The following table includes summaries of non-pregnant adult PK and drug-drug interaction studies from the three most recent major HIV conferences: 13th CROI, 45th ICAAC and 10th EACS.

Studies relating to pharmacology during pregnancy are covered in separate reports in this issue of HTB and the paediatric studies will be included in the May edition of HTB.

All abstracts are available online at the respective conference websites. Abstracts from EACS and CROI are also archived on the AEGiS.org conference database. ICAAC abstracts are usually removed from any public online access several months after the conference.

Please consult abstracts for full study for details.

The 13th Conference on Retroviruses and Opportunistic Infections

http://www.retroconference.org

45th Annual International Conference on Antimicrobial Agents and Chemotherapy (ICAAC)

http://www.eacs-conference2005.com

The 10th European AIDS Conference/EACS

http://www.eacs-conference2005.com

HIV / AIDS Information on the Internet, provided by AEGIS

http://www.aegis.org

Table 1: PK and drug interaction studies at CROI, ICAAC and EACS

COMMENT

The food interaction study with TMC114 was well designed with a specific range of different options. Although it is likely that TMC114 will be recommended to ‘take with food’ it is useful to know that ‘coffee and croissant’ is sufficient.

The interaction between the Meltrex formulation of lopinavir/r (Kaletra) and efavirenz is the first time that NNRTIs have been shown to increase levels of a PI. This is interesting, although patient variability may make this positive interaction less reliable in an individual patient, hence the recommendation to increase the Meltrex dose in treatment experienced patients.

The interaction between lopinavir/r (Kaletra) which increased rosuvastatin by 150-200% was unexpected as rosuvastatin is not mediated by CYP 3A4 pathway. This highlights the importance of real in vivo interaction studies, and the limitations of recommendations based only on a theoretical likelihood of an interaction.

HIV Pharmacology website:

http://www.HIVpharmacology.com

References

1. Sekar V et al. The effects of different meal types on the PK of TMC114 tablet formulation dosed with ritonavir in healthy volunteers. 10th European AIDS Conference. November 17-20, 2005. Dublin. Abstract PE4.1/1.
2. Sekar V et al. Pharmacokinetc interraction between TMC114/ritonavir and atazanavir in healthy volunteers. 10th European AIDS Conference. November 17-20, 2005. Dublin. PE 4.3/4.
3. Boffito M, Winston A, Fletcher C et al. Pharmacokinetics and ART response to TMC114/r and TMC125 combination in patients with high-level viral resistance. Abstract 575c.
4. Scholler et al. Significant decrease in TMC125 exposures when co-administered with tipranavir boosted with ritonavir in healthy subjects. 13th CROI. Abstract 583.
5. Hoetelmans R et al. Pharmacokinetic interaction between TMC278, and investigational NNRTI and lopinavir/r in healthy volunteers. 10th EACS. Abstract PE4.3/1.
6. Klein C, Zhu T, Chiu YL, et al. Effect of efavirenz on lopinavir/ritonavir pharmacokinetics from a new tablet formulation. 10th European AIDS Conference. November 17-20, 2005. Dublin. Abstract PE4.3/2.
7. Winston A, Back D, Fletcher C, et al. Effect of omeprazole on the pharmacokinetics of saquinavir 500 mg formulation with ritonavir in healthy male and female volunteers. 10th European AIDS Conference. November 17-20, 2005. Dublin. Abstract LBPE4.3/16.
8. Klein C et al. Lack of effect of acid-reducing agents on the pharmacokinetics of lopinavir/ritonavir tablet. 13th CROI. Abstract 578.
9. Tomilo et al. The effect of lansoprazole acid suppression on the pharmacokinetics of atazanavir in healthy volunteers. 45th ICAAC. Abstract A-1192.
10. Mallolas J et al. Pharmacokinetic interaction between rifampin and the combination of atazanavir and low dose ritonavir in HIV-infected patients. 45th ICAAC. Abstract A-1202.
11. Chen Y et al. Pharmacokinetic interaction between rifabutin (RFB) and fosamprenavir (FPV)/ritonavir (RTV) in healthy subjects. 45th ICAAC. Abstract A-1199.
12. Pujari S et al. Effect of rifampin hepatic induction on nevirapine levels in Indian volunteers. 13th CROI. Abstract574.
13. Van Der Lee M et al Pharmacokinetics and pharmacodynamics of combined use of lopinavir/ritonavir and rosuvastatin in HIV-infected patients. 13th CROI. Abstract 588
14. Judith A. Aberg, Susan L. Rosenkranz, Carl J. Fichtenbaum, Beverly L. Alston, Susan W. Brobst, Yoninah Segal, John G. Gerber, for the ACTG A5108 team. Pharmacokinetic interaction between nelfinavir and pravastatin in HIV-seronegative volunteers: ACTG Study A5108. AIDS 2006;20:725-729.
15. Kaul S et al A 2-way pharmacokinetic interaction between efavirenz and carbamazepine. 13th CROI. Abstract 575a.
16. Wyen C, Jetter A, Frank D, et al. CYP2D6 is inhibited by lopinavir/ritonavir in HIV-infected patients. European AIDS Conference. November 17-20, 2005. Dublin. Abstract PE4.1/6.

