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New protease inhibitors and non-nucleoside reverse transcriptase inhibitors.

INTRODUCTION

In spite of major progress in the field of antiretroviral drug development, there continues to be a need for more potent and better-tolerated antiretroviral treatments and in particular, therapies that are effective for the increasing pool of treatment-experienced patients.

This review focuses on the new protease inhibitors (PI) and non-nucleoside reverse transcriptase inhibitors (NNRTI) that are currently available for clinicians to prescribe and explores their potential niche in antiretroviral treatment choices. Drugs that are still in development and are inaccessible outside clinical trials are not discussed, nor are new formulations of well-established agents.

NEW PROTEASE INHIBITORS

Darunavir (TMC114, DRV) and tipranavir (TPV) are important new ritonavir-boosted protease inhibitors, with efficacy in patients who have had prior treatment failure with this class and whose viruses exhibit extensive resistance-conferring mutations in the protease gene. There are no head-to-head comparisons between these two new drugs, but the existing data can help guide the prescriber when deciding between them. The nuances of the mutation patterns that impair the efficacy of one more than the other can help identify which may perform better for individual patients. Tolerability and the potential for drug-drug interactions are also important considerations when choosing between these two agents.

Concerns regarding toxicity and drug-drug interactions make ritonavir-boosted tipranavir (TPV/r) an unlikely first choice for treatment-experienced patients whose resistance profiles indicate that they may respond to ritonavir-boosted darunavir (DRV/r). In addition to its efficacy when dosed at 600/100 mg twice daily in patients with protease-inhibitor resistance, DRV/r 800/100 mg once daily has also performed well head-to-head against ritonavir-boosted lopinavir (LPV/r) in naive patients, and competes favourably with the existing repertoire of first-line boosted PIs. Tipranavir is not recommended for treatment-naive patients who may choose from a range of more tolerable and less toxic regimens.

DARUNAVIR

Darunavir has a strong binding affinity for the HIV-1 protease and has been shown to be effective in vitro against wild type and multi-drug-resistant strains ofHIV [1-3]. The clinical efficacy of darunavir was first demonstrated in highly treatment-experienced patients with previous triple-class exposure and advanced HIV disease (POWER trials; [4]). The potential clinical use of darunavir was then explored in less treatment-experienced patients who were lopinavir-naive (TITAN), followed by ongoing trials in treatment-naive patients (ARTEMIS).

EFFICACY IN SALVAGE

The POWER trials [4] demonstrated the efficacy and safety of darunavir with low-dose ritonavir at week 48 in highly treatment-experienced patients. After 24-week dose-finding phases and primary efficacy analyses, patients were randomised to receive DRV/r 600/100 mg twice daily, and patients receiving investigator-chosen control protease inhibitors continued on assigned treatment into the longer-term, open-label phase; all patients continued on optimised background therapy (OBT). The use of enfuvirtide was permitted as part of the OBT, but not of tipranavir, another new and potent PI with good activity in the setting of multiple PI mutations [5]. Patients were assessed at week 48 in an intent-to-treat (ITT) analysis. The results for those who discontinued earlier were considered to be treatment failures for virological response (in a time to loss of virological response algorithm [TLOVR]). At week 48, 67 of 110 (61%) DRV/r patients compared with 18 of 120 (15%) control PI patients achieved a viral load drop of at least 1 [log.sub.10] copies/ml (primary end-point), with a highly significant difference in response rates (46%; 95% confidence interval [CI] 35-57%; P<0.0001).

