American Foundation for AIDS Research, February 2003
Kristen Kresge

Introduction

The FDA approved tenofovir (Viread) one year ago for treating HIV as either first-line or salvage therapy. Even as the debate persists over the drug's best use, tenofovir sales continue to climb. They reached $44.7 million in the second quarter of this year.

Tenofovir's initial approval was based solely upon data in heavily treatment-experienced populations. In these studies when tenofovir was added to a volunteer's current failing antiretroviral regimen, it provided a 75% drop in viral load for at least a year. This moderate potency was enough to be valuable in salvage situations when complete HIV suppression is elusive and even long-term stabilization at modest viral loads has been difficult to achieve. In an observational study reported at the International AIDS Conference in Barcelona last summer, 49 of 104 patients taking tenofovir as part of a salvage regimen had viral loads below 50 at six months. (Twenty-six of these also benefited from receiving a drug from a class to which they had never before been exposed – either a protease inhibitor or NNRTI.)

The drawback to adding tenofovir to a failing regimen is resistance, according to Dr. Joel Gallant, Associate Director of AIDS Services at Johns Hopkins School of Medicine.

Tenofovir is slow to develop resistance both in the laboratory and in people, but that does not mean that cross-resistance does not exist. Tenofovir does not work against HIV with several drug-resistance mutations acquired during prior AZT or d4T treatment. This is part of the reason why Gallant does not see salvage treatment as tenofovir's optimal use. "I think tenofovir is a better drug to use up front," said Gallant.

Tenofovir in Daily Life

Until recently, though, there was no indication that the drug presented any advantage over the standard nucleoside analogs that it would replace in first-line anti-HIV combinations. Now, a large new trial presented at the International AIDS Conference documents the effect of tenofovir in initial as well as salvage therapy.

That effect was not exceptional: The double-blinded study included 600 treatment-naïve volunteers taking efavirenz and 3TC plus either tenofovir or d4T. After 48 weeks, 82% of those receiving tenofovir had suppressed their viral loads to below 50 copies/mL, while 81% of volunteers in the d4T arm reached the same level. Total serious side effects also were similar for d4T and tenofovir.

d4T is one of the weaker nucleoside analogs. Potency is not what sets tenofovir apart from the drugs it can replace. Instead, tolerability, safety and simplicity are tenofovir's main drawing points.

"In the real world it [tenofovir] looks good," said Dr. Keith Henry, Director of HIV Clinical Research at Hennepin County Medical Center in Minneapolis.

Minor side effects like headache and stomachache, the ones most commonly complained about in the clinic according to Henry, are rare with tenofovir. "Patients generally like it," he commented.

Elevations in triglycerides and cholesterol also are common in those receiving HIV therapy. Volunteers receiving tenofovir in this study had a 29 mg/dL increase in total fasting cholesterol, while those in the d4T arm had a 57 mg/dL increase. Lower cholesterol could reduce long-term heart disease risk.

"Short term it makes no difference, but if you're looking at taking the medicine for 20 to 30 years then you don't want to get started on the wrong foot," said Henry.

Serious adverse events associated with d4T include neuropathy and high lactic acid in the blood. These side effects may be related to disruption of the energy-producing machinery in the cells' mitochondria, a common problem with nucleoside analogs. At 48 weeks, 7% in the d4T arm of the first-line trial experienced neuropathy, 4% reported lipodystrophy (body fat redistribution), and 1% lactic acidosis. This was compared to 2%, 1%, and 0% in the corresponding categories for the tenofovir arm.

d4T has a particularly harsh toxicity profile. It remains to be seen how tenofovir stacks up against more benign nucleoside analogs, like 3TC. But in addition to safety, tenofovir also has the advantage of once-a-day dosing. Gilead Sciences, its developer, has exploited this in the marketing of the drug as an important factor for clinicians.

"A lot of clinicians really like once a day. I usually try to leave it up to the patients," said Henry.

