Responses to atazanavir, Kaletra and side effects

15 June 2005. Related: Conference reports, Antiretrovirals, PK Workshop 6th 2005.

Mark Mascolini, for HIVpharmacology.com

As the newest protease inhibitor (PI), atazanavir has won the interest of pharmacologists curious to define its therapeutic range and to predict how people will respond to it. Other PI research presented at the 6th Pharmacology Workshop involved potential links between lopinavir levels and lofty lipids.

Defining atazanavir’s therapeutic range

Stefano Bonora (University of Turin) confirmed his preliminary finding that the therapeutic range of atazanavir stretches from 150 to 850 ng/mL [1]. Bonora’s analysis involved 51 people, 34 of them men, enrolled in an atazanavir expanded access program. Eleven already had a viral load below 50 copies/mL; in the others median viremia stood at 3.5 logs (interquartile range 1.79 to 4.9 logs). Seventeen people had never tried a PI, and the median number of previous PIs was 1 (range 0 to 6). Thirty people (59%) started atazanavir/ritonavir (300/100 mg).

Defining virologic response as fewer than 50 copies/mL or more than a 2-log drop in viral load, Bonora counted 40 responders among 50 people at week 12 (80%) and 34 among 45 people at week 24 (75.5%). At week 24 the atazanavir trough averaged 208 ng/mL among people taking unboosted atazanavir and 1046 ng/mL among those getting a lift from ritonavir.

Comparing 35 week-24 responders and 10 nonresponders, Bonora found three significant differences:

• Baseline viral load: 2.5 in responders versus 4.6 (P = 0.008)
• Previous PIs: 1 in responders versus 3 (P = 0.013)
• Atazanavir trough: 834 ng/mL in responders versus 191 ng/mL (P = 0.006)
• Genotypic inhibitory quotient (GIQ) (trough/number of PI mutations): 330 in responders versus 5.8 (P = 0.019).

A GIQ based on atazanavir-specific mutations did not significantly discriminate responders from nonresponders (412 versus 7, P = 0.08).

Among people with a trough above 150 ng/mL, 81% had a 24-week virologic response, versus 37.5% with a trough below that cutoff (P = 0.027). As a response predictor a trough above 150 ng/mL had 88% sensitivity but only 50% specificity. People with a trough under 150 ng/mL had a 4.1 times higher risk of failure.

Among people with a PI-based GIQ above 100, 88.8% had a virologic response at 24 weeks versus 33.3% with a GIQ under 100 (P = 0.006). A GIQ of 100 had 89.5% sensitivity and 85.7% specificity in predicting response. People whose GIQ languished below 100 had a 4.7 times higher risk of failure.

Foraging for the high end of the therapeutic range, Bonora found that an atazanavir trough higher than 850 ng/mL predicted total bilirubin readings above 2.5 mg/dL with 60% sensitivity and 78% specificity. The same trough predicted an unconjugated bilirubin of 2.0 mg/dL with 66.7% sensitivity and 78.6% specificity.

Among study participants whose atazanavir trough fell within the 150- to 850-ng/mL target range, 75% had a virologic response and 17% had elevated bilirubin (Table 3.1). Although everyone with a trough above 850 ng/mL responded, 40% of them had high bilirubin.

Table 3.1 Atazanavir trough, response & bilirubin at wk 24

*Fewer than 50 copies/mL or more than a 2-log drop in viral load.

Bonora concluded that 150 to 850 ng/mL represents a reliable therapeutic range for atazanavir. But a representative of Bristol-Myers Squibb wondered whether clinicians would sacrifice too many responses with top trough cutoff of 850 ng/mL. Everyone with a trough above that mark responded virologically. Although 40% of them had high bilirubins, the Bristol attendee argued, some may see that as only a “cosmetic” side effect. Only 2 people in Bonora’s group stopped atazanavir because of hyperbilirubinemia.

GIQ predicts response to atazanavir

Bruno Lacarelle (Timone Hospital, Marseille) also found that GIQ predicts virologic response to atazanavir [2]. But unlike Bonora, he determined that both a GIQ based on atazanavir-specific mutations and a GIQ based on all protease mutations predicted response. The different result may reflect (1) disparate response definitions, (2) more ritonavir boosting in Lacarelle’s cohort, and (3) the different populations studied: More people in Lacarelle’s group had PI experience. Lacarelle’s findings also differed from Bonora’s in that he could not define a trough cutoff that predicted response.

The Marseille cohort included 35 people with treatment experience and 1 naive to antiretrovirals. While 32 took ritonavir-boosted atazanavir, 4 took the unboosted PI. The group had tried a median of 2 PIs (range 0 to 5). They had a median of 3 (range 0 to 15) PI mutations and 1 (0 to 10) atazanavir-related mutations.

After 3 months of treatment, 26 people (72%) had a virologic response. This was defined as a viral load below 400 copies/mL or at least a 1-log drop in viremia. Atazanavir trough and a GIQ based on all protease mutations did not predict the month-3 response, but number of PI mutations, number of atazanavir-specific mutations, GIQ based on atazanavir mutations, and CD4 gain did correlate with response.

Table 3.2 Atazanavir response predictors in treatment-experienced people

In a multivariate analysis atazanavir trough, PI mutations, and atazanavir-specific mutations did not predict response, but both the PI mutation-based GIQ and the atazanavir mutation-based GIQ did. Lacarelle reckoned the atazanavir GIQ response cutoff at 2.3 because 25% of people with a GIQ under 2.3 responded versus 75% with a higher GIQ (P = 0.014).

