Tenofovir disoproxil fumarate (Viread, TDF)

- Sep 11, 2017 -

Approval


Tenofovir disoproxil fumarate (TDF) was approved by the FDA in 2001 for use in combination with other antiretroviral agents in adults with HIV infection. This recommendation was based primarily on a randomized, placebo-controlled Phase 3 study of HIV treatment-experienced individuals with detectable viral load on stable combination antiretroviral therapy. The addition of TDF to the existing regimen resulted in a significant decrease in viral load at week 24 of the study (0.61 log10 average decrease in viral load from baseline, compared with 0.03 log10 decrease in the placebo group; p < .0001). An increase in CD4 count of 12.6 cells/μL was seen in the TDF group, compared with a decrease of 10.6 cells/μL in the placebo group (p = .0008).(1) In 2012, FDA approval was extended to pediatric patients 2 years of age and older. Also in 2012, the FDA approved the combination of TDF and emtricitabine for use as preexposure prophylaxis 

by HIV-uninfected adults at high risk of sexually acquired infection with HIV (see Special Uses).


TDF is a prodrug of tenofovir; a different tenofovir prodrug, tenofovir alafenamide (TAF) was approved by the FDA in 2015; for further information see Tenofovir alafenamide.


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Generic Approval


The FDA has granted generic versions of TDF "tentative approval" status for purchase and use only as part of the President's Emergency Plan for AIDS Relief (PEPFAR) in resource-limited countries.


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Formulation and Dosing


TDF is available in tablet and oral powder formulations. TDF is available in combination with emtricitabine as a single tablet (Truvada). TDF also is available in multidrug tablet combinations: with efavirenz + emtricitabine (Atripla), with rilpivirine emtricitabine (Complera), and with elvitegravir + cobicistat + emtricitabine (Stribild). The newer tenofovir prodrug, TAF, is available as part of a single-pill combination with elvitegravir + cobicistat + emtricitabine (see Tenofovir alafenamide profile for more information).


Dosing of Tenofovir disoproxil fumarate

Adult 300 mg QD

Pediatric Age <2 years Not FDA approved for patients <2 years of age

Age 2 years to <12 years




Age ≥12 years and weight ≥35 kg


Oral powder or tablets:


8 mg per kg body wt QD (maximum 300 mg QD)


300 mg QD (adult dosage)


Abbreviations: QD = once daily.


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decorative spacer decorative item There are no food restrictions.


decorative spacer decorative item Dosage adjustment is recommended in renal insufficiency.


decorative spacer decorative item Dosage reduction is not necessary in hepatic impairment.


decorative spacer decorative item TDF interacts with the antiretroviral medications didanosine and atazanavir; see Dosage Adjustments for ARV-ARV Drug Interactions for information on recommended dosing adjustments for the tenofovir/didanosine interaction and tenofovir/atazanavir interaction.


decorative spacer decorative item Please consult product labeling for detailed dosing information.


decorative spacer decorative item FDA Pregnancy Category B.



Clinical Use



Use in Initial vs Subsequent Therapy


Adult and adolescent treatment guidelines of the U.S. Department of Health and Human Services designate TDF + emtricitabine as the dual-nucleoside backbone for use in several "recommended" and "alternative" regimens for initial therapy.


A direct comparison of TDF + lamivudine + efavirenz vs stavudine + lamivudine + efavirenz as initial therapy in antiretroviral-naive patients found the two treatments achieved similar rates of viral suppression, with 81% in each arm having viral loads of <50 copies/mL at week 48 (intention-to-treat analysis, with missing values counted as treatment failure).(2) A 48-week comparison of TDF + emtricitabine with zidovudine + lamivudine, each in combination with efavirenz in previously untreated patients, found higher rates of virologic suppression in the 

TDF + emtricitabine group (HIV RNA of <50 copies/mL in 80% vs 70%; p = .02), as well as greater increases in CD4 cell counts, and lower rates of treatment-limiting adverse effects.(3)


