UK-CAB 21 – African treatment issues – Merck

20 April 2007

Agenda: African treatment issues

9:00 – 9.45 Registration and coffee
9:45 -10:30 Feedback from CROI: new pipeline drugs
Simon Collins and others
10:30 -10:45 UK HIV Drug Resistance Database
David Dunn
10:45 – 11:00 Coffee
11:00 – 12:30 Merck: Integrase Inhibitors
12:30 – 1:30 Lunch
1:30 – 2:00 Genetic research related to higher NNRTI levels in African patients
Simon Collins
2:00 – 3:45 African treatment issues: response to treatment, side effects, treatment access and other issue
Dr. Charles Mazhude Consultant, Lewisham General Hospital
3:45 – 4.00 AOB
Upcoming BHIVA conference in Edinburgh
Gus Cairns

Reading material

Feedback from 14th Conference on Retrovirus and OIs

i) raltegravir (MK-0518) – a new integrase inhibitor (this will also be covered in the meeting with Merck)
ii) maraviroc – a new CCR5 inhibitor
iii) rilpivirine (TMC-278) – a new NNRTI
iv) elvitegravir (GS-9137) – a new integrase inhibitor from Gilead
v) TH9507 – a new treatment to reduce fat accumulation (TH9507), which showed redutions of 20% over 6 months and which importantly will be available in UK trials in April

UK HIV Drug Resistance Database PowerPoint Slides [200 Kb]
David Dunn Senior Statistician HIV Group MRC Clinical Trials Unit

Genetics, race and NNRTI drug levels in African patients

Feedback from 14th Conference on Retrovirus and OIs

Please find the following attached overview of important studies from the Retrovirus Conference that it is important to talk about in the feedback session of the meeting.

Reading material for other sections of the meeting will be sent separately.

14th Retrovirus Conference

The most important studies presented covered new drugs, as individually they all have activity against HIV that is resistant to current drugs.

Part of the feedback will include a discussion of how to use these drugs to get long-term benefit, and to reduce the risk of resistance.

In practice, this means using three active drugs when switching to a new combination. This is something that has not been possible before, but is possible in 2007 because several new drugs are available, including from new classes, and they are all being developed on a similar timeline.

It is an advocacy issue because if people just use 1 or 2 new drugs and recycle nukes, the combinations may not be strong enough to prevent resistance occurring to these drugs.

For example, 98% of people using raltegravir, darunavir and T-20 (for the first time) reached viral load less than 400 copies/mL at 16 weeks.

The overview will include:

i) raltegravir (MK-0518) – a new integrase inhibitor (this will also be covered in the meeting with Merck)

ii) maraviroc – a new CCR5 inhibitor

iii) rilpivirine (TMC-278) – a new NNRTI

iv) elvitegravir (GS-9137) – a new integrase inhibitor from Gilead

v) TH9507 – a new treatment to reduce fat accumulation (TH9507), which showed redutions of 20% over 6 months and which importantly will be available in UK trials in April

Links to the abstracts for these drugs are included.

Summaries reduced from articles in HIV Treatment Bulletin (March/April 2007)

i) raltegravir (MK-0518) – a new integrase inhibitor (this will also be covered in the meeting with Merck)

http://www.retroconference.org/2007/Abstracts/30687.htm

David Cooper and Roy Steigbigel presented 16-week results from the Phase 3 BENCHMRK-1 (Europe, Asia/Pacific, Peru) and BENCHMRK-2 (US, Canada and South America) studies. Both studies had the same design and similar patient characteristics and results, which were largely combined for these presentations.

Approximately 350 three-class resistant patients on failing therapy enrolled in each study. Patients optimised their background regimen (OBT) based on treatment history and resistance tests, and were randomised 2:1 to add raltegravir 400mg twice daily or placebo. Primary endpoints included viral load, CD4 and tolerability at week 16, after which patients could receive open-label raltegravir.

Patients were highly treatment experienced with over 90% having had a previous AIDS diagnosis, and a median of ten years previous ARV therapy with a median of 12 antiretroviral drugs. Mean baseline CD4 and viral loads were approximately 150 cells/mm3 and 4.6 log copies/mL respectively. Approximately 30% had a genotypic sensitivity score (GSS) of zero for the drugs in the OBT and 40% had a GSS of 1. Approximately 25% of patients used T-20 across both studies.

Darunavir use was higher in BENCHMRK-2 (approximately 50% vs 25% in BENCHMRK-1) due to the earlier access programmes for darunavir in the US. Mean age was 45, 85-90% of participants were male, and 75-80% and 55-65% were Caucasian in BENCHMRK-1 and -2 respectively.

