Clinical Science: Concise Communication
Efficacy and tolerability of long-term efavirenz plus nucleoside reverse transcriptase inhibitors for HIV-1 infection
Tashima, Karena; Staszewski, Schlomob; Nelson, Markc; Rachlis, Anitad; Skiest, Daniele; Stryker, Richardf; Bessen, Laurag; Overfield, Sandrag; Ruiz, Nancyg; Wirtz, Victoriah
From the aMiriam Hospital, Providence, Rhode Island, USA
bGoethe University, Frankfurt, Germany
cChelsea and Westminster Hospital, London, UK
dSunnybrook and Women's College Health Sciences Centre, Toronto, Ontario, Canada
eBaystate Medical Center, Springfield, Massachusetts, USA
fTower I.D. Medical Associates, Los Angeles, California, USA
gBristol-Myers Squibb Company, Princeton, New Jersey, USA
hBristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, Connecticut, USA.
Received 4 August, 2007
Revised 21 August, 2007
Accepted 12 September, 2007
Correspondence to Karen Tashima, MD, Brown University, The Miriam Hospital, 164 Summit Avenue, Providence, RI 02906, USA. Tel: +1 401 793 4089; fax: +1 401 793 4323; e-mail: email@example.com
Objective: To compare the long-term efficacy and tolerability of two efavirenz-containing regimens with those of an indinavir-containing regimen in the initial use of HAART.
Method: HIV-1-infected patients (N = 1266) were randomly assigned to receive one of three regimens: efavirenz, zidovudine plus lamivudine, n = 422; efavirenz plus indinavir, n = 429; or indinavir, zidovudine plus lamivudine, n = 415. Entrance criteria included baseline viral load greater than 10 000 copies/ml HIV-1 RNA, CD4 cell count 50 cells/μl or greater, and no previous use of lamivudine, any non-nucleoside reverse-transcriptase inhibitor or protease inhibitor. The primary endpoint was the proportion of patients (response rate) in each regimen with a viral load under 400 copies/ml at 168 weeks of treatment.
Results: Response rates at 168 weeks were 30% in the indinavir, zidovudine, lamivudine group, 48% in the efavirenz, zidovudine, lamivudine group (P < 0.0001, difference estimate; 97.5% confidence interval (CI) 18.5; 10.9, 26), and 40% in the efavirenz plus indinavir group (P = 0.0018, difference estimate; 97.5% CI 10.2; 2.9, 17.6). Median CD4 cell counts increased above respective baselines by 292 cells/μl (efavirenz, zidovudine, lamivudine and indinavir, zidovudine, lamivudine) and 300 cells/μl (efavirenz plus indinavir). Total discontinuations were 54% (efavirenz, zidovudine, lamivudine), 63% (efavirenz plus indinavir), and 69% (indinavir, zidovudine, lamivudine) of which 13, 12 and 26%, respectively, were caused by adverse events. No new or unexpected increases in the rates or severity of adverse events occurred from long-term treatment with efavirenz-containing regimens.
Conclusion: Long-term HIV therapy with efavirenz-containing regimens, particularly efavirenz, zidovudine, lamivudine, provides significantly greater antiviral activity and tolerability than a regimen of indinavir, zidovudine plus lamivudine.
The use of HAART as the standard treatment for HIV infection has led to a dramatic decline in HIV-associated morbidity and mortality [1–4]. The success of current regimens has transformed HIV infection into a chronic condition requiring management over the course of years and decades.
Efavirenz is a potent, once-daily non-nucleoside reverse transcriptase inhibitor (NNRTI) and is currently the preferred NNRTI in HIV treatment guidelines .
We previously reported 48-week follow-up results from an open-label study of 450 HIV-infected patients randomly assigned to receive either efavirenz, zidovudine plus lamivudine (n = 154), or efavirenz plus indinavir (n = 148), or indinavir, zidovudine plus lamivudine (n = 148) . The data indicated that efavirenz, zidovudine plus lamivudine had significantly greater antiviral activity and better tolerance than indinavir, zidovudine plus lamivudine. That study was subsequently amended to increase the enrollment to more than 1000 patients and the duration of treatment was increased to 3 years. We now report follow-up efficacy and safety results after 168 weeks of antiretroviral therapy.
