Overview of ARV studies at IAS

HIV Treat Bull - 2009 Sep/Oct;10(9/10): 03

Simon Collins, HIV i-Base

The conference included a broad range of important studies that could inform use of currently approved drugs, and first results of a new integrase inhibitor.

First results of new integrase compound: GSK1349572

Three posters at the meeting provided insight into a new compound in development from Shionogi and GSK.

Lalezari and colleagues presented first virological efficacy data from a 10-day Phase IIa dose-finding study (2, 10 and 50mg monotherapy or placebo, all once-daily) of GSK1349572 (GSK572) in 35 treatment-naïve patients.^[1]

Patients in the 50 mg arm showed a mean viral load drop of almost 2.5 logs and 7/10 patients in this arm had viral load reductions to <50 copies/mL.

The 10 mg and 2 mg doses reached mean viral load declines of approximately -2.0 and -1.5 logs respectively. No serious side effects were observed and reported events were generally similar to the placebo group.

Two pharmacology studies showed the advantages of limited interpatient variability and an indication that the 50mg dose left a significant safety buffer before activity dropped, and that higher doses were unlikely to increase activity. Median half-life was 15 hours. Steady state geometric mean (CV%) AUC_(0-24) and C_max ranged from 16.7 (15) µg.h/mL and 1.5 (24) µg/mL at 10 mg once daily to 76.8 (19) µg.h/mL and 6.2 (15) µg/mL at 50 mg once daily. The geometric mean steady-state C24 at 50 mg was 1.5 µg/mL which is ~23-fold higher than the in vitro protein-adjusted IC₉₀.^{[2, 3]}

In vitro results with a broad panel of resistant isolates, suggested minimal cross-resistance to elvitegravir and raltegravir. with high level resistance only developing after serial passaging for 56 and 84 days respectively.^[4]

A second resistance poster looking at GSK572 susceptibility to a range of common integrase mutation patterns seen in raltegravir and elvitegravir studies (based on limited in vivo data), suggested that cross-resistance with other integrase inhibitors might be sufficiently likely for GSK572 not to be able to rescue people with previous integrase resistance. For example, although G140S/Q148H resulted in a median fold-change in susceptibility of less than 4-fold (n=7), G140S/Q148R lead to a range of around 8-19-fold changes (n=2). By comparison both these dual mutations confer high-level phenotypic resistance to raltegravir (>87-fold).^[5]

Of note, in addition to greater virological impact during a short monotherapy than other currently used drugs, this compound is being developed as a once-daily drug, does not require boosting and PK is unaffected by food.

References:

1. Lalezari J et al. Potent antiviral activity of S/GSK1349572: a next generation integrase inhibitor (INI), in INI-naïve HIV-1-infected patients: ING111521 protocol. IAS Conf HIV Pathog Treat 2009 Jul 19-22;5th: Abstract TUAB105.
2. Song I et al. Pharmacokinetic (PK) and pharmacodynamic (PD) relationship of S/GSK1349572, a next generation integrase inhibitor (INI), in HIV-1 infected patients. IAS Conf HIV Pathog Treat 2009 Jul 19-22;5th: Abstract WEPEB250.
3. Min S et al. Pharmacokinetics (PK) and safety in healthy subjects of S/GSK1349572, a next generation, once-daily HIV integrase inhibitor (INI). IAS Conf HIV Pathog Treat 2009 Jul 19-22;5th: Abstract WEPEA099.
4. Sato A et al. S/GSK1349572 is a potent next generation HIV integrase inhibitor. IAS Conf HIV Pathog Treat 2009 Jul 19-22;5th: Abstract WEPEA097.
5. Underwood M et al. S/GSK1349572: a next generation integrase inhibitor with activity against integrase inhibitor-resistant clinical isolates from patients experiencing virologic failure while on raltegravir therapy. IAS Conf HIV Pathog Treat 2009 Jul 19-22;5th: Abstract WEPEA098.