In another randomized study, treatment-naive patients were given TDF + emtricitabine or 

abacavir + lamivudine, in combination with either efavirenz or ritonavir-boosted atazanavir. In patients whose pretreatment HIV RNA levels were ≥100,000 copies/mL, significantly higher rates of early virologic failure occurred in abacavir + lamivudine recipients than in TDF + emtricitabine recipients.(4) In those with pretreatment HIV RNA of <100,000 copies/mL, rates of viral suppression were not statistically different in recipients of either nucleoside analogue pair, whether combined with efavirenz or atazanavir + ritonavir.(5)


In initial therapy, TDF was compared with TAF, each in a fixed-dose combination with elvitegravir, cobicistat, and emtricitabine.(6) By FDA snapshot analysis, 90% and 92% of study subjects, respectively, had HIV RNA levels of <50 copies/mL at 48 weeks; the difference was not statistically significant. The two ARV regimens yielded similar rates of HIV suppression in patients with pretreatment HIV RNA levels >100,000 copies/mL and those with ≤100,000 

copies/mL. CD4 cell increases were 211 cells/μL for the TDF group and 230 cells/μL for the TAF group.


The nucleotide/nucleoside combination TDF + emtricitabine has been studied in many other regimens, including those with integrase inhibitors, nonnucleoside reverse transcriptase inhibitors, and protease inhibitors in initial therapy. It has proven to be a strong component of most initial therapies. Certain combinations, however, should be avoided. The triple-nucleoside regimens 

TDF + abacavir + lamivudine and TDF + didanosine + lamivudine showed very high rates of virologic failure,(7,8,9,10) and TDF + didanosine + efavirenz resulted in high rates of early virologic failure in treatment-naive individuals with high HIV RNA and low CD4 levels at baseline.(11,12) Tenofovir has an important role in subsequent therapy. It often retains some degree of activity against HIV strains with resistance to other nucleoside/nucleotide analogues,(13) and often is used in treatment-experienced patients.


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Potential Adverse Effects


In the Phase 3 study described above,(1) the addition of TDF did not result in an increased rate of severe side effects, severe laboratory abnormalities, or drug discontinuation compared with placebo over 24 weeks.


TDF has been associated with renal impairment in some individuals.(14) Cases of acute renal failure and Fanconi syndrome have been reported,(15) but more common is slowly progressive kidney disease. The cause is not definitively known but appears to involve proximal tubular impairment. Two large studies of treatment of patients without renal dysfunction at baseline found no significant differences in renal function were observed between subjects who received TDF and those treated with comparator NRTIs through 144 weeks of treatment.(2,3,16) Another study found that coadministration of TDF with a protease inhibitor led to greater decreases in estimated glomerular filtration rate (GFR) than did other combinations.(17) Other risk factors appear to include preexisting kidney disease.


In data available to date, tenofovir alafenamide appears to cause less significant changes in markers of renal function than TDF. In the comparison of TDF with TAF in initial therapy discussed above (see Use in Initial vs Subsequent Therapy) decreases in estimated glomerular filtration rate (eGFR) and worsening of markers of tubular function (eg, urinary protein and albumin) were greater at 48 weeks in the TDF group than in the TAF group(6) (see TAF profile for more information).


A switch study that randomized patients on TDF-containing regimens to continue their regimens or switch to the coformulation of elvitegravir/cobicistat/emtricitabine/TAF found that albuminuria, proteinuria, and other markers of tubular function worsened in those who continued TDF-containing ART, while creatinine increased slightly but proteinuria and albuminuria improved in patients switched to the TAF combination; differences were statistically significant.(18) The clinical significance of these differences in markers of renal function between the TAF-containing and 

TDF-containing regimens is not clear.


Renal function should be assessed before treatment with TDF, and regular monitoring should be performed for patients receiving TDF. TDF should be avoided, if possible, in patients with renal dysfunction; dosage reduction is recommended if the creatinine clearance is <50 mg/dL.


There is evidence that TDF may cause decreases in bone mineral density; these effects may be less with TAF monitoring and management of this effect is not certain.(19,6,18)


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Interactions with Other Drugs


Coadministration of TDF with atazanavir lowers serum atazanavir levels and increases tenofovir levels (20); boosting atazanavir with low-dose ritonavir is recommended. Ritonavir and cobicistat may increase tenofovir levels; monitoring for renal toxicity is recommended.


