Adenosine nucleotide analogue
| 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.
| 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)
| 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.
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|
| 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)|
|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.|
|The K65R mutation, which may be selected by prior nucleoside analogue therapy, is associated with a decrease in sensitivity to tenofovir. |
|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.
| 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.
|| || Squires K, Pozniak AL, Pierone G Jr, et al; Study 907 Team. Tenofovir disoproxil fumarate in nucleoside-resistant HIV-1 infection: a randomized trial. Ann Intern Med. 2003 Sep 2;139(5 Pt 1):313-20. |
|| || Gallant JE, Staszewski S, Pozniak AL, et al; 903 Study Group. Efficacy and safety of tenofovir DF vs stavudine in combination therapy in antiretroviral-naive patients: a 3-year randomized trial. JAMA. 2004 Jul 14;292(2):191-201.|
|| || Gallant JE, DeJesus E, Arribas JR, et al; Study 934 Group. Tenofovir DF, emtricitabine, and efavirenz vs. zidovudine, lamivudine, and efavirenz for HIV. N Engl J Med. 2006 Jan 19;354(3):251-60.|
|| || Sax PE, Tierney C, Collier AC, et al; AIDS Clinical Trials Group Study A5202 Team. Abacavir-lamivudine versus tenofovir-emtricitabine for initial HIV-1 therapy. N Engl J Med. 2009 Dec 3;361(23):2230-40.|
|| || Daar ES, Tierney C, Fischl MA, et al; AIDS Clinical Trials Group Study A5202 Team. Atazanavir plus ritonavir or efavirenz as part of a 3-drug regimen for initial treatment of HIV-1.Ann Intern Med. 2011 Apr 5;154(7):445-56.|
|| || Sax PE, Wohl D, Yin MT, et al. Tenofovir alafenamide versus tenofovir disoproxil fumarate, coformulated with elvitegravir, cobicistat, and emtricitabine, for initial treatment of HIV-1 infection: two randomised, double-blind, phase 3, non-inferiority trials.|
|| || Gallant JE, Rodriguez AE, Weinberg WG, et al; ESS30009 Study. Early virologic nonresponse to tenofovir, abacavir, and lamivudine in HIV-infected antiretroviral-naive subjects. J Infect Dis. 2005 Dec 1;192(11):1921-30.|
|| || Khanlou H, Yeh V, Guyer B, et al. Early virologic failure in a pilot study evaluating the efficacy of therapy containing once-daily abacavir, lamivudine, and tenofovir DF in treatment-naive HIV-infected patients. AIDS Patient Care STDS. 2005 Mar;19(3):135-40. |
|| || Landman R, Descamps D, Peytavin G, et al; TONUS (IMEA 021) Study Group. Early virologic failure and rescue therapy of tenofovir, abacavir, and lamivudine for initial treatment of HIV-1 infection: TONUS study. HIV Clin Trials. 2005 Nov-Dec;6(6):291-301.|
|| ||Jemsek J, Hutcherson P, Harper E. Poor virologic responses and early emergence of resistance in treatment-naive, HIV-infected patients receiving a once-daily triple nucleoside regimen of didanosine, lamivudine, and tenofovir DF. In: Program and abstracts of the 11th Conference on Retroviruses and Opportunistic Infections; February 8-11, 2004; San Francisco. Abstract 51.|
|| || Podzamczer D, Ferrer E, Gatell JM, et al. Early virological failure with a combination of tenofovir, didanosine and efavirenz. Antivir Ther. 2005;10(1):171-7.|
|| || Maitland D, Moyle G, Hand J, et al. Early virologic failure in HIV-1 infected subjects on didanosine/tenofovir/efavirenz: 12-week results from a randomized trial. AIDS. 2005 Jul 22;19(11):1183-8.|
|| || Schooley RT, Ruane P, Myers RA, et al; Study 902 Team. Tenofovir DF in antiretroviral-experienced patients: results from a 48-week, randomized, double-blind study. AIDS. 2002 Jun 14;16(9):1257-63.|
