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Dolutegravir plus Two Different Prodrugs of Tenofovir to Treat HIV
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NEJM Aug 29 2019 - W.D.F. Venter, M. Moorhouse, S. Sokhela, L. Fairlie, N. Mashabane, M. Masenya, C. Serenata, G. Akpomiemie, A. Qavi, N. Chandiwana, S. Norris, M. Chersich, P. Clayden, E. Abrams, N. Arulappan, A. Vos, K. McCann, B. Simmons, and A. Hill

Two drugs under consideration for inclusion in antiretroviral therapy (ART) regimens for human immunodeficiency virus (HIV) infection are dolutegravir (DTG) and tenofovir alafenamide fumarate (TAF). There are limited data on their use in low- and middle-income countries.
We conducted a 96-week, phase 3, investigator-led, open-label, randomized trial in South Africa, in which we compared a triple-therapy combination of emtricitabine (FTC) and DTG plus either of two tenofovir prodrugs - TAF (TAF-based group) or tenofovir disoproxil fumarate (TDF) (TDF-based group) - against the local standard-of-care regimen of TDF-FTC-efavirenz (standard-care group). Inclusion criteria included an age of 12 years or older, no receipt of ART in the previous 6 months, a creatinine clearance of more than 60 ml per minute (>80 ml per minute in patients younger than 19 years of age), and an HIV type 1 (HIV-1) RNA level of 500 copies or more per milliliter. The primary end point was the percentage of patients with a 48-week HIV-1 RNA level of less than 50 copies per milliliter (as determined with the Snapshot algorithm from the Food and Drug Administration; noninferiority margin, −10 percentage points). We report the primary (48-week) efficacy and safety data.
A total of 1053 patients underwent randomization from February 2017 through May 2018. More than 99% of the patients were black, and 59% were female. The mean age was 32 years, and the mean CD4 count was 337 cells per cubic millimeter. At week 48, the percentage of patients with an HIV-1 RNA level of less than 50 copies per milliliter was 84% in the TAF-based group, 85% in the TDF-based group, and 79% in the standard-care group, findings that indicate that the DTG-containing regimens were noninferior to the standard-care regimen. The number of patients who discontinued the trial regimen was higher in the standard-care group than in the other two groups. In the per-protocol population, the standard-care regimen had equivalent potency to the other two regimens. The TAF-based regimen had less effect on bone density and renal function than the other regimens. Weight increase (both lean and fat mass) was greatest in the TAF-based group and among female patients (mean increase, 6.4 kg in the TAF-based group, 3.2 kg in the TDF-based group, and 1.7 kg in the standard-care group). No resistance to integrase inhibitors was identified in patients receiving the DTG-containing regimens.
Treatment with DTG combined with either of two tenofovir prodrugs (TAF and TDF) showed noninferior efficacy to treatment with the standard-care regimen. There was significantly more weight gain with the DTG-containing regimens, especially in combination with TAF, than with the standard-care regimen. (ADVANCE ClinicalTrials.gov number, NCT03122262. opens in new tab.)
Weight gain has emerged as a major concern with respect to the integrase inhibitor class in the past year, which has resulted in a postmarketing change to package inserts, with some concern relating to ethnic group, sex, and CD4 count at initiation.28-31 In our trial, weight gain was associated with DTG, was less severe with TDF, and was significantly more severe in female patients and patients with lower CD4 counts and higher viral loads. Thus, such weight gain is unlikely to be simply a “return to health” effect, because viral suppression, CD4 recovery, and clinical events were similar across the groups. The weight gain in our trial among black male patients receiving the TAF-based regimen was similar to that seen in predominantly white men in registration studies comparing DTG with bictegravir.17,29,32 It is worrying that weight gain includes increases in truncal fat, which has been associated with known cardiovascular outcomes in other studies.33-35 Use of TDF has been associated with smaller increases in weight than TAF or other NRTI combinations29; however, it is unclear whether TAF amplifies or TDF mitigates the weight-gain effect of DTG.
TDF was associated with a small but significant decrease in bone mineral density, reduced creatinine clearance, and more effect on tubular markers than TAF. DTG was associated with a small decrease in creatinine clearance, presumably due to its effect on tubular secretion. Neuropsychiatric and sleep-related side effects have been a recurring concern with both DTG and EFV.2,4,36,37 It is reassuring that there was a very small number of neuropsychiatric-linked discontinuations of EFV that justified stopping randomized treatment (and none in the groups that received DTG-containing regimens) and that there was no effect on sleep across the groups.
In our trial, no safety issues were reported in female patients who were pregnant or in their infants, but numbers are too small to draw meaningful conclusions. The VESTED trial involving HIV-1-infected pregnant women and their infants (ClinicalTrials.gov number, NCT03048422. opens in new tab) includes the same randomized treatment regimens as the ADVANCE trial.
A low incidence of tuberculosis was presumably due to the use of isoniazid preventive therapy. Drug interactions between TAF and rifampin and between DTG and rifampin are an ongoing concern; current recommendations with respect to adjusting the dose of DTG during receipt of tuberculosis treatment add considerable supply-line complexities in low- and middle-income countries.7 The administration of TAF with rifampin is still being studied. IRIS was uncommon, and previous concern about an association between integrase inhibitors and an increased risk of IRIS37,38 was not confirmed.
