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Bictegravir and dolutegravir: head to head at 96 weeks, Comment + study
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Download the PDF here
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- Bictegravir combined with emtricitabine and tenofovir alafenamide versus dolutegravir, abacavir, and lamivudine for initial treatment of HIV-1 infection: week 96 results from
a randomised, double-blind, multicentre, phase 3, non-inferiority trial -
In The Lancet HIV, David Wohl and colleagues1 present 96 week data on bictegravir in a fixed-dose combination with emtricitabine and tenofovir alafenamide versus fixed-dose dolutegravir, abacavir, and lamivudine for initial treatment of HIV-1, while Hans-Jürgen Stellbrink and co-workers2 report 96 week data on co-formulated bictegravir, emtricitabine, and tenofovir alafenamide versus dolutegravir with emtricitabine and tenofovir alafenamide for the same indication, both from randomised, double-blind, placebo-controlled, multicentre, phase 3 non-inferiority trials. The study by Wohl and colleagues1 describes a comparison of two different, three-drug, co-formulated single-tablet regimens. By contrast, the study by Stellbrink and co-workers2 compares bictegravir directly with dolutegravir, given that the same emtricitabine plus tenofovir alafenamide backbone is used in both groups. Both studies had participants who were young (median ages were 31-34 years), included a small proportion of participants with advanced HIV (10-14% had CD4 counts <200 cells per μL) and included proportionately few women (11% across both studies).
Wohl and colleagues1 cite the well known practical advantages of the bictegravir, emtricitabine, and tenofovir alafenamide combination over dolutegravir, abacavir, and lamivudine—namely that HLA-B*5701 testing is not needed and that the drugs can be used in patients co-infected with hepatitis B. 629 participants were enrolled, randomly assigned to a treatment group, and received at least one dose of their assigned treatment. 48-week data were published previously,3 and in this 96-week extension, non-inferiority of the bictegravir regimen was shown, virological failure was rare, and no one developed treatment-emergent resistance to any study drug.
Study drug-related adverse events were reported for 28% of participants in the bictegravir group and 40% in the dolutegravir group, but these were primarily mild or moderate, and most occurred before week 48. The main driver of this difference was drug-related nausea. Nausea was reported by 11% of participants given bictegravir and 24% given dolutegravir and was attributed to the study drug in 6% and 17% (p<0⋅0001). A higher prevalence of nausea was reported in those receiving dolutegravir, abacavir, and lamivudine than in those receiving bictegravir, emtricitabine, and tenofovir alafenamide throughout the 96-week study period. Diarrhoea (48% vs 16%) and headache (13% vs 16%) occurred in similar proportions in both groups. Overall, few discontinuations were due to intolerance or adverse events in either group. No participant discontinued bictegravir, emtricitabine, and tenofovir alafenamide compared with five (2%) who discontinued dolutegravir, abacavir, and lamivudine.
Much has been made of the unfavourable effect of tenofovir alafenamide on lipid concentrations when compared with its predecessor, tenofovir disproxil fumarate.1, 4 In the study by Wohl and colleagues,1 increases from baseline in total cholesterol (p=0⋅002), LDL cholesterol (p<0⋅0001), and total cholesterol-to-HDL ratio (p=0⋅003) were greater in the bictegravir, emtricitabine, and tenofovir alafenamide group than in the dolutegravir, abacavir, and lamivudine group. Despite these difference, the use of lipid-lowering therapy was low in both groups, suggesting that over 2 years, in a young cohort, the clinical effect of these differences of about 10 mg/dL (1⋅67 mmol/L) between the groups was minimal. Longer-term follow-up with clinical outcomes, in older people in particular, will be essential to review cohorts treated with these regimens.
Another debated topic is that of possible excess weight gain in people receiving an integrase inhibitor as part of their antiretroviral regimen.5 Increases in weight after treatment initiation did occur in both groups in the study by Wohl and colleagues,1 although it is perhaps unsurprising that weight gain occurs in people living with HIV who are initiating treatment for the first time. The median weight gain was 3⋅6 kg (IQR 0⋅0-8⋅5) in the bictegravir, emtricitabine, and tenofovir alafenamide group and 2⋅4 kg (-0⋅4 to 5⋅8) for those in the dolutegravir, abacavir, and lamivudine group. Clearly, more long-term data are needed and studies switching patients from other stable regimens, rather than those who are treatment naive, might give a clearer indication whether there is a true adverse effect of these drugs on weight.