EFFICACY IN TREATMENT-EXPERIENCED PATIENTS

The efficacy and safety of DRV/r was further assessed in lopinavir-naive treatment-experienced patients (TITAN), where the main aim of the study was to show non-inferiority of DRV/r 600/100 mg twice daily compared with LPV/r 400/100 mg twice daily in terms of virological response. Both agents were given in addition to an OBT. In contrast to the POWER trials, where DRV/r already seemed superior to LPV/r, the patients selected here were less treatment-experienced and the use of enfuvirtide was not permitted, aiming to reduce selection bias and focus on the intrinsic antiviral efficacy of darunavir compared to lopinavir. Results from TITAN showed that more patients in the DRV/r arm compared to the LPV/r arm achieved HIV-RNA <400 copies/ml at 48 weeks (77% vs. 67%; 95% CI 2-17; P<0.0001). As the lower limit of the confidence limit (2%) in the intention-to-treat analysis did not include 0%, these results suggested superiority of DRV/r compared to LPV/r in this setting. The virological efficacy results of boosted lopinavir seen here were consistent with previously reported efficacy results in treatment-experienced patients [6,7]. There was no difference in the CD4 cell count increases in either treatment arm.

EFFICACY IN NAIVE PATIENTS

In ARTEMIS, DRV/r is being assessed as a single-dose agent 800/100 mg in treatment-naive patients against LPV/r in addition to the fixed-dose combination Truvada (tenofovir/emtricitabine) in both arms. Preliminary data analysis (ITT-TLOVR algorithm) at week 48 [8] showed that 84% of patients in the DRV/r arm achieved a viral load <50 copies/ml compared to 78%in the boosted lopinavir arm, and this was statistically significant (P<0.005), suggesting that darunavir is non-inferior to lopinavir in treatment-naive patients. Furthermore, DRV/r seemed superior to Kaletra in patients with high baseline viral loads greater than 100,000 copies/ml, where 79% in the DRV/r arm versus 67% in the LPV/r arm had viral loads less than 50 copies/ml (P<0.05).

SAFETY AND TOLERABILITY OF DARUNAVIR

As with most other members of the protease inhibitor class, gastrointestinal side-effects, predominantly diarrhoea and lipid disturbance, are the main toxicities to consider when prescribing darunavir. The safety and tolerability of DRV/r in TITAN was similar to that reported previously in the POWER studies where both ritonavir-boosted darunavir and lopinavir led to lipid abnormalities (incidence of hypertriglyceridaemia was 5% or greater in both groups), possibly due to the use of ritonavir as boosting agent. In terms of safety and tolerability DRV/r once daily 800/100 mg in treatment-naive patients (ARTEMIS) was well tolerated and the incidence of gastrointestinal side-effects and triglyceride elevations appeared to be lower than in the lopinavir arm. In the lopinavir arm, 7% of patients (vs. 3%) discontinued due to adverse events and specifically there was a significant difference in diarrhoea rates (4% darunavir arm vs. 10% lopinavir arm) [7]. There was no significant change in renal function in either boosted PI arm. Rates of hepatotoxicity were similar in both arms during the 48-week follow-up; however, there are increasing reports of darunavir-associated hepatotoxicity [9]

RESISTANCE PROFILE OF DARUNAVIR

Modelling and crystallography studies of the HIV-1 protease enzyme showed unusual binding characteristics for darunavir that predicted a higher genetic barrier to the development of resistance and greater activity against resistant virus compared to earlier PIs [2]. In vitro studies have shown that darunavir is not only active against wildtype and multi-drug-resistant viruses, but also that selection of darunavir-resistant HIV from wild type is slower than for other PIs, due to the strong binding characteristics of darunavir to the HIV protease. The resistance profile of darunavir was further studied through analysis of pooled week-24 clinical data from the POWER 1, 2 and 3 studies, where DRV/r 600/100mg was used twice daily in the setting of HIV-treatment-experienced patients [10].

Virological response to boosted darunavir occurred even in the presence of a high number of IAS-USA protease inhibitor resistance-associated mutations and a diminished response to DRV/r was seen if more than 14 PI resistance-associated mutations were present. Two predictors of response to darunavir were identified that may aid the clinician in making therapeutic decisions. First, 11 protease mutations associated with diminished DRV/r virological response were identified: V11I, V32I, L33F, I47V, I50V, I54L, I54M, G73S, L76V, I84V, and L89V. These darunavir resistance-associatedmutations occurred in the presence of a high number of IAS-USA protease resistance-associated mutations. Table 1 summarises the darunavir-associated mutations alongside mutations associated with tipranavir and etravirine resistance. Secondly, baseline darunavir fold change in EC50 (FC) was identified as a strong predictor of virological response and two phenotypic clinical cutoff (CCO) values for boosted darunavir were defined (low CCO=10 and upper CCO=40). These CCO values may aid clinicians who have access to phenotypic information. Whether patients with a few mutations in protease can be safely treated with the 800/100 mg dose of darunavir remains to be explored.

