Antiretroviral Therapy Update From the 48th ICAAC/46th IDSA Annual Meeting

The combined 48th Interscience Conference on Antimicrobial Agents and Chemotherapy/46th Infectious Diseases Society of America Annual Meeting (ICAAC/IDSA) was held in Washington, DC, from October 24 to 28, 2008. This combined conference provided some significant new insights into HIV therapeutics, including new data that may affect 2 important decisions clinicians and patients must make: when to start antiretroviral therapy and what therapies should be preferentially used in antiretroviral-naive patients.

WHAT IS THE OPTIMAL TIME TO START THERAPY?
While the current International AIDS Society (IAS)-USA¹ and the Department of Health and Human Services (DHHS)² guidelines recommend starting antiretroviral therapy for HIV infection at a CD4⁺ cell count of 350/µL or lower, recent data have emerged indicating that there may be significant benefit to starting earlier, ie, at higher CD4 counts.

The North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) group, composed of 22 study cohorts of HIV-infected patients in the United States and Canada, compared the differences for all the causes of mortality between 1996 and 2006 in patients who began antiretroviral therapy within 1.5 years of their CD4⁺ cell count falling to levels between 351/µL and 500/µL (n = 2473) with those in patients who deferred therapy (n = 5901) either by beginning treatment later or by not initiating antiretroviral therapy.³

Patients were excluded if they had ever received antiretroviral therapy or had a prior AIDS-related illness, and although all patients were initially included in the analysis, a patient’s data were censored if the patient had not initiated antiretroviral therapy within 1.5 years after reaching his or her target CD4 count. As a result, the study included 2478 patients who initiated therapy at CD4⁺ cell counts at 351/µL to 500/µL (median, 421/µL) and 1220 patients who deferred therapy until their CD4⁺ cell count dropped to 350/µL or lower (median, 275/µL).

Various antiretroviral regimens were used, but significant proportions of those initiating and deferring antiretroviral therapy used either an unboosted protease inhibitor (PI) regimen (46% and 37%, respectively) or a triple-NRTI regimen (7% and 8%, respectively).

In comparison with starting therapy when the CD4⁺ cell count is between 351/µL and 500/µL, deferral of treatment until the CD4⁺ cell count is between 200/µL and 350/µL was associated with a significant increase in risk of mortality, and this was not affected by adjusting for injection drug use or hepatitis C virus infection (Table).

The increased mortality risk of approximately 42% noted in the group who deferred antiretroviral therapy until the CD4⁺ cell count fell to 350/µL or lower is important and may influence clinical practice globally. Because of the limitations of observational studies, questions remain about what threshold of proof will be necessary to change clinical guidelines; a large randomized trial is being performed to assess this issue. The strength of these data, however, in combination with other data that have demonstrated the benefits of starting antiretroviral therapy before the CD4⁺ cell count declines to 350/µL or lower may start to change clinical practice even before the results of the randomized study are reported.

SUPERIORITY OF BOOSTED DARUNAVIR TO BOOSTED LOPINAVIR IN NAIVE PATIENTS
The ARTEMIS study compared once-daily ritonavir-boosted darunavir (DRV/r) with ritonavir-boosted lopinavir (LPV/r) in treatment-naive patients. Study patients also received coformulated tenofovir/emtricitabine as the NRTI component of treatment. The 48-week study results, which were published in 2008, demonstrated that DRV/r was noninferior to LPV/r and led to the recent FDA approval of a once-daily dose of darunavir 800 mg given with ritonavir 100 mg for treatment-naive patients.⁴ Additional findings in that study were a lower incidence of diarrhea and lower triglyceride levels with DRV/r than with LPV/r.

The 96-week follow-up data from this study were presented at the joint ICAAC/IDSA meeting.⁵ As background, 689 treatment-naive patients were enrolled and randomized to receive open-label DRV/r or LPV/r. The latter could be taken either once or twice daily, depending on the approval of once-daily LPV/r dosing at the study site; overall, 75% of LPV/r-treated patients took the drug twice daily. Most patients started the study receiving LPV/r in capsule formulation, but by the end of the study, 86% had switched to the current tablet formulation.

At baseline, patients were well matched, with 30% of the study population being female and more than half being nonwhite. The median CD4⁺ cell count was around 220/µL, and 35% had an HIV RNA level greater than 100,000 copies/mL. By week 96, 17% of the DRV/r group and 23% of the LPV/r group had discontinued the study for a variety of reasons; this included 4% and 9% for adverse events in the DRV/r and LPV/r arms, respectively.

At week 96, 79% of the DRV/r-treated patients versus 71% of the LPV/r-treated patients had an HIV RNA level below 50 copies/mL. Although the study was powered to demonstrate noninferiority and did so with a difference in response of 8.4% (P < .001), these 96-week study results met the criteria for DRV/r superiority as well, with a difference in response of 8.3% (P = .012). This DRV/r advantage was seen regardless of the criteria used for assessing response and the population assessed, including when DRV/r given once daily was compared with given twice-daily LPV/r. Virological failure also was less frequent in the DRV/r arm than in the LPV/r arm (7% vs 13%, respectively). When analyses were conducted using a stratification of high or low baseline HIV RNA level, ie, above or below 100,000 copies/mL, or a CD4⁺ cell count above or below 200/µL, DRV/r suppression rates were significantly higher in those patients with a high baseline viral load and a low baseline CD4 count (Figure 1).