|| || Hall AM, Hendry BM, Nitsch D, et al. Tenofovir-associated kidney toxicity in HIV-infected patients: a review of the evidence. Am J Kidney Dis. 2011 May;57(5):773-80.|
|| || Peyriere H, Reynes J, Rouanet I, et al. Renal tubular dysfunction associated with tenofovir therapy: report of 7 cases. J Acquir Immune Defic Syndr. 2004 Mar 1;35(3):269-73.|
|| || Gallant JE, Winston JA, DeJesus E, et al. The 3-year renal safety of a tenofovir disoproxil fumarate vs. a thymidine analogue-containing regimen in antiretroviral-naive patients. AIDS. 2008 Oct 18;22(16):2155-63.|
|| || Gallant JE, Moore RD. Renal function with use of a tenofovir-containing initial antiretroviral regimen.AIDS. 2009 Sep 24;23(15):1971-5.|
|| ||Mills A, Andrade-Billanueva J, DiPerri G, et al. Switching from a tenofovir disoproxil fumarate (TDF)-based regimen to a tenofovir alafenamide (TAF)-based regimen: data in virologically suppressed adults through 48 weeks of treatment. In: Program and abstracts of the 8th IAS Conference on HIV Pathogenesis, Treatment and Prevention; July 19-22, 2015; Vancouver, BC, Canada. Abstract TUAB0102.|
|| || McComsey GA, Kitch D, Daar ES, et al. Bone mineral density and fractures in antiretroviral-naive persons randomized to receive abacavir-lamivudine or tenofovir disoproxil fumarate-emtricitabine along with efavirenz or atazanavir-ritonavir: Aids Clinical Trials Group A5224s, a substudy of ACTG A5202. J Infect Dis. 2011 Jun 15;203(12):1791-801.|
|| || Piketty C, Gerard L, Chazallon C, et al; Agence Nationale de Recherche sur le SIDA 107-Puzzle 2 Study Group. Salvage therapy with atazanavir/ritonavir combined to tenofovir in HIV-infected patients with multiple treatment failures: randomized ANRS 107 trial. Antivir Ther. 2006;11(2):213-21.|
|| || Margot NA, Isaacson E, McGowan I, et al. Extended treatment with tenofovir disoproxil fumarate in treatment-experienced HIV-1-infected patients: genotypic, phenotypic, and rebound analyses. J Acquir Immune Defic Syndr. 2003 May 1;33(1):15-21.|
|| || Nelson M, Portsmouth S, Stebbing J, et al. An open-label study of tenofovir in HIV-1 and Hepatitis B virus co-infected individuals. AIDS. 2003 Jan 3;17(1):F7-F10. |
|| || Ristig MB, Crippin J, Aberg JA, et al. Tenofovir disoproxil fumarate therapy for chronic hepatitis B in human immunodeficiency virus/hepatitis B virus-coinfected individuals for whom interferon-alpha and lamivudine therapy have failed. J Infect Dis. 2002 Dec 15;186(12):1844-7. |
|| || Peters MG, Andersen J, Lynch P, et al; ACTG Protocol A5127 Team. Randomized controlled study of tenofovir and adefovir in chronic hepatitis B virus and HIV infection: ACTG A5127. Hepatology. 2006 Nov;44(5):1110-6.|
|| || Grant RM, Lama JR, Anderson PL, et al; iPrEx Study Team. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med. 2010 Dec 30;363(27):2587-99.|
|| || Baeten JM, Donnell D, Ndase P, et al; PrEP Study Team. Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. N Engl J Med. 2012 Aug 2;367(5):399-410.|
|| || Thigpen MC, Kebaabetswe PM, Paxton LA, et al; TDF2 Study Group. Antiretroviral preexposure prophylaxis for heterosexual HIV transmission in Botswana. N Engl J Med. 2012 Aug 2;367(5):423-34.|
|| || Abdool Karim Q, Abdool Karim SS, Frohlich JA, et al; CAPRISA 004 Trial Group. Effectiveness and safety of tenofovir gel, an antiretroviral microbicide, for the prevention of HIV infection in women. Science. 2010 Sep 3;329(5996):1168-74.|
|| || Van Damme L, Corneli A, Ahmed K, et al; FEM-PrEP Study Group. Preexposure prophylaxis for HIV infection among African women. N Engl J Med. 2012 Aug 2;367(5):411-22.|
|| ||Microbicide Trials Network. [MTN press release.] VOICE HIV prevention trial discontinues tenofovir gel arm for futility. November 25, 2011. Available at http://www.fhi360.org/en/Research/Projects/FEM-PrEP.htm.|