In this open-label study, 1266 HIV-infected patients were randomly assigned at 88 north American and European sites to one of three regimens: (i) efavirenz (600 mg once a day) plus zidovudine (300 mg twice a day) with lamivudine (150 mg twice a day) (n = 422); (ii) efavirenz (600 mg once a day) plus indinavir (1000 mg every 8 h) (n = 429); or (iii) indinavir (800 mg every 8 h) plus zidovudine (300 mg twice a day) with lamivudine (150 mg twice a day) (n = 415). Entrance requirements included a baseline viral load greater than 10 000 copies/ml HIV RNA, a CD4 cell count of 50 cells/μl or greater, and no previous treatment with lamivudine, any NNRTI or a protease inhibitor. The protocol and informed consent forms were approved by independent institutional ethics committees or institutional review boards. All patients provided voluntary written informed consent.
Efficacy was evaluated at 12-week intervals. A therapeutic response [intention-to treat (ITT) analysis, non-completer-equals-failure] was defined using the time to loss of virological response (TLOVR) algorithm, achieving at least two consecutive plasma HIV-RNA measurements less than 400 copies/ml maintained through 168 weeks of treatment. Additional efficacy measures included: (i) ITT response rate using a criterion of viral load less than 50 copies/ml (lowest limit of detectability); (ii) The proportion of virological responders (for patients still on treatment) at any specific follow-up timepoint with a viral load less than 400 copies/ml and 50 copies/ml [virological response–observed case (VROC) analysis]; (iii) Kaplan–Meier estimate of TLOVR, defined as the discontinuation of initial therapy (including never starting treatment, death and loss to follow-up) or confirmed increase in viral load to more than 400 copies/ml after suppression; (iv) CD4 cell count. Adverse events were assessed in all patients who received at least one dose of study medication.
A sample size of 400 patients per treatment arm provided 90% power to compare the durability of HIV-RNA suppression for each of the three regimens. Treatments were considered non-inferior if the 97.5% confidence interval (CI) for the difference estimates in the virological response rate (based on TLOVR algorithm) for either efavirenz group versus the indinavir, zidovudine plus lamivudine group had a lower limit of more than −12%. If non-inferiority was established, a superiority test at an alpha level of 0.025 was conducted. Kaplan–Meier estimates of TLOVR were also conducted. Analytical methods have been described previously .
Patients were randomly assigned between January 1997 and September 1998. The demographic characteristics of the ITT population were similar in the three treatment groups. Respectively, in the efavirenz, zidovudine plus lamivudine, efavirenz plus indinavir and indinavir, zidovudine plus lamivudine groups, men comprised 82, 86, and 80% of the patients, median age (range) for the three groups was 35 years (18–81), and the ethnic distribution (all groups) was 60% white, 20% black, and 17% Hispanic. Median (range) baseline viral loads and CD4 cell counts (all groups) were 4.8 (2.5–7.0) log10 copies/ml and 320 (2–1234) cells/μl, respectively. Previous nucleoside reverse transcriptase inhibitor therapy had been received by 18, 16, and 13% of patients in the efavirenz, zidovudine plus lamivudine, efavirenz plus indinavir and indinavir, zidovudine plus lamivudine groups, respectively. Follow-up was obtained up to week 252. Responses were compared among treatment groups at week 168, the protocol-defined time on study for the last subject enrolled. Median (range) time on study was 180 (0.1–262), 102 (0.1–259) and 76 (0.1–264) weeks for the efavirenz, zidovudine plus lamivudine, efavirenz plus indinavir, and indinavir, zidovudine plus lamivudine groups, respectively. Before week 168, discontinuations for any cause were 43% (efavirenz, zidovudine plus lamivudine), 54% (efavirenz plus indinavir), and 61% (indinavir, zidovudine plus lamivudine). Total study discontinuations were 54, 63, and 69%, of which 13, 12 and 26% were caused by adverse events for patients in the efavirenz, zidovudine plus lamivudine, efavirenz plus indinavir, and indinavir, zidovudine plus lamivudine groups, respectively. Approximately 70% of adverse event-associated discontinuations (all groups) occurred during the first 48 weeks of treatment .
