Comparison of Sequential Three-Drug Regimens as Initial Therapy for HIV-1 Infection: AZT/3TC vs d4T/ddI and nelfinavir vs efavirenz
New England Journal of Medicine, Volume 349:2293-2303 December 11, 2003 Number 24
Gregory K. Robbins, M.D., M.P.H., Victor De Gruttola, Sc.D., Robert W. Shafer, M.D., Laura M. Smeaton, M.S., Sally W. Snyder, B.S., Carla Pettinelli, M.D., Ph.D., Michael P. Dubé, M.D., Margaret A. Fischl, M.D., Richard B. Pollard, M.D., Robert Delapenha, M.D., Linda Gedeon, B.S., Charles van der Horst, M.D., Robert L. Murphy, M.D., Mark I. Becker, Pharm.D., Richard T. D'Aquila, M.D., Stefano Vella, M.D., Thomas C. Merigan, M.D., Martin S. Hirsch, M.D., for the AIDS Clinical Trials Group 384 Team
The results of this study have been presented at conferences previously. These results are the final published version, so much of the information is already known. The study compared starting HAART with 4 different regimens. The study authors concluded that patients starting with AZT/3TC/EFV were least likely to experience treatment failure after their first regimen and their second regimen compared to the other regimens used in this study. It’s important to bear in mind that the study conclusions are based on the drugs & regimens included in the study. Patients received either AZT/3TC or d4T/ddI nuke-based regimens and efavirenz or nelfinavir based regimens. The study is a bit complicated. Below you’ll find the data from this comparison. Following is the abstract/summary results of this study which compared a 4-drug regimen to starting with a 3 drug regimen, again using the study drugs mentioned above. And these reports are followed by an Editorial in the NEJM regarding the study results.
“...Subjects who initially received didanosine and stavudine had substantially more toxic effects than those who initially received zidovudine and lamivudine, particularly with respect to peripheral neuropathy. Given these results and those of earlier suggestive studies, the combination of didanosine and stavudine should probably no longer be considered for use as part of an initial antiretroviral regimen. Since the risk of a first serious toxic effect decreased over time in the groups that initially received didanosine and stavudine, the implications are less clear for persons who are currently tolerating this combination and have satisfactory viral suppression.... zidovudine, lamivudine, and efavirenz are still being explored, this combination provided greater antiretroviral potency than the other combinations tested and resulted in a lower rate of failure with genotypic resistance to each class of anti-HIV drugs…
Our results demonstrate the benefit of the combination of zidovudine, lamivudine, and efavirenz over the other three-drug combinations we studied. Furthermore, this benefit was apparent even within the subgroup of subjects who had HIV-1 RNA levels above 5.0 log10 (100,000 copies/ml) copies per milliliter at screening.
The AIDS Clinical Trials Group (ACTG) study 384 was a multicenter trial conducted in the United States and Italy that randomly assigned subjects to six treatment groups. The trial had three primary objectives: to compare the initiation of therapy with an antiretroviral regimen including efavirenz with initiation with a regimen including nelfinavir (both in combination with two nucleoside reverse-transcriptase inhibitors); to compare the initiation of therapy with an antiretroviral regimen including zidovudine and lamivudine with initiation with a regimen including stavudine and didanosine (in combination with either nelfinavir or efavirenz); and to compare the use of a four-drug regimen including two nucleoside analogues, efavirenz, and nelfinavir with the use of two sequential three-drug regimens.
Our study was designed to provide a minimum of two years of follow-up, and the primary end point was the failure of two successive regimens, as a result of inadequate viral suppression or toxic effects, or the premature discontinuation of study medications. This end point was chosen for the comparison of different strategies for the sequencing of antiretroviral drugs because it reflects the clinical goal of retaining patients in follow-up and keeping them under continuous treatment with tolerable and effective antiretroviral regimens. Secondary analyses included those of the failure of the initial regimen as assessed on the basis of virologic or toxicity-related criteria; the first and second virologic failures irrespective of treatment status; and the time to viral suppression.
Patients were initially randomized to 1 of 4 HAART regimens for firstline therapy in the part of this complicated study, which compares patient response to 1 of 4 three-drug HAART regimens. After failing the first regimen patients were reassigned to a second regimen, which was 1 of the other of the 4 regimens used in this study. Patients initially received either:
--AZT/3TC & efavirenz
--d4T/ddI & efavirenz
--AZT/3TC & nelfinavir
--d4T/ddI & nelfinavir
The researchers evaluated response to therapy by how many patients in each HAART regimen had premature discontinuation, virologic failure or toxicity related failure.