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Resistance


Resistance to TDF is associated with the selection of one or more of several resistance mutations.



Implications of tenofovir resistance for treatment with other antiretrovirals

The K65R mutation, which may be selected by tenofovir, is associated with resistance to most other nucleoside analogues. Zidovudine, however, retains activity in the presence of this mutation.



Implications of resistance to other antiretrovirals for treatment with tenofovir

decorative spacer decorative item Single and some double thymidine analogue resistance mutations do not appear to confer significant tenofovir resistance. However, in clinical trials, the presence of 3 or more thymidine analogue resistance mutations is associated with a decreased response to tenofovir, particularly if these mutations include M41L or L210W.(21)


decorative spacer decorative item The presence of the M184V reverse transcriptase mutation, associated with resistance to lamivudine and emtricitabine, does not reduce sensitivity to tenofovir, and when it occurs with thymidine analogue mutations, it may increase the susceptibility of HIV to tenofovir.


decorative spacer decorative item The K65R mutation, which may be selected by prior nucleoside analogue therapy, is associated with a decrease in sensitivity to tenofovir.


decorative spacer decorative item The T69S insertion mutations, associated with resistance to multiple nucleoside analogues, are associated with resistance to tenofovir as well.


Tenofovir should be considered in choosing therapy for individuals experiencing viral recurrence on prior regimens, but resistance testing may be helpful in assessing the utility of tenofovir in the individual situation.


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Special Uses



Treatment of hepatitis B

TDF is active against hepatitis B virus. In small studies of patients coinfected with HIV and hepatitis B, addition of TDF has been associated with improvement in laboratory markers of hepatitis B progression.(22,23) This improvement appears to extend to patients with 

lamivudine-resistant hepatitis B. A small randomized, controlled comparison of TDF and adefovir in coinfected patients found that TDF was not inferior to adefovir in reducing hepatitis B DNA levels and had a similar safety profile.(24) Some patients have experienced exacerbations of hepatitis B upon discontinuation of tenofovir.


In 2008, TDF was approved by the FDA for the treatment of hepatitis B. DHHS guidelines recommend inclusion of TDF plus either lamivudine or emtricitabine in the antiretroviral regimens of patients coinfected with HIV and hepatitis B. This will result in treatment of both HIV and hepatitis B infections.



Preexposure prophylaxis

Several studies have shown that preexposure prophylaxis (PrEP) using the combination of oral TDF and emtricitabine, taken daily by HIV-uninfected individuals, can reduce the risk of sexual acquisition of HIV.(25,26,27) These studies, performed in men who have sex with men and in heterosexual men and women, found that infection risk was reduced by 44% to 73%. One of these studies also examined the effect of oral TDF alone; it was 62% protective.(26) Another study of a tenofovir vaginal gel found a reduction in HIV infection rates in high-risk heterosexual women.(28) However, in other studies of high-risk women, oral TDF + emtricitabine, oral TDF alone, and vaginal tenofovir have not shown protective effects.(29,30) The reasons for the varied study results appear to include differences in adherence (in the studies that showed protective benefit, effectiveness appeared to be strongly correlated with adherence) and perhaps tissue penetration of the medication, and intracellular metabolism.


In 2012, the FDA approved the combination of oral TDF + emtricitabine for use as PrEP by adults at high risk of sexual acquisition of HIV; and the U.S. Public Health Service also recommends it for injection drug users at substantial risk of HIV acquisition. Prophylactic TDF + emtricitabine is intended only for those who are tested and confirmed to be HIV uninfected, and as one component in a comprehensive prevention strategy that includes other risk-reduction measures and adherence support. Regular ongoing HIV testing is required to identify persons who become infected with HIV while on prophylaxis; TDF + emtricitabine is not sufficient as treatment for established HIV infection, and in persons with HIV infection, its use risks the development of resistance to the antiretroviral agents.


For use as PrEP, TDF + emtricitabine is to be taken daily. Potential adverse effects of TDF used in HIV-uninfected persons, including possible risks to fetal development in women who become pregnant while taking PrEP, have not been fully studied; monitoring is recommended.



source: hivinsite

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