Figure 1.Proportion of patients who achieved an HIV RNA level below 50 copies/mL after 96 weeks of treatment with a ritonavir-boosted darunavir (DRV/r) regimen or a ritonavir-boosted lopinavir (LPV/r) regimen in the ARTEMIS study stratified by low and high baseline HIV RNA level and CD4 count. (Adapted with permission from Mills A et al. 2008.⁵)
The CD4⁺ cell count increases did not significantly differ between the 2 arms (DRV/r, +171/µL; LPV/r, +188/µL), and the adverse-event profiles between the 2 drugs were similar to those seen in the 48-week study results, namely, a greater incidence of GI side effects with LPV/r than with DRV/r (15% vs 7%, respectively) and a greater increase in triglyceride levels (median change of +56 mg/dL vs +18 mg/dL, respectively).

Overall, these results confirm that DRV/r in combination with tenofovir/emtricitabine is a highly effective and well-tolerated regimen for treatment-naive patients and validate the inclusion of DRV/r as a recommended option in the latest version of the IAS-USA and DHHS treatment guidelines.^1,2 While LPV/r has the advantage of coformulation and lower cost, DRV/r has a lower incidence of adverse effects and a higher virological suppression rate at 96 weeks. The recent approval of the 400-mg darunavir tablet, which represents a total of 4 pills daily when combined with 100 mg of ritonavir and the tenofovir/emtricitabine fixed-dose combination, offers a welcome new option for initial therapy.

COMPARISON OF RALTEGRAVIR AND EFAVIRENZ IN TREATMENT-NAIVE PATIENTS
The STARTMRK study was a phase 3, multicenter, double-blind, randomized clinical trial, in which 563 treatment-naive patients without genotypic evidence of baseline resistance were enrolled.⁶ Patients were randomized to receive either the integrase inhibitor raltegravir 400 mg twice daily or efavirenz. All patients also received a fixed-dose combination of tenofovir/emtricitabine, so the total daily dose of medications was 4 pills a day for all participants, including the raltegravir and efavirenz placebos. The primary study end point was the proportion of patients with HIV RNA levels below 50 copies/mL after 48 weeks of treatment.

At baseline, patients overall were well matched. Approximately 80% were male, and more than half were nonwhite. The mean HIV RNA level was around 100,000 copies/mL, and the mean CD4⁺ cell count was in the low 200/µL range. At study entry, 53% had an HIV RNA level at or above 100,000 copies/mL, and 47% had a CD4⁺ cell count below 200/µL. Patient disposition demonstrated low rates of study discontinuation, with 8.5% and 12.4% in the raltegravir and efavirenz arms, respectively, withdrawing from the study-a nonsignificant difference.

At week 48, 86% of the raltegravir-treated patients and 82% of those receiving efavirenz had achieved an HIV RNA level below 50 copies/mL; this 4% difference (95% confidence interval [CI], 21.9 to 10.3; P < .001) was well within the noninferiority threshold of 212% set by the study design. As noted in the phase 2 study comparing raltegravir with efavirenz, the raltegravir-treated patients had a faster decline in the number of HIV RNA copies, with a quicker time to virological response as defined by the protocol. There was also a greater CD4⁺ cell response in the raltegravir arm, with an increase of 189/µL for raltegravir and 163/µL for efavirenz (95% CI, 4 to 47).

There were 12 patients in the raltegravir-treated group in whom treatment failed. Of these, 9 underwent successful genotyping, and 5 had no drug resistance; of the 4 with resistance, all had genotypic resistance to raltegravir, with 3 having the M184V mutation-the signature mutation to emtricitabine (and lamivudine). In the efavirenz-treated group, there were 8 virological failures; out of the 6 patients with successful genotypes, 3 had efavirenz resistance, and 1 had the M184V mutation.

Using a broad definition of clinical adverse events, the study found that 90% of raltegravir-treated patients and 96% of efavirenz-treated patients had a clinical adverse event (P = .002). More important, there was also a difference in adverse events attributable to the study drugs (44% for raltegravir, 77% for efavirenz; P < .001). By week 8, CNS toxicity was more common in patients receiving efavirenz than raltegravir (17.7% vs 10.3%, respectively; P = .015), and at the end of the study, changes from baseline for total cholesterol, low-density lipoprotein cholesterol, and triglyceride levels were all lower in the raltegravir arm than in the efavirenz arm (P < .001 for each lipid parameter). The increase in high-density lipoprotein cholesterol level however was greater in the efavirenz group than in the raltegravir group (P < .001).

These results clearly show that raltegravir combined with tenofovir/emtricitabine is comparably active to efavirenz plus tenofovir/emtricitabine in treatment-naive patients and therefore is of major importance for clinical practice because, at present, the antiretroviral regimen tenofovir/emtricitabine plus efavirenz (coformulated as a single pill) is the most commonly used initial therapy. One potential limitation to this study arose from the inevitable increase in pill burden to both study arms in order to keep investigators and patients blinded to the study regimens through the use of placebo-with the efavirenz arm increasing from potentially 1 pill daily to 4 pills taken on a twice-daily basis-but this limitation is small compared with the benefits of doing a double-blind study to assess tolerability in an unbiased fashion.