Maida and colleagues from Hospital Carlos III, Madrid presented results on the degrees of fibrosis in HIV/HCV coinfected patients who have normal ALT levels. In HCV monoinfected patients about 30% of HCV monoinfected patients have ALT levels within normal limits and 11-19% of them show significant histologic liver damage.

They identified patients with detectable plasma HCV RNA who had not been treated for HCV, and who had persistently normal ALT levels throughout the prior 12 months of follow-up (≥ 4 determinations). Presence and grade of fibrosis was evaluated by FibroScan.

Out of 279 coinfected patients with positive HCV RNA, 25 (8.9%) had persistently normal ALT. Distribution of HCV genotypes was 13 (56.5%), 1 (4.3%), 1 (4.3%) and 8 (34.8%) for genotypes 1, 2, 3 and 4 respectively. FibroScan results were as follows: F1 8 (47.1%), F2 4 (23.5%), F3 2 (11.8%), F4 3 (17.6%).

There was a trend among patients with HCV-4 genotype (50%) to have more often severe fibrosis (F3-F4) compared to genotype HCV-1 (11.1%) (p= 0.07).

The authors concluded that 9% per cent of HIV-infected subjects with detectable HCV RNA present persistently normal transaminase levels, being HCV-1/4 genotypes more frequent than HCV-2/3. In this cohort, nearly one third of HIV-infected patients with chronic HCV infection and persistently normal ALT had advanced degrees of liver fibrosis that would indicate HCV-treatment. HCV-4 genotype showed a trend to higher degrees of fibrosis.

COMMENT

About a quarter of these patients seem to have relevant fibrosis despite persistent normal ALT, which is higher than the approx. 15% reported by Zeuzem et al in the HCV-monoinfected population. But, these are low numbers (n=25) and coinfected patients represent a population which consumes more alcohol and are on a higher number of medications and this may result in additional liver toxicities.

This adds to existing reports in patients with HCV mono-infection where the phenomenon of advanced fibrosis and even cirrhosis have been reported with ‘normal’ ALTs (see Shiffman et al, JID, 2000; 182: 155-1601, Puoti et al. J Hepatology, 2002; 37: 117-123). There are a number of issues to consider in appraising this phenomenon.

HCV not only has an effect on hepatocytes (damage of which causes release of the classical liver enzymes, ALT, AST), but may also have a direct effect on the activation and proliferation of hepatic stallete cells, which cause direct hepatic fibrosis, thus causing significant fibrosis in the presence of normal ALT.

It also rasies the issue of the definiton and use of the term ‘normal’ ALT. There is increasing evidence that values of ALT/AST at the upper end of the normal range may in fact be abnormal or high for some patients and are dependent on sex and body mass index. For example, an ALT of 30 iu/l (normal range 5-40 iu/l for most laboratories) may be ‘normal’ for an 80kg male, but ‘high’ for a 50kg female (see Kaplan MM, Ann Intern Med 2003; 137: 49-51).

Furthermore, this abstract illustrates the increasing utility of ‘non-invasive’ markers/tests for the assessment of hepatic fibrosis. Although these tests are currently being evaluated for their sensitivities and specificities in predicting various stages of fibrosis in HIV-infected patients, as this study shows, there is increasing utility especially in Europe. However, the ‘cut-off’ values for various stages of fibrosis and their sensitivities and specificities have yet to be defined in large populations with HIV-infection, so one must view these results in that context.

For an interesting debate on Fibroscan vs. Fibrotest see:

http://www.hivandhepatitis.com/hep_c/news/2006/020706_a.html

Ref: Maida I, Soriano V, Gonzalez G et al. Liver fibrosis stage in HIV/HCV-coinfected patients with persistently normal transaminases levels. Poster H-1483. 45th ICAAC, 16-19 December 2005, Washington.

• Understanding TMC114 power against resistant HIV

• New antiretroviral compounds at ICAAC: new PI brecanavir from GSK; maturation inhibitor PA-457; antiviral activity of monoclonal antibody; TNX-355 in treatment experienced patients

• Comparison of pharmacokinetics of originator and generic liquid formulations and split tablets in Malawian children

• African-Americans in ACTG 5095 had shorter time to virologic failure and grade 3/4 side effects

• Predictors of insulin resistance in first year of therapy

• Three measures confirm 144-week renal record of tenofovir

• Low rash risk with efavirenz after nevirapine rash

Abstracts from the ICAAC meeting only remain on the conference website for a few months, and are then only available through subscription.

