Nuke' Em: A Look at Triple Nucleoside Regimens

People with HIV have a bit more clarity about when to start anti-HIV treatment, thanks to the recently revised federal treatment guidelines. But the question regarding which regimen to start with remains unanswered. One type of regimen in particular -- a combination of three nucleoside analogues without either a protease inhibitor (PI) or a non-nucleoside reverse transcriptase inhibitor (NNRTI) -- is one of today's options. However, there are still a number of questions about how useful this strategy is in the long run for someone who is just starting treatment.

Nucleoside analogues are the oldest class of antiretrovirals, comprising Retrovir (AZT), Videx (ddI), Hivid (ddC), Zerit (d4T), Epivir (3TC), and Ziagen (abacavir). The nucleoside analogues block HIV's reverse transcriptase enzyme, preventing HIV's genetic information from converting its RNA into DNA, and therefore stopping it from being able to replicate inside cells.

Given the cross-resistance that plagues the PIs and NNRTIs, as well as the risk of long-term toxicities associated with these drugs, some people who are naive (new) to treatment are deciding against starting with PI- or NNRTI-containing combinations. But what is the likelihood of sparing both of these drug classes and still ending up with a powerful, effective, and safe drug combination?

When Is Simpler Better?

For years patients have been juggling complex regimens, choking down handfuls of pills, and living anxiously with the knowledge that missing as few as five to ten percent of doses -- that's less than one dose a month -- can lead to drug resistance and failure. As a result, healthcare providers and people living with HIV are constantly looking for regimens that are easier to take. Trizivir combines three nucleoside analogues in one pill: AZT, Epivir, and Ziagen, all manufactured by the same company, GlaxoSmithKline. Trizivir appears an attractive option -- one tablet, two times a day, with no food or water restrictions.

But is simpler always better? The federal guidelines give Ziagen-containing combinations -- including Trizivir -- "alternative" rather than the higher "strongly recommended" status. Ziagen is the only nucleoside analogue with any recommendation to be used in combination with two other nucleosides. There are several reasons for this distinction. One is Ziagen's potency -- it's stronger compared to the other nucleoside analogues individually. Also, several clinical trials have shown the combination of Ziagen, AZT and Epivir to be as effective as PI-containing combinations for first line treatment.

CNA 3005, a GlaxoSmithKline study, compared the impact of Ziagen/AZT/Epivir versus Crixivan/AZT/Epivir on viral load and CD4 cell counts. This trial was randomized (people were assigned to either arm randomly) and double-blinded (neither the study participants nor the study nurses and doctors knew which combination the patients had been randomly assigned to) and enrolled 562 patients who had never taken anti-HIV drug therapy before.

By 48 weeks, both groups were as likely to have viral load suppression below 400 copies/mL (51% of participants on either combination). However, there was a difference among patients who entered the study with high viral loads. Approximately 35% of the study patients started the trial with viral loads above 100,000. These patients were more likely to keep their viral load undetectable (less than 50 copies/mL) if they were in the Crixivan group than if they were in the Ziagen group (45% versus 31%).

CNA 3104, a trial of the same combinations, was open-label, meaning that both the participants and the study personnel knew which combination the participants were taking. The Ziagen group performed slightly better than the Crixivan group, but the difference wasn't statistically significant: 63% of patients on the Ziagen combination and 60% of patients on the Crixivan combination kept their viral loads below 50 copies/mL after 24 weeks of therapy. Adherence issues may have played a role in achieving such similar results. 74% of the people taking Ziagen reported taking all of their doses or missing only one dose of their twice a day regimen in the past week, compared to 45% of the people taking Crixivan three times a day.

Strangely, the 37% of patients who entered this trial with viral loads above 100,000 performed no worse on the Ziagen combination than on the Crixivan combination (56% versus 43% were below 50 copies/mL by week 24). This preliminary finding has not been reproduced in other, more controlled settings and should be monitored as the study progresses.

Risk Versus Benefit

For Trizivir and other triple-nucleoside analogue combinations, the potential for increased mitochondrial toxicities warrants close attention. Mitochondria are the powerhouse of our bodies' cells. They serve the critical function of producing energy for a host of life-sustaining cellular activities. Nucleoside analogues can affect the DNA in mitochondria. This can harm the mitochondria and irreversibly damage the function of certain cells. Some researchers believe that nucleoside analogue damage to mitochondria is to blame for a number of side effects, including fatigue, muscle weakness and loss (myopathy), peripheral neuropathy, and fat loss in the face, legs, and arms (lipoatrophy).

Nucleoside analogue treatment can also sometimes result in life-threatening toxicities, such as severe lactic acidosis with hepatomegaly, or fatty liver. Cells that contain too many severely damaged mitochondria must resort to an abnormal type of energy production that doesn't rely on the mitochondria. Lactic acid is the chemical byproduct of this sort of abnormal energy production. The liver is responsible for ridding the body of lactic acid; when the liver becomes too overwhelmed with lactic acid, lactic acidosis with hepatomegaly can result. Scientists are intensifying research on this neglected topic. However, there is no clinical information yet about whether or not triple nucleoside combinations intensify the risk for mitochondrial toxicities.

On a positive note, early results from one study indicate that triple-nucleoside analogue combinations may help remedy the cholesterol and triglyceride problems associated with protease inhibitors. The TRIZAL study (AZL 30002) randomly switched people whose viral loads were undetectable (<50 copies/mL) using a PI-based regimen to Trizivir, or continued them on their standard treatment. At 24 weeks, viral load rebounded to levels above 400 copies/mL in 17% of patients on the PI-based regimen and 20% of patients on Trizivir. Interestingly, triglycerides and total cholesterol levels improved significantly in the Trizivir group. Surprisingly, 10% of patients who were taking Trizivir reported hypersensitivity reaction, a dangerous allergic response to Ziagen that can be fatal. This unexpected finding is twice the typical 5% rate reported in other studies using regimens that contained Ziagen and warrants future study.

The Bottom Line

Trizivir seems like an attractive, dramatically simplified HIV therapy. But there is a potential danger that Trizivir will be prescribed more often among populations inappropriately labeled "bad" at taking medication. Without rigorous attention to baseline viral load, prior nucleoside analogue exposure, thorough education regarding Ziagen hypersensitivity reaction, and other factors, Trizivir's already restricted potential for therapeutic effect may become even more limited.

Asia Russell is a member of ACT UP Philadelphia and Health GAP Coalition, and coordinates an HIV treatment and activist training program for HIV positive ex-inmates at Project TEACH in Philadelphia.