TIPRANAVIR

Tipranavir is a novel protease inhibitor with a unique resistance profile.

EFFICACY IN SALVAGE

Two large clinical trials, RESIST 1 and 2 [5], looked at ritonavir-boosted tipranavir (TPV/r 500/100mg twice daily) in heavily treatment-experienced patients with triple-class exposure, who had failed at least two PI-based regimens and had no more than two PI mutations at position 33, 82, 84 or 90. Patients in the control group received investigator-chosen PIs (except darunavir, which was not available) and the use of enfuvirtide was permitted. Week 48 data showed that patients taking boosted tipranavir were twice as likely to experience a treatment response (defined as HIV viral load reduction of ?1.0 [log.sub.10] copies/ml) as those in the control group were. The response was maintained long term, especially in patients taking enfuvirtide or other active drugs, confirming that boosted tipranavir can produce greater viral suppression than previously boosted PI regimens. Although there are no head-to-head comparisons between tipranavir and darunavir, an analysis comparing results from the POWER and RESIST studies suggested that boosted darunavir may outperform tipranavir in patients not taking enfuvirtide. This data should be interpreted with caution, given the limitations of this type of analysis [11].

EFFICACY IN NAIVE PATIENTS

A study in naive patients using tipranavir in different dosing regimens (BI trial 1188.33) was recently stopped due to the increased liver toxicity in the tipranavir arm, making the earlier use of tipranavir unlikely.

SAFETY AND TOLERABILITY

The use of tipranavir, which is metabolised through the CYP3A4, is limited by significant drug interactions. There is a risk of serious adverse events if co-administered with certain anti-arrhythmics, antihistamines, ergot derivatives, sedatives, increased risk of rhabdomyolysis with simvastatin and subtherapeutic levels with rifampicin. Additionally, tipranavir may have an effect on the plasma levels of other antiretroviral drugs and dose adjustment has not yet been established (2005 Boehringer Ingelheim International GmbH) [12]. Co-administration of abacavir, zidovudine or double PI use in addition to tipranavir is so far not recommended [12]. The risk of hepatotoxicity is also increased.

TIPRANAVIR RESISTANCE

Primary tipranavir resistance develops slowly and involves several specific protease genemutations, such as I13V, V32I, L33F, K45I, I84V and V82L [13,14]. All these mutations have been previously associated with PI resistance, except V82L, which seems to be unique to TPV [15]. Although V82L alone does not confer resistance to tipranavir, it contributes to a 2.4-fold increase when selected on a background of five pre-existing protease mutations. The results also suggest that although the majority of mutations selected do not differ significantly from mutations selected by other PIs, the genetic barrier for the development of resistance is higher for tipranavir.

Interestingly, new data shows that patients who develop resistance to darunavirmay still benefit from tipranavir use [16,17].

NEW NNRTIS

The newly available NNRTI, etravirine (TMC-125) is the first drug available in this class to demonstrate activity against HIV-1 strains displaying the single or double mutations that are associated with resistance to efavirenz and nevirapine. It is important, however, for prescribers to note that the efficacy of etravirine in patients with NNRTI-resistance, has been demonstrated when the drug was given in conjunction with darunavir/ritonavir--a combination that provides a significant genetic barrier to the virus. Etravirine is an important component in the armamentarium to help treatment-experienced patients, but these results cannot be extrapolated to its use with just a dual nucleoside backbone in patients with NNRTI-resistance. There is no evidence to support switching from efavirenz/nevirapine to etravirine in a patient failing a first-line dual nucleoside-NNRTI regimen and this approach is not recommended, since the risk of losing etravirine as an important part of a future salvage regimen is too great.