Criteria for failure of regimen was virologic failure
--decrease by less than a factor of ten in HIV RNA level by week 8
--increase by a factor of more than 10 above nadir measurement (and >2000 copies/ml within 24 weeks)
--HIV RNA level above200 copies/ml in a patient with 2 previous measurements of less than 200 copies/ml, or at any time after wk 24
FAILURES OF FIRST REGIMEN: virologic & toxicity-related
You can see that AZT/3TC+efavirenz had the least failures (virologic+toxicity): 31 vs 69, 77, and 66 for other 3 regimens. The AZT/3TC regimens had less toxicity-related failures than the d4T/ddI regimens: 11 or 3 vs 20 or 19. The efavirenz regimens had less virologic failures than the nelfinavir regimens: 49 vs 58, and 20 vs 63.
26 premature discontinuations
49 virologic failures
20 toxicity-related failures
TOTAL 69 virologic and toxicity-related failures
29 premature discontinuations
58 virologic failures
19 toxicity-related failures
TOTAL 77 virologic and toxicity-related failures
30 premature discontinuations
20 virologic failuees
11 toxicity related failures
TOTAL 31 virologic & toxicity related failures
25 premature discontinuations
63 virologic failures
3 toxicity related failures
TOTAL 66 virologic & toxicity related failures
After failing the first regimen patients received a second regimen (1 of the 4 used in study). The results were similar as seen above. These results were the PRIMARY STUDY ENDPOINT. If they were taking AZT/3TC patients were switched to a d4T/ddI regimen; if they were initially taking d4T/ddI they were switched to AZT/3TC. If they were taking a nelfinavir regimen they were switched to a efavirenz regimen. If they were initially assigned to an efavirenz regimen they were switched to a nelfinavir regimen.
Patients who started on & switched after failure from ddI/d4T/EFV to AZT/3TC/NFV (n=56):
13 premature discontinuations before starting second regimen
8 premature discontinuations after starting second regimen
28 virologic failures
1 toxicity-related failure
TOTAL 76 virologic or toxicity-related failures or premature discontinuation
Patients who started on & switched after failure from ddI/d4T/NFV to AZT/3TC/EFV (n=64):
12 premature disct before starting 2nd regimen
9 premature discontinuations after starting 2nd regimen
15 virologic failures
1 toxicity related failure
TOTAL 66 virologic or toxicity-related failures or premature discontinuation
Patients who started on & switched after failure from AZT/3TC/EFV to ddI/d4T/NFV (n=19):
12 premature disct before starting 2nd regimen
4 premature discontinuations after starting second regimen
10 virologic failures
0 toxicity-related failures
TOTAL 56 virologic or toxicity associated failures or premature discontinuation
Patients who started on & switched after failure from AZT/3TC/NFV to ddI/d4T/EFV (n=46):
16 premature disct before starting 2nd regimen
8 premature discontinuations after starting 2nd regimen
22 virologic failures
3 toxicity-related failures
TOTAL 74 virologic or toxicity-related failure or premature discontinuation
The study authors concluded, based on the Primary Study Endpoint, that patients starting with AZT/3TC/EFV were least likely to experience treatment failure after their first regimen and their second regimen (56 vs 76, 66, or 74).
There was a significant difference among the four groups in the time to the first serious toxic effect (an effect of grade 3 or worse or necessitating a modification of the regimen or the dose; P<0.001 for the four-way comparison). The initial use of regimens containing zidovudine and lamivudine delayed the occurrence of the first serious toxic effect, as compared with regimens containing didanosine and stavudine (P<0.001) and delayed the occurrence of the first symptom or diagnosis of peripheral neuropathy (P<0.001).
Background: The optimal sequencing of antiretroviral regimens for the treatment of infection with human immunodeficiency virus type 1 (HIV-1) is unknown. We compared several different antiretroviral treatment strategies.
Methods: This multicenter, randomized, partially double-blind trial used a factorial design to compare pairs of sequential three-drug regimens, starting with a regimen including zidovudine and lamivudine or a regimen including didanosine and stavudine in combination with either nelfinavir or efavirenz. The primary end point was the length of time to the failure of the second three-drug regimen.
