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Two Out of Three Ain't Bad

Truvada Enters the Market at Full Blast


By Rob Camp

August 2004

In early August, FDA announced approvals of two fixed-dose combination (FDC) antiretroviral drug products for use with other antiretroviral agents in the treatment of HIV-1 infection: GlaxoSmithKline's Epzicom® (abacavir/lamivudine) and Gilead Sciences, Inc.'s Truvada® (tenofovir disoproxil/emtricitabine). These approvals provide simplified dosing regimens for one component of HIV therapy consisting of one pill, once daily.

Truvada® is a single pill containing 300mg of tenofovir disoproxil fumarate (Viread, TDF) and 200mg of emtricitabine (Emtriva, FTC). These two drugs were previously approved individually under the brand names of Viread® in 2001, and Emtriva® in 2003.

Summary

When administered separately, Viread is one pill once a day, and Emtriva is one pill once a day. Truvada is administered as one tablet once per day, and thus, represents a marginal improvement in pill burden over the two separate components.

Truvada is not a stand-alone combination—it still requires additional ARV(s) in order to constitute an effective regimen. An FDC that combines all needed ARVs into one pill is ultimately preferable.

TAG agrees with the accelerated approval of Truvada for use, in combination with many—but not all—antiretrovirals, in the treatment of adults with HIV infection. Any triple nucleoside regimens, including those containing Truvada, are not recommended. Triple nucleoside combinations of any sort have not worked well, and are not recommended (without a fourth drug—either an NNRTI or a PI).

Ziagen (ABC) and Videx (ddI) should probably never be used with Truvada, due to concerns about resistance and ultimately efficacy.

Further research needs and access concerns are highlighted at the end of this paper.pill burden over the two separate components.

1. Discussion

The approval of Truvada is based on bioequivalence studies demonstrating similar pharmacokinetic parameters to the individual products. Efficacy results from studies using the combination of TDF and lamivudine (3TC) [3TC has many similarities to FTC] are being extrapolated to support the use of Truvada, specifically the Viread registration studies 903 (TDF+3TC+EFV vs d4T+3TC+EFV) and 907 (TDF+standard background vs placebo+standard background), and the Emtriva registration studies 301A (FTC+ddI+EFV vs d4T+ddI+EFV) and 303 (FTC+stable background vs 3TC+stable background).

2. Safety

Bone density 

Since osteomalacia (softening of the bones in adults) was observed pre-clinically in rats, dogs, monkeys and juvenile monkeys, close monitoring for bone toxicity in humans was done. There was no evidence of bone abnormalities in two studies, 902 and 907.

The three-year results from 903 were presented this year at Bangkok and are also summarized in JAMA. Study 903 was a Phase III, blinded, placebo-controlled trial comparing TDF to d4T, with a background of 3TC+Sustiva. This was an international study, and 26% of the participants were women. Significant bone density decreases occurred during the 1st year with TDF; decreases leveled off after year 1.

The JAMA article and Bangkok abstracts summarize subgroup findings, which found significant hip (-2.2%) and spine (-2.8%) bone mineral density (BMD) decreases from baseline in women taking TDF (but not women in the d4T arm). This analysis did not find significant BMD decreases from baseline in men taking TDF.

In a small study pre-approval, TDF showed BMD issues in children. The pediatric development process stopped. Now, five years later, Gilead promises development of TDF pediatrics dosing. The liquid that was developed is not bioequivalent, so it will be a pill form. PACTG will begin a 100-person study of this by the end of 2005. Once again, children get short shrift (no pun intended). A Truvada liquid will not be developed.

Closer monitoring along with calcium and vitamin D intake should become routine in the HIV clinic, particularly for post-menopausal women, people with extensive PI experience, and people over 50. Outside of HIV, other risk groups include Caucasians, Asians, and people who are slender, and/or have a family history of osteoperosis.

Kidney

Phase III TDF studies excluded individuals with renal impairment. Subjects were closely monitored for evidence of renal toxicity. No nephrotoxicity was seen and changes in serum creatinine and phosphate were similar to those seen with placebo. However, clinical experience has since turned up evidence of kidney toxicity in some patients taking TDF.