The efficacy of etravirine was established by the DUET 1 and 2 studies [18,19], which differed only in their geographical locations. The trial recruited patients on failing antiretroviral combination regimens, with at least one NNRTI resistance-associated mutation at screening or on historical genotype. Other eligibility criteria included at least three primary protease mutations at screening, receipt of stable antiretroviral therapy for 8 weeks and HIV viral load greater than 5000 copies/ml. All patients received background antiretroviral therapy with DRV/r (600/100 mg twice daily), which was the only permitted PI in the study, in addition to optimised NRTI and optional enfuvirtide, based on screening genotype and historical treatment or resistance reports. DUET 1 data at week 48 [20,21] showed that 60% of 304 patients in the etravirine plus optimised background regimen had an HIV viral load <50 copies/ml compared to only 39% of the 308 patients on placebo and optimised background in the control arm (P<0.0001 in an ITTTLOVR analysis). Given the significant statistical interaction between the use of enfuvirtide and etravirine, patients were stratified according to use of enfuvirtide de novo or re-using/not using enfuvirtide. DUET 2 data analysis [21] showed that of the patients re-using or not using enfuvirtide, there were 57% in the etravirine arm compared to 33% in the placebo arm who maintained an HIV viral load <50 copies/ml at week 48 (P<0.0001).

SAFETY AND TOLERABILITY

Week 48 safety data [21] was similar to 24-week data [18,19], showing that the incidence and severity of adverse events in the etravirine arm were similar to placebo, as were treatment-emergent liver and lipid abnormalities. The incidence of rash was 22% in DUET 1 versus 11% in placebo (P=0.0003) and occurred in the second week of treatment [21]. The rash was only mild to moderate, only rarely leading to treatment discontinuation (2% DUET 1 and 2.4% in DUET 2). CNS side-effects were similar between the etravirine and control arms.

RESISTANCE PROFILE OF ETRAVIRINE

Results from the DUET studies suggest that the use of etravirine is possible after virological failure on first generation NNRTIs. Preliminary analysis from these studies identified 13 mutations associated with decreased response to etravirine: V90I, A98G, L100I, K101E, K101P, V106I, V179D, V179F, Y181C, Y181I, Y181V, G190A, and G190S. The presence of three or more mutations concurrently was required to substantially reduce efficacy [19,22].

The potential impact of etravirine-associated mutations was further analysed in a large number of clinical isolates, which were sent for routine clinical testing to Virco during 1999-2007 (226,491 samples of which approximately 40% had NNRTI resistance). The likelihood of a response to etravirine was estimated by determining the prevalence of each etravirine resistance-associated mutation and the frequency of various combinations [23].

The etravirine resistance-associated mutations with the highest impact on response in the DUET studies (V179D, V179F, Y181V and G190S) exhibited some of the lowest prevalence rates among routine clinical resistance testing samples, ranging from 0.4% (V179F) to 4% (G190S), and were rarely observed among the top five combinations of two mutations. These data suggest that the coexistence of three or more etravirine resistance-associated mutations is rare, and thus a diminished virological response is infrequent even in patients with evidence of resistance to first-generation NNRTIs [23].

Further emerging data [24] emphasises that single major mutations such as Y181C/I/V may also reduce etravirine susceptibility, although multiple mutations are required to confer a high level of resistance [25, 26].

SUMMARY

The arrival in our clinics of darunavir, tipranavir and etravirine is an important advance in the repertoire of treatments available to patients living with HIV, broadening their options and specifically enhancing the performance of therapy in those who have resistance in the protease inhibitor and NNRTI classes. Patients and their physicians can be further encouraged by the knowledge that there are several other compounds (such as the new NNRTI rilpivirine) that are advancing through clinical drug development and may soon be available in the clinic. New classes of antiretroviral agents are also coming into use, and the best ways to combine these agents are still being explored; however, the protease inhibitor class, in particular, continues to play an important role in most combinations for the treatment-experienced patient, and appears likely to do so in the future.