Raltegravir in treatment-naïve patients

In July 2009, raltegravir was approved in the US as first-line therapy, and also received a positive opinion from the CHMP for a similar indication in Europe, based on 48-week results from the STARTMRK trial.^{[5, 6]}

In summary, raltegravir showed similar virological efficacy compared to efavirenz (86% vs 82% <50 copies/mL at week 48), when used with tenofovir+FTC.^[7]

At the IAS conference, longer-term safety data was available from 144-week follow-up from the initial dose-finding study (Protocol 004), where, after the first year, all patients (n=160) were switched to, or continued receiving, raltegravir at the 400mg twice-daily dose.^[8]

Viral efficacy remained similar between the two arms (78% vs 76% <50 copies/mL). Drug-related side effects were similar or less frequent in the raltegravir arm, as were grade 3/4 laboratory abnormalities (except pancreatic amylase (>2xULN: 2.5% vs 0) and creatinine kinase (10 xULN: 8.8% vs 2.6%). Lipid changes in combined raltegravir groups were not sgnificant for total cholesterol, LDL-cholesterol or triglycerides and HDL-cholesterol increased by a mean of +6.6 mg/dL (compared to +11.7 in the efavirenz arm). This meant that there was no significant difference in the total:HDL ratio between the two groups (-0.5 vs -0.4, p=0.451).

Comment:

Although in a limited number of patients, this extended safety and efficacy data are encouraging.

To date, this more favourable lipid profile has not led to differences in body composition. A study presented at ICAAC as HTB went to press that we will report in full in the next issue showed similar DEXA results when compared to efavirenz at 48 weeks.^[9]

Given that fat accumulation is one of the principal concerns for patients, and the mechanism is still unexplained, preliminary data should be made available for bone and body fat changes with all new drugs at the same time as other efficacy and safety data.

Ten years after lipodystrophy was identified as a major side effect, it is not acceptable to have wait for years after approval for these results.

However, another study at ICAAC reported encouraging data in respect to raltegravir activity in the CSF.^[10]

Currently, access to raltegravir is imited for patients in the UK who could benefit from it’s tolerability profile, due to the high cost.

References:

5. Isentress (raltegravir) indication extended for the treatment of HIV-1 infection in treatment-naïve patients. FDA announcement (08 July 2009).
6. CHMP post-authorisation summary of postive opinion from Isentress. (23 July 2009).
7. Lennox JL et al. Safety and efficacy of raltegravir-based versus efavirenz-based combination therapy in treatment-naïve patients with HIV-1 infection: a multicentre, double-blind randomised controlled trial. Lancet 2009. Early online publication, 3 August 2009. doi:10.1016/S0140-6736(09)60918-1.
8. Gotuzzo E et al. Sustained antiretroviral efficacy of raltegravir as part of combination ART in treatment-naïve HIV-1 infected patients: 144-week data. IAS Conf HIV Pathog Treat 2009 Jul 19-22;5th: Abstract MOPEB030.
9. DeJesus E et al. Metabolic profiles and body composition changes in treatment-naïve HIV-infected patients treated with raltegravir 400 mg bid-based vs. efavirenz 600 mg qhs-based combination therapy: 48-week data. 49th ICAAC, 12-15 September 2009, San Francisco. Abstract H-1571.
10. Letendre S et al. Raltegravir concentrations in CSF exceed the median inhibitory concentration. 49th ICAAC, 12-15 September 2009, San Francisco. Abstract A1-1311.

Nevirapine vs atazanavir/in naïve patients: ARTEN study

A late breaker poster from Soriano and colleagues presented 48-week results from the ARTEN study. This international non-inferiority trial randomised 569 treatment-naïve patients to nevirapine 400mg once-daily (n=188), nevirapine 200mg twice-daily (n=188) or atazanavir/r (300/100mg) once-daily (n=193), all in addition to background tenofovir+FTC.^[11]

The lower margin for non-inferiority was -12% and patients were recruited based on with CD4 counts below the upper recommended upper limit (250 and 400 cells/mm³ for women and men respectively).

The primary end-point was suppression to < 50 copies/mL at weeks 48 by Intent-to-treat (ITT) analysis, with a secondary sensitivity analysis looking at time to virological failure (TLOVR).

Baseline demographics and HIV-related characteristics were similar between groups. Mean CD4 and viral load were 183 cells/mm³ and 5.1 log copies/mL, respectively. Although <10% patients had a CD4 count <50 cells/mm³, 64%had viral load >100,000 copies/mL.

In the main analyses, nerirapine was non-inferior to atazanavir/r. For the primary endpoint, by ITT analysis the combined nevirapine groups were non-inferior to atazanavir/r (66.8% vs 65.3%; <50 copies/mL: difference 1.9% [95% CI -5.9% to 9.8%]). Using the TLOVR algorithm, the results were 70% and 74% of NVP and ATZ/r patients, respectively [difference 2.9% (95% CI -10.4% to 4.5%)].