In the recently released 144-week data from 903, no one developed tubulopathy or Fanconi's syndrome (out of 600 pts). 4% of people on TDF had gr 1 serum creatinine toxicity, and less than 2% had gr 2. No other events were reported. Serum phosphorus was the same for both the TDF arm and the d4T arm, at 4%. All 10/296 pts who developed gr 2 or 3 serum phosphorus increases, did so before wk 48. Proteinuria increases were similar between arms, at 12% and 17% for gr 1, 6% and 7% for gr 2. Glucosuria, gr 1—3, was reported not above 1% in any arm. Creatinine clearance quickened by 5 at wk 144 for TDF, and by 19 for d4T.

In the European and Australian Expanded Access Cohorts, 0.3% and 0.6% of people had gr 3 or 4 elevations in serum creatinine and reductions in serum phosphate, although any report was 2.5% (all grades) at 6 months for creatinine, and 18.9% for phosphate abnormalities.

People with abnormal renal function may need to lower the dose of TDF, which of course can't be done with Truvada. What may have to be done is a different timing of medications, TDF every 36 hours or 3 times a week (M-W-F) or never (for those severely renally impaired), while FTC stays QD, which means two different drugs and not the Truvada pill. A small Truvada study is planned in renally impaired people.

Liver 

They have looked at hepatic impairment and there is no adjustment needed. There is a black box warning about HBV flare-ups in the HBV-coinfected population. Up to 25% of people when stopping TDF can get flare ups, including gr 4. People with HBV need to be "monitored more closely". Sequencing and safety/efficacy of FTC need to be studied in a coinfected population. A strategy for avoiding this isn't clear.

FTC has been studied in Phase III clinical studies for the treatment of chronic hepatitis B with sound results. When will Gilead apply to FDA for an FTC indication for HBV?

Pancreas

Pancreatitis can be a concern with TDF+ddI. TDF inhibits the phosphorylation of ddI, and as a result, ddI stays in the blood at higher concentration than is safe. Even with ddI at a reduced dose (the recommended dose of ddI with TDF is 250 mg / day), women, people who weigh less than 60 kg, and women who weigh less than 60 kg all independently have increased risks for pancreatitis. People who already are on the lower dose (250mg) should probably be lowered again to 125mg, but there is no recommendation currently.

Skin

With FTC, skin discoloration has been seen in up to 6% of patients. Medium time to onset is 88 days (range 10—490 days). Resolution happens without changing treatment in some 17% of those affected. Although no one has discontinued due to this skin discoloration (hyperpigmentation on the palms and/or soles, sometimes the tongue, sometimes "other" places), it has been seen in a higher rate in black patients (up to 13% vs 6% overall). In Asians it is seen in up to 4% of people, and in Hispanics up to 3%. Caucasians get it much less (<1%). In an HBV trial (non-HIV), the incidence was some 2%, not broken down by race.

Other 

Other commonly reported side effects for TDF include asthenia (19%), headache (14%), diarrhea (22%), nausea (20%), and pharyngitis (18%). Depression occured after 48 weeks of Study 902 in 6% of subjects in the TDF 300 mg daily arm.

For FTC, headache, malaise/fatigue, nausea, sleep interference and dizziness are the side effects, all hovering around 5%. Lab abnormalities do not reach 2% at 24 weeks.

3. Efficacy

Interestingly, in 903, while the overall virologic and immunologic response to therapy was roughly similar in men and women, women in both the TDF and the d4T arms had higher average CD4+ increases from baseline than men.It has been studied extensively and positively with Sustiva. It has not been studied with PIs, although it has PK issues with Kaletra (Viread AUC up 32%, Cmin up 51%, no change to Cmax, no effects seen to Kaletra) and Atazanavir (Viread AUC up 24%, Cmin up 22%, Cmax up 14%, ATV without ritonavir is not advised, with ritonavir the data is unclear).

FTC has been seen as a competent first-line cytidine analog. FTC is active both on HIV-1 and HBV. Its activity against HIV-1 is approximately 4-10 fold greater than that of 3TC, which is probably why it still works well with TDF although TDF lowers its Cmax by 24%.