Before there is widespread adoption of raltegravir for treatment-naive patients, some clinicians may wish to see longer-term safety and tolerability data; nonetheless, these excellent results and the ongoing successful use of raltegravir in treatment-experienced patients may move up the use of this agent to earlier stages in HIV treatment strategies.

MERIT STUDY REANALYSIS USING TROFILE ES
The MERIT study was presented more than a year ago.⁷ This randomized trial compared the use of either efavirenz or the CCR5-coreceptor inhibitor maraviroc with 2 NRTIs-primarily zidovudine and lamivudine-in treatment-naive patients. The results of the twice-daily maraviroc arm at week 48 were notable for being similar to those for efavirenz, although there were a higher number of virological failures in the maraviroc-treated group. Since the lower boundary of the 95% CI was slightly more than 10%, and the prespecified limit to define noninferiority was 10%, this study could not conclude that maraviroc was noninferior to efavirenz. As a result, the use of maraviroc has been targeted to treatment-experienced patients.

It is critical to note, however, that the tropism assay used in this study was the first version of the Trofile assay (Monogram Laboratories, South San Francisco, Calif), which was found to lack the sensitivity to detect low levels of dual/mixed tropic virus populations. As a result, although the MERIT study intended to enroll a population of patients who only had CCR5-tropic virus, some patients who harbored dual/mixed tropic virus were also enrolled. Recently, an improved version of this assay, the Enhanced Sensitivity Trofile assay (Trofile ES), which has a 30-fold improvement in sensitivity to detect dual/mixed tropic virus compared with the first assay, has now been introduced, and the first version is no longer commercially available.

Since the use of Trofile ES is likely to lead to the detection of the presence of CXCR4-tropic virus in more patients, the use of this assay for screening might be better in selecting a population of patients who would respond to maraviroc treatment, thereby decreasing the failures that are associated with the emergence of CXCR4-tropic virus.

In order to understand the implications of using Trofile ES in a treatment-naive population, stored samples from the screening period of the MERIT study were reanalyzed using the Trofile ES, allowing a comparison of what might have been observed if the MERIT population had been enrolled on the basis of a more sensitive assay.⁸ All screening samples were rerun by Monogram Laboratories whose employees were blinded to any clinical outcomes of the patients in the study. On the basis of the Trofile ES study results, 15% of patients (102 of 667) in the MERIT study were reclassified as having dual/mixed tropic virus instead of the original screening classification of CCR5-tropic virus only. As a result, the percentage of patients achieving virological suppression at week 48 using an intent-to-treat analysis was the same in both arms, with 68% in both arms achieving below 50 copies/mL. On the basis of this analysis, maraviroc twice daily would be considered noninferior to efavirenz because the CI no longer crosses -10% threshold.

Reassuringly, these overall results are supported by the data when the study population was stratified by baseline viral load, with maraviroc and efavirenz performing similarly in patients with lower and higher viral loads.

While these data are a retrospective look at a population rather than a formal prospective study using the Trofile ES assay, the reanalysis was done in a blinded manner on samples that were used in screening and appears to be a robust answer to what would reasonably be expected if the trial were repeated. Whether this is sufficient to lead to renewed interest in the use of maraviroc as part of an initial drug regimen is the question raised by these results and in the context of other new data about initial therapy; these data add to the challenges posed by an increasing number of choices for first-line regimens in the treatment of HIV infection.

UPDATE ON ONCE-DAILY BOOSTED FOSAMPRENAVIR
Ritonavir-boosted fosamprenavir (FPV/r) at a once-daily dose of 1400/100 mg (FPV/r100) was approved by the FDA for use in antiretroviral-naive patients mainly on the basis of pharmacokinetic data, but questions about long-term efficacy, resistance consequences, metabolic advantages, and overall benefit of this dosage over the standard FPV/r 1400/200 mg (FPV/r200) once-daily dose remained unanswered. Several presentations at this conference provided some answers with data collected from 2 randomized clinical trials: the COL100758 and LESS studies.

The COL100758 Study
The COL100758 study is an open-label trial conducted in treatment-naive patients to evaluate the efficacy, safety, and tolerability of FPV/r100 versus FPV/r200, when used in combination with abacavir/lamivudine. This 96-week study provided data about the efficacy, resistance, safety, and metabolic effects of FPV/r.⁹ Using an intention-to-treat (ITT, missing equals failure) analysis at week 96, of the FPV/r100-treated patients, 78% achieved HIV RNA levels of less than 400 copies/mL and 66% achieved less than 50 copies/mL, compared with 53% and 53%, respectively, of the FPV/r200-treated patients. The CD4 count gains in both arms were nearly identical.

It is worth noting that this is a pilot study, not powered statistically, and the P values provided in the study results were used only for descriptive purposes. Protocol-defined virological failure occurred in 9% of the FPV/r100 arm and in 14% of the FPV/r200 arm; none of these patients had a major PI resistance mutation, and only 2 developed a significant new resistance mutation in the reverse transcriptase gene (eg, M184V mutation or M184M/V mixtures).¹⁰ The incidence of any treatment-related grade 2 to 4 adverse event was not significantly different between the 2 groups.

