Once-daily nevirapine extended release (XR) is non-inferior to current formulation

26 August 2010. Related: Conference reports, Antiretrovirals, World AIDS 18 Vienna 2010.

Simon Collins, HIV i-Base

First-line nevirapine is rarely used in developed countries and yet still widely used in resource-limited settings. The short-term risk of serious rash and hepatic toxicity, especially during the first two months, make the risk vs benefit less favourable when alternative drugs are easily available. After the initial two months, long-term tolerability is rarely problematic and includes a favourable lipid profile. Although originally approved as a twice-daily combination, the current formulation is commonly used once-daily, especially once viral load has been successfully suppressed to <50 copies/mL.

In this study, a new extended release (XR) formulation was compared to the currently approved ‘immediate release’ (IR) formulation. Both formulations require two weeks initial treatment with 200 mg once-daily IR.

The VERxVE study was a double-blind, placebo-controlled study run by Boehringer Ingelheim predominantly in North America, Australia and Western Europe, with approximately 10% participants from Latin American (Argentina) and 10% from Africa (South Africa and Botswana). From 1068 patients starting the lead-dose, 55 discontinued, leaving 1013 who were stratified by viral load (< and > 100,000 copies/mL) and randomised 1:1 to XR (n=505) or IR (n=508). All patients used background tenofovir/FTC.

Baseline characteristics included mean CD4 count 228 cells/mm3, median viral load 4.7 log copies/mL, with just over 25% having a previous AIDS diagnosis, Gender ratio was 75% male: 25% female and mean age 38 years.

The primary endpoint of viral suppression to <50 copies/mL at week 48 (TLOVR criteria) was achieved by 81% and 76% of the XR and IR arms respectively (adjusted difference 4.92%: 95%CI –0.11, +9.96), meeting the pre-specified margin for non-inferiority of –10%. Virologic response was reported as being independent of age, gender, race or geographic region. Results were not presented by baseline viral load.

Approximately 20% patients discontinued prior to week 48, primarily due to side effects (7%) or virological failure (5%). Other reasons included loss to follow up, withdrawn consent and poor adherence (all approximately 1.5%). Six patients died (5 IR, 1 XR) none judged related to study drug (atherosclerosis, TB meningitis, 2 x sepsis, myocardial infarction, respiratory alkalosis).

Around 90% of patients reported at least one side effect, but this only led to discontinuation in 6% and 9% of the XR and IR groups. Serious side effects were reported in 11% of patients in each group, with grade 3/4 events in 14% vs 18% and grade 4 events in 3.2% vs 4.5% of the XR and IR groups respectively.

However, there were five cases of Steven’s Johnson Syndrome, three prior to randomisation and two in the IR arm afterwards. Discontinuations due to hepatic toxicity occurred in 5 vs 9 patients, and due to rash in 9 vs 12 cases, in the XR vs the IR arms respectively.

The lipid profile of XR was similar to IR formulation: triglycerides reduced by –7%, cholesterol increased by +11%, LDL-cholesterol increased by 7% and HDL-cholesterol by 27%. This resulted in a similar reduction in the TC/HDL ratio of –12% in the XR vs –14% in the IR formulations respectively.

The 24-hour PK sub study in 50 patients at day 28 showed a flat profile, with lower Cmax and Cmin and target levels of 3 ug/mL. From the limited results presented, individual patient variability was wide and approximately 50% patients had trough levels below this target. However, reduced response rates only correlated with Ctrough levels that were less than 1 ug/mL (3/9 patients, 33% response). Rates at 1–2 ug/mL, 2–3 ug/mL, 3-4 ug/mL and >4 ug/mL were all >80%, which lead investigators to state that therapeutic levels were achieved by most patients.

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Even for a late-breaker, this presentation was data-lite, which was disappointing given the significant size of the study: no range for baseline demographics, VL, CD4 etc; no results by viral load stratification +/- 100,000 copies/mL, or for CD4 response; no laboratory markers results ALT, AST etc; no range or IQR was given for the PK sub study, with half the patients achieving a Ctrough below the target of 3 ug/mL.

More critically, no details were included about the discontinuations during the lead period, there was no accounting for these in an overall ITT analysis (even though the randomisation occurred after this), and the most important safety issues were edited out.

A question from the audience had to specifically ask about incidence of Stevens-Johnson Syndrome, rash-associated discontinuations and hepatotoxicity and the presenter laughed when she had to answer, as if she had been caught out. Even though this was a non-inferiority study, it provided little understanding of whether the improved PK profile has an impact on reducing serious adverse events.

Reference:

1. Gathe J et al. Comparison of 48 week efficacy and safety of 400 mg QD nevirapine extended release formulation (Viramune XR) versus 200 mg BID nevirapine immediate release formulation (Viramune IR) in combination with Truvada in antiretroviral (ARV) naive HIV-1 infected patients (VERxVE). 18th IAS Conference, 18–23 July 2010, Vienna. Oral abstract late breaker THLBB202. http://pag.aids2010.org/Abstracts.aspx?SID=1990&AID=17270 Webcast: http://pag.aids2010.org/flash/?pid=113133