CD4 responses were also similar (+170 vs +185 cells/mm³ in the NVP and ATZ/r groups, respectively).

Although side effects were similar, there were significantly higher discontinuations in the nevirapine arms: 22% in QD, 28% BID and 9% with ATZ/r.

Grade 3/4 events occurred in 12%/5% of NVP and 16%/3% of ATZ/r patients. Rash was reported in 16% of NVP and 12% of ATZ/r patients, but more NVP patients were discontinued due to rash compared with ATZ/r (5% vs 0%). Most nevirapine-associated rashes developed during the lead-in phase, with no Grade 4, SJS or TEN and no deaths due to liver or skin toxicity.

Nevirapine had a better impact on HDL-cholesterol and triglycerides (both p<0.0001) but not for for total cholesterol (p=0.41) or LDL-cholesterol (p<0.011). Overall though, the change in the TC:HDL ratio favoured nevirapine (-0.24 vs +0.13, p=0.0001).

Grade 3/4 increases in liver enzymes occurred in <5% patients but were higher in nevirapine patients, (see Table 1). Although exclusion criteria excluded active HBV or HCV infection, numbers of coinfected patients or response were not reported by this hepatitis status. Only one patient discontinued atazanavir/r due to increased bilirubin.

Comment:

It is reassuring that the high virological failure rate observed in smaller studies when nevirapine was used with tenofovir+FTC [12, 13] and which is highlighted in US guidelines^[14], was not seen in ARTEN.

The data also support a reduced risk of nevirapine-associated severe reactions when prescribed to patients within the recommended CD4 thresholds. Although no cases were reported of fulminant liver failure, this remains the main reason for reduced use of nevirapine in Western countries.

The results are important, as nevirapine-based regimens remain widely used as first-line therapy, usually with d4T/3TC.

References:

11. Soriano V et al. Prospective comparison of nevirapine and atazanavir/ritonavir both combined with tenofovir DF/emtricitabine in treatment- naïve HIV-1 infected patients: ARTEN study week 48 results. IAS Conf HIV Pathog Treat 2009 Jul 19-22;5th: Late breaker poster abstract LBPEB07.
12. Rey D et al. Early virolgic non-response to once daily combination of lamivudine, tenofovir, and nevirapine in ART-naïve HIV-infected patients: preliminary results of the DAUFIN Study. 14th CROI, 2007, Los Angeles. Abstract 503.
13. Lapadula G et al. Risk of early virological failure of once-daily tenofovir-emtricitabine plus twice-daily nevirapine in antiretroviral therapy–naïve HIV-infected patients. Clin Infect Dis. 2008 Apr 1;46(7):1127-9.
14. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. November 3, 2008; 1-139. Table 6, page 38.

Darunavir/r monotherapy studies

Several studies presented results from using darunavir/r monotherapy.

José Arribas and colleagues from the Tibotec sponsored MONET study. This study randomised 256 patients, who had been suppressed on their current HAART (< 50 copies/mL) for at least six months, to switch to darunavir/r 800/100 mg once-daily, either as monotherapy (n=127) or with 2 nukes (n=129).^[15]

The primary endpoint was virological suppression at week 48 by TLOVR analysis (time to loss of virologic response) and the study had 80% power to show non-inferiority for the monotherapy arm (lower limit -12%).

Participants generally had responded well to their initial treatments (median CD4 ~570 cells/mm³ with only 12-14% with CD4 counts below 350 cells/mm³. Mean (+SD) prior ARV use was 6.4 (4.0) and 7.4 (4.2) years in the triple and mono arms respectively, with 48% and 35% still on their first NRTI combination. About a quarter of each group were PI-naïve at baseline. A lower percentage of patients in the triple therapy arm were coinfected with HCV (11% vs 19%).

At week 48, both the per protocol and ITT analyses by TLOVR <50 copies/mL showed non-inferiority for the monotherapy arm, with 87.8% vs 86.2% (-1.6%; lower limit 95%CI: -10.1%) and 85.3% vs 84.3% (-1%; lower limit 95%CI: -9.9%), in the triple vs mono arms respectively.

CD4 remained stable at baseline levels and tolerability was good and generally similar between the two groups.

As with monotherapy studies using lopinavir/r, patients using darunavir/r monotherapy experienced more blips (n=1 vs 7) but were similarly resuppressed when nukes were added, and PI mutations were rare (in only one patient). Two patients in each arm had viral load rebounding consistently to >400 copies/mL. Nine patients per arm discontinued randomised treatment for either adverse events or other reasons. No new or unexpected safety signals were detected.

