New Advances in Antiretroviral Therapy

Key words: Antiretrovirals, Integrase inhibitors, CCR5 antagonists, Nonnucleoside reverse transcriptase inhibitors, Protease inhibitors

It is estimated that approximately 33.2 million persons worldwide were living with HIV infection in 2007.¹ With the development of effective antiretroviral treatment strategies, HIV infection has now become a manageable chronic disease.² Despite advances in treatment, drug resistance, long-term adverse effects, and high adherence requirements represent ongoing challenges to durable viral suppression.

The nucleoside reverse transcriptase inhibitors (NRTIs), nonnucleoside reverse transcriptase inhibitors (NNRT

Is), and protease inhibitors (PIs) have served as the cornerstone for therapeutic management of HIV infection.³ The introduction of novel treatments (integrase inhibitors, chemokine receptor antagonists) and new agents within the PI and NNRTI classes expand the treatment options available to patients with established resistance or intolerance. The clinical evidence, resistance, adverse effects, and dosing for new antiretroviral drugs released in the past several years will be discussed in this article. Table 1 provides a summary of dosing recommendations for the agents discussed.

INTEGRASE INHIBITORS
HIV integrase is responsible for transport and attachment of proviral DNA to the cellular genome, allowing transcription of viral proteins and subsequent assembly of virus particles. Two catalytic reactions are involved in the multistep process of proviral integration: 3′ processing to prepare the proviral DNA nucleotide ends for attachment and strand transfer to covalently link the viral and cellular DNA components.⁴ In 2007, raltegravir became the first integrase inhibitor to be approved by the FDA. An investigational integrase inhibitor that is in phase 3 clinical trials is elvitegravir (GS-9137).⁵ Both agents competitively inhibit the second stage (strand transfer reaction) of proviral DNA integration by metallic ion binding in the active site and exhibit activity against HIV-1 and HIV-2.^6,7

Clinical studies
The efficacy of raltegravir has been examined in treatment-experienced and treatment-naive patients. A multicenter, randomized, phase 2, dose-ranging study (Protocol 005) compared raltegravir (200, 400, or 600 mg orally twice daily) with placebo combined with optimized background therapy (OBT) in 178 triple-class–resistant patients. At week 24, HIV-1 RNA levels were less than 400 copies/mL in 70% to 71% of patients in the raltegravir arms and in 16% in the placebo arm (P < .0001).⁸

BENCHMRK-1 (Europe, Asia/Pacific, Peru) and BENCHMRK-2 (North America and South America) were identical, multicenter, phase 3 studies that included 350 and 349 triple-class–resistant patients, respectively. Patients in both studies were randomly selected (2:1) to receive either raltegravir (400 mg twice daily) or placebo combined with OBT. Both studies have yielded comparable results. The HIV-1 RNA level was less than 50 copies/mL in 65% and 60% of patients receiving raltegravir and in 31% and 35% of patients receiving placebo in BENCHMRK-1 and BENCHMRK-2, respectively, at 48 weeks (P < .001).

Increases in CD4⁺ cell counts also were greater in patients receiving raltegravir than in those receiving placebo. The frequency of adverse events with raltegravir was similar to that seen with placebo. The 2 studies are ongoing, with a total planned duration of 156 weeks.^9,10

Protocol 004 was a randomized, multicenter, double-blind, dose-ranging study comparing either raltegravir (100, 200, 400, or 600 mg orally twice daily) or efavirenz (600 mg/d) in combination with tenofovir (300 mg/d) and lamivudine (300 mg/d) in treatment-naive patients. Participants were enrolled from 29 sites in the United States, Canada, Thailand, Latin America, and Australia.

After 48 weeks, the proportion of patients with an HIV-1 RNA level of less than 400 copies/mL was similar: 92% on average for patients in all raltegravir groups and 87% for patients receiving efavirenz.

