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New Antiretroviral Agents: Update

Optimizing Therapy for Patients With Multidrug-Resistant HIV -- Part III

July 31, 2006


Most HIV-infected individuals who maintain good adherence to appropriately selected antiretroviral regimens will achieve virologic and immunologic success. However, in other cases, the development of antiviral resistance usually requires alterations in the drug regimen to regain treatment success. Each successive regimen change may lead to the accumulation of additional resistance mutations, often resulting in broad cross-resistance to many or all available agents. While there are currently 21 unique antiretroviral drugs approved for the treatment of HIV infection, patients with resistant viruses may benefit from new antiretroviral agents to which they have not previously been exposed. Recently approved agents include the viral entry inhibitor enfuvirtide (T-20) and the non-peptidic protease inhibitor (PI) tipranavir and the PI darunavir (TMC114); clinical trials have demonstrated the efficacy and safety of these agents in highly treatment-experienced patients. Another antiretroviral agent that is in the later stages of clinical development is the entry inhibitor maraviroc, a CCR5 antagonist. In addition, development continues on new reverse transcriptase inhibitors, new non-nucleoside reverse transcriptase inhibitors, and other new CCR5 inhibitors. Finally, promising research into new targets has led to the early clinical development of integrase inhibitors and maturation inhibitors.


Many of the recent gains in reduced morbidity and mortality of treatment-experienced HIV patients have occurred as a result of improved dosing and tolerability of existing antiretroviral agents, which have made it easier to successfully control HIV replication. Nevertheless, the continuing need for new agents that are active against drug-resistant HIV is clear. Pharmaceutical companies continue to focus on this goal, with the result that two new drugs have been approved in the last 2 years. Enfuvirtide (T-20) is the first fusion inhibitor to be approved, and tipranavir is a novel non-peptidic protease inhibitor (PI). In addition, a variety of drugs have been or are being evaluated in phase II and III clinical trials, including nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), and PIs as well as agents from new drug classes including entry inhibitors, integrase inhibitors, and maturation inhibitors.

Recently Approved Antiretroviral Agents


This fusion inhibitor is indicated for use in combination with other antiretroviral agents for the treatment of HIV-1 infection in treatment-experienced patients failing therapy. Enfuvirtide prevents viral fusion with host cells by binding to glycoprotein gp41 in the HIV envelope. Although enfuvirtide has been available for almost 3 years, relatively few physicians have extensive clinical experience with it, so it will be considered a new drug for the purposes of this review.

The safety and efficacy of enfuvirtide have been demonstrated in the T-20 Versus Optimized Background Regimen Only (TORO 1 and TORO 2) trials in HIV-infected patients experienced with all three available classes of antiretroviral agents (NRTIs, NNRTIs, and PIs). TORO 1 enrolled participants in the United States, Canada, Mexico, and Brazil, while TORO 2 enrolled participants in Europe and Australia.

TORO trials: study design
Participants were randomized 1:2 to either an optimized background regimen alone (three to five antiretroviral agents) selected by the clinical investigator based on genotypic and/or phenotypic drug resistance test results, or an optimized background regimen plus enfuvirtide (90 mg subcutaneous, bid). A switch in therapy was permitted at virological failure or for toxicity reasons.1

TORO trials: efficacy and safety
The pooled intent-to-treat population from the two TORO studies comprised 995 patients (661 in the enfuvirtide groups and 334 in the control arm).1 The proportion of patients with improved virological outcomes was significantly higher in the enfuvirtide group compared with the control group (Figure 1). Furthermore, more than 65% of patients who responded at week 24 maintained their response at week 48.1

Figure 1. The TORO trials: efficacy of enfuvirtide (ENF) plus optimized background (OB) versus OB alone in intent-to-treat population.
Figure 1. The TORO trials: efficacy of enfuvirtide (ENF) plus optimized background (OB) versus OB alone in intent-to-treat population.3

With regard to safety, most patients in the trials experienced at least one antiretroviral drug-related adverse event during the 48-week study period, excluding local injection site reactions. However, the overall number of treatment-related adverse events was lower among those randomized to enfuvirtide than to the control group (96.2 events vs 149.9 events per 100 patient-years),2 and more patients in the control group than in the enfuvirtide group discontinued study therapy before 48 weeks (37% vs 26%).2 Injection site reactions occurred in almost all (98%) enfuvirtide-treated participants and accounted for approximately 4% of discontinuations in this group.2 The proportion of patients experiencing pain or discomfort with enfuvirtide injection remained steady throughout the treatment period, with 46-53% reporting mild tenderness, 15-20% reporting moderate pain and 1-3.5% reporting severe pain requiring analgesics or limiting usual activities; injection site reactions typically lasted for 3-7 days.2 The most frequent signs and symptoms of injection site reactions were pain and/or discomfort, erythema, and induration, which occurred in over 90% of cases, while nodules and cysts developed in 80% of cases.2