An interesting observation was the lack of a significant reduction in lipid levels with the use of the lower boosted dose (FPV/r100). When these data were paired with measurements for adherence, it was discovered that a lower level of adherence (based on pill counts) to ritonavir was observed in the FPV/r200 arm. It was postulated that this may have affected virological responses in the FPV/r200 group and could possibly have contributed to the lack of difference between the arms with regard to changes in lipid parameters and incidence of adverse events.

The study also looked at changes in regional fat and bone mineral density (BMD) after 96 weeks of treatment between both FPV/r doses by total body dual-energy x-ray absorptiometry obtained in 71 patients pretreatment and at weeks 48, 72, and 96 of treatment.¹¹ The median percent change in fat mass in all regions studied was not significantly different between the study groups. A loss of fat greater than 20% in upper limbs was observed in 18% of the patients in the FPV/r100 group and in 13% of the FPV/r200 group and in lower limbs in 15% and 6%, respectively; a gain in trunk fat of 20% or more occurred in 38% and 45% of patients in the FPV/r100 and FPV/r200 groups, respectively. No patient had simultaneous limb fat loss greater than 20% and trunk fat gain greater than 20%. BMD changes were small in both study arms.

Overall, the use of the lower ritonavir dose in this study decreased the daily pill burden (which can potentially reduce cost); enhanced patient adherence to treatment; and provided comparable virological, immunological, and safety outcomes when compared with the higher 200-mg dose of ritonavir.

The LESS Study
A validation of the COL100758 study data was seen in the results of the LESS study.¹² The LESS study was a phase 3b, open-label study in which 210 virologically suppressed patients receiving a full dose of boosted fosamprenavir (FPV/r200) (taken once daily or divided twice daily) were randomized to continue their current dosage or to switch to FPV/r100. The results at week 24 are depicted in Figure 2 and demonstrate continued suppression after the switch to FPV/r100.

Figure 2.Virological response to fosamprenavir boosted with a ritonavir dose of 100 mg (FPV/r100) or 200 mg (FPV/r200) at week 24 in the LESS study. Results of 2 different data analyses shown: time to loss of virological response (TLOVR) and missing or discontinuation equals failure (MD = F). (Adapted with permission from Cohen C et al. 2008.¹²)

The proportion of patients whose treatment had not failed by week 24 was similar regardless of the baseline regimen (ie, FPV/r200 once daily or twice daily) or previous treatment (no previous PI use, unboosted PI, or boosted PI). Only 1 case (in the FPV/r200 arm) of protocol-defined virological failure occurred during the 24-week study period, and no major PI mutations emerged during treatment. Overall, both regimens were generally well tolerated, and no patient experienced a treatment-related serious adverse event. Lipid changes were similar between the treatment groups

The data presented in these studies are reassuring about the use of a lower-boosting dose (ie, 100 mg of ritonavir) with fosamprenavir, and the long-term safety and durability of boosted fosamprenavir in treatment-naive patients.

ANTIRETROVIRAL OUTCOMES IN CLINICAL PRACTICE
It is often said that patients receiving antiretroviral therapy while in a clinical trial have better treatment outcomes than patients followed up in routine clinical practice. This is believed to be caused by the selection bias with clinical trials that excludes patients from trial participation who have characteristics or behaviors perceived to be associated with poorer patient adherence to treatment. Several cohort studies were presented at the joint conference that directly or indirectly compared antiviral response rates in clinical practice with those reported for clinical trials.

Treatment-Naive Patients
A retrospective analysis assessed the virological, immunological, and clinical responses among 452 patients starting antiretroviral therapy during 1996 to 2005; 305 were followed through clinical practice and 147 participated in clinical trials.¹³ The results of the analysis showed that the proportion of patients obtaining durable virological suppression in clinical practice was similar to that in clinical trials, 45% versus 50%, respectively. However, there were more opportunistic infections and greater rates of hospitalization and death seen in the clinical practice group.

The authors concluded that there were no differences in long-term virological suppression between patients in their clinical practice and those participating in a clinical trial, but patients in clinical practice had a greater severity of illness. The authors cautioned that by excluding patients who had more comorbidities or greater illness from participation in clinical trials, critical data may be lost that are necessary to better understand the effect of starting antiretroviral treatment across the entire spectrum of patients in care.

Treatment-Experienced Patients
For treatment-experienced patients, better virological outcomes have come on the heels of the availability of new antiretroviral agents from new classes as well as new “next-generation” NNRTIs and PIs. The performance of raltegravir, darunavir, or the second-generation NNRTI etravirine in clinical practice was reported in 2 studies.

Beginning in July 2006, a prospective study assessed factors associated with achieving an undetectable viral load (defined as an HIV RNA level of less than 50 copies/mL) in triple-class–experienced patients starting a new antiretroviral regimen who had not participated in a clinical trial.¹⁴ Among 87 patients, 52% achieved an undetectable viral load after 24 weeks of therapy. Of those who received a regimen with boosted darunavir, raltegravir, or both, an undetectable viral load was achieved by 66%, 66%, and 70% of patients, respectively. In a multivariate analysis, a low baseline HIV RNA level and treatment with a regimen containing both darunavir and raltegravir were the factors most likely to predict virological suppression.

