The shift to Tenofovir Alfenamide can maintain undetectable viral load prevents a worsening kidney function and helps the forgiveness of osteoporosis and osteopenia
People who pass the current version of tenofovir (TDF) to tenofovir alafenamide (TAF) - a new formulation that achieves higher serum levels in patients with HIV who also had kept their viral loads undetectable; there was improvement in biomarkers of renal function and an increase in bone density, according to a pair of studies presented at 8.ª International AIDS Conference last month in Vancouver.
Gilead Sciences "tenofovir disoproxil fumarate (Viread) is one of the most widely used antiretroviral drugs. It is a component of co-formulation of Truvada - used both for HIV and for treating pre-exposure prophylaxis (PrEP) - outline of a tablet with only Atripla Complera and Stribild. TDF is an antiretroviral drug generally considered safe and well tolerated, but can cause bone loss more quickly after the beginning of treatment and lead to kidney problems in people sensitive to medication.
TAF is a new prodrug that delivers the active agent, tenofovir diphosphate, more efficiently to the cells. TAF produce adequate levels of drug in the intracellular sphere with lower doses, which means much lower concentrations and at lower plasma drug exposure to the kidneys, bones and other organs and tissues.
A couple of clinical trials 3 stage, presented at this year's Conference on Retroviruses and Opportunistic Infections (ELEVEN) showed that TAF is as effective as TDF for people previously untreated, but has fewer adverse effects on the kidneys and bones compared to the current version.
In this year's IAS conference (2015), Tony Mill, the group medical Southern California men in Los Angeles presented results of another study phase 3 (GS-US-292-0109), with the difference that it takes a Look at've ever experienced in treating patients who switched from the old to the new formulation of tenofovir.
This analysis included 1.436 seropositive persons with normal renal function at baseline had suppressed viral load (<50 copies / mL) in one of the following at least 96 weeks schemes.
- TDF / emtricitabine / elvitegravir / cobicistat (Stribild).
- TDF / emtricitabine / efavirenz (Atripla).
- Atazanavir (Reyataz), reinforced with ritonavir (Norvir) or cobicistat (Tybost), plus TDF / emtricitabine (Truvada) .The who want to keep their current regimen containing TDF and those who want to switch to a new treatment regimen with one pill consists of TAF (10 mg), emtricitabine (200 mg), elvitegravir (150 mg), and cobicistat (150 mg) - a new version of Stribild replacing TAF TDF.
- Most of the study participants (about 90%) were male, two-thirds were white, 19% were black (one TDF Group increased risk of kidney problems), and the average age of 41 years. The median line of T-CD4 cell count was approximately 670 cells / mm3. At baseline, they took to an estimated glomerular filtration rate (eGFR) - a measure of kidney function - above 50 ml / min using the Cockcroft & common Gault method, with a median line 107 ml / min (> 90 ml / min is typically considered normal). About 9 1% showed grade rod or mild proteinuria (protein in urine) but less than 1 2% had moderate grade or proteinuria.
- Participants in this open label study were randomly assigned (2: 1) as follows:
- Both treatments were highly effective, showing that the change of TAF scheme was not less than is used in a DFT scheme.
- The virologic response rates were high in both groups in 48ª week: 97% of people who moved into the co-formulation with TAF had undetectable viral load (<50 copies / ml) compared to 93% of those who changed their regimen - a significant difference in favor of TAF.
- Virological failure was also low in both groups (about 1%).
- People who switched from Atripla or atazanavir / TDF / emtricitabineto for co-formulation with TAF saw significantly better responses, while those who changed their Stribild did the same.
- The overall level of safety and tolerability was good in both treatment groups, with few dropouts in any arm of the study for adverse events account (0,9% in the TAF group vs 2,5% in the TDF group).
- Most types of side effects and laboratory abnormalities were similar in 2 groups, although bilirubin levels were higher in the arm of the preexisting regime (probably attributable to certain participants using atazanavir).
- However, there are some important differences related to kidney function and bone health.
- 2 Participants who switched to the TAF regimen and 5 people who remained on their regimens with therapy based on TDF had to discontinue their treatment regimens due to adverse events related to renal function.
- There was no case Fanconi syndrome, a type of severe kidney disease, the study arm with TAF and 1 case in the arm containing TDF.
- People who moved to the TAF showed improvements in markers of renal function while those that remained in the schematic diagrams worsened with TDF, with these changes, starting from the 2 week and persisted throughout the study until week 48ª.
- Statistically significant improvements were observed in creatinine protein in the urine (-21% vs + 10% change), urinary albumin creatinine (-18% vs + 9%), proteins that cause blindness - retinol creatinine (-33% vs (+ 18%) and beta-globulin micro creatinine 2 (- 52% vs. + 19%).
- The mineral density of bone in the vertebral column (BMD) increased on average by + 1.79% in TAF arm, while the average fall of -0,28% among those who stayed in existing schemes with TDF.
- The corresponding mean changes in hip BMD were (+ 1,37% and -0,26%, respectively, and both differences were statistically significant.
- People who moved to the TAF seen significant improvements in osteopenia or osteoporosis of the spine and hip, which remained the same in the TDF arm.
- All views in the study were fractures due to trauma, and not fragile.
