Simplification of Therapy: Caution Needed

Since the early days of potent combination therapy for HIV (commonly called ART or HAART), doctors and their patients have wanted fewer and safer drugs in treatment regimens. There are many reasons for this but perhaps the main one is to reduce the potential for long-term side effects.

Some long-term side effects are thought to arise from exposure to nucleoside analogues, commonly called "nukes" by some doctors and patients. The basis for this concern about nukes arose in part from at least several experiences over different periods, as follows:

• Initial treatment for HIV was nuke based and one nuke in particular, AZT (zidovudine, Retrovir), was initially used at very high doses in the 1980s and injured the bone marrow.

• In the early 1990s, there were reports that other nukes, so-called "d" drugs -- ddC (zalcitabine, Hivid), ddI (didanosine, Videx) and d4T (stavudine, Zerit) -- could cause injury to the nerves in the hands, feet and legs. This type of toxicity is called peripheral neuropathy and can persist for years if it is not caught in the early stages and the use of d-drugs is discontinued.

• In the late 1990s another problem appeared -- the HIV lipodystrophy syndrome. The most disturbing feature of this syndrome is the loss of the fatty layer just under the skin (subcutaneous fat). This could lead to distressing changes in the appearance of the face. It took several years after the appearance of the syndrome for researchers to determine that exposure to the nuke d4T, and to a lesser extent AZT, were the main culprits behind the loss of subcutaneous fat.

This legacy of bad news has tainted all nukes even though today the nukes recommended by treatment guidelines in high-income countries as part of the initial treatment of HIV are easier to tolerate and do not cause injury to nerves, bone marrow or fat cells. These nukes are as follows:

• Kivexa -- a fixed-dose combination of two nukes: abacavir + 3TC

• Truvada -- a fixed-dose combination of two nukes: tenofovir + FTC

Kivexa and Truvada

Large randomized clinical trials have generally found that Kivexa and Truvada, when used as part of ART, are effective and generally safe for most patients. However, there can be exceptions to these general results and we discuss a few of them next.

Focus on Abacavir

Abacavir, one of the drugs in Kivexa, can cause a hypersensitivity reaction. However, there is a simple blood test available that can predict the likelihood of such a reaction occurring with a relatively high degree of accuracy. By using this test to assess which patients are at risk for a hypersensitivity reaction before starting therapy, doctors can steer susceptible people away from abacavir.

In some cases, abacavir can also cause moderate increases in cholesterol levels.

Several years ago one large observational study suggested that the use of abacavir was associated with a temporarily increased risk of heart attacks. Bear in mind that observational studies, due to built-in limitations, can never prove cause and effect. That is, they can never prove that abacavir can temporarily cause an increased risk of heart attack. Another large observational study, the French Hospital Database also assessed the risk of heart attack among its participants who used abacavir. French researchers found that after adjusting for use of cocaine (a powerful stimulant that by itself can cause heart attacks), exposure to abacavir was not linked to an increased risk for heart attacks. Furthermore, a review by the U.S. Food and Drug Administration (FDA) of randomized clinical trials with abacavir has not found any such risk. Also, there have been recent randomized clinical trials with Kivexa and the new integrase inhibitor dolutegravir (Tivicay) in several thousand HIV-positive people and heart attacks have not been reported.

Abacavir does have advantages: It can be taken once daily, it does not harm bone cells and it penetrates the brain. This latter property is important, as HIV-infected cells can reside in the brain and not all anti-HIV drugs get into or can stay in the brain.

Focus on Tenofovir

Large clinical trials have found that, like abacavir, tenofovir is generally safe and effective. However, in some cases, this drug, which is processed by the kidneys, has been linked to kidney injury. This is usually reversible when patients stop taking tenofovir. Its use has also been linked to thinning bones in some patients.

Tenofovir also has advantages: It can be taken once daily, in some cases it may help reduce cholesterol levels and it penetrates the kidneys well. Research has found that the kidneys are rich in HIV-infected cells.

Not Approved

Despite the benefits of using nukes, some patients and their doctors may prefer to avoid nukes entirely, even if the risk of potential side effects is relatively low. Other doctors and patients wish to use simplified regimens and may jettison nukes (or other classes of drugs). However, so far such strategies are not recommended as routine therapy by leading treatment guidelines in North America. Also, bear in mind that some nuke-free regimens may not be able to suppress HIV replication in the brain.

Relatively small studies have been done with simplified therapy and in some cases they show beneficial effects. The problems with such trials are as follows:

• they are small

• they probably have highly selected patients who are very motivated and therefore likely to be highly adherent

• they have other factors that prevent results from being extended to everyday use in clinics and, most importantly, approval by regulatory authorities

Still, sometimes -- because of prolonged toxicity or intolerance to some medicines in patients -- doctors are forced to devise unusual regimens, some of which may be nuke free.

In this issue of TreatmentUpdate we provide readers with results from some clinical trials of simplified therapy should doctors and their patients wish to discuss this topic. In our next issue of TreatmentUpdate we will have further clinical trial results from a large study of simplified therapy.

Resources

Is protease inhibitor monotherapy sufficient to keep HIV under control in the brain? -- CATIE News

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