Increases in CD4⁺ cell counts and rates of virological failure over 48 weeks were comparable between the raltegravir and efavirenz groups. With the exception of patients receiving 200 mg of raltegravir, drug-related adverse effects were less common in patients receiving raltegravir than in those receiving efavirenz (P = .04). Increases in total cholesterol and low-density lipoprotein levels were more likely to occur in patients receiving efavirenz (P < .001 and P = .016, respectively, compared with raltegravir). Grades 3 and 4 laboratory abnormalities were uncommon and similar in frequency between raltegravir and efavirenz.¹¹

The STARTMRK trial (Protocol 021) was a large, phase 3 study examining raltegravir (400 mg twice daily) versus efavirenz (600 mg/d) in treatment-naive patients.¹² Patients were randomly selected (1:1) to either raltegravir (n = 281) or efavirenz (n = 282) in combination with fixed-dose tenofovir/emtricitabine. The primary study objective was to demonstrate whether raltegravir was noninferior to efavirenz in virological efficacy at 48 weeks. After 48 weeks, 86% of patients in the raltegravir arm and 82% in the efavirenz arm achieved an HIV-1 RNA level of less than 50 copies/mL, meeting the prespecified criteria for noninferiority of raltegravir (P < .001).

More rapid decline in HIV-1 RNA levels between weeks 2 and 24 was also observed in patients receiving raltegravir (P < .001). The CD4⁺ cell count increases were greater in patients receiving raltegravir than in those receiving efavirenz (189/µL and 163/µL, respectively). Drug-related adverse events occurred less commonly in the raltegravir group (44%) than in the efavirenz group (77%; P < .001); however, there were no differences between the groups in the frequency of serious adverse events.

Resistance
Genetic pathways associated with virological failure in patients receiving raltegravir include primary mutations at Q148K/R/H (25-fold decrease in susceptibility) and N155H (10-fold decrease in susceptibility), with high-level resistance emerging with the addition of E138K and G140S/A with Q148 mutations or L74M, E92Q, and G163R with N155H.¹³ Site-directed mutagenesis studies suggest that cross-resistance is likely to occur with other integrase inhibitors in development such as elvitegravir.¹⁴

Adverse effects
Common adverse effects reported to date with raltegravir include GI problems (nausea, diarrhea) and headache.^9-11,15 Grades 3 and 4 laboratory abnormalities observed during the 2 BENCHMRK studies were decreased absolute neutrophil count and elevated creatine kinase, alanine aminotransferase, and aspartate aminotransferase levels.^9,10 Raltegravir also was associated with grades 3 and 4 lipid abnormalities in these trials but not in studies with antiretroviral-naive patients. Patients who had hepatitis B or C coinfection tolerated raltegravir in a way similar to that seen in other patients.

Myopathy and rhabdomyolysis have been reported during raltegravir therapy; however, a causal relationship with raltegravir has not been established.^16,17 Analysis of all raltegravir double-blind phase 2 and phase 3 studies showed the relative risk of malignancy to be 1.2 cases per 100-patient years (95% confidence interval, 0.4 - 4.1).^9,10

Indications and dosing
Raltegravir is indicated for treatment-experienced HIV-1–infected adults with evidence of ongoing viral replication and multiple-drug resistance.¹⁷ It is available as pink 400-mg film-coated tablets and is administered as a 400-mg twice-daily dose without regard to food.¹⁷ No dose adjustment is required in patients with mild to moderate hepatic insufficiency or renal insufficiency.¹⁵

Raltegravir’s potential to affect the metabolism of other medications is low. Antacids should be avoided, however, because of the potential of the drug to bind to polyvalent cations (calcium, magnesium, iron). No interaction with gastric acid suppressants, such as proton pump inhibitors and H₂ antagonists, is anticipated.¹⁸

CHEMOKINE RECEPTOR ANTAGONISTS
More than 10 years ago, the chemokine receptors CCR5 and CXCR4 were identified as major coreceptors for the entry of HIV into target cells.^19,20 CCR5-tropic strains predominantly infect monocyte-derived macrophages and activated CD4⁺ cells, whereas CXCR4-tropic strains infect naive and resting T cells.