Virological response rates (viral load < 400 copies/ml) in the ITT population at 168 weeks therapy were 48% in the efavirenz, zidovudine plus lamivudine group and 30% in the indinavir, zidovudine plus lamivudine group, (P < 0.0001), difference estimate (efavirenz, zidovudine plus lamivudine minus indinavir, zidovudine plus lamivudine) 97.5% CI 18.5; 10.9, 26, and 40% in the efavirenz plus indinavir group (P = 0.0018), difference estimate (efavirenz plus indinavir minus indinavir, zidovudine plus lamivudine) 97.5% CI 10.2; 2.9, 17.6. Virological failure based on the TLOVR algorithm through 168 weeks was lowest in patients who received efavirenz, zidovudine plus lamivudine (12%), compared with 19 and 17% in the efavirenz plus indinavir and efavirenz, zidovudine plus lamivudine regimens, respectively. Kaplan–Meier analysis (Fig. 1) suggests that the virological response and differences in response continue through 4 years. Therapeutic response rates with a viral load less than 50 copies/ml at 168 weeks were 43% in the efavirenz, zidovudine plus lamivudine group compared with 23% in the indinavir, zidovudine plus lamivudine group (P < 0.0001), difference estimate; 97.5% CI 19.5; 12.2, 26.8, and 31% in the efavirenz plus indinavir group (P = 0.0082), difference estimate; 97.5% CI 8.1; 1.2, 15.0. For the VROC efficacy analysis at 168 weeks, virological response rates (viral load < 400 copies/ml) were 95% (efavirenz, zidovudine plus lamivudine), 95% (efavirenz plus indinavir), and 91% (indinavir, zidovudine plus lamivudine). Using a criterion of viral load of less than 50 cells/ml, the VROC response rates were 91% in the efavirenz, zidovudine plus lamivudine group compared with 81% in the indinavir, zidovudine plus lamivudine group (P = 0.0053, difference estimate; 97.5% CI 10.1; 2.0, 18.2, and 87% in the efavirenz plus indinavir group (P = 0.11, difference estimate; 97.5% CI 6.6; −2.6, 15.7.
Mean HIV-RNA plasma levels declined rapidly from baseline by −2.95, −2.76 and −2.67 log10 copies/ml within the first 16 weeks of therapy and this reduction in viral load was sustained, with mean decreases of −3.07, −2.98 and −2.88 log10 copies/ml at week 168 in the efavirenz, zidovudine plus lamivudine, efavirenz plus indinavir and indinavir, zidovudine plus lamivudine groups, respectively. Higher baseline plasma HIV-RNA levels significantly diminished the virological response rate of patients in the two indinavir-containing regimens, but did not effect antiviral activity in those who received efavirenz, zidovudine plus lamivudine. Maximal viral suppression (viral load < 50 copies/ml) at week 168 for patients with baseline viral loads less than 100 000 copies/ml was 44% in the efavirenz, zidovudine plus lamivudine group, 38% in the efavirenz plus indinavir group, and 25% in the indinavir, zidovudine plus lamivudine group. For those patients with baseline viral loads between 100 000 and 300 000 copies/ml, maximal viral suppression was 38, 26 and 20%, and for those with baseline viral loads greater than 300 000 copies/ml, virological response rates were 46, 9 and 19%, respectively. At week 168, the median CD4 cell counts (cells/μl) were 636 (efavirenz, zidovudine plus lamivudine), 647 (efavirenz plus indinavir), and 593 (indinavir, zidovudine plus lamivudine).
