The current HIV treatment guidelines from the Department of Health and Human Services (DHHS) recommend the use of the non-nucleoside reverse transcriptase inhibitor efavirenz (Sustiva) or the boosted protease inhibitor lopinavir/ritonavir (Kaletra) with a combination of 2 nucleoside agents for initial therapy. The preferred nucleoside agents are zidovudine (Retrovir/AZT) or tenofovir DF (Viread) plus lamivudine (Epivir/3TC) or emtri?citabine (Emtriva). Many trials have shown that the combination of these drugs is capable of suppressing the plasma viral load (HIV-RNA) to an undetectable level while producing substantial increases in CD4+ cell count in the majority of patients who take them.
The New Evidence
The new multinational "Study 934" (N Engl J Med. 2006;354:251-260) has now compared the traditional regimen with a newer one in 517 adults aged >=18 years from the United States, France, Germany, England, and Spain. The patients had never used antiretroviral therapy, and their plasma HIV-RNA levels were >10,000 copies/mL.
The patients were randomized to receive 1 of 2 once-daily regimens that included either (1) efavirenz, 600 mg, plus tenofovir DF, 300 mg, and emtricita?bine, 200 mg, or (2) efavi?renz, 600 mg once-daily, plus fixed-dose zidovudine, 300 mg, and lamivudine, 150 mg twice daily, in an open-label manner.
The investigators sought to determine whether the regimen containing tenofovir DF and emtricitabine was equal to that of the AZT and lamivudine regimen based on the number of patients with an HIV-RNA level <400 copies/mL at 48 weeks of treatment. Secondary end points were the number of patients with a viral load of <50 copies/mL and the increase in the CD4+ lymphocyte count from baseline.
At 48 weeks, 206 of 244 patients (84%) taking tenofovir plus emtricita?bine maintained a viral load of <400 copies/mL compared with 177 of the 243 patients (73%) taking AZT and lamivudine. In addition, 80% of the patients in the tenofovir?emtricitabine arm had HIV-RNA levels of <50 copies/mL compared with 70% of those in the AZT?lamivudine group. These 2 differences not only demonstrated that the tenofovir?emtricitabine regimen was not inferior to AZT?lamivudine, but that it produced a significantly greater res?ponse when combined with efavirenz.
By the more stringent intent-to-treat analysis, 77% of patients in the first arm had viral loads of <50 copies/mL compared with 68% in the AZT?lamivudine arm. The patients who re?ceived tenofovir? lami?vudine and efavirenz had a mean increase in CD4+ counts from baseline of 190 cells/mm3 versus 158 cells/mm3 in patients taking AZT and lamivudine.
Another key finding from the study was a 90% adherence rate among the tenofovir?emtricitabine patients compared with 87% in the AZT group ?(P = .04). There was an equal number of adverse events (63%) in both study groups. How?ever, 9% of patients in the AZT arm stopped therapy compared with only 4% in the tenofovir group.
Although tenofovir has been associated with renal dysfunction, there was no difference in this study in treatment withdrawals as a result of renal toxicity or renal events. The most common cause of discontinuation in the AZT group was marked anemia, a relatively common side effect of AZT therapy.
Improved Patient Adherence
The data from this trial were first presented in July 2005 at the 3rd Inter?national AIDS Society meeting and thus were available for several months before actual publication. Many clinicians, including those at our HIV program, have already been increasingly prescribing the combination of tenofovir and emtricitabine?but more for reasons of convenience related to its once-daily formulation and thus the ability to pair it with a once-a-day non-nucleoside agent or protease inhibitor.
The data as presented and subsequently published were for only 48 weeks of treatment. It will be of great interest to see if these differences persist at 96 weeks.
Regardless, the findings of Study 934 are quite significant for both patients and physicians. For all 3 clinical outcomes (HIV-RNA <400 and <50, CD4+ cell count), the combination of tenofovir DF, emtricitabine, and efavirenz ?outperformed the combination of zidovudine?lamivudine and efavirenz.
These surrogate markers of HIV control and immune recovery have been shown to be important predictors of morbidity and mortality in patients with HIV/AIDS. The tolerability of antiretroviral agents is a common problem for patients. Drug side effects are the most frequent reasons cited for poor adherence as well as for treatment change or discontinuation.
The improved tolerability of several of the new antiretroviral agents makes it easier for patients to maintain the same regimen for months or even years, lessening the concern for viral resistance and subsequent treatment failure.
Other advantages of the tenofovir? emtricitabine regimen include the availability of a fixed-dose combination of these 2 drugs (Truvada), which limits the number of pills a patient must take to just 2 (ie, Truvada and efavirenz), and both are taken only once daily.
Moreover, a recent effort to triformulate efavirenz?tenofovir?emtricita?bine into 1 tablet was successful, and the formulation is awaiting FDA approval. Although not definitely proven, the simplicity of such a regimen would be expected to improve patient compliance.
Along with waiting for the 96-week data, it will also be of interest to see if the DHHS treatment guidelines panel will be persuaded enough by Study 934 to change their recommendations regarding "preferred" first-line therapy for treatment-na?ve HIV-infected adults. I do believe that any changes must be made from the perspective that generic formulations are now available for 2 agents that have a long track record of being quite effective?zidovudine and lamivudine?and thus they would be available at a significantly reduced cost.
An important question facing physicians and patients over the next few years may be: Will minor (even statistically significant) increases in efficacy and tolerability trump drug cost for the >1 million persons living with HIV/AIDS in the United States and the many millions more throughout the world who have the disease?
HIV Subtype Better Predictor of AIDS Death than Viral Load
DENVER?New data presented at the 13th Conference on Retroviruses and Opportunistic Infections suggest that an infected patient's HIV subtype is a better predictor of the likelihood of rapid death from AIDS than viral load; currently, viral load level is used to determine the patient's risk of death associated with HIV/AIDS.
The new data showed that an HIV-infected patient with viral subtype D was at greater risk of dying rapidly compared with a person with viral subtype A. The study participants came from a cohort of 12,000 Ugandans who are being monitored for the spread of HIV in the country.
"Knowing a person's HIV subtype is important for the management of the infection, because the disease can progress more rapidly in those infected with subtype D and recombinant virus incorporating subtype D than in those with other subtypes," said lead investigator Oliver Laeyendecker, MS, MBA, of the Johns Hopkins University School of Medicine, Baltimore, and the National Institute of Allergy and Infectious Disease.