February 28, 2007
The first antiretroviral regimen an HIV-infected patient receives may be the most crucial for stifling viral replication and thwarting the emergence of drug-resistant variants that can undermine treatment success. To that end, it is critical for the clinician to devise a potent regimen to which the patient will adhere. With more than 29 approved formulations of antiretroviral agents now available in the United States, there are a seemingly limitless number of three-drug regimens for first-line treatment. However, many combinations have never been assessed in clinical studies and only a handful have been named as "preferred" in the U.S. Department of Health and Human Services (DHHS) treatment guidelines.1
Several studies presented at the 14th Conference on Retroviruses and Opportunistic Infections (CROI 2007), held from Feb. 25-28, 2007, in Los Angeles, Calif., evaluated the efficacy of understudied once-daily regimens in treatment-naive individuals. Whereas some of these regimens proved to be effective, others were found to have suboptimal potency -- a lesson that all clinicians should take to heart when administering an understudied or unstudied first-line regimen.
When administering a new regimen the clinician may want to keep in mind that, according to one study presented at CROI 2007, it may be possible to predict the patient's response to a new treatment combination based on the initial viral decay observed shortly after therapy initiation.2 Additional important studies presented at CROI 2007 assessed the prevalence of primary drug resistance among treatment-naive individuals and determined the clinical impact of these mutations on treatment success.
There were several interesting presentations at CROI 2007 dealing with relatively understudied, once-daily, first-line regimens. The first study I will discuss demonstrated the efficacy of an all once-daily regimen of didanosine (ddI, Videx), given with food, along with lamivudine (3TC, Epivir) and efavirenz (EFV, Sustiva, Stocrin) in treatment-naive individuals. In contrast, the second study mentioned below raised concerns regarding early virologic failure in those treated with an all once-daily regimen of tenofovir (TDF, Viread) + lamivudine + nevirapine (NVP, Viramune). Finally, the third study that I will discuss showed that although there was equivalent efficacy between once-daily and twice-daily lopinavir/ritonavir (LPV/r, Kaletra) soft-gel capsules (SGC) in treatment-naive individuals, this was found to be true only among patients with low baseline viral loads.
Once-Daily Didanosine + Lamivudine + Efavirenz
Juan Berenguer and colleagues reported the results from a planned 24-week interim analysis of the GESIDA 39/03 Study, a prospective, randomized, open-label noninferiority trial in Spain of the combination of didanosine + lamivudine + efavirenz, all given once daily and with food, versus twice-daily zidovudine/lamivudine (AZT/3TC, Combivir) + efavirenz.3 Although the pharmacokinetic data for didanosine capsules are favorable when the capsules are given with food, didanosine capsules have been primarily studied in patients who have taken them on an empty stomach, and consequently it is still recommended that they be taken in this way. The current study attempted to simplify the regimen by giving it once daily with food.
There were 369 patients enrolled and included in this interim analysis. Both study groups were similar with regard to baseline characteristics: The median plasma viral load was 100,000 copies/mL and the median CD4+ cell count was about 210 cells/mm3 for both groups. The outcomes at 24 weeks are summarized in the table below.
Overall, treatment discontinuation due to adverse events was somewhat more common in the zidovudine/lamivudine + efavirenz arm, but no difference was found between the two arms with regards to the proportion of patients who achieved plasma HIV-1 RNA levels below 50 or 400 copies/mL. There was a greater median increase in CD4+ cell counts in those treated with didanosine + lamivudine + efavirenz than in patients receiving the other regimen.
|Table 1. Outcome at 24 Weeks in GESIDA 39/03|
|Outcome||AZT/3TC + EFV||ddI + 3TC + EFV||P Value|
|Study discontinuations, n (%)||39 (21.3)||25 (13.4)||.03|
|• Lost to follow-up||7 (3.8)||5 (2.7)||.37|
|• Adverse events||22 (12.0)||11 (5.9)||.03|
|HIV-1 RNA < 400 copies/mL*, %||72.7||77.8||.16|
|HIV-1 RNA < 50 copies/mL*, %||65.9||71.0||.18|
|Median CD4+ cell count increase, cells/mm3||110||128||.03|
|* Intent-to-treat, missing = failure analysis.|
Although preliminary, these results suggest that didanosine + lamivudine given once daily with food may be a viable nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) backbone for an efavirenz-based regimen in treatment-naive individuals. Nevertheless, further follow-up on these results is needed before this combination, and particularly the use of didanosine with food, can be routinely recommended.