REFERENCES

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[2.] Surleraux DL, Tahri A, Verschueren WG et al. Discovery and selection of TMC114, a next generation HIV-1 protease inhibitor. J Med Chem, 2005, 48, 1813-1822.

[3.] King NM, Prabu-Jeyabalan M, Nalivaika EA et al. Structural and thermodynamic basis for the binding of TMC114, a next-generation human immunodeficiency virus type 1 protease inhibitor. J Virol, 2004, 78, 12012-12021.

[4.] Clotet B, Bellos N, Molina JM et al. Efficacy and safety of darunavirritonavir at week 48 in treatment-experienced patients with HIV-1 infection in POWER 1 and 2: a pooled subgroup analysis of data from two randomised trials. Lancet, 2007, 369, 1169-1178.

[5.] Hicks CB, Cahn P, Cooper DA et al. Durable efficacy of tipranavirritonavir in combination with an optimised background regimen of antiretroviral drugs for treatment-experienced HIV-1-infected patients at 48 weeks in the Randomized Evaluation of Strategic Intervention in multi-drug reSistant patients with Tipranavir (RESIST) studies: an analysis of combined data from two randomised open-label trials. Lancet, 2006, 368, 466-475.

[6.] Johnson M, Grinsztejn B, Rodriguez C et al. Atazanavir plus ritonavir or saquinavir, and lopinavir/ritonavir in patients experiencing multiple virological failures. AIDS, 2005, 19, 685-694.

[7.] Benson CA, Deeks SG, Brun SC et al. Safety and antiviral activity at 48 weeks of lopinavir/ritonavir plus nevirapine and 2 nucleoside reverse-transcriptase inhibitors in human immunodeficiency virus type 1-infected protease inhibitor-experienced patients. J Infect Dis, 2002, 185, 599-607.

[8.] DeJesus E, Ortiz R, Khanlou H, et al. Efficacy and safety of darunavir/ritonavir versus lopinavir/ritonavir in ARV treatment-naive HIV-1-infected patients at week 48: ARTEMIS. 47th Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, September 2007. Abstract H-718b.

[9.] Vispo E.Warning on hepatotoxicity of darunavir. AIDS Rev, 2008, 10, 63.

[10.] de Meyer S, Vangeneugden T, van Baelen BG et al. Resistance profile of darunavir: combined 24-week results from the POWER trials. AIDS Res Hum Retroviruses 2008, 24, 379-388.

[11.] Hill A, Moyle G. Relative antiviral efficacy of ritonavir-boosted darunavir and ritonavir-boosted tipranavir vs. control protease inhibitor in the POWER and RESIST trials. HIV Med, 2007, 8, 259-264.

[12.] Boffito M, Maitland D, Pozniak A. Practical perspectives on the use of tipranavir in combination with other medications: lessons learned from pharmacokinetic studies. J Clin Pharmacol, 2006, 46, 130-139.

[13.] Doyon L, Tremblay S, Bourgon L et al. Selection and characterization of HIV-1 showing reduced susceptibility to the non-peptidic protease inhibitor tipranavir. Antiviral Res, 2005, 68, 27-35.

[14.] Naeger LK, Struble KA. Food and Drug Administration analysis of tipranavir clinical resistance in HIV-1-infected treatment-experienced patients. AIDS, 2007, 21, 179-185.

[15.] Johnson VA, Brun-Vezinet F, Clotet B et al. Update of the drug resistance mutations in HIV-1: Fall 2005. Top HIV Med, 2005, 13, 125-131.

[16.] Poveda E, de Mendoza C, Parkin N et al. Evidence for different susceptibility to tipranavir and darunavir in patients infected with distinct HIV-1 subtypes. AIDS, 2008, 22, 611-616.

[17.] Pierone G, Jr, Urban T, Martin A et al. Successful use of a tipranavir/ritonavir-based antiretroviral regimen following development of viral resistance to darunavir. HIV Clin Trials, 2008, 9, 140-141.