CCR5-tropic virus has been found to be common in early HIV infection and to then shift to CXCR4-tropic virus as the disease advances.²¹ CCR5- and CXCR4-receptor antagonists have been developed; however, only CCR5-receptor antagonists (maraviroc, vicriviroc) have advanced in clinical development to date.²² In late 2007, the FDA approved maraviroc as the first CCR5-coreceptor antagonist for the treatment of CCR5-tropic HIV-1 infection. Maraviroc is active against CCR5 strains of HIV-1 and not CXCR4 or dual-tropic strains.²³

Use of a tropism assay is necessary to identify patients who are likely to benefit from maraviroc therapy.²³ Inhibition of the CCR5 coreceptor prevents binding by the viral envelope protein (gp120), resulting in loss of membrane fusion.²⁴

Clinical studies
MOTIVATE-1 was a phase 3, multicenter, randomized trial involving 601 patients from the United States and Canada.²⁵ Participants received placebo, maraviroc 300 mg/d, or maraviroc 300 mg twice daily in addition to OBT. After 48 weeks of therapy, HIV-1 RNA levels decreased from baseline by 0.80, 1.66, and 1.82 log₁₀ copies/mL in the treatment arms, respectively. CD4⁺ cell counts increased by 54/µL, 113/µL, and 122/µL, respectively. The percentage of patients in whom an HIV-1 RNA level of less than 50 copies/mL was achieved was 16.1%, 41.8%, and 46.8%, respectively.

MOTIVATE-2 was identical in design to MOTIVATE-1 but enrolled patients in Europe, Australia, and North America.²⁶ After 48 weeks of therapy, HIV-1 RNA levels decreased from baseline by 0.76, 1.72, and 1.87 log₁₀ copies/mL, and CD4⁺ cell counts increased by 69/µL, 121/µL, and 128/µL in the placebo, maraviroc 300 mg/d, and maraviroc 300 mg twice-daily arms, respectively. The percentage of patients who achieved an HIV-1 RNA level of less than 50 copies/mL was 18%, 45%, and 45%, respectively.

The MERIT study was a 48-week worldwide trial that evaluated treatment-naive patients with CCR5-tropic virus.²⁷ Patients were randomly selected to receive maraviroc (300 mg/d or 300 mg twice daily) or efavirenz (600 mg/d) in combination with fixed-dose zidovudine/lamivudine twice daily. After 16 weeks of therapy, the once-daily maraviroc arm was discontinued because noninferiority to efavirenz could not be demonstrated.

After 48 weeks of therapy, the percentage of patients who achieved an HIV-1 RNA level of either less than 400 copies/mL or less than 50 copies/mL was 70.6% and 65.3%, respectively, in the maraviroc twice-daily arm and 73.1% and 69.3%, respectively, in the efavirenz arm. CD4⁺ cell counts increased from baseline by 170/µL and 143/µL in both arms, respectively. The MERIT study is planned to continue for a total of 96 weeks.

Resistance
Resistance to maraviroc emerges slowly and is associated with mutations at A316T and I323V in the V3 region of gp120.²⁸ Substitutions in the other variable regions of V1, V2, V4, and V5, as well as the conserved regions C1-C4 also may contribute.²⁹ Glycoprotein 120 mutants are capable of binding to drug-bound CCR5 receptors, resulting in noncompetitive inhibition of maraviroc.^28,28 Clinical failures in the MOTIVATE-1 and the MOTIVATE-2 trials may be attributable to the fact that the tropism assay’s sensitivity in detecting small populations of CXCR4-tropic virus at baseline was poor. A second-generation tropism assay that should minimize the problem is now available.^30,31

Adverse effects
In clinical studies of maraviroc, including the MOTIVATE-1 and the MOTIVATE-2 trials, the most frequently reported adverse reactions were cough, pyrexia, upper respiratory tract infections, rash, musculoskeletal symptoms, abdominal pain, and dizziness.^25-27 A black box warning for hepatotoxicity is found in the package insert.³¹ Hepatotoxicity may be preceded by a systemic allergic reaction that includes rash, eosinophilia, and an elevated IgE level.³¹

Indications and dosing
Maraviroc is indicated as combination therapy for the treatment of CCR5-tropic HIV-1 infection in adult patients with evidence of viral replication and resistance to multiple agents.³¹ The dosage is 300 mg twice daily without regard to meals. Maraviroc is metabolized primarily by cytochrome P-450 (CYP) 3A4.³² When it is administered with 3A4 inhibitors, the dosage is 150 mg twice daily; when administered with 3A4 inducers, the dosage is 600 mg twice daily.³¹ Caution should be used in patients who have a history of liver disease, hepatitis B or C coinfection, or renal dysfunction. Before initiation of therapy, viral tropism testing should be conducted to confirm the presence of CCR5-tropic strains.³³