At 16 weeks approximately 77% of patients achieved viral suppression to <400 copies/mL in the raltegravir arm compared to just over 40% in the placebo group. Results down to <50 copies/mL were just over 60% vs 33-35%. In both studies CD4 increases were approximately +80 cells/mm3 vs + 30 cells/mm3 in favour of raltegravir, and average viral load changes were -2 logs vs -1 log reductions, with these being sustained out to 24 weeks in patients for whom extended follow-up data was available (approximately half the study group). All differences between raltegravir and placebo were statistically significant (P<0.001).

As with results from any new drug, an analysis the choice of drugs in the optimised background regimen is essential in order to understand the individual impact of each component, and results from these breakdowns are almost more important than the bottom line results.

98% (44/45) patients using raltegravir with T-20 and darunavir for the first time achieved viral reductions to <400 copies/mL – compared to an impressive 87% in the placebo + OBT group. Using either one of these drugs in the OBT dropped response rates to 90% in the raltegravir arm (vs 55-63% in the placebo groups). Using neither drug still produced a 74% response in the raltegravir group (vs 29% with placebo).

While this may make understanding the contribution of each drug a challenge, the availability of other sensitive drug to support the investigational agent is both essential for sustained benefit and to minimise the short term wasting of new agents for patients who take part in registrational trials.

Baseline viral load had an impact on response rate (88%/64% for raltegravir, when above/below 100,000 copies/mL versus 55%/19% in the placebo arm). Patients with baseline CD4 cells count <50 cells/mm3 were around 20% lees likely to achieve a virological response in both arms, compared to patients with higher baseline counts.

A summary of clinical and serious laboratory adverse events in this advanced population showed no significant differences between treatment arms (approximately 80% patients had at least one side effect, only 10% of which were classed as serious and <3% classed as a drug-related serious event, with more drug-related discontinuations in the placebo group). There were no specific side effects relating to raltegravir over placebo that showed a consistent concern in the two studies.

Virological failure was reported in 16% (n=76) of patients receiving raltregavir and 51% on placebo (n=121).

Genotypic analysis available from 41 patients showed that 75% (n=32) developed mutation in integrase and that this followed one of two main pathways: either via N155 (with additional mutations at E92Q, V151I, T97A, G163R, L74M) or Q148K/R/H (withG140S/A, andE138K). These were similar to mutations seen from earlier in vitro passaging studies.

ii) maraviroc – a new CCR5 inhibitor

http://www.retroconference.org/2007/Abstracts/30636.htm

Results from a planned 24-week analysis of the Phase2b/3 studies of maraviroc (MVC) (Motivate 1 and 2) were presented by Howard Meyer and Elna van der Ryst in two linked late-breaker oral presentations. [1, 2]

Both studies had a similar design comparing the CCR5 antagonist maraviroc or placebo, both with optimised background therapy (OBT) in triple-class experienced R5-tropic patients, with Motivate-1 (n=601) based in the US and Canada and Motivate-2 (n=475) based in Europe, Australia and the US.

Patients were randomised 1:2:2 to receive placebo or MVC (300-mg dose equivalent) once daily (QD) or twice daily (BID) plus OBT (3 to 6 ARVs with or without low-dose ritonavir). The MVC dose was reduced to 150 mg once or twice daily when all PI’s except tipranavir, or if the NNRTI delavirdine, were included in the OBT. The primary endpoint was the mean change in HIV-1 RNA from baseline to week 24.

Baseline CD4 and viral load were similar in each study, approximately 150-180 cells/mm3 (range 1->900 cells/mm3) and 4.8 logs (range 2.5-7.1 logs) across the arms. Approximately 60-75% of patients had 2 or fewer active drugs in their background regimen, and 37-45% used T-20.

Maraviroc produced an approximate 1log drop in viral load compared to placebo.

Aprroximately 50% of patients using 2 active drugs and 60-68% of patients using 3 active drugs had viral loads reduced to less than 60 copies/mL.

Although these results were in highly experienced patients, only just over half the people screened for these studies (56%) had R5-tropic virus, making it more likely that maraviroc will need to be placed earlier in treatment failure.