These data show a significant benefit of enfuvirtide in treatment-experienced patients. Unfortunately, because it is administered twice daily by injection, it is a difficult drug to take consistently. This and cost are currently the principal barriers to its more widespread use. A recent evaluation of a Biojector needle-free gas-powered injection device as an alternative delivery system has shown that plasma levels of enfuvirtide are similar after administration with the Biojector or needles.4 Importantly, the Biojector device reduced symptoms of injection site reactions by approximately 50% compared to needles, and on average, patients found it easier to use than needles.4 Thus, this delivery method may extend the clinical utility of enfuvirtide. Interestingly, the next generation of fusion inhibitors includes two candidates that demonstrate substantial improvements in potency, durability, and pharmacokinetics that may enable the evaluation of sustained-release formulations at once-weekly dosing.5


A non-peptidic HIV PI,6 tipranavir became available in 2005 for use in combination with ritonavir (r) in treatment-experienced HIV-infected patients. The unique binding interactions of tipranavir with HIV protease make it active against a substantial range of HIV variants that are resistant to other PIs.7 Furthermore, it appears that multiple PI mutations may be required before any significant loss in susceptibility to tipranavir occurs.8

The safety and efficacy of tipranavir have been demonstrated in the "Randomized Evaluation of Strategic Intervention in multi-drug reSistant patients with Tipranavir" trials (RESIST 1 and RESIST 2) in HIV-infected patients with triple-class failure, failing their current HAART regimen. RESIST 1 was conducted in North America and Australia, while RESIST 2 was conducted primarily in Europe.

RESIST trials: study design
The study design of the RESIST trials was similar to that described above for the TORO trials, i.e., optimized background (including a comparator-boosted PI) versus optimized background plus tipranavir in place of the comparator PI.9

RESIST trials: efficacy and safety
A pooled analysis of RESIST 1 and 2 showed that adding tipranavir/r to an optimized background regimen increased the proportion of patients achieving a viral load of P < 0.0001).10 This demonstrated the durability of the treatment response for the majority of patients who achieved <400 copies/mL by 24 weeks (35% vs 17%).9 In a combined analysis of data from RESIST 1 and 2, the CD4+ cell response at 48 weeks was significantly higher among patients who received tipranavir/r (+45 cells/µL vs +21 cells/µL, P <0.001).10 With regard to safety, tipranavir/r was associated with increased grade 3/4 liver enzyme levels (alanine transaminase 9.7% vs 4.2% and aspartate transaminase 6.1% vs 1.8%) and lipid levels, particularly cholesterol and triglycerides (2.1% vs 0.4% and 24.9% vs 13.0%, respectively), compared to patients on comparator-boosted PIs.10

Adding tipranavir/r to an optimized background regimen can provide a durable virological response in treatment-experienced patients, particularly in combination with other active agents, such as enfuvirtide (52% of patients with first-time enfuvirtide use achieved <400 copies/mL by 48 weeks compared to 20% of control group).10 A limitation of tipranavir is its association with liver toxicity; therefore, liver function tests should be performed prior to initiating therapy with tipranavir and periodically during treatment.11 It can be administered to patients with hepatitis B and/or C, although extra diligence with regard to monitoring for hepatotoxicity is recommended for these patients, as they are at heightened risk of liver toxicity.11 Tipranavir is contraindicated for those with moderate to severe hepatic insufficiency (Child-Pugh Class B and C).11


Darunavir, a new PI developed by Tibotec (Belgium), was designed to be active against HIV resistant to currently available PIs. A phase IIA proof-of-principle trial showed that ritonavir-boosted darunavir (darunavir/r) had potent short-term antiviral activity in HIV-infected patients with high-level PI resistance. Upon replacing PIs in a failing regimen with darunavir/r, a decrease in plasma HIV RNA of 1.0 log10 copies/mL was attained by 76% of patients (mean of three groups on different doses of darunavir/r) compared with only 17% of a control group.12 A viral load of <400 copies/mL was achieved by 40% of patients receiving darunavir/r versus 8% of control patients.12 A single case of hepatotoxicity was reported in this trial, which resolved upon the discontinuation of highly active antiretroviral therapy (HAART).12

Darunavir/r has subsequently been evaluated in phase IIB trials known as the "Performance Of TMC114/r When evaluated in 3-class-Experienced patients with PI Resistance" (POWER) trials (POWER 1 and POWER 2). POWER 1 was conducted in Europe, Australia, Brazil, and Canada, while POWER 2 was conducted in the United States. These studies evaluated four doses of darunavir/r in triple-class-experienced patients, with evidence of at least one primary PI resistance mutation.

