Through 30 years of HIV infection, knowledge of HIV virus structure, mode of action and replication has led to great advances in the development of antiretroviral drugs. Since monotherapy with zidovudine (AZT) (NRTI) in 1987 [1], different treatment strategies were implemented until 1996 [2], when combined antiretroviral therapy (cART) of two nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs/NUCs) plus a third active drug from a different class [non-nucleoside reverse transcriptase inhibitors (NNRTI), protease inhibitors (PI) [3] or, more recently, integrase strand transfer inhibitors (INSTIs)] was established. Today, INSTIs are recommended for initiation and maintenance therapy in guidelines [4-6] worldwide due to their high efficacy, especially when associated with Tenofovir disoproxil fumarate/Emtricitabine (TDF/FTC). However, renal and bone toxicity related to TDF has been a concern in the long-term management of HIV infection as a chronic condition.

Since the introduction of cART, stander of care (SOC) showed that 3 drugs enabled a more effective control of viral suppression, a more sustained recovering of the immune response and a decrease of resistance induction capacity so it became widely recommended by international guidelines [4-6]. Further studies with the combination of more than 3 drugs demonstrated no better efficacy results and worst safety profile, with more toxicity [7,8]. However, as previously presented, the development of non-AIDS comorbidities [9-11] (diabetes, arterial hypertension, dyslipidemia, cardiovascular events, etc.) and the onset of metabolic, renal and bone toxicities associated to cART, namely to NRTIs, led to new therapeutic strategies, such as NUCs sparing regimens. Although with limited data on this strategy, 2 drug combination (dual) therapies based on PI and INSTI were adopted in well-controlled and highly adherent patients to avoid toxicity, including TDF related renal impairment aside, clinically relevant drug-drug interactions with boosted agents [12].

Studies with dual therapies with PI and INSTI, provided insights into potential benefits of these regimens. ATLAS [13], DUAL [14] and SWORD [15] are examples of randomized controlled studies, and all demonstrated non-inferiority efficacy results. Nevertheless, these treatment strategies should be considered experimental [4-6] due to lack of sufficient data from randomized, appropriately powered clinical trials, well-matched and compared studies with SOC. Regarding the metabolic impact of TDF, Tenofovir alafenamide (TAF), a novel prodrug of TDF [21-23] that results in 80-90% lower plasma TDF levels, was developed, and demonstrated improved renal and bone safety profile in a broad population, including patients with mild to moderate renal impairment (eGFR - estimated Glomerular Filtration Rate (eGFR) by CKD-EPI formula or CrCl – Creatinine Clearance - in 24 h urine >30 ml/min). Nowadays, the combination TAF/FTC became a based regimen in clinical studies [24,25].

Bictegravir (BIC) is a novel once daily INSTI [26-28] that, as a single-tablet regimen (STR) [29] TAF/FTC/BIC, combines the potency and genetic barrier of BIC with the advantages of TAF [30] safety profile, overcoming safety previous limitations that led to alternative regimens [31,32]. However, this combination aside their proven benefit regarding renal impairment is not widely recommended for patients currently under treatment with dual therapy who had a recovery from renal and bone toxicity.

Evaluate patients in alternative dual regimens due to previous renal impairment induced by TDF with proven recovery by normalization eGFR or CrCl >60 ml/min switch to TAF/FTC/BIC regarding renal function improvement (primary endpoint) and maintaining efficacy and safety profile through 48 weeks (secondary endpoint).

Pilot, unmask, phase IV, single-arm, open label, switch study of adult HIV-1 infected patients with an undetectable plasma HIV-1 RNA for at least 6 months switch to TAF/FTC/BIC, after a full recovery of renal function (eGFR or CrCL > 60 ml/min) with NUC spearing regimen after renal dysfunction induced by TDF. The inclusion and exclusion criteria are presented in Table 1. Patients data were collected from medical charts at baseline and weeks 4, 12, 24 and 48 of follow-up.Most relevant data to be collected are presented in Table 2. Data collection respected patients’ confidentiality and no identifiable data was registered in the study case report form. Database was anonymized and only aggregated data presented in the study publication.

Table 1: Inclusion and exclusion criteria.

Table 2. Patients data collected.

At the design of the study, several concerns were outlined and defined as primary and secondary endpoints, which are presented in Table 3. By study definition, any discontinuation by any causes (toxicity, miss doses, AE) reported as failure.

Table 3. Primary and secondary endpoints.

Sample size

Due to the nature of this study, no sample size was previously defined. The total of patients with inclusion criteria were 14 that voluntary agree to participate after full and detailed explanation and assent was obtained.

Fourteen patients agreed to switch to the therapeutic regimen of dual therapy started after a decrease in eGFR <60 ml/min and which allowed the recovery to normal values of the eGFR to a single tablet regimen of TAF/FTC/BIC. The switch occurred between November 2019 and August 2020. The majority were female (8) with the ages ranging from 36 to 83 (62.14 ± 12.84) years old. Regarding the HIV status, the time of infection ranged from 7 to 20 (13.64 ± 3.52) years. The major risk was heterosexual infection in 9, drug addiction in 4 and “accidental” in 1. At baseline, the HIV RNA was negative in 12, one with 28 and other 103 copies/mL (cps/mL); the average CD4⁺ count was 725 cells/uL (194-1516) and the staging was done according to the Centre for Disease and Prevention Control (CDC) criteria, 10 patients were at stage A (9 at stage A1 and 1 at A2); 4 were at stage C (2 at stage C1 and 1 at C2) when they were proposed to switch therapy.