It is essential for a tropism test to be used prior to using CCR5 inhibitors. This will limit the ability to use maraviroc as a switch treatment as, similar to resistance tests, the current test needs a viral load level of at least 1000 copies/mL to produce a result.

iii) rilpivirine (TMC-278) – a new NNRTI

http://www.retroconference.org/2007/Abstracts/30659.htm

48-week results from a Phase2 TMC-278 dose-finding study, of a second generation NNRTI in development from Tibotec were presented in an oral session by Anton Pozniak from Chelsea and Westminster Hospital, London.

Rilpivirine (TMC-278) is a once-daily compound that has a similar resistance profile to TMC-125 which is being researched as a second-line treatment after first NNRTI failure.

368 patients (33% women) were randomised 1:1:1:1 to TMC278 25, 75, or 150 mg once daily, or to EFV 600 mg once daily. All arms included investigator-selected background nucleosides: AZT/3TC (Combivir) was used by 76% of patients and tenofovir/FTC (Truvada) by 24%. The primary endpoint was the proportion of patients with confirmed viral load <50 copies/mL (TLOVR definition, non-completer = failure) at 48 weeks.

Baseline median CD4 and viral load were 203 cells/mm3 (range 3-970) and 4.85 log copies/mL (range 2.16-7.13). Median duration of HIV infection was 1 year (range 0-21 years).

48-week results showed a similar 80% patients achieving viral suppression <50 copies/mL across all arms and are detailed in Table 1. All arms showed a mean viral load change of approximately -2.5 logs at week 48 with no differences between arms.

Table 1: Responses at week-48 in TMC-278 C204

TMC278
25mg
75mg 150mg efavirenz
N 93 95 91 89
% <50 copies/mL 81% 80% 77% 81
Mean change VL -2.63 log -2.65 log -2.63 log -2.64 log
change in CD4 +125 +145 +143 +127

The tolerability and side effect profile was also similar between groups but there were fewer CNS side effects in the rilpivirine arm and a slightly better lipid profile compared to efavirenz (see Table 2). Mean (SD) changes from baseline of total and LDL cholesterol were 5 mg/dL (30) and 0 mg/dL (24) in combined rilpivirine arms versus 31 mg/dL (30) and 16 mg/dL (26), respectively with efavirenz. There was one death due to sepsis, not attributed to study drug in the 75mg rilpivirine arm.

iv) elvitegravir (GS-9137) – a new integrase inhibitor from Gilead

http://www.retroconference.org/2007/Abstracts/30571.htm

Andrew Zolopa from Stanford University presented results from a Phase 2 study of Gilead’s integrase inhibitor elvitegravir (GS-9137) in treatment experienced patients.

This was a partially blinded, active-controlled, 48-week dose-finding study that randomised 278 patients to 20mg, 50 mg or 125mg doses of GS-9137 (given once-daily with 100mg boosting dose of ritonavir) or to boosted comparator protease inhibitors (CPI/r) in treatment-experienced subjects (>/=1 PI mutation). Background regimens included investigator choice of NRTI with or without T-20. Choice of CPI included darunavir and tipranavir for 49% and 27% patients respectively in the CPI/r arm.

After week 8, the 20mg arm was closed because of a high rate of virologic failure. However, although the primary endpoint is change in viral load at week 24 (DAVG24), the 16 week analyses reported here, will be less complicated by later use darunavir or tipranavir to GS-9137 arms, which was allowed (mainly after week 16 for most patients) when new data showed a lack of drug-drug interactions.

Baseline mean CD4 and viral load was 185 cells/mm3 and 4.59 log copies/mL. Mean age was 45 years, 90% were male, and 73% were Caucasian. T-20 was used by 19% of patients in the CPI/r arm compared to around 25% patients in the 50 and 125 mg arms. 50% of patients across all arms had no sensitive RTIs (GSS=0), and patients had a median of 10-11 IAS-defined PI mutations.

Prior to week 16, the majority of GS-9137 patients received only 2 NRTI as background therapy; 26% of the GS-9137 50 mg and 125 mg patients added a PI by week 24, mainly after week 16.

The mean changes in viral load at week 16 were -1.5 and -1.7log in the 50mg and 125 mg arms respectively compared to -1.2 log in the CPI/r arm

Inclusion of at least one other active drug in the OBT was essential for durability of virological response. Patients in the 125mg arm averaged viral load reductions of -2.0 to -2.4 logs by week 8 but this was only sustained to weeks 16 and 24 in patients (n=47) with either >/= one active RTI, or new use of T-20. In people with no active drugs (n=26) viral load rebounded to approximately -0.7 log below baseline by week 16.