POWER trials: study design
The study design for the POWER trials was essentially as described earlier for the TORO and RESIST trials, except that four different doses of darunavir/r (400/100 mg once daily, 800/100 mg once daily, 400/100 mg bid, 600/100 mg bid) were evaluated versus an optimized background regimen alone.13

POWER trials: efficacy and safety
A week 24 interim analysis of POWER 1 showed that a significantly higher percentage of patients receiving darunavir/r at the highest dose (600/100 mg bid) achieved a viral load reduction from baseline of >1.0 log10 copies/mL compared to the optimized background regimen alone (77% vs 25%, P <0.001), and mean CD4+ cell count increases were significantly higher in the darunavir/r group than in the control group (+124 cells/µL vs +20 cells/µL).13 As with tipranavir/r, the antiviral effect of darunavir/r was improved by concomitant use of enfuvirtide, although the magnitude of the difference in POWER 1 was quite modest (63% of patients receiving enfuvirtide plus darunavir/r [600/100 mg bid] achieved a viral load of <50 copies/mL, compared with 56% of patients who did not receive enfuvirtide in the optimized background regimen).13 The most commonly reported adverse events among patients receiving darunavir were headache, diarrhea, nausea, insomnia, and fatigue, the frequency of which was not dose-dependent or significantly higher than reported for the control group.14 No significant liver abnormalities occurred with darunavir/r during the first 24 weeks of follow-up.14 A week 24 interim analysis of POWER 2 showed similar results: 62% of patients in the darunavir/r (600/100 mg) group achieved virological response (>1 log10 copies/mL reduction in viral load), versus 14% of the control group. Mean CD4+ count increases were +59 cells/µL in the darunavir/r group versus +12 cells/µL in the control group.15 Patients in the darunavir/r group also reported the same most common adverse events as in POWER 1 (insomnia, headache, fatigue, nausea, and diarrhea), which were of mild-to-moderate severity, not dose-dependent, and comparable to the control group.16

Adding darunavir/r to an optimized background regimen represents a promising new alternative for treatment-experienced patients with PI resistance who are failing therapy, particularly when it is added with another active antiretroviral agent such as enfuvirtide. In contrast to tipranavir/r, darunavir/r did not show an association with liver toxicity, and may therefore be a better option for patients co-infected with hepatitis B and/or hepatitis C virus, although head-to-head comparisons have not been done.

Antiretroviral Agents in Clinical Trials


Reverset (dexelvucitabine, D-D4FC)
This NRTI has in vitro activity against HIV isolates resistant to other NRTIs, including zidovudine and lamivudine, and has shown potent antiretroviral activity in vivo in phase I trials (mean viral load decrease of approximately 1.6 log10 HIV RNA copies/mL).17 Despite these promising initial results, a review by the Food and Drug Administration of phase II data concluded that the viral load changes in these studies were insufficient to support proceeding to phase III trials. The development program for this drug was discontinued in April 2006.

Amdoxovir (DAPD)
The development program for this drug was discontinued in April 2006. This NRTI showed good antiviral activity against HIV isolates with mutations associated with resistance to other NRTIs,18 as well as antiviral activity in treatment-naive and treatment-experienced HIV-infected patients (median decreases of 1.5 log10 HIV RNA copies/mL and 0.7 log10 HIV RNA copies/mL, respectively).19 Unfortunately, additional studies did not support its role in treating patients with resistant HIV infections, and it is not currently in active clinical development.

Tibotec is developing two NNRTIs known as TMC125 (etravirine) and TMC278. Both of these drugs are being evaluated in clinical trials.