- The lipids increased fasting appeared in a small amount of people who moved into the scheme with TAF, although the average total cholesterol and HDL average rate has stayed the same special nível.Em for women and others at risk bone loss, or for people at risk for kidney function problems, TAF "offers a great new option," Mills sugeriu.Samir Gupta Indiana University followed the findings of a phase 3 in progress (GS-US- 292-0112) evaluating TAF in people with impaired renal function or mild moderado.Esta 242 analysis included participants with stable viral suppression. Most (about 80%) were men, about 18% were Black, the average age was 58 years and the median score of CD4 was approximately 630 cells / mm3. Many had risk factors for kidney disease, including about 40% with hypertension and 14% with diabetes.No open this study participants increased from existing schemes - which could contain TDF or not - the same FAT-containing regimen single tablet pordia (regimen used in the study described above). Before changing the picture was the following:
- At the beginning of the study participants had a mild degree of renal impairment to moderate with eGFR ranging from the 30 69 ml / min, using the Cockcroft & Gault method showed a median rate 56 ml / min). About a quarter had 1 degree and 10 2% had grade rods proteinuria, but none had grade 3-4. [Translator's Note: To better understand the concept rod proteinura click on this link. Opens in another browser tab]
- Many experts advise against the use of TDF in people with impaired renal function unless the expected benefits outweigh the risks. The current prescription should be used to dose reductions for people with pre-existing renal impairment.
Impaired renal function
- "Participants who switched to [the TAF coformulation] were significantly more likely to maintain virologic tests with undetectable results," the researchers concluded, and they "had significant improvements in bone mineral density of the spine and hip, w that iveram significant reductions in osteopenia / osteoporosis and there were significant improvements in proteinuria and other markers of renal function. "
- 65% were taking TDF,
- 22% were taking abacavir (Ziagen),
- 7% were schemes with other reverse transcriptase inhibitors, nucleotide analogs,
- And 5% were taking drugs in the same class.
- Furthermore, 44% were taking protease inhibitors,
- 42% were on NNRTI,
- and 24% were on integrase inhibitors.
Gupta noted that the baseline characteristics were compared among the groups containing TDF and TDF regimens without the baseline, with a larger number of women and black in TDF and more hypertension, proteinuria, in the group with TDF.
To 24ª week there were no significant changes in the current RFG (using off test with iohexol), regardless of whether people have moved from TDF, whether or non-TDF schemes for TAF co-formulation [Translator's note. I found nothing really enlightening to this term "Iohexol clearance test. If you reading me know or understand better the term, please send me the definition using the form that will be the end of this text
In 48ª week between the PTO switch participants to TAF, estimated GFR, a median rate of + 2.7 ml / min / 1,73m2 by Cockcroft & Gault using cystatin C, the latter of which was statistically significant. Among the people who have non-TDF schemes to TAF, eGFR decreased - 1,8 ml / min and -1,4 ml / min / 1,73m2 respectively, none of which was statistically significant.
Looking at the various significant proteinuria measurements, - and in some major cases - the improvements were seen in the protein creatinine and urine albumin creatinine in urine, protein blinding retinol creatinine, and beta-2-microglobulin creatinine between people exchanging of TDF for TAF. However, the changes were small and not significant among those switching schemes with use of TDF for schemes with TAF.
Last week 48 kidney markers in people who changed the TDF the TAF "seemed approach" of those who are not in schemes with tenofovir, said Gupta.
The proportion of subjects with clinically significant UPCR proteinuria (> 200 mg / g) decreased 47% to 13%, whereas those with clinically significant creatinria albuminuria (> 30 mg / g) decreased 55% to 22% when changing schemes TDF satisfaction for TAFT schemes - t both with significant differences. Here too, the changes were not significant for those changes regimens with TDF.
Again, significant increases in average spine BMD (+ 2.95%) and BMD hip (+ 1.85%) were observed in 48 weeks between the PTO switching participants PAT, with significant changes from those of the PTO switching combined .
"TDF participant's at the moment that the interrupt had no change in glomerular filtration rate, significant improvements n urine markers and renal function, and there were significant improvements in BMD [e] significant lipid increases," summarized researchers . "Participants who are not part of the arm change to TDF instead of stopping it experienced no change in the current RFG, urinary markers and stable renal function, and in BMD [and] significant reductions in cholesterol fractions."
"The data from these 48 weeks support renal and bone security scheme to a tablet in a once per day, [coformulation TAF] HIV and for adults with impaired renal function," he concluded.
Asked about the mechanism of improvement after the passage of the TDF the TAF, Gupta suggested that it might be "off the fuel source of mitochondrial dysfunction," but stressed that this was "only speculation at this moment."
Based on the study's findings to date, Gilead presented the co-formulation TAF / emtricitabine / elvitegravir / cobicistat co-formulation for regulatory review in the US and Europe. It is expected that the US Food and Drug Administration to make a decision before the start of November.
In addition, Gilead has requested approval of a double co-formulation of TAF and emtricitabine - what could be a successor of Truvada - and is developing two other schemes of one tablet a day, one containing the NNRTI rilpivirine (Edurant) and with another HIV protease inhibitor darunavir (Prezista). And the TAF also being developed as a treatment for hepatitis C that a dose of one tablet per day. Gilead has indicated that he is collaborating with the Centers for Disease Control and Prevention (CDC) in a study in monkeys with TAF / emtricitabine for PrEP
Translated from original Switching to Tenofovir Alafenamide Keeps HIV Suppressed, Helps Kidneys and Bones by Claudio S. Souza and reviewed by Mara Macedo in 19 / 08 / 2015
Mills t, J Andrade, DiPerri G, et al. Switching from a disoproxil fumarate tenofovir (TDF) -based regimen to a tenofovir alafenamide (TAF) -based regimen: data in virologically suppressed adults through 48 weeks of treatment. 8th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention. Vancouver, July 19-22, 2015. Abstract TUAB0102.
S Gupta, The Pozniak, Arribas J, et al. Subjects with renal impairment tenofovir disoproxil fumarate from switching to tenofovir alafenamide have improved kidney and bone safety through 48 weeks. 8th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention. Vancouver, July 19-22, 2015. Abstract TUAB0103.