Limitations of the trial include the open-label design and lack of standardized pill quantity per group. The trial was conducted in inner-city Johannesburg, with patients from across the region (almost 40% of patients were from outside South Africa, since Johannesburg is a major hub for economic migrants from both within and outside South Africa) and recruited from routine patient care, factors that strengthen generalizability. We were unable to recruit adequate numbers of adolescents to analyze separately and thus were unable to specifically study outcomes in this important group.
The concern around the potential teratogenicity of DTG and a dearth of pregnancy safety data with TAF pose complex challenges for practitioners in low- and middle-income countries that rely on health systems with limited options, especially for women. The increased risk of weight gain with both DTG-containing regimens and the limited knowledge base regarding TAF in pregnancy need to be evaluated against improvements in side-effect profile and adherence, slight reductions in time to virologic control, and effect on bone mineral density and renal function.
At week 48, absolute weight gain and the percentage of patients in whom obesity emerged during treatment were highest in the TAF-based group (6 kg, 14% new obesity), but the values in the TDF-based group (3 kg, 7% new obesity) were also higher than those in the standard-care group (1 kg, 6% new obesity) (Table 2, and Fig. S3 in the Supplementary Appendix). Weight gain was significantly higher in female patients than in male patients across all three groups, with no clear plateau in the increase (Figure 3). The percentage of patients in whom underweight emerged during treatment was higher in the standard-care group (4%) than in the other two groups (1% in each group) (Table 2). There were increases in DXA-assessed lean and fat mass in the limbs and trunk, with significant differences according to treatment group and sex (Table 2, and Fig. S2 in the Supplementary Appendix). Regression analysis showed that obesity that emerged during treatment at week 48 was associated with a lower CD4 count, a higher viral load, and older age. There was no substantial between-group difference in mean systolic or diastolic blood pressure, and there were small differences in lipid and glucose levels (Table S9 in the Supplementary Appendix).
The TDF-containing regimens had a greater effect on lumbar and hip DXA-assessed bone density and renal tubular markers than the TAF-based regimen (Table 2, and Table S10 in the Supplementary Appendix). Changes in creatinine clearance were minor. There were three fractures, all associated with major trauma.
Sleep questionnaires showed that sleep quantity and quality changed little over time, with no significant difference according to group. There were slightly more reported cases of grade 3 or 4 insomnia in the TAF-based group than in the other groups but no discontinuations of the trial regimen due to insomnia (Table 2, and Tables S12 and S13 in the Supplementary Appendix).
After virologic failure, no resistance to integrase inhibitors was observed in patients receiving the DTG-containing regimens; four patients receiving EFV and one patient receiving DTG showed new resistance to nucleoside reverse-transcriptase inhibitors (NRTIs) or nonnucleoside reverse-transcriptase inhibitors (NNRTIs) during viremic episodes (Table S3 in the Supplementary Appendix). In multivariate logistic-regression analysis, the strongest predictors of viral suppression at week 48 were older age and employment (Figure 2). Most patients with an HIV-1 RNA level of 50 copies or more per milliliter at week 48 showed resuppression at a level of less than 50 copies per milliliter in longer-term follow-up with no change in regimen, after interventions to improve adherence.
A first-line regimen of tenofovir disoproxil fumarate (TDF) with either lamivudine (3TC) or emtricitabine (FTC) plus efavirenz (EFV) for the treatment of human immunodeficiency virus infection (HIV) is recommended by the World Health Organization (WHO) because it can be safely used in pregnancy and during tuberculosis treatment. However, the regimen has a low resistance barrier, and there are relatively high incidences of toxic effects among some patients.1-4 Other antiretroviral agents are recommended in high-income countries.5,6
Two drugs under consideration for inclusion in new regimens are dolutegravir (DTG), to replace EFV, and tenofovir alafenamide fumarate (TAF), to replace TDF, both prodrugs of tenofovir.7,8 DTG has potency, resistance, and side-effect benefits over EFV, and there are widespread plans to rapidly expand its use in low- and middle-income countries.7-13 However, associations of DTG with teratogenic effects (specifically, neural-tube defects), neuropsychiatric symptoms, and weight gain have aroused concern, as has the complexity of twice-daily administration with rifampin-containing tuberculosis treatment.7,14 TAF has similar efficacy to that of TDF, with fewer effects on markers of renal or bone toxicity, but lacks data in low- and middle-income countries and in patients who are receiving rifamycins for tuberculosis therapy and in those who are pregnant. For these reasons, the use of TAF has not yet been included in WHO recommendations.7,15-18 We conducted an investigator-led, randomized clinical trial, ADVANCE, to evaluate the efficacy and safety of two antiretroviral therapy (ART) combinations, TAF-FTC-DTG and TDF-FTC-DTG, as compared with the current first-line regimen of TDF-FTC (or 3TC)-EFV used in the majority of patients in low- and middle-income countries.13

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