Once-Daily Tenofovir + Lamivudine + Nevirapine
In contrast to the promising results seen in the Spanish GESIDA 39/03 Study, David Rey and colleagues reported the results of the DAUFIN Study in France, which was prematurely terminated, because of an unexpectedly high rate of virologic failure.4
The DAUFIN Study was a randomized, open-label, multicenter noninferiority trial comparing tenofovir + lamivudine + nevirapine, all given once daily, with zidovudine/lamivudine + nevirapine, all given twice daily. The study was to enroll approximately 250 patients, but was stopped due to a high failure rate in the once-daily arm.
A total of 71 patients were randomized, with virologic failure occurring in nine out of 36 (25%) of the patients in the once-daily arm compared with one out of 35 (3%) in the twice-daily comparator group.
Particularly alarming was the fact that patients who failed were found to harbor highly drug-resistant virus (Table 2), despite the fact that baseline resistance was only found in one of eight individuals and all had adequate nevirapine exposure levels.
|Table 2. Mutations That Emerged in Those With Early Virologic Failure on Once-Daily TDF + 3TC + NVP|
The reason for failure in these individuals is unknown given that there is considerable clinical trial data with once-daily lamivudine and nevirapine, but not when combined together or with tenofovir. Until more information becomes available, this study should serve as a reminder to clinicians that the use of untested regimens in clinical practice should be undertaken with great caution.
Once-Daily Lopinavir/Ritonavir SGC
Lopinavir/ritonavir has been designated a preferred protease inhibitor (PI) in the U.S. treatment guidelines for many years, because of its potency and high genetic barrier to resistance.1 Recent studies have demonstrated that once-daily administration of the SGC formulation of lopinavir/ritonavir in treatment-naive individuals achieves drug levels and efficacy equivalent to that seen when lopinavir/ritonavir is used twice daily.5
However, in previous studies, patients who were treated with once-daily therapy did experience considerably more diarrhea than those given twice-daily lopinavir/ritonavir. Since the first once-daily lopinavir/ritonavir studies were performed, a new tablet formulation of lopinavir/ritonavir has become available that reduces pill burden and hopefully also decreases the incidence of diarrhea, although these data are still being collected.
Mildvan and colleagues presented the results of the AIDS Clinical Trials Group (ACTG) Study 5073 at CROI 2007.6 Like the two studies previously discussed, this study also assessed a once-daily treatment regimen for treatment-naive individuals, but with the possibility of employing directly observed therapy (DOT) to enhance patient adherence to treatment.
ACTG 5073 enrolled treatment-naive individuals who were given either daily extended-release stavudine (d4T, Zerit; 100 mg) or daily tenofovir (300 mg) with once-daily emtricitabine (FTC, Emtriva; 200 mg). Study participants were then randomized 2:2:1 to the SGC formulation of lopinavir/ritonavir administered as:
Approximately 400 patients were enrolled in A5073 and stratified by plasma HIV-1 RNA greater than or less than 100,000 copies/mL. The baseline characteristics included a median plasma HIV-1 RNA of 4.8 log10 copies/mL for each group and a median CD4+ cell count of 194 cells/mm3 for the twice-daily self-administered group, 218 cells/mm3 for the once-daily self-administered group and 137 cells/mm3 for the once-daily DOT group. The primary endpoints were the proportion of individuals with sustained virologic suppression at 48 weeks between the once-daily and twice-daily self-administered groups and at 24 weeks between the once-daily self-administered and DOT groups.
No difference in virologic suppression was seen between the once-daily and twice-daily self-administered groups at 48 weeks, with the difference being 0.03 (95% confidence interval [CI] = -0.07 to 0.12).
However, there was a difference noted by screening plasma HIV-1 RNA (P = .038). When comparing individuals with screening plasma HIV-1 RNA levels less than 100,000 copies/mL in the once-daily and twice-daily self-administered groups, there was no significant difference found (difference = -0.08; 95% CI = -0.23 to 0.06). In contrast, when comparing outcomes between these arms for patients with plasma HIV-1 RNA levels greater than 100,000 copies/mL, there was a significant difference favoring twice-daily dosing (difference = 0.13; 95% CI = 0.01 to 0.25). There was no difference in the sustained virologic response rate at 24 weeks among those given once-daily self-administered therapy versus DOT. In addition, no differences were seen across study groups in the frequency of grade 3/4 adverse events.
Similar to a previous study of lopinavir/ritonavir SGC, A5073 showed equivalent efficacy overall between once-daily and twice-daily lopinavir/ritonavir SGC in treatment-naive individuals. However, unlike the previous study with once-daily lopinavir/ritonavir, there was a difference in efficacy seen in A5073 in patients with higher baseline viral loads that favored twice-daily over once-daily therapy. The reason for the difference between the studies is not known, although this study did include a larger number of individuals in the high viral load group.