The incidence, frequency, and severity of adverse events were consistent with those established for the study drugs. Treatment-related adverse events (TRAE), grade 2–4, which occurred with 5% or greater frequency in any regimen are shown in Table 1. Patients receiving indinavir, zidovudine plus lamivudine reported the highest percentage (34%) of grade 3/4 TRAE compared with 24 and 22% in the efavirenz, zidovudine plus lamivudine and efavirenz plus indinavir groups, respectively. The most common TRAE (all grades) in the indinavir, zidovudine plus lamivudine patients were hyperbilirubinemia (17%), nausea (54%), fatigue (22%), vomiting (24%), diarrhoea (18%), and renal calculus (5%); in the efavirenz, zidovudine plus lamivudine group, nausea (31%), dizziness (30%), diarrhoea and vomiting (15%), and granulocytopenia (5%). The incidence of treatment-related neurological symptoms (grade 2 or higher) within the first 24 weeks of therapy was highest in patients receiving efavirenz (> 50%), as was maculopapular rash. After 24 weeks, the incidence of these symptoms was comparable in all groups. Symptoms were usually transient and not treatment limiting. One or more treatment-related psychiatric symptoms (aggressive reaction, suicide attempt, manic reaction, paranoid reaction, psychosis, grade 3/4 depression) were reported in 8% of efavirenz, zidovudine plus lamivudine patients, 5% of efavirenz plus indinavir patients and 3% of indinavir, zidovudine plus lamivudine patients. Grade 3/4 depression occurred in 4% of patients taking efavirenz, zidovudine plus lamivudine. New-onset grade 3 (more than five times the upper limit of normal) transaminase elevations occurred in 5–8% of patients among all groups. Patients who were co-infected with hepatitis B or C and treated with efavirenz (n = 137) experienced more grade 3/4 transaminase abnormalities than their hepatitis co-infected counterparts (n = 84) treated with indinavir, zidovudine plus lamivudine. The higher risk of liver enzyme abnormalities in the co-infected efavirenz-treated patients did not translate into more frequent discontinuations as a result of hepatic and biliary system disorders. Hepatitis co-infected patients with abnormal liver enzymes at baseline appeared to be more likely to experience grade 3/4 transaminase and gamma glutamyltransferase abnormalities than patients with normal liver enzymes. Lipodystrophy was not systematically assessed, but was reported as an adverse event in 3, 4 and 5% of patients treated with efavirenz, zidovudine plus lamivudine, efavirenz plus indinavir and indinavir, zidovudine plus lamivudine, respectively. Other lipodystrophy-associated adverse events occurred in 2% or fewer of patients in all regimens, except obesity, which occurred in 3% of patients in both efavirenz-containing regimens and 4% of patients in the indinavir, zidovudine plus lamivudine regimen. Sixteen deaths were reported during the study, of which one in the indinavir, zidovudine plus lamivudine group was considered to be possibly related to study treatment (hepatic failure).
As previously reported, a regimen of efavirenz, zidovudine plus lamivudine was more effective and better tolerated than an indinavir, zidovudine plus lamivudine regimen after 48 weeks of therapy . The 168-week follow-up results presented in this report demonstrate that the superior antiretroviral activity and tolerability of an efavirenz, zidovudine plus lamivudine regimen compared with a regimen of indinavir, zidovudine plus lamivudine are sustained for more than 3 years of therapy. The efavirenz plus indinavir regimen also produced more effective viral suppression than indinavir, zidovudine plus lamivudine, but because dual therapy is not currently clinically recommended, discussion will be limited to comparisons between efavirenz and indinavir triple therapies. Higher virological response rates were observed in the efavirenz, zidovudine plus lamivudine group at all time points from weeks 2 to 168. Furthermore, the greater maximal viral suppression produced by efavirenz, zidovudine plus lamivudine (viral load < 50 copies/ml), was not compromised by a higher initial baseline viral load as was observed in patients treated with indinavir, zidovudine plus lamivudine. The superiority of efavirenz, zidovudine plus lamivudine over indinavir, zidovudine plus lamivudine may be related to a combination of: (i) better tolerability, as demonstrated by the fewer discontinuations as a result of adverse events; (ii) improved antiviral durability, as suggested by the lower virological failure rate in the primary ITT analysis; and (iii) higher rate of virological response at a viral load of less than 50 HIV-RNA copies/ml (VROC analysis). Other studies have corroborated the efficacy of combination antiviral therapy regimens as first-line therapies for HIV infection [7–11], and recent data suggest that efavirenz, zidovudine plus lamivudine produces better virological results than a regimen of three nucleoside reverse-transcriptase inhibitors . These long-term results demonstrate that initial HAART therapy with efavirenz, zidovudine plus lamivudine in previously untreated or NRTI-only treated HIV-infected patients produces significantly greater viral suppression and tolerability than an indinavir-containing regimen, which are maintained for more than 3 years of treatment.