In Wohl and colleagues' subgroup analyses,1 older age seemed to favour bictegravir, emtricitabine, and tenofovir alafenamide, with all of 40 participants aged 50 years or older achieving undetectable viral loads (<50 copies per mL) at week 96 compared with 35 (85%) of 41 in the dolutegravir, abacavir, and lamivudine group (p value could not be calculated). Perhaps surprisingly, dolutegravir, abacavir, and lamivudine was favoured in those with worse cumulative adherence (established by pill count showing adherence of <95%): in the dolutegravir, abacavir, and lamivudine group, 103 (86%) of 120 of those meeting the low adherence criteria achieved undetectability compared with 71 (74%) of 96 in the bictegravir, emtricitabine, and tenofovir alafenamide group (p=0⋅029).
In the study by Stellbrink and co-workers,2 645 participants were randomly assigned and received at least one dose of their assigned treatment. 48-week data were reported previously6 and the results at 96 weeks remain reassuring. Non-inferiority was shown, viral rebound was rare, no treatment-emergent resistance occurred in either group and, in fact, no participants met criteria for resistance testing between weeks 48 and 96. At week 96, study drug-related adverse events were reported in both groups (20% in the bictegravir group vs 28% in the dolutegravir group). These differences were greatest for gastrointestinal and neuropsychiatric and sleep-related symptoms. No participants discontinued the bictegravir regimen because of an adverse event between weeks 48 and 96; by contrast, three discontinued the dolutegravir regimen in this period.
Both bictegravir and dolutegravir clearly have important roles in managing HIV-1 infection, and these studies support the use of both, with slightly less favourable results for dolutegravir than bictegravir when paired with abacavir and lamivudine because of tolerability, but a less clear picture when emtricitabine and tenofovir alafenamide is used. Cost, of course, will be important in some settings, but it is also important to consider that although long-term data are available for dolutegravir, abacavir, lamivudine, and emtricitabine, both bictegravir and tenofovir alafenamide are quite new. Neither long-term clinical experience nor long-term cohort data are available to assess possible signals that might not be evident in short randomised studies. For example, are the concerns about weight gain and lipid concentrations justified? Furthermore, increasing data are available on the efficacy and tolerability of oral two-drug regimens based on dolutegravir7, 8 and injectable two-drug regimens based on cabotegravir.9, 10, 11
Some unanswered questions remain about these regimens and the long-term implications and safety of two-drug regimens is unclear. Nonetheless, a paradigm shift has arrived. Bictegravir might be important, but future studies will need to closely scrutinise how two-drug regimens fare against three-drug regimens, even those containing novel drugs.
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Bictegravir combined with emtricitabine and tenofovir alafenamide versus dolutegravir, abacavir, and lamivudine for initial treatment of HIV-1 infection: week 96 results from
a randomised, double-blind, multicentre, phase 3, non-inferiority trial
David A Wohl, Yazdan Yazdanpanah, Axel Baumgarten, Amanda Clarke, Melanie A Thompson, Cynthia Brinson, Debbie Hagins,
Moti N Ramgopal, Andrea Antinori, Xuelian Wei, Rima Acosta, Sean E Collins, Diana Brainard, Hal Martin
Three women had confirmed pregnancies while on study, two in the bictegravir group and one in the dolutegravir group. One of the two participants in the bictegravir group was taken off study treatments when pregnancy was confirmed and subsequently delivered a healthy full-term infant. The other woman in the bictegravir group had a spontaneous abortion at an estimated 2 weeks' gestation; the participant recovered from the event without complications. The pregnancy in the dolutegravir group was terminated with an elective abortion and study drugs were continued.