Consequently, until more data are available, these findings must be considered when discussing treatment options with a given patient. Finally, no difference was seen between those given self-administered therapy versus DOT. An important caveat for the latter conclusion is that patients who enroll into clinical trials are unique, and there may be select groups or individuals who are at high risk for nonadherence and who may benefit from the DOT strategy.
As more agents to treat HIV become available, the number of different antiretroviral combinations for managing treatment-naive individuals becomes enormous. Because of this, there will never be a comprehensive set of large, randomized, controlled trials comparing all possible regimens. Without such data, however, clinicians must be extremely cautious in order to avoid initiating regimens that may have inferior efficacy.
One proposed strategy for assessing the efficacy of novel drug combinations is to define the relationship between the initial viral declines on treatment to long-term outcomes. Richard Haubrich and colleagues attempted to address this issue using data from a substudy of ACTG 5142 called A5160s, along with the complete data from the parent study. The primary efficacy results of A5142 were previously presented at the XVI International AIDS Conference in Toronto, Canada.7
A5142 enrolled approximately 750 individuals into one of three arms: two NRTIs + lopinavir/ritonavir, two NRTIs + efavirenz or lopinavir/ritonavir + efavirenz. Although the efficacy results for patients in all arms were very good, viral suppression was better in those who received efavirenz-containing therapy, and CD4+ cell count increases were greater in those who received lopinavir/ritonavir-containing regimens.
In A5160s, a subset of 68 individuals equally distributed between the study arms of A5142 underwent intensive blood draws to determine phase-1 viral decay.2 This included plasma HIV-1 RNA measurements at days 0, 2, 7, 10, 14, 28 and 56 with decay calculated for each individual. The investigators found that phase-1 decay was greater in those who received two NRTIs with efavirenz rather than with lopinavir/ritonavir (P = .03), consistent with the virologic efficacy data from the parent study.
The researchers further showed a strong correlation between the phase-1 decay rate and the change in plasma HIV-1 RNA from baseline to day 7 (r = 0.68; P < .001). With this information, they then looked at the relationship between the change in plasma HIV-1 RNA at day 7 by group and showed that it was significantly greater in those who received two NRTIs with efavirenz as opposed to lopinavir/ritonavir (P < .001). A logistic regression model was then fit to demonstrate how the change in plasma HIV-1 RNA at day 7, regardless of treatment, predicted viral suppression at weeks 24, 48 and 96 (Table 3).
|Table 3. Logistic Regression Model of Day 7 Plasma HIV-1 RNA Reduction Predicting Viral Suppression (Adjusted for Baseline Plasma HIV-1 RNA)|
|HIV RNA Outcome||Odds Ratio*||P Value|
|Week 24||(n = 526)|
|• > 200 copies/mL||0.56||.037|
|• > 50 copies/mL||0.21||< .001|
|Week 48||(n = 504)|
|• > 200 copies/mL||0.45||.005|
|• > 50 copies/mL||0.64||.036|
|Week 96||(n = 434)|
|• > 200 copies/mL||0.54||.045|
|• > 50 copies/mL||0.56||.018|
|* Per 1 log10 copies/mL plasma HIV-1 RNA reduction.|
This is one of the largest studies to validate the potential utility of phase-1 viral decay to predict long-term outcomes. Although further study is needed to confirm these findings, as well as expand them to other regimens, this work does offer a potential strategy for piloting new drug combinations.
A significant limitation of antiretroviral therapy is the emergence of drug-resistant virus. Over the last decade, there have been increasing reports of transmitted drug-resistant strains present in newly infected individuals. The prevalence of these viruses, along with preliminary data on the clinical relevance of these observations, has resulted in modifications in the DHHS treatment guidelines, which now recommend that drug resistance testing be performed in both recently infected as well as newly diagnosed, chronically infected individuals.1 At CROI 2007, there were reports that strongly support current guidelines as well as a study demonstrating that the problem may be greater than currently appreciated with routine drug resistance testing alone.
During a symposium on HIV drug resistance, Susan Little summarized data from a variety of studies as well as analyses from her own primary infection cohort in San Diego, Calif., and from participants enrolled in the Acute Infection and Early Disease Research Program (AIEDRP) cohort, a multinational natural-history cohort of persons with primary HIV-1 infection.8 She reported that although the results vary, several studies demonstrate that approximately 11% to 15% of newly infected people have evidence of drug-resistant virus. The prevalence among those newly diagnosed with chronic infection is approximately 7% to 11%. It is believed that the lower prevalence of resistance seen in those with chronic infection may be a reflection of sampling differences and/or the timing of infection. Some of the differences may also relate to the fact that transmitted resistance may be overgrown with time by wild-type virus.
