Getting Started with Antiretrovirals: Thoughts on Initial Therapy
Triple combination therapy has been around for over five years now -- we should all be getting the hang of it, right? Well, we certainly know a lot about treating HIV disease. But with more medications to choose from, more knowledge of the long-term side effects of therapy, and more sophisticated laboratory tests such as drug resistance profiling, things are getting trickier. The goals of therapy are straightforward -- getting viral load as low as possible and keeping it there, boosting the immune system and keeping it strong, reducing illness and death, and improving quality of life. But the best way to achieve those goals is not always so clear.
One question in particular -- "Which therapy should I start with?" -- doesn't have an answer. Recent research has addressed the question, but there isn't one right way to begin treatment.
What's Out ThereThe first regimen is generally a protease inhibitor (PI)- or non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimen. Another possibility is a triple nucleoside reverse transcriptase inhibitor (NRTI) regimen with Ziagen (abacavir) as its base. The PI-based and NNRTI-based regimens both include two NRTIs.
PIs work by stopping the action of the protease enzyme. The protease enzyme is a protein that is used during the assembly of new copies of the virus. Six protease inhibitors have been approved by the US Food and Drug Administration (FDA): Crixivan (indinavir), Fortovase (saquinavir soft gel, called Invirase in the old hard gel formulation), Viracept (nelfinavir), Agenerase (amprenavir), Norvir (ritonavir) and Kaletra (lopinavir, with a small dose of ritonavir to increase lopinavir blood levels).
NRTIs and NNRTIs also block enzyme action, in this case, the reverse transcriptase enzyme, which HIV uses to copy its genetic information. The FDA has approved six NRTIs: Retrovir (AZT), Zerit (d4T), Videx (ddI), Epivir (3TC), Hivid (ddC) and Ziagen (abacavir); and three NNRTIs: Sustiva (efavirenz), Viramune (nevirapine), and Rescriptor (delavirdine).
Using the GuidelinesThe federal treatment guidelines' recommendations for initial therapy are based on what is known about the safety and effectiveness of different medications over time, as well as quality of life considerations such as number of pills, dosing convenience and side effects. The guidelines separate these medications into two categories: "Strongly Recommended" and "Recommended as Alternatives." Within each category, they're listed alphabetically by generic name, not in any order of preference.
The "strongly recommended" medications follow:
Comparing PIsA quick glance at the guidelines reveals that most of the drugs in Column A are PIs. PIs have been around for over five years, and there is long-term evidence from clinical trials that they are effective in lowering viral load, boosting the immune system and preventing HIV-related illness and death. PIs are powerful drugs that can reduce the amount of HIV both in the blood and in other places in the body where HIV is found (like the lymph nodes). The Column A PIs have all been shown to be effective in initial therapy, so how do doctors and patients choose between them?
Some recent clinical trials have compared PIs to each other. Abbott Laboratories' M98-863 study compared a Viracept-based regimen with a Kaletra-based regimen for initial therapy. At Week 48 of the study, 67% of patients on Kaletra and 52% of patients on Viracept had an undetectable viral load (less than 50 copies), a statistically significant difference. The study showed no statistically significant difference in CD4 cell count increases between the two treatment groups. Interestingly, Kaletra is the only protease inhibitor that has been shown to be as effective in individuals with high baseline viral load measurements (viral load greater than 100,000 copies) as those with lower measurements.
At the 8th Conference on Retroviruses and Opportunistic Infections, results were presented from an international study comparing two PI choices from Column A -- Crixivan vs. Crixivan + Norvir. The researchers found the two regimens to be equally effective after a year of therapy. Crixivan + Norvir is more convenient than Crixivan because it is taken twice a day instead of three times a day. The convenience of the regimen alone makes it preferable for many people. [For more information on regimens containing two PIs, refer to Tim Horn's article in this issue.]
At last year's International AIDS Conference in Durban, a group of Spanish researchers compared the effectiveness of three protease inhibitors -- Norvir, Fortovase and Crixivan. Patients who enrolled in the study had taken therapy before, but had never taken a PI. The study showed the three treatments were equally effective for patients who stayed on therapy for a year. Of the patients who began treatment with Fortovase, 75% stayed on Fortovase for the entire year, while only 28% of patients who started with Norvir and 50% of patients who started with Crixivan completed the year on those treatments. Of the patients who stopped Fortovase, 95% stopped for treatment failure and 5% stopped for intolerance. Of the patients who stopped Norvir, 19% stopped for failure and 73% stopped for intolerance. The figures were 57% for failure and 38% for intolerance with Crixivan.
With so many powerful drugs to choose from, the safety and tolerability of a regimen, its effect on quality of life, and the impact of resistance on future treatment options all influence decision-making in initial therapy. Both short- and long-term side effects must be carefully considered. Possible side effects of a PI-based regimen include fat redistribution, high cholesterol and/or triglycerides, and insulin resistance that may contribute to the development of diabetes. Others to watch for include kidney stones (with Crixivan), elevated liver enzymes, hepatitis (liver inflammation) and pancreatitis (inflammation of the pancreas). The short-term side effects of PIs are extensive and can significantly impact quality of life. The Column A PIs are all associated with gastrointestinal upset (nausea, vomiting, diarrhea, stomach pain, gas or a combination of those side effects). Rash is a possible side effect of Crixivan and Viracept, and patients on Norvir may experience oral tingling or numbness.