TMC125, a diarylpyrimidine derivative, is highly active against wild-type HIV and retains significant activity (EC50 <10 nM) against a majority (77%, compared to only 23% for efavirenz) of clinical isolates resistant to at least one of the currently available NNRTIs (delavirdine, efavirenz, and nevirapine).20 Administration of this drug in a phase IIA monotherapy trial in antiretroviral-naive patients resulted in a significant reduction in viral load compared to placebo (1.99 log10 copies/mL vs 0.06 log10 copies/mL P 21 TMC125 has subsequently been evaluated in a phase IIB trial of HIV-infected patients failing an NNRTI-containing (efavirenz or nevirapine) HAART regimen and with evidence of NNRTI resistance. Substituting TMC125 for the NNRTI in the failing regimen was associated with a median viral load decrease of 0.89 log10 copies/mL, after 7 days of treatment.22 A phase II dose-finding study of TMC125 also demonstrated potent antiviral activity of this agent in heavily pre-treated patients with substantial NNRTI and PI resistance compared to a standard-of-care regimen, at 24 weeks.23

However, it is worth noting that another, similar phase II study of TMC125 efficacy in HIV-infected patients with NNRTI resistance was stopped early due to a poorer antiviral response than that of the control group. The reasons for these inconsistencies are not yet clear. To overcome the low solubility and permeability of TMC125, several new formulations using hydroxypropyl methylcellulose (a polymeric emulsifier) have been developed. Test formulations showed a marked increase in relative oral bioavailability that will allow a reduced pill burden in phase III trials, which are now under way (DUET 1 and 2).24 These trials will evaluate the safety and efficacy of a combination of the experimental drug TMC125 and the recently approved darunavir.

TMC278, another diarylpyrimidine derivative from Tibotec, has also exhibited good antiretroviral activity in a phase IIA trial of antiretroviral-naive patients (viral load decreases of >1.0 log10 copies/mL).25 TMC278 has been shown to provide an increased barrier to resistance compared to existing NNRTIs, and a good safety profile and pharmacokinetic profile that facilitates its development as a once-daily regimen.26

Entry Inhibitors

One of the major targets for new classes of antiretroviral agents is HIV entry (Figure 2). The first drug approved that inhibits viral entry was enfuvirtide, which prevents the fusion of the viral envelope and CD4+ cell membrane by interfering with the gp41 viral helical bundle formation. Another approach to preventing viral entry is to block virus interaction with the chemokine co-receptors (CXCR4 and CCR5) that are required for successful viral entry. Three CCR5 co-receptor antagonists have entered clinical trials to date: aplaviroc (GlaxoSmithKline), vicriviroc (Schering-Plough), and maraviroc (Pfizer).

Aplaviroc (873140)
This drug demonstrated prolonged binding to the CCR5 receptor with a half-life of approximately 5 days, and exhibited sustained viral suppression for up to 48 hours after therapy discontinuation.28 Aplaviroc exhibited potent antiviral activity in a mixed group of treatment-naive and -experienced HIV infected patients, with all subjects achieving >1 log10 copies/mL reduction in viral load at all doses.29 Unfortunately, phase III trials of aplaviroc in antiretroviral-naive patients were discontinued in September 2005 due to liver toxicity, including two emergent cases of drug-related severe hepatotoxicity. Enrollment of treatment-experienced patients has been stopped and the development program for aplaviroc terminated.30

Figure 2. Entry inhibitors.
Figure 2. Entry inhibitors.27

Vicriviroc (SCH-D)
This compound reduced viral load in a dose-dependent fashion by approximately 1.0-1.6 log10 copies/mL in phase II trials.31 Phase II trials of vicriviroc in treatment-naive patients were initiated but subsequently discontinued due to poor virologic control relative to the control group receiving efavirenz.32 Treatment-naive patients were randomized to receive vicriviroc (25, 50, or 75 mg once daily) or placebo. After 14 days, co-formulated lamivudine/zidovudine was added, and efavirenz replaced placebo in the control group. At 2 weeks, vicriviroc showed a significantly greater decrease in viral load from baseline compared to placebo (P <0.001 for each vicriviroc arm vs placebo), but at the time the study was closed, the rate of virologic breakthrough (RNA 50 copies/mL) was 8% in the control group versus 57%, 45%, and 22% for the 25, 50, and 75 mg doses of vicriviroc, respectively (P <0.001 for the pooled vicriviroc arms versus control). Virologic rebound was associated with the presence of the M184V mutation for lamivudine resistance.33 The phase II study of vicriviroc in treatment-experienced patients is continuing in a study being conducted by the National Institutes of Health-sponsored Adult AIDS Clinical Trials Group (ACTG). In March, the ACTG Study Monitoring Committee reported that five cases of cancer (four cases of lymphoma and one of gastric adenocarcinoma) were detected in treatment-experienced patients on vicriviroc. However, a causal relationship was not shown, and as of March 3, 2006, the study was to continue.34