NNRTIs
NNRTIs are common components of initial antiretroviral therapy.³ However, treatment failure can occur with a single amino acid substitution in HIV-1 reverse transcriptase, resulting in cross-resistance to existing NNRTIs and exclusion of the entire class as a treatment option in treatment-experienced patients.³⁴ In January 2008, the FDA approved etravirine, an NNRTI with activity against HIV-1, including a virus with NNRTI resistance–associated mutations. Etravirine has a highly flexible molecule that allows it to rotate in the binding pocket, enabling multiple binding conformations in the presence of mutations that cause resistance to first-generation NNRTIs.³⁵

Clinical studies
The efficacy and safety of etravirine in treatment-experienced patients are derived from an analysis of 24-week data from 2 ongoing, randomized, phase 3 trials (DUET-1 and DUET-2) with identical study designs.^36,37 DUET-1 enrolled a total of 612 patients from South America, Mexico, and the United States. Study patients received etravirine 200 mg or placebo twice daily in addition to darunavir with low-dose ritonavir and investigator-selected NRTIs. Enfuvirtide use was optional.

After 24 weeks of therapy, 56% of patients in the etravirine group and 39% of patients in the placebo group achieved HIV-1 RNA levels of less than 50 copies/mL (P = .005). The mean decrease in HIV-1 RNA level from baseline was 2.41 log₁₀ copies/mL compared with 1.70 log₁₀ copies/mL in the 2 treatment arms, respectively (P < .0001). CD4⁺ cell counts increased from baseline by 89/µL and 64/µL in the etravirine and placebo arms, respectively (P = .0002).³⁶

DUET-2 enrolled a total of 591 patients from Australia, Canada, and Europe. After 24 weeks of therapy, 62% of patients in the etravirine group and 44% of patients in the placebo group achieved HIV-1 RNA levels of less than 50 copies/mL (P = .0003). HIV-1 RNA levels decreased from baseline by 2.34 log₁₀ copies/mL compared with 1.67 log₁₀ copies/mL in the 2 treatment arms, respectively (P < .0001). CD4⁺ cell count increases between the 2 groups were not significantly different.³⁷

In the pooled DUET-1 and DUET-2 pre-planned analysis, 94% (DUET-1) and 90% (DUET-2) of patients in the etravirine groups who achieved HIV-1 RNA levels of less than 50 copies/mL at week 24 were able to sustain virological response to etravirine at week 48. HIV-1 RNA level decreased by 2.25 log₁₀ copies/mL and 1.49 log₁₀ copies/mL in the combined etravirine and placebo groups, respectively, at week 48 (P < .0001). CD4⁺ cell counts increased from baseline by 98/µL in the combined etravirine group versus 73/µL in the placebo group by week 48 (P = .0006). By week 48, the pooled etravirine group achieved higher virological responses than the placebo group regardless of the number of active agents used in the background regimen.^36,37

Resistance
Virological response to etravirine has been demonstrated to be dependent on the number and presence of sp

ecific mutations, with individual etravirine resistance–associated mutations that were assigned a relative weight score on the basis of the extent that they diminish etravirine activity (Table 2). A cumulative score of 0 to 2 is associated with a 74% response rate, whereas cumulative scores of 2.5 to 3.5 and 4.0 or greater are associated with response rates of 52% and 38%, respectively.³⁸ Presence of the K103N mutation at baseline is not associated with a reduced virological response.³⁹

Adverse effects
In clinical studies of etravirine, the most frequently reported adverse reactions were rash, diarrhea, nausea, headache, and fatigue. Most cases of rash were mild to moderate in severity, occurring primarily in the second week of therapy. Rash generally resolved within 1 to 2 weeks of therapy. In the clinical trials, 2.2% of patients discontinued treatment because of rash.^36,37

Indications and dosing
Etravirine is approved for use in combination therapy for HIV-1 infection in adult treatment-experienced patients with evidence of viral replication and resistance to NNRTIs and other antiretroviral agents. The recommended oral dosage of etravirine is 200 mg (two 100-mg tablets) twice daily following a meal. Patients who are unable to swallow the whole tablet may disperse it in a glass of water.⁴⁰