Both treatments were generally well tolerated, with most adverse events reported as mild or moderate in severity. The most common adverse events were nausea, which was more common in the dolutegravir group than the bictegravir group (p=0⋅0001), diarrhoea, and headache (table 3). Prevalence and incidence of nausea declined over the 96-week study period (appendix p 10). No participants in the bictegravir group had adverse events that led to study drug discontinuation, whereas five (2%) participants in the dolutegravir group did. No neuropsychiatric adverse events met the more than 5% difference in incidence threshold for statistical testing. However, the frequency of dizziness and sleep disorder (MedDRA preferred terms) were two times higher in the dolutegravir group than in the bictegravir group (18 [6%] of 315 vs nine [3%] of 314 for dizziness and 13 [4%] vs three [1%] for sleep disorder). 36 (11%) participants in the bictegravir group versus 39 (12%) participants in the dolutegravir group had a serious adverse event. Five participants had adverse events that led to study drug discontinuation in the dolutegravir group: one nausea and generalised rash (day 4); one thrombocytopenia (day 50); one chronic pancreatitis and steatorrhoea (day 134); one depression (day 248); and one renal failure (day 621). All except the renal failure were considered by the investigator to be related to study drugs; all were grade 3 except one nausea and one depression, which were grade 2 (table 3). Participants in the bictegravir group had a lower incidence of drug-related adverse events than did those in the dolutegravir group (89 [28%] of 314 vs 127 [40%] of 315, p=0⋅002); these events were primarily mild or moderate in severity and most occurred before week 48. The difference between groups was driven mainly by the significant difference in drug-related nausea which occurred in 18 (6%) of 314 in the bictegravir group versus 55 (17%) of 315 in the dolutegravir group (p<0⋅0001). Study drug-related serious adverse events were originally reported for three participants in the bictegravir group (one sudden death, one generalised tonic-clonic seizure, and one spontaneous abortion) versus one patient in the dolutegravir group (gastroenteritis, steatorrhoea, and acute pancreatitis). One event in the bictegravir group (sudden death) was subsequently attributed to suicide and not related to study drug. Adverse events were similar to those reported at week 48, with no new safety findings between weeks 48 and 96 for either treatment group. No abnormal electrocardiogram findings were associated with either treatment.
One or more grade 3 or 4 laboratory abnormalities were reported for 71 (23%) of 314 participants in the bictegravir group and 62 (20%) of 315 in the dolutegravir group; incidence and types of abnormalities were generally balanced between treatment groups (appendix p 8). Most abnormalities were transient and resolved on therapy. The overall laboratory safety profiles were similar to those observed at week 48. No proximal tubulopathy or Fanconi syndrome were reported in either group. No study participant in the bictegravir group discontinued because of a renal adverse event. One individual in the dolutegravir group with a medical history of poorly controlled diabetes and hypertension discontinued treatment because of an adverse event of renal failure on day 621. Small increases from baseline in median serum creatinine and decreases in eGFR occurred at week 96 for both groups (table 4). At 96 weeks, percentage changes in quantitative proteinuria (total urinary albumin-to-urine creatinine ratio) and tubular proteinuria (retinol binding protein and β2-microglobulin-to-urine creatinine ratios) were also similar between groups (table 4).
Changes from baseline in fasting high-density lipoprotein and triglycerides were similar between groups at week 96 (appendix p 9). Significant differences were measured in the median changes from baseline in fasting total cholesterol, low-density lipoprotein, and total cholesterol-to-high-density lipoprotein ratio at week 96 (appendix p 9). Initiation of lipid-modifying drugs during the study through week 96 was not different between the groups.
There were small changes from baseline in hip and lumbar spine bone mineral density that were similar between the two groups; mean percentage changes at week 96 in hip density were -1⋅13% (SD 2⋅77) in the bictegravir group versus -1⋅26% (2⋅85) in the dolutegravir group (p=0⋅59) and changes in lumbar spine density were -0⋅71% (3⋅87) versus -0⋅22% (3⋅52; p=0⋅14; figure 3). Weight increases after treatment initiation occurred in both groups. The median change was 3⋅6 kg (IQR 0⋅0-8⋅5) in the bictegravir group and 2⋅4 kg (-0⋅4 to 5⋅8) in the dolutegravir group.