A second study evaluated virological response rates in patients who were given raltegravir and etravirine through expanded access programs before FDA approval.¹⁵ In this study, 53 patients were evaluated. At study entry, the median HIV RNA level was 4.36 log₁₀ copies/mL, and the median CD4⁺ cell count was 171/µL; patients had a mean of 5 PI mutations. The antiretroviral regimens included DRV/r in 83% of patients, LPV/r in 4%, boosted atazanavir in 25%, and no PI in 11%. At week 24, 94% of patients (50 of 53) had an HIV RNA level below 75 copies/mL and 96% had levels below 400 copies/mL. Outcomes did not differ by the number of etravirine-associated mutations.

These 2 studies confirm other reports that the new antiretroviral agents perform as well in the clinic as they do in clinical trials.

Overall Improvement in Success Rates
The chronological trend in virological suppression rates among patients who received antiretroviral therapy from 2001 through 2006 was analyzed using 2 databases: the HIV Research Network, a database of 19 clinical sites across the United States, and the Massachusetts cohort, a database that includes a sample of patients from 21 publicly funded clinics.¹⁶ Both cohorts included patients entering care and already in care.

In the HIV Research Network, the proportions of patients with persistent virological suppression and those with their last HIV RNA level being less than 400 copies/mL increased from 34% and 53% of 11,595 patients, respectively, in 2001 to 51% and 67% of 9816 patients, respectively, in 2006.

Similarly, in the Massachusetts cohort, the proportions of patients with persistent virological suppression and those with their last HIV RNA level of less than 400 copies/mL increased from 49% and 63% of 809 patients, respectively, in 2001 to 68% and 82% of 857 patients, respectively, in 2006.

Of importance, from 2003 onward, there were no differences in virological suppression rates by racial group, reversing the trend of lower rates of virological suppression for racial minorities than those for whites reported in 2001 and 2002. These new data document the temporal improvement in HIV treatment outcomes with the recent improvements in antiretroviral therapy and parallel the improved virological suppression rates in clinical trials of newer agents.

SWITCHING VIROLOGICALLY SUPPRESSED PATIENTS TO A SINGLE-TABLET REGIMEN
The coformulation of efavirenz/tenofovir/emtricitabine has significantly simplified the treatment of HIV infection, and the long-term efficacy and safety of this regimen has been demonstrated.¹⁷ Questions still remain, however, about whether treatment-naive patients who originally started on other regimens and are now virologically suppressed would benefit from treatment simplification by switching their current regimen to the single-tablet regimen (STR) of efavirenz/tenofovir/emtricitabine. Two large studies prospectively evaluated the efficacy, safety, and tolerability of this therapeutic strategy.

In a multicenter, open-label study, 300 patients who had no history of virological failure and had an HIV RNA level of less than 200 copies/mL while they were on a stable NNRTI- or PI-based regimen were randomized to stay on their baseline regimen (SBR) or switch to the STR.¹⁸ The patient baseline characteristics were well balanced between the treatment groups with about half of the study participants taking an NNRTI rather than a PI at baseline. The study randomization inadvertently affected the STR arm in that there were more patients on a non–efavirenz-containing regimen at baseline in the switched group (66%) than in the SBR group (58%); therefore, more patients in the switched group were expected to developed efavirenz-related adverse events after switching their baseline regimen.

At week 48, the percentage of patients maintaining an HIV RNA level below 50 copies/mL was similar in both treatment groups (87% STR vs 85% SBR), and treatment failure occurred in only 4 patients (3 STR vs 1 SBR). On the negative side, the overall incidence of adverse events in the STR arm, as well as the rate of adverse events leading to study discontinuation, were higher in the STR arm than in the SBR arm. This was mainly driven by CNS adverse events associated with the use of efavirenz. There were no significant differences between arms regarding changes in the median estimated glomerular filtration rate (GFR) calculated by both the Cockcroft-Gault (CG) and Modification of Diet in Renal Disease (MDRD) equations. Of, course, the patients in the SBR group were intrinsically less likely to report adverse events because they had already been successfully taking their baseline regimen for quite some time (median of 3 years). On the positive side, patients who switched treatment, on average, experienced mild improvement in triglyceride levels and 85% reported that the new regimen was “much better” than their previous one.

The second study to evaluate a switch-simplification strategy was an extension of the GS-934 study.¹⁹ After 144 weeks of randomized drug treatment during which patients took efavirenz plus tenofovir/emtricitabine or efavirenz plus zidovudine/lamivudine, all patients with HIV RNA levels below 400 copies/mL were offered to switch to the efavirenz/tenofovir/emtricitabine single-tablet coformulation, and 286 patients were enrolled (160 from the efavirenz plus tenofovir/emtricitabine arm and 126 from the efavirenz plus zidovudine/lamivudine arm). The proportion of patients maintaining an undetectable viral load at 48 weeks was similar in both treatment groups (Figure 3). The incidence of efavirenz-associated adverse events was low (less than 2%), and all adverse events in general were mild (ie, grade 1 or 2). No drug-related adverse event resulted in study discontinuation.