GS-9137 was well tolerated. No dose relationship was observed in treatment-emergent grade 3 or 4 adverse events or laboratory abnormalities, and fewer patients in the GS-9137 treatment arms discontinued study drug because of adverse events than in the CPI/r arm.

v) TH9507 – a new treatment to reduce fat accumulation (TH9507), which showed reductions of 20% over 6 months and which importantly will be available in UK trials in April

http://www.retroconference.org/2007/Abstracts/30478.htm

Stephen Grinspoon, from Massachusetts General Hospital, presented 26 weeks results from a Phase 3 study of TH9507, a growth hormone releasing factor analogue (GHRF) produced by Theratechnologies (Canada), in patients with central fat hypertrophy.

The study randomised 410 patients on stable HAART (80% <50 copies/mL) with central fat accumulations (mean waist:hip ratio 1.1 +/-0.1; waist circumference 104 +/- 10 cms) 2:1 to either 2mg/day TH9507 (n=273) or placebo (n=137) subcutaneously for 26 weeks. The primary endpoint was the percentage of change in visceral adipose tissue (VAT) by abdominal CT at L4-L5.

Secondary endpoints included triglyceride level, cholesterol-to-HDL ratio, and IGF-I. Based on FDA requirements, the study had 90% power to detect an 8% reduction in VAT between TH9507 and placebo. The group was 86% male, wth an average age of 48 years (+/-9). 19% patients at baseline had type-2 diabetes or glucose intolerance.

There was approximately 20% drop out in both arms of the study: 211 patients in the GHRF and 115 patients in the placebo group completed the study.

At week 26, absolute VAT decreased significantly by -27.8cm3 in the GHRF group compared to an increase of +4.9 in the placebo group (p <0.001). Trunk fat by DEXA also decreased (-1.0±1.9 vs +0.4±1.6 kg, p <0.001), with a smaller impact on abdominal SAT (+0.4±15.8 vs +1.8±14.5%, p = 0.05) and limb fat (-0.0±0.8 vs +0.2±1.0 kg, p = 0.01). The lipid profile improved in the GHRF group with significant reduction in triglycerides (-0.6±1.7 vs +0.1±1.3 mmol/L, p <0.001) and in cholesterol to HDL ratio (-0.3±1.0 vs +0.2±1.0, p <0.001).

Side effect profile was similar between the two arms (ie headache 16% vs 17 %; arthralgia 13% vs 10%). A higher proportion of patients in the GHRF arm reported drug-related side effects though (53% vs 34%) and discontinuation due to side effects (12% vs 3%), but not for serious side effects (5% vs 2%). Approximately 2% patients had skin reactions, generally after four months treatment. There were no effect on glucose or insulin parameters in the study, nor increase in percentage of patients shifting to impaired glucose tolerance.

Earlier studies have shown that recombinant Human Growth Hormone (rHGH) has a similarly beneficial impact on central fat accumulation, although the dose-dependent response at the higher dose of 6mg/day was associated with unacceptable levels of side effects including hyperglycemia, though lower doses may have a therapeutic role with more acceptable tolerability.

Download as a Word file. [72 Kb]

Genetics, race and NNRTI drug levels in African patients

Summary

A couple of years ago there were several studies that showed that a genetic variation that was more common in African patients, was also related to how NNRTIs are metabolised.

The research from Birmingham supported this with case studies showing 4 people whose drug levels were 10 times at high as normal and whose had therapeutic drug levels 3-4 weeks after stopping efavirenz.

The genetic change is in one of the liver enzymes responsible for drug metabilism (called CYP2B6) at codon (junction) 516. The ‘normal’ structure is to have a guanine (G) base at this junction. When there is a mixture of this G and thymine (T) efavirenz metabolism is slowed, and when there is a only thymine at this junction, the metabolism is slowed even further (and drug levels are higher).

The implications of this are:

i) higher risk of side effects for African people using efavirenz, because drug levels can be much higher. This should include taking more care with African patients, and perhaps use of drug level monitoring.

ii) that anyone stopping treatment needs to be aware that drug levels continue for weeks afterwards, especially long after any other drugs have been completely eliminated. This would increase the risk of developing drug resistance. The recommendation in BHIVA guidelines (not addressing African patients specifically) is to either stops nukes 1-2 weeks earlier or to switch to a protease inhibitor for the last few weeks. The results below, suggest that switching to the PI is probably best, and doing this for 4 weeks rather than two may be better for African patients.