A final consideration in choosing a specific PI-based regimen is the role that drug resistance plays in the course of HIV treatment. For example, we know that the mutation that leads to Viracept resistance is at site D30N in HIV's genetic material. This resistance mutation is unique to Viracept, so it does not lead to resistance to other PIs. If the decision is made to begin treatment with a protease inhibitor, Viracept may be a good first choice because it may leave other PI treatment options available for later use.
While we generally think of resistance in a negative context since it can make treatment less effective, there is evidence that some drug-resistant strains of HIV are less "fit" than other strains. A virus that is less fit is not as good at making copies of itself or infecting other cells. In a study out of the University of California at San Francisco, researchers showed that some HIV that is resistant to PIs is less fit than wild-type virus (virus with no resistance mutations). This may keep viral load low even when PI-resistant virus is present. We're just starting to learn how to use this information to make decisions about treatment. In the future, it may be possible to use resistance mutations to turn wild-type HIV into mutated virus that is unfit and cannot do its dirty work on the immune system. Currently, there is not enough information to determine if this is a reasonable possibility.
Comparing PIs with NNRTIsNNRTI-based regimens are generally considered to be more "patient-friendly" than PI-based regimens -- NNRTIs have fewer side effects and easier dosing schedules than PIs. In addition to being easier to take, NNRTIs are powerful treatment options that lower viral load and increase CD4 cells. Sustiva is a first choice from Column A for initial therapy, while Viramune and Rescriptor are alternatives that may be considered (there isn't enough data to support the inclusion of either as a first choice). Sustiva was included as a first choice after data from study DMP-006 (first reported at the Geneva AIDS Conference in 1998) showed that it was at least equivalent to Crixivan in an open-label study, even in patients with high initial viral loads. Three years later, the data still support the recommendation.
In the study, 422 patients received Sustiva, and 80% of those patients achieved and maintained an undetectable viral load (below 50 copies) after two years of therapy. 415 patients received Crixivan, and 65% had an undetectable viral load after two years of therapy. The study team concluded that if current trends continue, the Sustiva regimen could be effective for over six years. Interestingly, patients with less than 200 CD4s when they started treatment were more likely to have virologic failure -- an increase in viral load to above the limit of detection -- on Crixivan after three years of treatment than patients with more than 200 CD4s, but there was no difference in virologic failure rates based on initial CD4 count in patients taking Sustiva.
The Combine study, conducted in Spain and Argentina, compared a PI-based regimen containing Viracept with an NNRTI-based regimen containing Viramune. After 36 weeks, there was no statistically significant difference between the two groups in terms of the number of patients who achieved undetectable viral loads. Gains in CD4 cell counts were also similar for the two treatment groups.
Viramune has also been compared with a PI-based regimen containing Crixivan and a triple-NRTI (Epivir/Zerit/Videx) regimen in the international Atlantic study. After a year of treatment, about half (49%) of patients on the Viramune and Crixivan regimens had an undetectable viral load (less than 50 copies), and 40% patients on the triple-NRTI regimen were undetectable. The differences were not statistically significant using the strictest data analysis. Using a more lenient analysis (patients who dropped out were not included), patients on Crixivan did better than patients on Epivir, but no other significant differences were seen. It can be concluded from these studies that Viramune may be considered for initial therapy.
An NNRTI-based regimen spares PI side effects but comes with its own toxicities. One long-term side effect of NNRTIs is increased transaminase levels, which can indicate liver damage. Additionally, a long-term side effect specific to Viramune is severe hepatitis. In the short term, Sustiva can cause rash, drowsiness, insomnia, central nervous system side effects (confusion, inability to concentrate, dizziness, vivid dreams), gastrointestinal side effects (nausea, stomach pain), and fever, while Viramune is associated with rash, stomach upset and headaches.
These drugs have simple dosing schedules with fewer pills than PIs. Sustiva is taken once daily in combination with NRTIs that are taken twice daily, and the Sustiva dose is three capsules. The Viramune dose is one tablet twice a day. To simplify things even further, researchers have been testing NNRTI-based regimens that are taken once daily.
A final consideration when comparing NNRTIs with PIs is that only one mutation in the genetic material of HIV causes NNRTI drug resistance, and once that mutation occurs, resistance to the entire class develops. With PIs, the development of resistance is a multi-step process, and resistance to one PI does not necessarily result in resistance to the entire class.
Comparing NNRTIsPatients who want to start treatment with an NNRTI may wonder how to choose between Sustiva and Viramune. Side effects will certainly factor into the decision -- patients at risk for hepatitis may wish to avoid Viramune, and some patients choose to avoid Sustiva because of the central nervous system side effects described above.
There has not been a controlled study directly comparing Sustiva and Viramune, but information was collected from a group of over 1,900 European patients who were treated with either Viramune (1,202 patients) or Sustiva (730 patients) since July 1997. In total, 525 patients experienced virologic failure, and individuals taking Sustiva were more likely to stay undetectable than those taking Viramune. This data must be verified by a controlled trial.
Final ThoughtsThere is no single approach to treating HIV infection that works for everyone and no "best" first regimen. Complicated choices are par for the course in HIV infection. With new treatments on the way, these choices may get tougher -- but a knowledgeable HIV care provider who stays on top of current research can provide guidance to help you make choices that work for you.
Anne Monroe is Research Coordinator for the Division of Pediatric Infectious Diseases at New York Presbyterian Hospital in New York City and a writer on HIV/AIDS topics.
This article was provided by AIDS Community Research Initiative of America. It is a part of the publication CRIA Update. Visit ACRIA's website to find out more about their activities, publications and services.