Results: A total of 620 subjects who had not previously received antiretroviral therapy were followed for a median of 2.3 years. Starting with a three-drug regimen containing efavirenz combined with zidovudine and lamivudine (but not efavirenz combined with didanosine and stavudine) appeared to delay the failure of the second regimen, as compared with starting with a regimen containing nelfinavir (hazard ratio for failure of the second regimen, 0.71; 95 percent confidence interval, 0.48 to 1.06), as well as to delay the second virologic failure (hazard ratio, 0.56; 95 percent confidence interval, 0.29 to 1.09), and significantly delayed the failure of the first regimen (hazard ratio, 0.39) and the first virologic failure (hazard ratio, 0.34). Starting with zidovudine and lamivudine combined with efavirenz (but not zidovudine and lamivudine combined with nelfinavir) appeared to delay the failure of the second regimen, as compared with starting with didanosine and stavudine (hazard ratio, 0.68), and significantly delayed both the first and the second virologic failures (hazard ratio for the first virologic failure, 0.39; hazard ratio for the second virologic failure, 0.47), as well as the failure of the first regimen (hazard ratio, 0.35). The initial use of zidovudine, lamivudine, and efavirenz resulted in a shorter time to viral suppression.
Conclusions The efficacy of antiretroviral drugs depends on how they are combined. The combination of zidovudine, lamivudine, and efavirenz is superior to the other antiretroviral regimens used as initial therapy in this study.
Comparison of Four-Drug Regimens and Pairs of Sequential Three-Drug Regimens as Initial Therapy for HIV-1 Infection
Robert W. Shafer, M.D., Laura M. Smeaton, M.S., Gregory K. Robbins, M.D., M.P.H., Victor De Gruttola, Sc.D., Sally W. Snyder, B.S., Richard T. D'Aquila, M.D., Victoria A. Johnson, M.D., Gene D. Morse, Pharm.D., Mostafa A. Nokta, M.D., Ana I. Martinez, R.Ph., Barbara M. Gripshover, M.D., Pamposh Kaul, M.D., Richard Haubrich, M.D., Mary Swingle, R.N., S. Debra McCarty, B.S., Stefano Vella, M.D., Martin S. Hirsch, M.D., Thomas C. Merigan, M.D., for the AIDS Clinical Trials Group 384 Team
Background- It is unclear whether therapy for human immunodeficiency virus type 1 (HIV-1) should be initiated with a four-drug or two sequential three-drug regimens.
Methods- In this multicenter trial we compared initial therapy involving four-drug regimens containing efavirenz and nelfinavir in combination with either didanosine and stavudine or zidovudine and lamivudine with therapy involving two consecutive three-drug regimens the first of which contained either efavirenz or nelfinavir.
Results- A total of 980 subjects were followed for a median of 2.3 years. There was no significant difference in the occurrence of regimen failures between the group that received the four-drug regimen containing didanosine, stavudine, nelfinavir, and efavirenz and the groups that received the three-drug regimens beginning with didanosine, stavudine, and nelfinavir (hazard ratio for regimen failure, 1.24) or didanosine, stavudine, and efavirenz (hazard ratio, 1.01). There was no significant difference between the group that received the four-drug regimen containing zidovudine, lamivudine, nelfinavir, and efavirenz and the groups that received the three-drug regimens beginning with zidovudine, lamivudine, and nelfinavir (hazard ratio, 1.06) or zidovudine, lamivudine, and efavirenz (hazard ratio, 1.45). A four-drug regimen was associated with a longer time to the first regimen failure than the three-drug regimens containing didanosine, stavudine, and nelfinavir (hazard ratio for a first regimen failure, 0.55); didanosine, stavudine, and efavirenz (hazard ratio, 0.63); or zidovudine, lamivudine, and nelfinavir (hazard ratio, 0.49), but not the three-drug regimen containing zidovudine, lamivudine, and efavirenz (hazard ratio, 1.21).
Conclusions- There was no significant difference in the duration of successful HIV-1 treatment between a single four-drug regimen and two consecutive three-drug regimens. Among these treatment strategies, initiating therapy with the three-drug regimen of zidovudine, lamivudine, and efavirenz is the optimal choice.
