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The Antiretroviral Pipeline

September 2011

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Update on Recent Approvals and Other Compounds in Development

This section includes a review of other compounds in further development.


Rilpivirine was approved in the United States in May 2011 for treatment-naive patients, based on 48-week results from the ECHO and THRIVE phase III studies and safety results from a phase II study out to 192 weeks.39

These studies, while reporting rilpivirine to be statistically non-inferior when compared to efavirenz, indicated less effective viral suppression when baseline viral load was >100,000 copies/mL with a higher risk of resistance in the context of treatment failure, and a greater loss of efficacy at lower than 95% adherence. These disadvantages were balanced by fewer side effects.40,41

However, FDA approval is as a treatment for people who have not previously used treatment, when study results suggest use for an early switching of people with intolerance to efavirenz. The prescribing information highlights the poorer virological response at high viral load, and higher risk of resistance.

Rilpivirine is a 25mg tablet that needs to be taken once daily with food. Exposure is reduced by approximately 40% when taken fasted compared to with a normal meal or high-fat meal (defined as 533 kcal and 928 kcal, respectively). Exposures were reduced by 50% when taken with only a high-protein drink.

It was developed at a 25 mg dose due to phase II studies showing similar efficacy at 25, 50 and 75 mg and a caution over cardiovascular toxicity (QTc interval) at higher doses (75 and 150 mg). While the low dose offers exciting future potential for the development of coformulations, it results in a low pharmacokinetic threshold for people with poorer drug absorption.


The phase III studies had a similar design apart from use of background nucleosides. ECHO used tenofovir/FTC for all patients, and THRIVE allowed investigator choice. Each study randomized close to 700 treatment-naive patients without NNRTI or NRTI resistance. The primary endpoint was viral load suppression <50 copies/mL at week 48 (ITT-TLOVR analysis) with a lower margin of -12% difference for non-inferiority. Follow-up continues to week 96.

In the pooled analysis, baseline characteristics of the 1,368 patients included approximate median CD4 count 250 cells/mm3 (range 1-1140), median viral load 5 log copies/mL (range 2-7), with just over 25% of patients having a previous AIDS diagnosis. Gender ratio was 75% male:25% female and mean age 36 years. Racial demographics were roughly 60% white, 24% black, and 12% Asian. Between 7% and 9% of patients were those coinfected with hepatitis B or C. Nucleoside choice in THRIVE was 60% tenofovir/FTC, 30% AZT/3TC, and 10% abacavir/3TC.

At week 48, suppression to <50 copies/mL was achieved in 84% versus 82% patients in the rilpivirine versus efavirenz groups (pooled results difference +1.6; 95%CI -1.7 to +8.8) with the lower bound for the confidence interval significantly above the prespecified limit. CD4 increases were similar at +192 versus + 176 cells/mm3, respectively.

Differences between the arms were more apparent when looking at reasons for treatment failure. In rilpivirine versus efavirenz, respectively, 9% versus 5% reported virological failure and approximately 2% versus 7% discontinued due to side effects. Around 5% patients discontinued from each arm for other reasons.

In the rilpivirine versus efavirenz groups, 5.5% versus 2.6% of people never suppressed to <50 copies/mL and 3.5% versus 2.2% patients who suppressed later rebounded.

No differences in virological response were reported by gender, race, geographical region, or nucleoside backbone. However, by baseline viral load the pooled response rates were 90% versus 84% (difference +6.6: 95%CI +1.6, +11.5) in favor of rilpivirine in the <100,000 group and 77% versus 81% (difference -3.6: 95%CI -9.8, +2.5) in favor of efavirenz in the >100,000 group. The vulnerability of the low dose was also reflected in the adherence analysis. Viral efficacy was similar between arms when adherence rates were reported as >95% and when viral load was low. However, when adherence dropped to less than 90% efficacy rates were lower with rilpivirine at both high and low viral loads.

People whose treatment failed on rilpivirine developed higher rates of both NNRTIassociated (63% vs 54%) and NRTI-associated (68% vs 32%) mutations. Rilpivirine was associated with the E138K mutation, with 90% of these patients showing phenotypic cross-resistance to etravirine, essentially losing the NNRTI class. People experiencing virological failure on efavirenz commonly developed K103N, which should retain sensitivity to etravirine.

Tolerability results favored rilpivirine with comparisons below for rilpivirine versus efavirenz. While >90% of patients in each arm reported at least one side effect, grade 2-4 events related to study drug occurred in 16% versus 31% (p <0.0001) and discontinuations due to toxicity occurred in 3% versus 8% (p = 0.0005). Neurological side effects occurred in 17% versus 38% (p <0.0001), psychiatric side effects in 15% versus 23% (p = 0.0002), abnormal dreams in 8% versus 13% (p = 0.0061) and rash in 3% versus 14% (p <0.0001).

Grade 3-4 laboratory abnormalities occurred in 11% versus 18% patients (p<0.001), with higher rates of elevated ALT (1.5% vs 3.4%, p <0.05) as well as increases in LDL cholesterol (0.7% vs 4.1%, p <0.0001), triglycerides 0.3% vs 2.2%, p <0.001), and total cholesterol (0.1 vs 2.5%, p <0.0001), all favoring rilpivirine.

There was minimal change in mean serum creatinine in both groups, with no grade 3/4 creatinine increases and no discontinuations due to renal side effects or cases of acute renal failure. No difference was seen in changes in QTc interval between the TMC278 and efavirenz groups.

Several posters at CROI 2011 provided greater details on side effects and tolerability, again from pooled analysis of the same studies. While these generally show a broadly better profile compared to efavirenz, most side effects including central nervous system-related events are reduced rather than eliminated: rilpivirine has a similar profile to efavirenz, though just a little lighter. Some of the differences that are highly statistically significant may have limited clinical impact.