Six patients had comorbidities, with more than one in the same patient. From those, was reported diabetes mellitus in 4, hypertension in 2, dyslipidemia in 5, thyroid disease in 1 and 1 patient had fully recovered from a non-Hodgkin lymphoma treated with chemotherapy 7 years ago. These patients were under medication to those comorbidities – statins, anti-hypertension drugs, levothyroxine and metformin. However, only <50% of the patients with diabetes, hypertension and dyslipidemia were controlled due to bad adhesion to prescription.

Prior to the switch to TAF/FTC/BIC, all patients were switched from previous antiretroviral therapy due to TDF-induced renal impairment, documented by creatinine clearance (CrCl) in urine of 24 h <60 ml/min to RAL+ETR (12 patients), 1 to DTG/RPV and another to ABC/3tc/DTG and these therapies had a follow-up time between 51-93 (80 ± 12) weeks. The major reason for switch to TAF/FTC/BIC was simplification in 12 and renal toxicity in both cases with DTG. The eGFR of the 14 patients at the time of switch was presented in Table 4.

Table 4: eGFR and regimens prior to switch to TAF/FTC/BIC.

The evolution of the patients regarding their HIV status, namely RNA HIV-1 and lymphocytes T CD4⁺ count since the time of the switch through the 48 weeks of follow –up is listed in Table 5. It is important to say, that the RNA HIV-1 cut off was <50 cps/mL. As the evolution of the renal parameters is a concern, they are presented in the Table 6.

Table 5: Evolution of the HIV status through the 48 weeks of the 14 patients.

Table 6: Evolution of the renal parameters through the 48 weeks of the 14 patients.

Considering TAF is associated to an increase in cholesterol levels, the variation of cholesterol levels was collected and the results are presented in Table 7.

Table 7: Evolution of the cholesterol parameters through the 48 weeks of the 14 patients.

Regarding the lack or no data to the experience of treating patients with prior renal damage induced by TDF with TAF after renal recovering or stabilization, this pilot study permits to say that TAF/FTC/BIC is safe on the evaluated parameters of efficacy and security. During the 48 weeks, none of the patients in the study experience therapy failure, and only in two there was a “positive” viral load, both <100 cps/µL the rest had negative viral loads. The same was observed in the lymphocytes T CD4⁺ count, where 2 patients were exception, one with 560 cells/µL at switch to 468 and another with 685 to 432 cells/µL, at the 48 weeks; in both the viral load was always negative.

While observing the evolution of the renal parameters through the 48 weeks of the 14 patients, all patients at 48 weeks presented a stabilization of the eGFR, presenting all >30 ml/min. Four (patients 1, 5, 6, 7) had a negative variation, understood as related due to non-controlled comorbidities, i.e., decompensated hypertension or diabetes already reported at the time of the switch. That conclusion was observed by the fact that was a positive response when those comorbidities were controlled vs. the time that they were non-controlled along the study. In one case, the aggravation of the eGFR was related to the fact that the patient was diagnosed with a prostatic infection due to Klebsiella pneumonia ESBL positive, that become a “chronic” infection. In fact, this is the oldest patient in this series with 83 years old. During the 48 weeks, no renal insufficiency was observed with need of switch or stopping ARV therapy in course.

To the fact that TAF is related to an increase of the dyslipidemia, in most patients no aggravation was observed after the switch to TAF/FTC/BIC. However, in two patients an anti-dyslipidemic therapy was needed to add to control the cholesterol LDL and the triglycerides, namely the patients 3 and 6. The patients that were already in anti-dyslipidemic therapy maintained the treatment without any report.

In conclusion, in this series, TAF/FTC/BIC demonstrated to be safe in patients with prior renal damage induced by TDF that had recovered or stabilized with previous dual therapy and no relapse of the renal function was observed. No major concerns were observed, regarding the efficacy and the tolerability of this scheme, like no major aggravation or decompensation of the cholesterol parameters during the 48 weeks. So, for patients currently under treatment with 2 drug combination regimens (NUC spearing regimes) to prevent or recover from renal toxicity, triple therapy with TAF/FTC/BIC should be considered as a valid treatment option, however, more studies are needed in this population to consider as a full recommendation to its use or even therapies with TAF.

Due to the risk of interference with the renal function, special attention is advised in patients with underlying non-AIDS comorbidities such as diabetes and arterial hypertension. In fact, renal function recovered after the TDF-induced change is so fragile that in patients with these comorbidities, even the smallest decompensation of those comorbidities, has a substantial impact in renal function. So the recommendation is that these patients always require special attention and monitoring.

R. Correia de Abreu has disclosed that he has received consulting fees from Gilead Sciences, Janssen, Merck Sharp & Dohme and ViiV Healthcare and funds for research support from Gilead Sciences, Merck Sharp & Dohme, and ViiV Healthcare.

C. Batista has nothing to disclose.

S. Caetano has nothing to disclose.

 Isabel Neves has disclosed that she has received consulting fees from Gilead Sciences, Janssen, Merck Sharp & Dohme, ViiV Healthcare and Pfizer and funds for research support from Merck Sharp & Dohme.