EDITORIAL in NEJM
HIV Therapy — What Do We Know, and When Do We Know It?
Paul R. Skolnik, M.D.
Center for HIV/AIDS Care and Research, Boston University Medical Center, Boston University School of Medicine, Boston.
The studies by Robbins et al.1 and Shafer et al.,2 reported in this issue of the Journal, used a complicated factorial design, but the basic conclusions are straightforward. There are currently 20 agents that have been approved by the Food and Drug Administration for the treatment of HIV infection. We have learned that potent combination therapies are the most efficacious and durable approaches to the use of these agents. The study by Robbins et al. tells us that one of these combinations — zidovudine, lamivudine, and efavirenz — is a particularly good choice with which to begin therapy for patients with previously untreated HIV infection.
Perhaps just as important, these studies provide firm data from prospective clinical trials that confirm what many have recently suspected: that the combination of stavudine and didanosine should not be used for the initial treatment of HIV infection, if other choices exist, because of unacceptably high rates of adverse effects.
Beyond these lessons, the current reports raise several important issues about study design that may alter future practice. First, the definition of what constitutes the failure of a regimen is an important consideration. This issue mirrors clinical practice, in that treatment goals differ during different stages of this chronic viral infection, for which a "cure" will elude us unless new pathogenic and treatment paradigms are discovered. If sequential therapies are needed, perhaps the overall outcome, not the effects of the initial regimen alone, should be used as an end point. If adverse effects, or events other than strict virologic failure, result in the failure of a regimen, then perhaps this end point should be included in the assessment to mirror clinical practice accurately. Although one may take issue with the exact parameters used to define "premature discontinuation" of therapy, the current studies attempt to use this reasonable assumption in the study design. (Editorial note from Jules Levin: I’m not sure I agree. Selection of a very good first regimen can be the only regimen a patient will need to take if it’s potent and the patient can be fully adherent over time).
In drawing conclusions, it is always important not to generalize beyond the conclusions justified by the data. For example, although some may be tempted to use the current data to support the notion that an initial treatment regimen consisting of two nucleoside reverse-transcriptase inhibitors (such as zidovudine and lamivudine) combined with a nonnucleoside reverse-transcriptase inhibitor (such as efavirenz) is superior to a regimen of two nucleoside reverse-transcriptase inhibitors combined with a protease inhibitor, this conclusion would be a mistake. Several lines of evidence suggest that nelfinavir, which was tested in the current studies, may be less effective than other protease inhibitors for the initiation of HIV treatment. Newer strategies that make use of the pharmacologic actions of ritonavir on the hepatic P-450 system to "boost" plasma levels of coadministered protease inhibitors, or that use new, more potent protease inhibitors, may well constitute important options for initial treatment in combination with other agents.
Might regimens consisting of four drugs be even better? For the particular drugs studied here, the answer is probably no. Again, definitions of success and failure are paramount. In the study by Shafer et al., with respect to the end points defined, there was no advantage to the four-drug regimens; however, the data concerning viral resistance are provocative. The four-drug regimens resulted in fewer mutations that rendered the circulating HIV quasispecies resistant to currently available drugs than all three-drug regimens (except that consisting of zidovudine, lamivudine, and efavirenz — another indication of the potency of this regimen). Since, for patients in whom initial therapy fails, drug resistance is often the primary difficulty in devising subsequent drug regimens, this advantage might be an important one. Future studies should include analyses of this possibility to determine the efficacy of regimens based on a potent, boosted protease inhibitor or, if tolerable, a more complex initial regimen.
Determining what constitutes the best choice for initial therapy is a balancing act, and adherence is another factor that must be considered. Can and will the patient take the prescribed treatment reliably? Clinical trials are particularly ill-suited to answer this question because study populations often do not reflect the populations of patients that doctors see in the clinic. The high rates of failure documented in several large urban clinics around the world bear witness to this phenomenon.8 Some general principles are clear: adherence is usually better with twice-daily regimens than with those that include a midday dose, and certain side effects result in unacceptably low levels of adherence, but much remains to be learned. Perhaps, for individual patients, the exact balance of risks and benefits — namely, the chance for long-term viral suppression, the risk of certain side effects, the possibility of induction of drug resistance, and the ability to adhere to a particular regimen — is best addressed by open discussions between care providers and their patients.