineral density and fractures in antiretroviral-naive persons randomized to receive abacavir-lamivudine or tenofovir disoproxil fumarate-emtricitabine along with efavirenz or atazanavir-ritonavir: Aids Clinical Trials Group A5224s, a substudy of ACTG A5202. J Infect Dis. 2011;203(12):1791-1801. Available at: https://www.ncbi.nlm.nih.gov/pubmed/21606537.
- Perrot S, Aslangul E, Szwebel T, Caillat-Vigneron N, Le Jeunne C. Bone pain due to fractures revealing osteomalacia related to tenofovir-induced proximal renal tubular dysfunction in a human immunodeficiency virus-infected patient. J Clin Rheumatol. 2009;15(2):72-74. Available at: https://www.ncbi.nlm.nih.gov/pubmed/19265350.
- Lucas GM, Ross MJ, Stock PG, et al. Clinical practice guideline for the management of chronic kidney disease in patients infected with HIV: 2014 update by the HIV Medicine Association of the Infectious Diseases Society of America. Clin Infect Dis. 2014;59(9):e96-138. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25234519.