Because of the potential for metabolic interaction with other antiretrovirals, etravirine should not be coadministered with tipranavir/ritonavir, fosamprenavir/ritonavir, atazanavir/ritonavir, full-dose ritonavir, unboosted PIs, and other NNRTIs.⁴⁰ Lopinavir/ritonavir increases the etravirine area under the curve (AUC) by 85% and should be used with caution.⁴⁰ Etravirine should not be coadministered with carbamazepine, phenobarbital, phenytoin, rifampin, rifabutin, or St Johns wort because of the potential for subtherapeutic etravirine concentrations.⁴¹

PROTEASE INHIBITORS
PIs continue to serve a pivotal role in the therapeutic management of HIV infection in treatment-naive and treatment-experienced patients. However, increasing drug resistance among first-generation PIs has resulted in the need for newer agents that retain activity in the presence of multiple PI mutations.⁴² In 2006, the FDA approved darunavir for treatment-experienced patients. Approval for once-daily dosing in treatment-naive patients was granted in 2008.⁴³ The mechanism of action of darunavir is similar to that of other PIs in that it selectively inhibits cleavage of gag-pol polyproteins in infected cells, thereby preventing maturation of new virus particles.^43,44

Clinical studies
The efficacy and safety of darunavir in treatment-experienced patients are primarily based on 24-week data from 2 ongoing, randomized, placebo-controlled, phase 2b trials: POWER-1 and POWER-2.^45,46 The trials are identical in design. Their only difference is geographical location. A total of 637 patients have been enrolled.

Study patients were randomly selected to receive either 1 of 4 darunavir/ritonavir regimens (400/100 mg or 800/100 mg once daily, 400/100 mg or 600/100 mg twice daily) or an investigator-selected PI with OBT. OBT consisted of at least 2 NRTIs with or without enfuvirtide and excluded NNRTIs. Enfuvirtide was used in 47% of patients, 35% of whom were enfuvirtide-naive.

After 24 weeks of therapy, 63% of patients in the combined darunavir group and 19% of patients in the comparator PI group achieved HIV-1 RNA levels of less than 400 copies/mL (P < .001); 45% versus 12% achieved HIV-1 RNA levels of less than 50 copies/mL, respectively (P < .001). HIV-1 RNA levels decreased from baseline by 1.89 log₁₀ copies/mL and 0.48 log₁₀ copies/mL in the treatment arms, respectively (P < .001). CD4⁺ cell counts increased from baseline by 92/µL and 17/µL, respectively (P < .001). After the primary analysis cut-off date, all patients receiving darunavir were switched to a 600/100 mg twice-daily regimen.⁴⁷

The efficacy of darunavir/ritonavir in less treatment-experienced patients was assessed in the ongoing 96-week phase 3 TITAN trial that enrolled adult patients who had received a minimum of 12 weeks of antiretroviral therapy and were lopinavir-naive. Study patients were randomly selected to receive darunavir/ritonavir (600/100 mg twice daily; n = 298) or lopinavir/ritonavir (400/100 mg twice daily; n = 297) with an investigator-selected OBT. The OBT consisted of at least 2 antiretroviral agents (NRTIs with or without NNRTIs); enfuvirtide use was not allowed.

Prior or current use of lopinavir, darunavir, tipranavir, enfuvirtide, or current use of investigational agents also was exclusionary. The primary objective of the study was to determine whether darunavir/ritonavir was noninferior to lopinavir/ritonavir in virological response (HIV-1 RNA level less than 400 copies/mL) at week 48.

The intent-to-treat (ITT) analysis showed that after 48 weeks, 77% and 67% of patients achieved HIV-1 RNA levels of less than 400 copies/mL (P < .0001) and 71% and 60% achieved HIV-1 RNA levels of less than 50 copies/mL (P < .005) in the darunavir and lopinavir groups, respectively. HIV-1 RNA levels decreased from baseline by 1.95 log₁₀ copies/mL and 1.72 log₁₀ copies/mL in the 2 treatment arms, respectively (P = .046). CD4⁺ cell count changes in the 2 groups were not statistically different (P = .33).

