The First 3-Drug Combination Pill for Patients with HIV/AIDS

May 31, 2007
Jeffrey T. Kirchner, DO, AAHIVM

Internal Medicine World Report, September 2006, Volume 0, Issue 0

Dr Kirchner is Medical Director, Comprehensive Care Center for HIV, Lancaster General Hospital, Lancaster, Pa.

In March 1987, zidovudine (AZT; Retrovir) became the first effective therapy to be approved by the FDA for the treatment of HIV infection. The drug was excitedly welcomed 6 years into the epidemic. When initially released, the dosing schedule for AZT was 2 capsules every 4 hours. Patients awoke with their alarm throughout the night to avoid missing doses. The initial enthusiasm for the drug ended in 1990, when the Concord trial showed no survival benefit with AZT alone, although patients seemed to do better for a short period of time. Despite the subsequent approval of several other nucleoside agents, including didanosine (Videx EC in 1991) and stavudine (Zerit in 1994), the picture for patients with AIDS remained bleak through 1995, and the death toll in that year alone exceeded 50,000. In December of that year, the protease inhibitor (PI) saquinavir (Invirase) was approved, followed by indinavir (Crixivan) and ritonavir (Norvir). Indinavir had the remarkable distinction of being the quickest drug approved in the history of the FDA, making it to market in 1.4 months. It was this class of PIs that ushered in the era of highly active antiretroviral therapy (HAART) that has dramatically changed the course of the disease.

Over the past several years, we have seen a gradual decline in "pill burden" for patients, as well as newer agents that, at least for now, seem to be less toxic. In addition, there has been a gradual proliferation of combination therapies that included drugs from the same class, with zidovudine and lamivudine (3TC; Combivir) approved in 1997, followed by zidovudine/lamivudine/abacavir (Trizivir) in 2000.

In the past 2 years we have seen the addition of combinations of tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC), called Truvada, and abacavir and lamivudine, known as Epzicom. The pairing of these antiviral drugs has made it easier for patients and physicians to effectively treat HIV disease in terms of pill burden as well as daily dosing.

In December 2004, Bristol-Myers Squibb (BMS) and Gilead Sciences made a decision unprecedented in the HIV pharmaceutical industry, announcing a joint venture to develop a fixed-dose combination of Gilead's TDF and emtricitabine with BMS's efavirenz (Sustiva). Efavirenz is a highly effective non—nucleoside reverse transcriptase inhibitor (NNRTI) that has been on the market since 1998. It is currently listed with lopinavir (Kaletra)/ritonavir on the "preferred" first-line therapy list in the Health and Human Services Adult HIV treatment guidelines.

After several attempts, all 3 agents were successfully combined, resulting in the first once-daily, single-pill regimen, Atripla, for the treatment of HIV infection. A key issue with combining drugs from 2 different classes was establishing bioequivalence with current drugs. In April, results of the Bioequivlence of Efavirenz/Emtricitabine/Tenofovir DF Single Tablet Regimen study were presented by Anita Mathias and colleagues at the 7th International Pharmacology Workshop in Lisbon, Portugal (April 2006, Abstract # 82). This crossover study included 48 healthy patients who were given the fixed-dose combination and the individual drugs. It was conducted in 2 phases that included a 7-day washout period. Bioequivalence was established by meeting the FDA criterion of confidence intervals falling between 80% and 125% when comparing levels of each drug in patients dosed with the coformulation compared with the individual compounds.

N Engl J Med

The key clinical data that support the use of Atripla come from the Gilead 934 trial; its 48-week data were published in January (. 2006;354:251-260). This trial of almost 500 patients compared TDF, emtrictabine, and efavirenz with zidovudine, lamivudine, and efavirenz. Patients in the TDF/FTC arm had superior virologic responses compared with the AZT/3TC arm. The TDF/FTC arm also had fewer adverse events than the other arm. The 96-week data from Gilead 934 were presented at the World AIDS Conference in August, and the study is slated to continue for at least 144 weeks.


Additional data that support the use of Atripla come from the Gilead 903 trial, which compared efavirenz, TDF, and lamivudine with efavirenz, stavudine, and lamivudine (. 2004; 292:191-201). In this trial, which included patients from the United States, Europe, and South America, the 2 regimens had equivalent virologic efficacy, with about 80% from each group attaining undetectable HIV-RNA levels. Patients who received TDF, however, had more favorable changes in lipid profiles and less lipodystrophy over a 3-year period.

As with the individual agents, adverse events with Atripla can be expected, including the potential for renal toxicity from the TDF component; therefore, this new combination agent should not be used in patients with a creatinine clearance <50 mL/min. Common central nervous system (CNS) effects often seen with efavirenz include dizziness (28%), insomnia (16%), impaired concentration (8%), and abnormal dreams (6%). Efavirenz has also been reported to cause a rash in about 25% of patients when first taking the drug, but it is usually self-limiting and does not require discontinuation. Also of note, efavirenz is a pregnancy category D drug, because of reported cases of neural tube defects. Thus, if Atripla is to be used in women of childbearing age, baseline pregnancy testing is recommended, as well as documentation of appropriate contraception, according to the manufacturer's package insert.

Some have raised concerns about whether a single pill would increase the risk of resistance to efavirenz, which, like the other currently available NNRTIs, has a low genetic barrier to resistance. Current dogma in the HIV treatment world is that patients must take 95% of their daily medication doses to avoid drug resistance. According to a commentary by Courtney Fletcher, PharmD, professor and chair, Department of Clinical Pharmacy, University of Colorado Health Sciences Center, Denver, the plasma half-life of efavirenz is about 24 hours, and the intracellular half-life of the other 2 agents is even longer?about 30 hours for FTC and 60 hours for TDF (, June 30, 2006). Thus, this combination may be more forgiving in allowing for occasional, but not repeated, missed doses. Clinical experience and prospective data will determine the validity of this concern. However, if adherence is indeed better with Atripla, as many clinicians expect, then the incidence of resistance could be even less than is currently seen with the individual agents.

Where I see an immediate role for Atripla in clinical practice is to transition over to a single pill those patients who are currently stable and tolerating efavirenz with TDF and emtricitabine or lamivudine. This will simplify therapy from 2 or 3 daily pills to just 1. In addition, for many patients it will decrease the number of copays through their prescription drug programs. The cost of the combination tablet is supposed to be about $1100 per month—the same as the individual components.

One of my own concerns with Atripla is that physicians who do not have as much experience with antiretroviral prescribing may be more likely to prescribe what appears to be a very simple approach to HAART. However, as noted above, if all 3 agents are started concurrently, very close patient monitoring is absolutely essential during the first several weeks of therapy.

Clinical decisions will need to be made regarding changing or stopping therapy based on the adverse events the patient may be having with this drug. So my recommendation would be to approach this therapy with appropriate caution. Physicians may also want to prescribe the individual agents first, and then transition the patient over to the 3-drug combination after a month or two if tolerability is not a problem.

Atripla truly represents a landmark in the history of antiretroviral treatment, but it is hardly the end of the story. We will continue to see newly infected patients with drug-resistant virus (especially to NNRTIs), for which this agent will not be an option. In addition, intolerable adverse CNS events and contraindications, such as renal insufficiency, will also eliminate this combination drug as an option for many patients. However, as agents with different mechanisms of action, such as integrase inhibitors and CCR5 receptor-antagonists, work their way through clinical trials, we can generally be more optimistic about the future of HIV therapies.

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