[18.] Lazzarin A, Campbell T, Clotet B et al. Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-2: 24-week results from a randomised, double-blind, placebo-controlled trial. Lancet, 2007, 370, 39-48.

[19.] Madruga JV, Cahn P, Grinsztejn B et al. Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-1: 24-week results from a randomised, double-blind, placebo-controlled trial. Lancet, 2007, 370, 29-38.

[20.] Haubrich R, Cahn P, Grinsztejn B et al.; on behalf of the DUET-1 study group DUET-1: week-48 results of a phase III randomized double-blind trial to evaluate the efficacy and safety of TMC125 vs placebo in 612 treatment-experienced HIV-1 infected patients. 15th Conference on Retroviruses and Opportunistic Infections, Boston, February 2008. Abstract 790.

[21.] Johnson M, Campbell T, Clotet B et al.; on behalf of the DUET-2 study group. DUET-2: week-48 results of a phase III randomized double-blind trial to evaluate the efficacy and safety of TMC125 vs placebo in 591 treatment-experienced HIV-1-infected patients. 15th Conference on Retroviruses and Opportunistic Infections, Boston, February 2008. Abstract 791.

[22.] Vingerhoets J, Buelens A, M et al. Impact of baseline NNRTI mutations on the virological response to TMC125 in the Phase III clinical trials DUET-1 and DUET-2. XVI International HIV Drug Resistance Workshop, Barbados, June 2007. Abstract 32.

[23.] Picchio G, Vingerhoets J, Staes M et al. Prevalence of TMC125 resistance-associated mutations in a large panel of clinical isolates. 15th Conference on Retroviruses and Opportunistic Infections, Boston, February 2008. Abstract 866.

[24.] Vingerhoets J, Peeters M, Azijn H et al. An update of the list of NNRTI mutations associated with decreased virological response to etravirine: multivariate analysis on the pooled DUET-1 and DUET-2 clinical trial data. XVIIth International HIV Drug Resistance Workshop, Sitges, June 2008. Abstract 24.

[25.] Peeters M, Nijs S, Vingerhoets J et al. Determination of phenotypic clinical cut-offs for etravirine: pooled week 24 results of the DUET-1 and DUET-2 trials. XVIIth International HIV Drug Resistance Workshop, Sitges, June 2008. Abstract 121.

[26.] Coakley E, Chappey C, Benhamida J et al. Biological and clinical cutoff analysis or etravirine in the PhenoSense HIV assay. XVIIth International HIV Drug Resistance Workshop, Sitges, June 2008. Abstract 122.

Correspondence to: Dr R. Monica Lascar, Mortimer Market Centre, off Capper St, London WC1H 6AU, UK. Email: monix@doctors.net.uk
Table 1: Summary of current knowledge on darunavir, tipranavir and
etravirine resistance-associated mutations

Resistance-associated
mutations List Comments

Darunavir-associated V111, V321, L33F, Gradual reduction in
mutations I47V, I50V, I54L/M, efficacy with
 T74V, L76V, I84V, and increasing number of
 L89V mutations (at least
 three or more on
 background of >14
 protease associated
 mutations) [9]

Tipranavir-associated I13V, V32I, L33F, Darunavir-resistant
mutations K45I, I84V#, V82L# virus may retain
 tipranavir
 sensitivity (15,16]

Etravirine-associated V90I, A98G, L100I, Three or more
mutations K101E, K101P, V106I, mutations may lead to
 Y181C#, Y181I#, decreased response
 Y181V#, G190A/S,V179D,
 V179F

Drug resistance-associated mutations in bold are those with the
greatest impact on virological response

Note: bold are those with the greatest impact on virological response,
indicated with #.
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Title Annotation:LEADING ARTICLE
Author:Lascar, Monica; Cartledge, Jonathan D.
Publication:Journal of HIV Therapy
Article Type:Drug overview
Geographic Code:4EUUK
Date:Jun 1, 2008
Words:3759
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