Lipid differences statistically favored rilpivirine over efavirenz, with greater increases in total cholesterol (TC), LDL cholesterol (LDLc), and triglycerides (TG) from baseline to week 48 reported with efavirenz compared to no significant changes in the rilpivirine group. No patients, however, discontinued treatment due to lipid changes. Grades 3/4 lipid-related abnormalities were lower with rilpivirine but also generally low in the study as a whole: TC (0.1% vs 3%, p ≤0.001), LDLc (1% vs 4%, p ≤0.001), and TG (0.3% vs 2%, p ≤0.001). These differences did not result in differences between the two groups in TC/HDL cholesterol ratio or cardiovascular risk as measured by the Framingham score.42

There were differences in the impact on vitamin D levels, measured as 25(OH)D (nmol/L). Mean (SD) baseline and week 48 reductions were statistically greater in patients using efavirenz: 61.8 (26.3) and 60.8 (22.8) [mean change -0.6 (17.9, p = 0.57] vs 64.1 (30.2) to 58.6 (26.9) [mean change -6.1 (18.0), p <0.0001]. The percentage of patients defined as severely deficient remained unchanged in the rilpivirine group at around 4.5% but increased from 5.2% to 9.0% (p = 0.03) in the efavirenz group.43

While neurological complications occurred significantly more frequently in the efavirenz arm, they still occurred in a significant proportion or patients using rilpivirine.44

Rilpivirine Fixed-Dose Combination With Tenofovir/FTC

The new NNRTI-based fixed-dose combination of tenofovir/FTC/rilpivirine (Complera) from Gilead and Tibotec received FDA approval in August 2011,14 with an indication for treatment-naive patients. Approval was based on bioequivilence to the individual drugs taken separately,45 together with the phase III registrational studies for rilpivirine (ECHO and THRIVE) detailed above.

Alternative once-daily NNRTI-based single pill combinations clearly benefit patient choice but the efficacy results for this FDC suggest this would be most useful as a rapid switch option from Atripla for people with efavirenz-related side effects. Technically this might be considered to be off-label use unless the treatment-naive for the indication given for rilpivirine is interpreted as non-resistant.

Elvitegravir and Quad: Fixed-Dose Integrase-Based Combination

Clinical data on elvitegravir in treatment-naive patients includes 48-week results comparing two fixed-dose combinations -- Quad (elvitegravir/cobicistat/tenofovir/FTC) versus Atripla (efavirenz/tenofovir/FTC) -- were presented at ICAAC in September 2010.16,17,18 This updated the 24-week (primary endpoint) results presented earlier at CROI 2010, which showed significantly faster viral responses in the integrase group.

Entry criteria included treatment-naive patients with no documented resistance who were HBV/HCV negative. Baseline demographics included a mean age of 35, approximately 90% of participants were Caucasian, baseline CD4 was 389 versus 450 in the Quad versus Atripla groups and 4-6% had an AIDS diagnosis. However, mean baseline viral load was low at Viral response rates at week 48 were the same as at week 24: 90% versus 83% (p = NS) of patients in the Quad versus Atripla groups respectively had an undetectable viral load (<50 copies/mL) at 48 weeks by intent-to-treat, missing = failure analysis. Mean CD4 increases were higher in the Quad arm at +240 versus +162 cells/mm3.

Tolerability results also matched 24-week data: Quad was better tolerated in terms of lack of efavirenz-related side effects (35% vs 57% with any grade 1-4 drug-related adverse event). This was driven by reduced central nervous system toxicity.

A potentially new once-daily single pill integrase FDC will clearly improve patient options, but if approved, access and use in both first and second-line therapy, is likely to be widely dependent on its price being comparable to currently available options.

At the IAS in Rome, 48-week results were presented from Gilead's phase III non-inferiority study comparing elvitegravir favourably to raltegravir in treatment-experienced patients.46


The pharmacokinetic booster cobicistat has so far reported similar boosting efficacy and side effects compared to ritonavir, without residual direct antiretroviral activity. Latest clinical data comes from elvitegravir studies (discussed above) and direct-booster comparison to ritonavir, both presented at the 50th ICAAC in September 2010. As with the studies on Quad in the same population, this showed that 24-week results were maintained out to 48 weeks.16,17,18

The comparator-booster study randomized treatment-naive patients to atazanavir boosted by either cobicistat (n = 50) or ritonavir (n = 29). At week 48, the percentage of patients with viral load suppressed to <50 copies/mL by intent-to-treat analysis (missing = failure) was similar with 82% in the cobicistat versus 86 % in the ritonavir groups (p = NS). Changes in mean estimated glomerular filtration rate (eGFR) at week 24 were similar and didn't develop with longer follow-up. Other grade 1-4 side effects were seen in 36% versus 48%, respectively. Changes in eGFR seen through 24 weeks were stable and similar to that seen in those receiving ritonavir. No additional discontinuations occurred between weeks 24 and 48: five versus three people in cobicistat versus ritonavir, respectively (relating to side effects in two people vs one).

The primary mechanism for boosting works through inhibition of the cytochrome P450 CYP 3A4. A study in HIV-negative volunteers using phenotype probes to investigate non-3A4-mediated interactions reported only weak inhibition of CYP2D6 and concluded that further interaction studies with metabolites of CYP2D6, CYP2B6, and the P-glyoprotein transporter (P-gp) would not be required.47

An agreement was also announced by Gilead on 28 June to collaborate on a co-formulation of cobicistat with Tibotec's darunavir.48

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This article was provided by Treatment Action Group and HIV i-Base. It is a part of the publication 2011 Pipeline Report.
See Also
More on HIV Medications
HIV Drugs in Development

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