The authors gratefully acknowledge the individuals with HIV infection who volunteered for this study, and the institutions and investigators who participated in Study 006. Stacey Shehin, PhD i3 Statprobe (Ann Arbor, Michigan, USA) provided assistance in preparing and editing the manuscript.
Sponsorship: This study was sponsored by DuPont Pharmaceuticals Company, now Bristol-Myers Squibb.
Conflicts of interest: None.
1. Hammer SM, Squires KE, Hughes MD, Grimes JM, Demeter LM, Currier JS, et al
. A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. N Engl J Med 1997; 337:725–733.
2. Murphy EL, Collier AC, Kalish LA, Assmann SF, Para MF, Flanigan TP, et al
. Highly active antiretroviral therapy decreases mortality and morbidity in patients with advanced HIV disease. Ann Intern Med 2001; 135:17–26.
3. Van Sighem AI, Van De Wiel MA, Ghani AC, Jambroes M, Reiss P, Gyssens IC, et al
. Mortality and progression to AIDS after starting highly active antiretroviral therapy. AIDS 2003; 17:2227–2236.
4. Palella FJ Jr, Delaney KM, Moorman AC, Loveless MO, Fuhrer J, Satten GA, et al
. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. N Engl J Med 1998; 338:853–860.
6. Staszewski S, Morales-Ramirez J, Tashima KT, Rachlis A, Skiest D, Stanford J, et al
. Efavirenz plus zidovudine and lamivudine, efavirenz plus indinavir, and indinavir plus zidovudine and lamivudine in the treatment of HIV-1 infection in adults. N Engl J Med 1999; 341:1865–1873.
7. Robbins GK, De Gruttola V, Shafer RW, Smeaton LM, Snyder SW, Pettinelli C, et al
. Comparison of sequential three-drug regimens as initial therapy for HIV-1 infection. N Engl J Med 2003; 349:2293–2303.
8. Gulick RM, Meibohm A, Havlir D, Eron JJ, Mosley A, Chodakewitz JA, et al
. Six-year follow-up of HIV-1-infected adults in a clinical trial of antiretroviral therapy with indinavir, zidovudine, and lamivudine. AIDS 2003; 17:2345–2349.
9. Hicks C, King MS, Gulick RM, White AC Jr, Eron JJ Jr, Kessler HA, et al
. Long-term safety and durable antiretroviral activity of lopinavir/ritonavir in treatment-naive patients: 4 year follow-up study. AIDS 2004; 18:775–779.
10. Gallant JE, Staszewski S, Pozniak AL, DeJesus E, Suleiman JMAH, Miller MD, et al
. Efficacy and safety of tenofovir DF vs stavudine in combination therapy in antiretroviral-naive patients: a 3-year randomized trial. JAMA 2004; 292:191–201.
11. Shafer RW, Smeaton LM, Robbins GK, De Gruttola V, Snyder SW, D'Aquila RT, et al
. Comparison of four-drug regimens and pairs of sequential three-drug regimens as initial therapy for HIV-1 infection. N Engl J Med 2003; 349:2304–2315.
12. Gulick RM, Ribaudo HJ, Shikuma CM, Lustgarten S, Squires KE, Meyer WA III, et al
. Triple-nucleoside regimens versus efavirenz-containing regimens for the initial treatment of HIV-1 infection. N Engl J Med 2004; 350:1850–1861.
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