Figure 3.Proportion of patients maintaining viral suppression after switching treatment to the single-tablet regimen (STR) of efavirenz/tenofovir/emtricitabine in the GS-934 extension study. Before switching to the STR, patients had been treated for 144 weeks with efavirenz (EFV) plus either tenofovir/emtricitabine (TDF/FTC) or zidovudine/lamivudine (ZDV/3TC). Results of missing equals failure analysis shown for the 48-week extension study. (Adapted with permission from DeJesus E et al. 2008.¹⁹)

As would be expected, patients who switched from the zidovudine-containing regimen had a modest improvement in lipid parameters and a mild improvement in CD4⁺ cell count (+21/µL) and in limb fat levels (+0.2 kg). There were no elevations in the serum creatinine or phosphorus levels or any further decline in the median estimated GFR after switching therapy.

Current treatment guidelines are very clear about the initiation of antiretroviral treatment and about which patients can benefit from initiation of antiretroviral treatment with a simple daily regimen. These 2 studies provide important reassurance that a simple once-daily regimen, such as the efavirenz/emtricitabine/tenofovir coformulation, can also be used as a simplification treatment strategy in select patient populations (such as the ones represented in these studies) without compromising virological suppression while potentially gaining other benefits.

ANTIRETROVIRAL THERAPIES IN DEVELOPMENT
Studies of a number of antiretrovirals in phase 1 and 2 clinical development were presented, and their results give a good picture of which drugs are moving ahead in clinical development.

Bevirimat
This is the only oral drug in a completely new drug class-maturation inhibitors-that is in active investigation. Bevirimat interferes with one of the last steps in the assembly of a “mature” infectious virus particle inside the host cell.

In a phase 2, placebo-controlled study, the safety and efficacy of bevirimat in heavily treatment-experienced patients was better defined.²⁰ The study enrolled 88 patients with detectable HIV RNA levels, most of whom were on a stable but failing antiretroviral regimen. They were given bevirimat once daily for 14 days in a range of doses and in tablet and liquid formulations. Since data indicate that mutations in the gag region of the virus affect the activity of bevirimat, the virus population of each patient was characterized with the use of a gag gene resistance assay. Bevirimat was well tolerated with few adverse events, which were more frequent in the placebo group. Virological response, when restricted to a subset of patients who entered the study without polymorphisms at 3 gag sites, had a mean decrease of 1.08 log₁₀ HIV RNA copies/mL compared with a decrease of 0.2 log₁₀ copies/mL in the placebo group. When the analysis was further restricted to those who achieved the target drug exposure, a 21.26 log₁₀ copies/mL decline was noted. Since more than 60% of patients were found to have a virus with the gag genotypic pattern that leads to a response to bevirimat, this drug is being further developed on the basis of these results.

Elvucitabine
Elvucitabine is a compound whose structure and profile are similar to those of lamivudine and emtricitabine, but it appears to be more potent, with a much lower dosage needed to gain a full antiviral effect. Phase 1 monotherapy studies documented an approximate 1.9 log₁₀ copies/mL decline in the HIV RNA level at day 28 of therapy.

A randomized comparison of elvucitabine and lamivudine in combination with tenofovir and efavirenz in 77 treatment-naive patients used a double-blind design for the first 12 weeks, followed by an open-label period, for a total of 48 weeks.²¹ The mean CD4⁺ cell count was about 320/µL, and the mean HIV RNA level was about 4.8 log₁₀ copies/mL. Over the first 12 weeks, there was a higher number of study discontinuations in the elvucitabine arm, although there were several, apparently unrelated, reasons to account for this.

The additional open-label follow-up from weeks 12 to 48 provided more reassuring data, with only 1 patient discontinuation considered potentially related to elvucitabine toxicity (severe neutropenia). For efficacy, similar rates of viral suppression for elvucitabine and lamivudine were noted, and nearly all patients achieved an HIV RNA level below 50 copies/mL by week 48. As expected, NNRTI or NRTI resistance was observed in the few cases of virological failure.

These data provide evidence that elvucitabine may be an alternative to lamivudine. Whether there are sufficient advantages favoring elvucitabine over lamivudine or emtricitabine is not clear from these data; other studies that are assessing the effect of elvucitabine in patients who harbor the M184V mutation are ongoing.

RDEA806
The investigational NNRTI RDEA806 has in vitro activity against HIV with the K103N mutation, the most common mutation seen after efavirenz treatment failure. In a dose-ranging, placebo-controlled study, 48 HIV-infected male patients, who were either treatment-naive or off therapy after minimal previous antiretroviral use, were randomized to 1 of 4 RDEA806 dosage groups-400 mg twice daily or 600 mg once daily with a capsule formulation or 800 mg once daily or 1000 mg once daily with an enteric-coated tablet formulation, all for 7 days.²²

At day 8, all patients who received RDEA806 400 mg twice daily, 800 mg once daily, and 1000 mg once daily achieved a decrease in their HIV RNA level of at least 1 log. The mean changes in HIV RNA level (log₁₀ copies/mL) for each dosage group were as follows: placebo, +0.2; 400 mg twice daily, -1.8; 600 mg once daily, -1.5; 800 mg once daily, -1.8; and 1000 mg once daily, -1.8. A clear pharmacokinetic/pharmacodynamic relationship was observed across all 4 dosage groups; all patients who achieved a 20 ng/mL serum drug exposure also achieved a drop of 1 log or more in the number of HIV RNA copies/mL. The mean elimination half-life was 8.5 to 12.1 hours, which is consistent with that seen in healthy volunteer studies.