Maraviroc (UK-427,857)
Early studies of maraviroc have shown good tolerability and potent antiviral activity in HIV-positive patients, resulting in mean reductions in viral load of 1.60 (300 mg once daily) and 1.84 (300 mg bid) log10 copies/mL after 10 days of therapy.35 Further evaluation indicated that doses of 100 mg or more resulted in viral load reductions of 1 log10 copies/mL when given as short-term monotherapy either once daily or twice daily.36 The most common treatment-associated adverse events were headache, dizziness, nausea, asthenia, flatulence, and rhinitis, and the adverse event profile was similar to that of placebo.35 Phase II trials of maraviroc were initiated and are ongoing in treatment-naive and -experienced HIV-infected patients. It should be noted that discontinuation of the once-daily maraviroc (300 mg) phase III treatment arm in antiretroviral-naive subjects was recommended by Pfizer's independent data safety monitoring board in January 2006, due to failure to meet pre-specified non-inferiority criteria. However, maraviroc remains the most promising first drug of this class to date.

Integrase Inhibitors

Integrase inhibitors exert their antiviral effect by preventing HIV integrase from catalyzing the integration of HIV derived from viral DNA into the host cell chromosome DNA via an effect on strand transfer. This potently inhibits HIV replication. Two HIV integrase inhibitors have advanced to clinical trials.

This integrase inhibitor is under development by Merck & Co. It has potent in vitro activity against HIV and good bioavailability in healthy volunteers.37 A dose-ranging study of MK-0518 in HIV-infected patients showed MK-0518 to be very well tolerated and resulted in viral load reductions of 1.7 to 2.2 log10 copies/mL after 10 days of monotherapy, with at least 50% of patients achieving a viral load of <400 copies/mL.37 A dose-ranging evaluation of MK-0518 in combination with an optimized background regimen versus an optimized background regimen alone in treatment-experienced HIV-infected patients resulted in 63% to 67% of patients receiving MK-0518, versus 8% in the control group achieving a viral load of <50 copies/mL, while 85% to 92% versus 24% achieved viral load <400 copies/mL.38

GS-9137 (JTK-303)
This drug, being developed by Gilead Sciences, is also a potent inhibitor of HIV integrase. A 10-day dose-ranging study in a mixed group of antiretroviral-naive and -experienced patients demonstrated GS-9137 to be well tolerated at all dosages tested. A dose-dependent median decrease in viral load was observed, ranging from 1.48 log10 copies/mL when administered alone (200 mg bid), to 2.03 log10 copies/mL when boosted with ritonavir (50 mg/100 mg once daily).39 This drug is about to enter into large-scale phase II clinical trials. In contrast to MK-0518, GS-9137 is a cytochrome P (CYP) 3A4 substrate, and its pharmacokinetics are significantly affected by ritonavir or other inhibitors of CYP3A4.

Antiretroviral Agents in Early Development

Maturation Inhibitors

HIV maturation inhibitors exert their antiviral effect by blocking processing of the Gag proteins. This inhibits normal viral maturation and HIV infectivity.40

This agent is a potent inhibitor of HIV replication in vitro, including the replication of isolates resistant to reverse transcriptase inhibitors and PIs. As noted, its mechanism of action includes creating defects in Gag processing that prevent cleavage of the capsid pre-protein p25 to the mature capsid protein p24.40 As a consequence, new HIV virions released from host cells are rendered non-infectious. PA-457 has been found to be well tolerated and suitable for once-daily oral dosing, which at the highest dose (250 mg) tested resulted in a dose-dependent median reduction in viral load of 0.51 log10 copies/mL, compared to 0.17 log10 copies/mL for placebo (P <0.05).41 Although this drug appears to have less potent activity than the integrase inhibitors or the CCR5 antagonists, it may offer considerable value in extensively treatment-experienced patients with multiclass resistance.


Today, the availability of over 20 antiretroviral agents has transformed HIV infection into a chronic manageable disease, and many infected individuals appear likely to be able to live longer and healthier lives. However, multiple factors may limit the value of antiretroviral therapy, particularly for patients who have been on therapy for many years. For extensively treated patients who are failing therapy, new drugs, particularly those targeting new steps in the viral replication process, offer new therapeutic opportunities and considerable promise for the future.

Read Part I, Part II and Part III of this article.


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