A similar study design was used for the French MONOI study, presented by Cristine Katlama as a late-breaker.^[14]

In this study, 242 patients on HAART who were suppressed to < 400 copies/mL for at least 18 months were, after an 8-week induction phase of darunavir/r (600/100 mg bid), randomised to either continuing the triple-drug regimen (2NRTI+DRV/r) or switching to DRV/r monotherapy. Virologic failure was defined as two consecutive viral load results above 400 copies/mL, or modification/discontinuation of study treatment by week 48. The trial had 80% power to show non-inferiority for the DRV/r arm (lower limit = -10%).

Virological responses at week 48 in the Per Protocol and ITT analysis were 99.0% vs 94.2% (difference -4.9% [- 9.0 to - 0.7%]; and 92.0% vs 87.5% (difference -4.5% [-11.2 to 2.1%], for the triple and monotherapy arms respectively.

Therefore, in this study, non-inferiority was only proven for darunavir/r monotherapy in the per protocol and not the ITT analysis (although the lower margin was -10% compared to the commonly used -12%).

Comment:

Even with promising results using either lopinaivr/r or darunavir/r monotherapy, there is limited data on some aspects of this strategy, including the importance of penetration into the CNS and other compartments. For patients in the UK, many of these questions will be answered by the currently-enrolling MRC-sponsored PIVOT study.^[17]

This MRC study randomises people stable on first-line HAART to continue on their current treatment or switch to ritonavir-boosted PI monotherapy. Choice of PI is not specified and follow-up continues for five years.

References:

15. Arribas J et al. The MONET trial: darunavir/ritonavir monotherapy shows non-inferior efficacy to standard HAART, for patients with HIV RNA < 50 copies/mL at baseline. Oral abstract late breaker TULBAB106.
16. Katlama C et al. Efficacy of darunavir/ritonavir as single-drug maintenance therapy in patients with HIV-1 viral suppression: a randomized open-label non-inferiority trial, MONOI-ANRS 136. Oral abstract late breaker WELBB102.
17. PIVOT: Protease Inhibitor monotherapy Versus Ongoing Triple-therapy in the long-term management of HIV infection. MRC website.

Maraviroc results similar to efavirenz when analysed using more sensitive tropism test

Several studies provided results that might increase the confidence in using the CCR5 inhibitor maraviroc. Although approved over two years ago, the potential use was has been limited because Phase III studies, using background AZT/3TC, did not shown non-inferiority compared to efavirenz, and it was not approved in Europe as a first-line option.

However, the efficacy of CCR5 inhibitors are dependent on accurately screening and enroling patients who are CCR5-tropic, which in turn is dependent of the accuracy of the available tropism test.

A post-hoc analysis of the 48-week results from the MERIT study (called MERIT-ES), using the recently developed more sensitive Trofile ES tropism test, provided an indication of current results that could be expected based on this change in standard of care diagnostics.^[18]

The initial analysis from MERIT also showed poorer responses in patients from the Southern compared to Northern hemispheres and in patients with higher baseline viral load (> vs <100,000 copies/mL.

Virologic results, summarised in Table 1, showed that using Trofile ES, maraviroc produced comparable results to the efavirenz group at any baseline viral load, and for patients in the Northern hemisphere. A difference remains for Southern hemisphere patients that has yet to be explained.

Significantly more patients changed treatment due to side effects in the efavirenz arm (13.6% [49/361] vs 4.2% [15/360]), with changes occurring earlier (78.0% vs 60.0% by week 16) and at higher viral load (69.0% vs 60.0% = 50 copies/mL) before discontinuation.

The sustainability of these results out to week 96, together with a modelled analysis for the impact on the non-inferiority criteria (defined lower limit -12%) were presented by Saag and colleagues, and are summarised in Table 2 (though neither MERIT nor MERIT ES studies were powered to assess results at this time point).^[19]

References:

18. Nelson M et al. Virologic suppression on maraviroc in treatment-naïve patients with R5 HIV-1 is similar to efavirenz at high baseline viral load, and maraviroc discontinuations for adverse events are less likely to show drug resistance: 48-week results from the MERIT Study. Poster abstract MOPEB040.
19. Saag M et al. The MERIT study of maraviroc in antiretroviral-naïve patients with R5 HIV-1: 96-week results. Oral abstract TUAB103.

2009-09-10
IB2009-09-03

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