Discussion
Maximal and durable suppression of plasma HIV-1 RNA as well as the enhancement of quality of life are among the major goals of treatment of HIV-1 infection.2 Here, we report data showing non-inferiority of co-formulated bictegravir, emtricitabine, and tenofovir alafenamide over co-formulated dolutegravir, abacavir, and lamivudine at 96 weeks after initiation in treatment-naive people living with HIV-1 infection. Viral rebound was rare throughout the study. Overall, these virological outcomes data are consistent with those reported at week 48.6
As expected, given the inhibition of renal creatinine transporters by both bictegravir and dolutegravir, both groups had small median increases from baseline in serum creatinine and decreases in eGFR that occurred early and were sustained.11 Likewise, small but similar decreases in bone mineral density occurred in both study groups. Larger changes from baseline in total cholesterol and direct low-density lipoprotein cholesterol occurred in participants in the bictegravir group. Use of lipid-lowering therapy during the trial was low in both study groups, suggesting the clinical relevance of this 10 mg/dL difference between the two groups was minimal. The greater increase in low-density lipoprotein cholesterol in the bictegravir group was unexpected given previously reported week 48 data on the lipid profiles of both study regimens. Notably, in a study of treatment-naive individuals initiating bictegravir, emtricitabine, and tenofovir alafenamide versus dolutegravir, emtricitabine, and tenofovir alafenamide, significant differences in the median change in lipid concentrations at 96 weeks, including low-density lipoprotein cholesterol, were not observed.12
Several observational studies have described differential increases in weight after the initiation of or switch to different classes of antiretrovirals.13, 14, 15
Some, but not all, of these reports suggest that weight gain is greater among those treated with INSTIs.16, 17, 18
As expected for a treatment-naive trial, median increases from baseline in weight were observed in both study groups. Longer-term trends in weight and the factors associated with changes from baseline will be examined in future planned analyses.
Overall, these results show that both regimens were efficacious and well tolerated. In distinguishing between the two, the higher frequency of investigator-reported and patient-reported nausea should be considered. Additionally, the limitations of the use of dolutegravir, abacavir, and lamivudine, including among those with hepatitis B virus co-infection or with an eGFR less than 50 mL/min, as well as the requirement for HLA-B*5701 screening, might favour the use of bictegravir, emtricitabine, and tenofovir alafenamide in some individuals.
As described previously, there are limitations to this investigation that should be considered when interpreting these data. Foremost, the proportion of women enrolled in the trial was low. However, in a study that enrolled only women (n=470) with suppressed plasma HIV-1 RNA who were randomly assigned either to continue prestudy antiretroviral therapy or to switch to bictegravir, emtricitabine, and tenofovir alafenamide, more than 95% of the participants in each treatment group maintained viral suppression at week 48 with no discontinuations of study drug due to adverse events.19 Neuropsychiatric adverse effects of INSTI-containing regimens have been previously reported; however, each individual adverse effect is described as relatively uncommon. 20, 21, 22
Therefore, this trial probably had too few participants to detect differences between the regimens in any neuropsychiatric adverse event as reported by investigators. Furthermore, although 96-week data provide a valuable assessment of the durability of the efficacy and safety of these regimens, the need for HIV therapy remains lifelong. Longer-term data is needed to provide insights into the advantages and disadvantages of these therapeutic options. Participants in this study will continue to be followed up until week 144.
In summary, as was observed at week 48, bictegravir, emtricitabine, and tenofovir alafenamide after 96 weeks of therapy was non-inferior to dolutegravir, abacavir, and lamivudine, with no emergent drug resistance or tubulopathy detected, but with a better gastrointestinal tolerability profile. Bictegravir, emtricitabine, and tenofovir alafenamide can be used in those co-infected with hepatitis B virus and eGFRs as low as 30 mL/min and does not require HLA-B*5701 screening. Therefore, bictegravir, emtricitabine, and tenofovir alafenamide is a potent and well tolerated option for people with HIV-1 infection initiating treatment.
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