The rate of discontinuation because of adverse events was similar (7%) in the 2 groups; however, more patients discontinued lopinavir/ritonavir because of diarrhea and liver and lipid abnormalities. On the basis of the criterion specified at the onset of the trial, virological response with darunavir/ritonavir was superior to that with lopinavir/ritonavir in the ITT study population.⁴⁸

ARTEMIS was a phase 3 open-label trial that examined the efficacy of darunavir/ritonavir (800/100 mg once daily) versus lopinavir/ritonavir (either 400/100 mg twice daily or 800/200 mg once daily), both with the fixed-dose combination of tenofovir/emtricitabine. A total of 689 treatment-naive patients were enrolled. The primary objective of the study was to demonstrate whether darunavir/ritonavir was noninferior to lopinavir/ritonavir on the basis of virological response (HIV-1 RNA level less than 50 copies/mL) at week 48. Follow-up to 96 weeks has been reported and the results are consistent with the 48-week results.

After 96 weeks, 79% of the patients in the darunavir group and 71% of the patients in the lopinavir group achieved HIV-1 RNA levels of less than 50 copies/mL (P < .001 for noninferiority; P = .012 for superiority). CD4⁺ cell counts increased from baseline by 188/µL and 171/µL in the 2 groups, respectively.

Virological failure and diarrhea were more common in patients receiving once-daily lopinavir/ritonavir; elevations in cholesterol and triglyceride levels were more common with lopinavir/ritonavir than with darunavir/ritonavir.⁴⁹

Resistance
Eleven specific darunavir resistance–associated mutations have been identified and include V11I, V32I, L33F, I47V, I50V, I54L, I54M, G73S, L76V, I84V, and L89V. A reduced virological response to darunavir/ritonavir has been observed in patients with 3 or more of these mutations at baseline.^50,51

Adverse effects
In clinical studies of darunavir, the most frequently reported adverse effects were diarrhea (14%), nausea (10%), headache (15%), and nasopharyngitis (11%).⁴⁷ Diarrhea and neutropenia were the most frequently seen grade 3 or 4 abnormalities (2%).

Laboratory abnormalities included elevations in amylase and lipase levels, but no clinical cases of pancreatitis were reported. The lipid parameters in the POWER studies remained largely unchanged from baseline in the darunavir arms after 24 weeks. The frequency of elevations in liver enzyme levels in patients with hepatitis B or C coinfection receiving darunavir was similar to that observed in the remaining study population.⁴⁷

Indications and dosing
Darunavir is indicated for the treatment of HIV-1 infection in treatment-naive adult patients and for those treatment-experienced patients who have resistance to 1 or more PIs when used in combination with ritonavir and other antiretrovirals.⁴³ For treatment-naive patients, the recommended oral dosage is 800 mg (two 400-mg tablets) coadministered with 100 mg of ritonavir twice daily following a meal. For treatment experienced patients, 600 mg (one 600-mg tablet) coadministered with 100 mg of ritonavir twice daily following a meal is recommended.⁴³

Ritonavir inhibits darunavir metabolism, resulting in a 14-fold increase in darunavir AUC and is used clinically to optimize darunavir’s serum concentration profile.^43,52 Lopinavir/ritonavir should not be used concomitantly with darunavir because of reduction in the darunavir minimum concentration by 55% despite darunavir and ritonavir dosage increases to compensate for the interaction.⁵³

ROLE OF THESE NEW AGENTS
The role of raltegravir, maraviroc, darunavir, and etravirine in therapy needs to be more fully defined. With the exception of darunavir, all are currently approved only for treatment-experienced patients.

Raltegravir, darunavir, and etravirine are commonly used in patients with extensive drug resistance, particularly when multiple PI mutations are present.⁵⁴ Preliminary study findings on raltegravir in treatment-naive patients seem promising; however, no definitive conclusions can be made until the study results are published in a peer-reviewed journal.

Etravirine has not been studied without concurrent PI therapy, so its efficacy when combined solely with NRTIs has not been determined.^36,37 Once-daily darunavir has recently been added to the list of preferred agents for initial treatment of antiretroviral-naive patients.^3,55

Maraviroc use in treatment-experienced patients is limited by the high frequency of dual or mixed tropic virus in the HIV-infected population and the high cost of the tropism assay. Further study is needed to define its role in earlier stages of HIV infection.

References:

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