Tenofovir's Financial Punch

The value of tenofovir to Gilead is inarguable. In the second quarter of 2001, the firm posted a net loss of $32.4 million. Losses have been continual for the 15-year-old company. This spring, with tenofovir accounting for nearly half of Gilead's sales, it announced a second quarter profit of $19.7 million.

Even if patients appreciate its simple dosing schedule, they may not be so thrilled with the price tag that comes with it. Tenofovir – which costs at least $5,200 for a year's supply – is more expensive than the previously approved nucleoside analogs. Its price is 50% over that of once-daily ddI (Videx EC), for example. Tenofovir turns out to be as expensive as efavirenz (Sustiva), a much more potent once-daily drug with which it could be combined.

But while those filling the prescriptions and state AIDS Drugs Assistance Programs may worry about pricing, clinicians seem unconcerned.

"I'm more interested in what I'm trying to accomplish for my patients. The cost of a drug is not a major issue when there are a lot of budget buster drugs coming along," said Henry.

Two once-daily drugs should receive approval in 2003 – the protease inhibitor atazanavir (Zrivada) and the nucleoside analog FTC (Coviracil). Both offer their own special strength and safety advantages. Once-daily extended-release d4T is also set for approval. Along with ddI, tenofovir and efavirenz, the new medications can form various once-daily combinations for use in different patient populations. HIV regimens will become easier and safer in the near future, but with tenofovir's price as the new benchmark, they will also be considerably more expensive.

Tenofovir-ddI: Use Caution with this Combo

It is tempting to combine tenofovir and enteric-coated ddI (ddI EC; Videx EC) in a once-daily combination. But unexpected drug interactions make this move problematic.

ddI EC is usually taken on an empty stomach to improve absorption whereas tenofovir is taken with food to reduce digestive distress. That is a much more common arrangement. When ddI and tenofovir are ingested together with a light meal, ddI levels are on average 60% above normal. The mechanism behind this increase is unclear, but it may be that tenofovir increases the intestinal absorption of ddI. Taking ddI EC two hours before tenofovir and a light meal causes ddI levels to reach 48% above normal. Excess ddI in the body heightens the risk of life-threatening pancreatitis and other serious side effects such as peripheral neuropathy and high lactic acid levels.

A ddI EC capsule containing 250 mg is also available commercially. Physicians prescribe it to people weighing less than 60 kilograms (132 pounds), a largely female population. Tenofovir's manufacturer, Gilead Sciences, looked into the possibility of reducing the ddI EC dose to 250 mg in heavier individuals when coadministering tenofovir.

If study participants took 250 mg ddI EC two hours before tenofovir and a light meal, the resulting ddI levels were nearly identical to those attained in persons who took 400 mg ddI EC alone on an empty stomach. Even when volunteers took 250 mg ddI and tenofovir together with the light meal, the ddI levels were not much different than with ddI EC alone between meals — overall ddI exposure was reduced by 11% in this scenario. These results raise the possibility that people could take ddI together with tenofovir (and other anti-HIV drugs) at mealtime. The greater convenience could improve adherence to combination regimens' dosing schedules.

Lighter-weight patients probably will still have excessive ddI levels with tenofovir plus the 250 mg ddI capsules. Bristol-Myers Squibb, which produces ddI, is now conducting a ddI/tenofovir study that examines ddI doses of 200 mg and 125 mg as well as 250 mg.

Gilead plans to submit the new data to the FDA early in 2003. In the meantime there has been no change in the official labeling for either ddI or tenofovir. They continue to warn that people taking the two should be carefully monitored for ddI side effects. That is judicious advice in any case.

Another issue is that tenofovir and ddI are nearly the same molecule and act the same way. They both terminate HIV's attempt to infect new cells by hindering the reverse transcriptase process. Rather than helping each other, the two drugs might compete when combined and yield little added anti-HIV activity. But Gilead says that its lab studies found that there is indeed an additive effect to the combination. Bristol-Myers is planning an efficacy study to see how well the combination suppresses HIV in the real world.

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