4. Pharmacokinetics and Drug-Drug Interactions

TDF is 20-40% orally bio-available. Food (a high fat meal) enhances the oral bioavailability by 40%. TDF is recommended to be taken with food. While food intake slightly decreases the rate of absorption for FTC, it does not affect overall oral bioavailability.

A 200 mg daily dose had an intracellular half-life for FTC-triphosphate of approximately 39 hours. FTC triphosphate has an intracellular half-life of approximately 39 hours.

Tenofovir is not a substrate, inhibitor or inducer of the cytochrome P450 family of liver enzymes. It therefore has a low potential for drug-drug interactions involving this family of liver enzymes. While that is true, it has been shown to be an inducer of ATV excretion and if the two are taken together, /r should be taken to maintain ATV blood levels (see above in the efficacy section). At the same time, ATV increases the blood levels of TDF, which may cause more adverse events. ATV/r + TDF needs cleaner data.

Drug interactions between tenofovir and some agents from three licensed classes of antiretrovirals have been conducted. Although all 3 classes showed safety at first, it is now known that TDF raises the AUC of ddI by some 60% and interacts with ABC in such a way that this combo should be avoided. SPD-754, an NRTI under investigation, is intracellualrly nixed by TDF.

ddI needs to be dose-reduced when taken with TDF, to 250mg (from 400), and if you are <60kg, reduced to 125mg, although that is not clearly stated in the package insert.

In a retrospective safety and efficacy study of TDF + ddI, people were started on ddI full dose (400mg) and at month 3, switched to 250mg. 12 people with viral rebound by month 4 were switched to TDF+FTC+KAL or TDF+FTC+ATV/r. One person got pancreatitis, and two others died during the study. No details of when these events happened (at high-dose ddI?). 29/105 were lost to follow up by month 7.

In the large HOPS cohort, with 260 people on TDF and ddI, 28% of people on the high dose or high-switch-to-low dose discontinued due to any toxicity event: 12% due to PNP, 4% due to acute pancreatitis, 1% due to renal insufficiency, 2% due to hyperlactemia. These data again highlight how unexpected drug-drug interactions among treatment regimens can result in significant adverse reactions. Caution should be exercised in implementing novel or untested treatment combinations.

There is no hepatic metabolism of tenofovir and it is excreted unchanged by the kidneys. Thus, there is potential for interaction with other drugs that are renally excreted and there is a need for dosage adjustment in individuals with renal impairment (see above in safety as well as package insert).

Both 3TC and ddI are excreted primarily by the kidneys. Interaction studies were randomized, multiple- dose, open-label, 3-way cross over Phase I studies. There was no clinically relevant effect of 3TC 150 mg BID on the PK of tenofovir 300 mg QD. 3TC absorption was delayed to Tmax by 0.9 hr and Cmax was decreased by 24%. There was no significant change in 3TC AUC. These results should parallel those with FTC, which were not done directly.

There is "limited" data on pregnancy. It is Category B (no clinical data), and should be used only when there are no other choices. Pregnant women are generally advised to switch to Combivir where there is a healthy volume of data.

In pediatrics, an FTC liquid has been submitted to the EMEA in London. It will be launched in Europe by early 2005. A neonate PK study is being done for the FDA and will then be submitted (mid-2005). But this is only for FTC and does not apply to Truvada.

TDF seems to have a slight effect on the PK parameters of TMC114, whereby the Cmin, Cmax and AUC are all extended by some 25%. In this 8-day trial, lipids rose in all patients.

5. Failure, I mean resistance

The suboptimal virologic response of TDF with ABC and ddI seen in many studies as well as in real life may be due to a weak resistance barrier. There should be a black box warning to not use TDF-containing regimens (Truvada) with ABC-containing regimens (ie, Epzicom).

Once resistant to 3TC, can someone take Truvada? Not unless they want to maintain the 184 (a possibly less fit virus) and are taking at least two other drugs, none of which are 3TC/FTC, ABC or ddI. It is important that persons with detectable viral load who plan to switch therapy from 3TC to Truvada, which contains FTC, have genotypic testing performed to determine whether the M184I or V mutation is present. Patient treatment history will also help. If 3TC has failed in the past, the 184 is archived, thus rendering FTC unaffective.