Yet in a study presented earlier this year, Stefano Bonora’s colleague Daniel Gonzalez de Requena set a PI-based GIQ cutoff at 60 [3]. Lacarelle explained that the wide difference between that result and his reflects the log transformation of his GIQ calculation. One attendee observed that if HIV pharmacologists expect clinicians to start using GIQ, they will have to agree on methods.

Who needs 300/200 or 400/200 of ATV/RTV?

Authorities in British Columbia recommend the 300/100-mg dose of atazanavir/ritonavir and therapeutic drug monitoring (TDM) for everyone starting this once daily PI. But do some people need even higher doses?

To find out, Chris Alexander (University of British Columbia) sorted TDM records of people starting atazanavir/ritonavir between September 2003 and December 2004 [4]. Alexander found that 34 people (25%) had a PI dose adjustment. As a result the Vancouver team made 42 pairwise comparisons:

• 28 switches from 300/100 to 300/200 mg once daily
• 6 switches from 300/200 to 400/200 mg once daily
• 8 switches from 300/100 to 400/200 mg once daily

Looking at steady-state atazanavir and ritonavir levels in people not changing other antiretrovirals around sampling time, Alexander found that the first 28 dose changes bolstered the percentage of people with a detectable ritonavir level (>80 ng/mL) from 21% to 58% (P < 0.01). The 8 switches from 300/100 to 400/200mg lifted the percentage of people with a detectable ritonavir level from 12.5% to 75% (P < 0.01). Although 35% of study participants also had at least a 30% jump in their atazanavir trough with the dose adjustment, overall atazanavir exposure did not climb significantly.

The British Columbia team concluded that the recommended 300/100-mg dose yields adequate atazanavir concentrations for most people. While raising the dose to 300/200mg once daily improves atazanavir exposure in a subset of people, the 400/200-mg dose “may more reliably increase atazanavir levels without further increasing the cost.”

Lopinavir trough tied to high lipids

Research to date has proved inconsistent in weighing the impact of lopinavir levels of lipids and glucoses [5-8]. The latest look at this question, a retrospective analysis involving 20 people, found that a lopinavir trough above 7 mg/L may drive dangerous jumps in total cholesterol and triglycerides [9].

Of the 20 people studied, 5 were starting lopinavir/ritonavir as part of their first regimen. The group had a mean baseline CD4 count of 181 cells/uL (+ 141 standard deviation [SD]) and a mean viral load of 4.5 logs (+ 1.1 SD). For the whole group, fasting glucose and triglycerides did not change significantly during 6 months of lopinavir therapy, but total cholesterol climbed significantly by treatment month 1 and remained elevated at month 6.

Table 3.3 Mean lipid and glucose changes (+SD) through 6 months of lopinavir

*P = 0.034 versus baseline †P = 0.051 versus baseline SD = standard deviation

Total cholesterol at month 6 correlated significantly with lopinavir’s trough (r = 0.583, P < 0.001). In 4 people with a lopinavir trough above 7 mg/L, triglycerides climbed 111% and cholesterol 56%. In comparison 8 people with a trough between 3 and 7 mg/L averaged a 22% gain in cholesterol and a 35% triglyceride spurt.

Mark Mascolini writes about HIV infection (markmascolini@earthlink.net).

References:

Workshop slides and posters are available at:
http://www.hivpresentation.com

1. Gonzalez de Requena D, Bonora S, Cavechia I, et al. Atazanavir Ctrough is associated with efficacy and safety at 24 weeks: definition of therapeutic range. 6th Intl Workshop on Clinical Pharmacology of HIV Therapy. 28-30 April 2005. Québec. Abstract 60.
2. Solas C, Colson P, Ravaux I, et al. Predictive factors of atazanavir response including genotypic inhibitory quotient in treatment-experienced patients. 6th Intl Workshop on Clinical Pharmacology of HIV Therapy. 28-30 April 2005. Québec. Abstract 1.
3. Gonzalez de Requena D, Bonora S, Canta F, et al. Atazanavir Ctrough is associated with efficacy and safety: definition of therapeutic range. 12th Conference on Retroviruses and OIs. 22-25 February, 2005. Boston. Abstract 645.
4. Alexander C, Harris M, Joy R, et al. Effect on atazanavir (ATV) and ritonavir (rtv) plasma levels of increasing ATV/rtv daily dosing from 300/100 mg to 300/200 mg and 400/200 mg. 6th Intl Workshop on Clinical Pharmacology of HIV Therapy. 28-30 April 2005. Québec. Abstract 91. Poster 8.3.
5. Gutierrez F, Padilla S, Navarro A, et al. Lopinavir plasma concentrations and changes in lipid levels during salvage therapy with lopinavir/ritonavir-containing regimens. JAIDS 2003;33:594-600.
6. Clevenbergh P, Garraffo R, Dellamonica P. Impact of various antiretroviral drugs and their plasma concentrations on plasma lipids in heavily pretreated HIV-infected patients. HIV Clin Trials 2003;4:330-336.
7. Gonzalez de Requena D, Blanco F, Garcia-Benayas T, et al. Correlation between lopinavir plasma levels and lipid abnormalities in patients taking lopinavir/ritonavir. AIDS Patient Care STDS 2003;17:443-445.
8. Valerio L, Fontas E, Pradier C, et al. Lopinavir/ritonavir combination and total/HDL cholesterol ratio. J Infect 2005;50:229-235.
9. Le Guellec C, Veillon S Arsac, et al. High lopinavir plasma concentrations are associated with changes in lipid levels at M6 in HIV-infected patients. 6th Intl Workshop on Clinical Pharmacology of HIV Therapy. 28-30 April 2005. Québec. Abstract 44. Poster 3.10.