HTB: APRIL 2004
http://www.i-base.info/pub/htb/v5/htb5-3/PK.html

Drug levels can persist for more than two weeks after stopping efavirenz

How to stop treatment safely is arguably as important a management issue as how to correctly initiate treatment, but it has been the focus of far less research. As antiretroviral drugs have different plasma and intracellular half-lives, a strategy to safely discontinue treatment may be essential in order to avoid resistance.

Indeed, several treatment interruption studies have reported cumulative risk for developing NNRTI resistance with each interruption when using efavirenz (EFV, Sustiva, Stocrin) based regimens, when all drugs have been stopped at the same time. Other regimen-switching or cycling studies have shown greater virological benefits when efavirenz is included, and residual antiviral activity may be a plausible explanation for the improved results in those arms.

Steve Taylor from Birmingham Heartlands Hospital presented results from patients who were either stopping or switching efavirenz due to treatment failure or toxicity, or after a planned short course of treatment. Drug elimination takes five times the half-life of a compound and as the plasma half-life of efavirenz is estimated at 40-55 hours this theoretically risks monotherapy with a drug with a low genetic resistance barrier for a significant time.

Ten patients (six Caucasian men, four African women) were followed in an intensive PK study with EFV plasma levels measured at days 0, 4, 7, 14 and 21 by HPLC. A second group of 25 patients who were stopping a short course of antiretroviral therapy initiated following seroconversion, stopped efavirenz five to seven days prior to the other drugs in their regimen. Resistance testing was used at different times for each group.

Median (ng/mL) Range (ng/mL)
Baseline 3004 894 – 8216
Day 7 310 894 – 8216
Day 14 149 <40 – 1845
Day 21 62 <40 – 637

Individual cases included in the oral presentation at the conference showed this extreme variability between patients. A 64-year-old Caucasian man retained levels of efavirenz >100ng/mL three weeks after stopping efavirenz (he continued to take Combivir plus tenofovir) and showed a plasma half-life close to 150 hours. The other four Caucasian men had expected half-lives of 40-50 hours.

The four African women in the study had considerably longer half-lives than the expected mean ranging from 116 –115 hours. Two of these women were found to have extremely high baseline concentrations close to 10,000 ng/mL at baseline and three of the four women maintained ‘therapeutic’ levels of efavirenz (>1000ng/mL) two to three weeks after stopping treatment.

The 25 patients stopping treatment in the virologic study (23 Caucasian men, one Black man, one Black woman) continued Combivir for one week after discontinuation of efavirenz. No new resistance was detected between baseline and week 4 in this group.

The study concluded with a reference to the BHIVA (British HIV Association) guidelines, which recommend, when stopping an NNRTI, to either continue nucleoside for a further week, or to switch the NNRTI to a PI and use three drugs with similar (short) half-lives when stopping all drugs at the same time. A suggestion from the audience was that ritonavir could be used to speed up elimination, but this was unsupported by research.

On the basis of these data, even further caution may be necessary in many individuals, and the results from ACTG 5095 below suggest this is true for Black women in particular, if efavirenz is to be stopped without risk of developing resistance.

Ref: Taylor S, Allen S, Fidler S et al. Stop study: after discontinuation of efavirenz, plasma concentrations may persist for two weeks or longer. 11th CROI 2004, Abstract 131.

HTB: APRIL 2004
http://www.i-base.info/pub/htb/v5/htb5-3/Race.html

Race affects absorption and clearance of efavirenz

Heather Ribaudo followed the UK efavirenz study with particularly supportive results from a sub-study from ACTG 5095 that randomised patients in a double-blind placebo controlled trial to either efavirenz (EFV, Sustiva, Stocrin) + Trizivir (AZT+3TC+abacavir) or to Trizivir alone. This sub-study looked at efavirenz-related toxicity over the first 24 weeks of treatment. Plasma levels of efavirenz at 1, 4, 12 and 24 weeks obtained from 190 patients (36 women and 154 men) were analysed in relation to toxicity and virological response. [1]

Race distribution was 53% Caucasian, 32% Black and 15% Hispanic. Median weight was 75kg (range 46-186kg).

Caucasian non-Hispanic patients had a 32% increase (95 CI, 15 – 51%; p <0.001) in clearance compared to Black and Hispanic subjects. Both clearance and volume of distribution were associated with weight (p<0.001). There was no apparent association with gender (p >0.26) or HCV coinfection.

There was some evidence of an increasing rate of EFV discontinuation with decreasing clearance (p=0.052) and increasing Cmax (p=0.048). Sixteen percent of patients discontinued efavirenz during the first 24 weeks (n=31) due to CNS symptoms (n=5), rash (n=5), other toxicity (n=4), subject/clinician decision (n=6), and non-compliance (n=6). There was no apparent association between EFV pharmacokinetics and rates of first CNS toxicity or viral load of <200 copies/mL (for clearance, p=0.99, p=0.46, respectively).