Dr. Little showed data from 14 patients studied in San Diego who presented with primary drug resistance -- 10 of 14 with resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs). These individuals were followed for a median of 2.1 years off of therapy, with resistant virus remaining detectable by routine genotypic testing in 13 of 14. The time until even a mixture of wild-type and resistant virus was detectable was 103 weeks (95% CI = 49 to 216 weeks). These data support the current DHHS guidelines recommending that drug resistance testing be performed on all treatment-naive patients regardless of the duration of infection.4
Dr. Little also reported data assessing the clinical relevance of transmitted drug resistance in individuals enrolled in the AIEDRP.8 From the cohort data, she identified individuals who initiated therapy with baseline resistance to NNRTIs (n = 67), PIs (n = 18) and NRTIs (n = 25). Analyses were carried out to compare outcomes between these groups and those treated without baseline resistance. A log-rank test demonstrated a trend toward lower response rates in those with any drug resistance (P = .07) and significantly lower response rates in those with PI resistance (P = .002) or a mutation at codon 215 in reverse transcriptase (P = .03).
In contrast, there was no significant relationship between the response to treatment in those with versus without NNRTI resistance. She further demonstrated that a lack of response was most notable in those who received less than three active drugs, again emphasizing the importance of performing drug resistance testing prior to initiating therapy.
In another study, Dan Kuritzkes assessed the clinical relevance of transmitted drug resistance by analyzing data from patients enrolled into the NNRTI-containing arms of ACTG 5095, a randomized controlled trial of treatment-naive individuals receiving zidovudine/lamivudine/abacavir (AZT/3TC/ABC, Trizivir), zidovudine/lamivudine + efavirenz or zidovudine/lamivudine/abacavir + efavirenz.9
Previous reports demonstrated an inferior response to the triple-NRTI regimen and equivalent responses to the efavirenz-based arms.10,11 A cohort study of randomly sampled cases was performed that included 191 individuals who met the criteria for viral failure with consecutive plasma HIV-1 RNA levels greater than or equal to 200 copies/mL after 16 weeks of therapy along with 151 nonfailure controls. The prevalence of drug resistance to efavirenz at baseline in the viral failure cases was 8% versus only 2% in the controls.
Consistent with other studies, A5095 demonstrated that approximately 5% of individuals had evidence of drug resistance at baseline. In addition, pre-existing NNRTI-resistant viruses were more common in those who experienced virologic failure, which was not seen in those with pre-existing NRTI or PI resistance. Finally, the investigators found that the presence of efavirenz resistance was associated with a 2.27-fold increased risk of virologic failure. These findings are consistent with the observations of Little and colleagues and demonstrate the clinical relevance of transmitted drug-resistant virus.
Although the data outlined above clearly show that drug resistance testing should be performed in all treatment-naive individuals, Jeffrey Johnson from the U.S. Centers for Disease Control and Prevention showed that even this may not be enough to assure that transmitted resistant virus will not contribute to treatment failure.12
Johnson's group used real-time, allele-specific polymerase chain reaction (PCR) to detect minority resistant variants that exist below the limit of detection of standard genotype testing (~20%). One cohort analyzed included newly diagnosed, treatment-naive individuals from Los Angeles and Chicago who were studied between 2003 and 2005. The researchers found that 20% of these individuals had evidence of drug-resistant virus by standard genotype testing. However, by using real-time PCR on 205 individuals who were found to not have detectable drug-resistant virus by standard genotype testing, the investigators identified additional individuals with resistance (Table 4).
|Table 4. Drug-Resistant Mutations in Individuals Previously Shown to Harbor Wild-Type HIV by Standard Genotype Testing|
Johnson and colleagues also retrospectively analyzed individuals from the CNA30021 and CNA30024 studies, two clinical trials that randomized treatment-naive individuals to lamivudine + efavirenz and either abacavir (ABC, Ziagen) or zidovudine (AZT, Retrovir). Logistic modeling showed that having minority variants for NNRTI resistance (Y181C or K103N) or lamivudine resistance (M184V) was associated with an 11-fold greater odds of experiencing virologic failure (P = .004).
Although these data are compelling, the technology to detect low-level variants is currently not available in the clinic. Consequently, every effort should be made to perform routine genotypic drug resistance testing on all persons initiating therapy for the first time. Regardless of the outcomes of these assays, patients should be followed closely to gauge whether an adequate virologic response is being achieved. In situations where viral load declines are inadequate, follow-up resistance testing should be performed to detect the emergence of resistant viral species.
|Please note: Knowledge about HIV changes rapidly. Note the date of this summary's publication, and before treating patients or employing any therapies described in these materials, verify all information independently. If you are a patient, please consult a doctor or other medical professional before acting on any of the information presented in this summary. For a complete listing of our most recent conference coverage, click here.|