TDF selects for the K65R mutation. This then causes cross-resistance to ABC, ddI and 3TC/FTC. d4T and AZT may potentially have cross-resistance issues.

Some 22% of naïve people failing on TDF get the K65R. TDF+ddI as a backbone was almost 5x as likely to select for the K65 as TDF alone. The triple nuke regimen of ABC +TDF+ddI, either alone or as the nuke backbone, doubled the likelihood of the K65 as the TDF+ddI alone.

Mutations are probably not independent, but in fact form a web of multiple cross-class failures, where the presence of either the 103 (from the NNRTI class) or the 184 (3TC or FTC) probably contributes to the 65, and sooner or later, left to their own devices, the 65 would emerge in these people. Thus, a virologic failure rate of 15.7% constitutes a considerable concern for people on TDF+3TC+EFV. Because after failing Truvada, where do you go?

In study FTC-302, of the virologic failures in the FTC treatment arm, 30% developed the M184V mutation, vs 65% of the failures in the 3TC treatment arm. The difference was statistically significant (p=0.01). The frequency of mutations associated with resistance to the NNRTIs was somewhat higher, although not statistically significant, in the FTC arm.

6. To do

There is "probably" no effect on renal filtration with FTC. When will the Truvada study in renally impaired people happen?

Will there be controlled studies in the developing world re: how best to take this FDC+a third available agent? In settings where the health care infrastructure is minimal, economically and strategically, does this FDC make sense? The skin discoloration in blacks is especially worrisome.

Is there a clinical benefit to keeping the 184V active? Is an interesting question that needs to be answered. Although replication capacity is diminished by approximately 50% (implying a 'yes'), a well designed study could be funded by Gilead. They are looking for one.

The intracellular half-life of both components is very long, as it is of Sustiva. Stopping these three drugs together probably makes sense. But if the regimen is composed of Truvada + a PI (with a relatively short half-life), should Truvada be stopped before the PIs? For example, can people be put on Kaletra monotherapy for two weeks after stopping Truvada? In time-sensitive STIs (rather than clinically-sensitive), what is the role of any long half-life drug? It needs to be looked at clinically.

What is the correct dosage for someone who weighs less than 60kg, is already on ddI 250, and wants to take Truvada (with a fourth drug, obviously).

Is there a role for triple nucleosides, and can Truvada make up part of that? Not with ddI, not with ABC. Maybe with AZT or d4T?

A study of CBV+Sustiva vs TRV+Sustiva and looking at next-line regimens would be very helpful.

What drugs besides Sustiva can TRV work well with? There is limited data on Truvada with Kaletra or with Reyetaz/r. It would be helpful to do these strategy studies. After failure with Truvada + Sustiva, where does one go? AZT or d4T may be the only nukes left that might work, and they don't work together.

Drug-drug interaction studies needed: TRV + drugs that inhibit renal tubular secretion such as trimethoprim (or cotrimoxazole) and probenecid; drugs that are excreted by the kidneys and are likely to be used concomitantly by some HIV-infected individuals, such as stavudine (d4T), certain antibiotics (including aminoglycosides, cephalosporins, and penicillins), narcotic analgesics (such as demerol and morphine), lithium and digoxin; and the studies which the sponsor has indicated that it plans to conduct with ddI EC, methadone, oral contraceptives and adefovir.

ACTG study 5015 (accelerated disease and aging) is looking at Kaletra+d4T+FTC by age, and ACTG 5073 (a DOT study looking at Kaletra+d4T+3TC or Kaletra+TDF+FTC) are fully enrolled. Results should start coming in by late 2005.


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In the bioequivalence study, all measures met the 90% CI mean ratio. The T1/2 of EMT was slightly longer in the FDC than alone (15.5 hours vs 14.5). 18% of patients developed traeatment related side effects, one fourth of whom decided to stop the study. This study was well balanced, with 26 males vs 18 females, 19 caucasian, 18 hispanic and 7 black.