In a second presentation from the same ACTG sub-study Haas and colleagues looked for a genetic basis of efavirenz clearance by identifying single nucleoside polymorphisms in CYP2B6, 3A4, 3A5 and MDR1 enzymes using real-time PCR. [2]

The functional G to T change at position 516 that identifies CYP2B6 *6 and *7 haplotypes was found in 20% of Black patients compared to only 3% of Caucasian patients, and was associated in higher efavirenz concentrations and lower clearance in all populations.

G/G G/T T/T
number of patients 78 60 14
Median AUC24 ug.h/L 44 60 130

The CYP3A4 1B (A392G) G/- genotypes were also associated with higher EFV levels (p <0.001) although A/A genotype was rare among non-whites. The CYP3A A392G genotype was also associated with AUC24h. The CYP2B (G516T) T/T genotype was significantly associated with adverse CNS symptoms (p = 0.04). None of the genotypes studied showed significant associations with initial or short-term virologic or immunologic response to treatment.

Comment

The PK case studies showing therapeutic efavirenz levels three weeks after discontinuation of the NNRTI shows that extremely slow clearance may not be so unusual. The genetic research from the US studies supports particular caution in African patients.

References

1. Ribaudo H, Clifford D, Gulick R et al. Relationships between efavirenz pharmacokinetics, side effects, drug discontinuation, virologic response, and race: results from ACTG A5095/A5097s. 11th CROI 2004, Abstract 132.
2. Haas D, Ribaudo H, Kim R et al. A common CYP2B6 variant is associated with efavirenz pharmacokinetics and central nervous system side effects: AACTG Study NWCS214. 11th CROI 2004, Oral abstract 133.

HTB: January 2005
http://i-base.info/htb/8558

Further genetic link to efavirenz absorption

Further relevance to genetics and efavirenz (EFV) absorption were presented in a late breaker poster by Novoa and colleagues from Hospital Carlos III, Madrid.

Over 100 consecutive Caucasian adherent patients on EFV-containing combinations for over one month were studied with reference to codon 516 of the CYP2B6 isoenzyme. Median age was 40 years and 36% were coinfected with HCV. 80% patients were men and 20% were women.

Genotyping showed 52% were wild-type GG (39 men, 13 women); 43% carried the heterozygote GT mutation associated with African patients, slower drug clearance and higher drug concentrations (36 men, 7 women); and 5% carried homogygote TT mutations (5 men). Mid-dose drug levels were measured by HPLC at 12 weeks,

The study identified a wide range of interpatient variability in efavirenz levels (0.33-6.88ug/mL, target range = 1.0-4.0 ug/mL). Median plasma levels were higher in patients with 516 polymorphism and highest in patients with homogygote TT variant. All patients with sub-therapeutic levels had the wild-type GG. 19% and 40% of patients with GT and TT variants respectively had drug levels > 4ug/mL associated with higher toxicity.

Effect of genotype on efavirenz absorption

G516G (wild-type) G516T T516T
Median (IQR) EFV levels (ug/mL) 1.71 (1.09-2.53) 2.6 (1.73-3.50) 3.57(2.55-6.07)
% sub-optimal (<1ug/mL) 19% 2% 0%
% toxicity (>4ug/mL) 5% 19% 40%

Neither age, gender or HCV coinfection, were associated with different efavirenz levels.

This supports earlier findings presented by two different groups at the Retrovirus conference earlier this years (see HTB Vol5No3, April 2004). Those studied highlighted the risk for higher efavirenz exposure in African of African/American patients, referring to both toxicity and risk for resistance due to extended periods of monotherapy on stopping efavirenz-based combinations.

The significance prevalence of GT and TT variants in these Caucasian Spanish patients indicates a higher influence of genetic factor for tolerance or efficacy than is probably so far recognised.

Comment

The Novoa study is difficult to interpret since one third of the patients had Hepatitis B. However there appears to be a gene-dose effect TT>GT>GG.Since genetic variation will have different effects on different populations, it is important to replicate these studies in diverse populations.

Ref: Novoa SR et al. Prediction of efavirenz plasma levels by determining the G516T polymorphism at the CYP2B6 isoenzyme – clinical implications. 41st ICAAC, Washington, 2004. Abstract H-584a.

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Published: April 20, 2007
Last edited: August 14, 2013