On the basis of β-hydroxycortisol/cortisol ratios, no cytochrome P-450 3A (CYP3A) induction was observed. A dose-dependent change in uric acid level was observed. The frequency and intensity of adverse events in the RDEA806 treatment groups were similar to those in the placebo group, and no patient discontinued because of an adverse event.

These data support the continued development of this drug in phase 2 trials; however, the relative merits of this drug versus other “second-generation” NNRTIs is yet to be defined.

Dr Boyle has reported no potential conflict of interest relevant to this article. Dr Cohen reports having received consulting fees and grant or research support from Abbott, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Merck, Pfizer, Roche Laboratories, and Virco Labs; speaking fees from Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Merck, Pfizer, Roche Laboratories, and Tibotec; and honoraria from all of the above. Dr DeJesus reports having received research support from Abbott, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Hoffman-LaRoche Laboratories, Merck, Pfizer, Schering Plough, and Tibotec and having served as a consultant or on an advisory board for Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences (regional consultant), GlaxoSmithKline, Merck, Tibotec, and Vertex Pharmaceuticals. Dr Elion reports having received grant or research support from Gilead Sciences, GlaxoSmithKline, Koronis, Panacos, and Tibotec; consulting fees from Bristol-Myers Squibb, Gilead Sciences, and GlaxoSmithKline; speaking fees from Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, and Tibotec; and honoraria from all of the above. Dr Frank reports having received research grants from Bavarian Nordic, Merck, and Tibotec; having served as an advisor for Abbott, Bristol-Myers Squibb, Gilead Sciences, Pfizer, and Tibotec; and having received honoraria from Abbott, Bristol-Myers Squibb, Gilead Sciences, Pfizer, and Tibotec. Dr Moyle reports having received grant or research support from Ardea Biosciences, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, NeurogesX, Theratechnologies, and Tibotec; consulting fees from Ardea Biosciences, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Incyte, Merck, Monogram Biosciences, Pfizer, Roche Laboratories, Tobira, and Tibotec; speaking fees from Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Merck, Pfizer, Roche Laboratories, and Tibotec; and honoraria from all of the above. Dr Sax reports having received grant support from GlaxoSmithKline; having served as a consultant for Abbott, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Merck, and Tibotec; and having received teaching honoraria from Abbott, Bristol-Myers Squibb, Gilead Sciences, and Merck.

References:

References1. Hammer SM, Eron JJ Jr, Reiss P, et al; International AIDS Society-USA. Antiretroviral treatment of adult HIV infection: 2008 recommendations of the International Aids Society-USA panel. JAMA. 2008;300:555-570.
2. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Rockville, MD: Department of Health and Human Services; November 3, 2008:1-139. http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed December 9, 2008.
3. Kitahata MM, Gange SJ, Moore RD; North American AIDS Cohort Collaboration of ReSearch and Design. Initiating rather than deferring HAART at a CD4⁺ count between 351 and 500 cells/mm³ is associated with improved survival. 48th ICAAC/46th IDSA Annual Meeting; October 25-28, 2008; Washington, DC. Abstract H-896b.
4. Ortiz R, Dejesus E, Khanlou H, et al. Efficacy and safety of once-daily darunavir/ritonavir versus lopinavir/ritonavir in treatment-naive HIV-1-infected patients at week 48. AIDS. 2008;22:1389-1397.
5. Mills A, Nelson M, Jayaweera D, et al. ARTEMIS: Efficacy and safety of darunavir/ritonavir (DRV/r) 800/100 mg once-daily versus lopinavir/ritonavir (LPV/r) in treatment-naive, HIV-1-infected patients at 96 wks. 48th ICAAC/46th IDSA Annual Meeting; October 25-28, 2008; Washington, DC. Abstract H-1250c.
6. Lennox J, DeJesus E, Lazzarin A, et al. STARTMRK, a phase III study of the safety & efficacy of raltegravir (RAL)-based vs efavirenz (EFV)-based combination therapy in treatment-naive HIV-infected patients. 48th ICAAC/46th IDSA Annual Meeting; October 25-28, 2008; Washington, DC. Abstract H-896a.
7. Saag M, Ive P, Heera J, et al. A multicenter, randomized, double-blind, comparative trial of a novel CCR5 antagonist, maraviroc versus efavirenz, both in combination with Combivir (zidovudine [ZDV]/lamivudine [3TC]), for the treatment of antiretroviral naive subjects infected with R5 HIV-1: week 48 results of the MERIT study. 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 22-25, 2007; Sydney, Australia. Abstract WESS104.
8. Saag M, Heera J, Goodrich J, et al. Reanalysis of the MERIT study with the enhanced Trofile™ assay. 48th ICAAC/46th IDSA Annual Meeting; October 25-28, 2008; Washington, DC. Abstract H-1232a.
9. DeJesus E, Sloan L, Sension M, et al. 96-Week efficacy/safety data comparing two doses of ritonavir (/r) to boost once-daily (QD) fosamprenavir (FPV), used in combination with abacavir (ABC)/lamividine (3TC). 48th ICAAC/46th IDSA Annual Meeting; October 25-28, 2008; October 25-28, 2008; Washington, DC. Abstract H-1246.
10. Ross L, DeJesus E, Sloan L, et al. Week 96 virology analysis of COL100758, a study of once-daily (OD) fosamprenavir (FPV) boosted with 100 mg or 200 mg ritonavir (/r) with abacavir/lamivudine in antiretroviral na
•ve HIV-infected patients. 48th ICAAC/46th IDSA Annual Meeting; October 25-28, 2008; Washington, DC. Abstract H-360.
11. Wohl D, DeJesus E, Sloan L, et al. Limb and trunk fat changes by total body DEXA after 96 weeks of treatment with once-daily (QD) fosamprenavir (FPV) boosted with either 100 mg or 200 mg of ritonavir (/r) plus abacavir (ABC)/lamivudine (3TC): COL100758. 48th ICAAC/46th IDSA Annual Meeting; October 25-28, 2008; Washington, DC. Abstract H-2302.
12. Cohen C, DeJesus E, Lamarca A, et al. Switching from a 200mg-ritonavir (RTV, r)-boosted fosamprenavir (FPV) regimen (700mg/200mg BID or 1400mg/200mg QD) to a 100mg RTV-boosted FPV regimen (1400mg/100mg QD) yields similar efficacy and safety. 48th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy/Infectious Diseases Society of America 46th Annual Meeting; October 25-28, 2008; Washington, DC. Abstract H-1250e.
13. Forrester JW, Ying J, Coehlo-Prabu N, Fichtenbaum CJ. Differences in clinical efficacy and effectiveness: a comparison of clinical trials to clinical practice. Annual Interscience Conference on Antimicrobial Agents and Chemotherapy/Infectious Diseases Society of America 46th Annual Meeting; October 25-28, 2008; Washington, DC. Abstract H-1257.
14. Mugavero M, Lin H, Willig J, et al. The impact of darunavir/ritonavir (DRV/r) & raltegravir (RAL) in the clinic: a new era for treatment-experienced patients? 48th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy/Infectious Diseases Society of America 46th Annual Meeting; October 25-28, 2008; Washington, DC. Abstract H-1262.
15. Kerrigan H, Towner W, Follansbee S, Klein D. Treatment response among HIV patients co-enrolled in the etravirine (ETR) and raltegravir (RAL) expanded access programs (EAPs) at Kaiser Permanente. 48th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy/Infectious Diseases Society of America 46th Annual Meeting; October 25-28, 2008; Washington, DC. Abstract H-1263.
16. Hirschhorn LR, Kunches L, Hicks PL, et al. Trends in viral suppression rates in 2 large multi-site HIV cohorts. 48th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy/Infectious Diseases Society of America 46th Annual Meeting; October 25-28, 2008; Washington, DC. Abstract H-1261.
17. Arribas JR, Pozniak AL, Gallant JE, et al. Tenofovir disoproxil fumarate, emtricitabine, and efavirenz compared with zidovudine/lamivudine and efavirenz in treatment-naive patients: 144-week analysis. J Acquir Immune Defic Syndr. 2008;47:74-78.
18. DeJesus E, Young B, Flaherty J, et al. Simplification of antiretroviral therapy (ART) with efavirenz (EFV)/emtricitabine (FTC)/tenofovir DF (TDF) single-tablet-regimen vs. continued unmodified ART in virologically-suppressed, HIV-1-infected patients. 48th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy/Infectious Diseases Society of America 46th Annual Meeting; October 25-28, 2008; Washington, DC. Abstract H-1234.
19. DeJesus E, Pozniak A, Gallant J, et al. The 48-week efficacy and safety of switching to fixed-dose efavirenz/emtricitabine/tenofovir DF in HIV-1-infected patients receiving HAART. 48th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy/Infectious Diseases Society of America 46th Annual Meeting; October 25-28, 2008; Washington, DC. Abstract H-1235.
20. Lalezari J, McCallister S, Gigliotti M, et al. A phase 2 safety and efficacy study of bevirimat (BVM) in heavily treatment experienced HIV+ patients identifies the target phase 3 study profile. 48th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy/Infectious Diseases Society of America 46th Annual Meeting; October 25-28, 2008; Washington, DC. Abstract H-891.
21. DeJesus E, Saple D, Morales-Ramirez J, et al. Elvucitabine phase II 48 week interim results show safety and efficacy profiles similar to lamivudine in treatment naive HIV-1 infected patients with a unique pharmacokinetic profile. 48th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy/Infectious Diseases Society of America 46th Annual Meeting; October 25-28, 2008; Washington, DC. Abstract H-892.
22. Moyle G, Boffito M, Shen Z, et al. RDEA806, a novel HIV non-nucleoside reverse transcriptase inhibitor, shows positive outcome in treatment of naive HIV patients. 48th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy/Infectious Diseases Society of America 46th Annual Meeting; October 25-28, 2008; Washington, DC. Abstract H-893.