This year’s ICAAC afforded a 24-week look at results of the POWER 2 trial pitting TMC114/ritonavir against a standard PI salvage regimen in people with plentiful PI experience. But wait. Haven’t we already heard 24-week POWER 2 results? Or was that POWER 1?

Both, as it turns out. In February 2005, at the Conference on Retroviruses, Richard Haubrich spelled out findings on 497 people enrolled in either POWER 1 or 2 [1]. Twenty-six weeks later, Christine Katlama gave a more focused look at POWER 1 results, but still only 24 weeks’ worth [2]. At ICAAC, 46 weeks after Haubrich’s talk, Timothy Wilkin from the University of California, San Diego, homed in on a still-maturing 24-week data set from POWER 2 [3]. Perhaps Tibotec, maker of this potent PI, will unveil 48-week data at next February’s Retrovirus conference.

Both POWER studies randomised people with triple-class experience and at least one major PI mutation to take one of four TMC114/ritonavir doses or the best-feasible PI-based control regimen. The protocols blinded researchers to the TMC114 dose. Wilkins’ POWER 2 enrollees had more advanced HIV infection than their POWER 1 counterparts (Table 1), but the two study groups had similar PI experience and equivalent resistance to PIs.

Table 1: Differences between POWER 1 and POWER 2 studies of TMC114/r

* P < 0.001; ** P < 0.01

The more advanced disease in POWER 2 than in POWER 1 may figure in the more modest 24-week virologic response-a 1.7-log copies/mL drop with the highest dose of TMC114/ritonavir (600/100 mg twice daily) in POWER 2 versus 2.13 log copies/mL in POWER 1. Also, a lower proportion in POWER 2 than in POWER 1 (39% versus 53%) had a 24-week viral load under 50 copies/mL in an intent-to-treat analysis. Both responses in the TMC114 groups handily exceeded 24-week RNA wanings in the control arms.

People in POWER 2 also got less from 600/100 mg of TMC114/ritonavir than POWER 1 enrollees if they had three or more primary mutations, if they did not mix the fusion inhibitor enfuvirtide into their regimen, or if they had no other active agent in their background regimen (Table). But among enfuvirtide-naive people starting that drug, POWER 2 participants did as well as POWER 1 enrollees. By all these measures, TMC114/ritonavir worked much better than control PI regimens. Phase 3 studies will use the 600/100-mg twice-daily dose.

Daniel Berger from Chicago’s Northstar Medical Center detailed side effect findings in POWER 2, reporting that 8% quit the TMC114/ritonavir arms because of side effects versus 4% in the control arm [4]. The primary reason for the between-arm difference appears to be that people dropped out of the control group because of virologic failure before they could quit because of side effects. By week 24 the virologic failure dropout rate measured 47% with standard PI salvage regimens versus 9% with TMC114/ritonavir.

More than one quarter of POWER 2 participants taking the new PI had grade 3 or 4 problems (32% in the 600/100-mg arm), and 15% had a “serious adverse event” (9% in the 600/100-mg arm). Rash was the most common clinical problem with TMC114/ritonavir, affecting 5%. AST elevations, in 4%, were the most frequent lab abnormality.

Mark Mascolini writes about HIV infection.

markmascolini@earthlink.net

Source:

http://www.natap.org

References

1. Katlama C, Berger D, Bellos N, et al. Efficacy of TMC114/r in 3-class experienced patients with limited treatment options: 24-week planned interim analysis of 2 96-week multinational dose-finding trials. 12th Conference on Retroviruses and Opportunistic Infections. February 22-25, 2005. Boston. Abstract 164LB.
2. Katlama C, Carvalho MTM, Cooper D, et al. TMC114/r outperforms investigator-selected PI(s) in 3-class-experienced patients: week 24 primary efficacy analysis of POWER 1 (TMC114-C213). 3rd IAS Conference on HIV Pathogenesis and Treatment. July 24-27, 2005. Rio de Janeiro. Abstract WeOaLB0102.
3. Wilkin T, Haubrich R, Steinhart CR, et al. TMC114/r superior to standard of care in 3-class-experienced patients: 24-wks primary analysis of the Power 2 study (C202). 45th Interscience Conference on Antimicrobial Agents and Chemotherapy. December 16-29, 2005. Washington, DC. Abstract H-413.
4. Berger DS, Bellos N, Farthing C, et al. TMC114/r in 3-class-experienced patients: 24-wk primary safety analysis of the Power 2 study (C202). 45th Interscience Conference on Antimicrobial Agents and Chemotherapy. December 16-29, 2005. Washington, DC. Abstract H-1094.

There was only one oral slide session at ICAAC for HIV studies. Luckily this included results on several new drugs that were all worth reporting and are included below.

New PI from GSK: brecanavir

Optimistic results were presented from a proof-of-concept study of a protease inhibitor in development by GSK. In vitro, bracanavir (GSK 640385) has antiviral activity against multi-PI resistant HIV and is up to 100-fold more potent than currently marketed PIs. It needs to be taken with food, and also requires ritonavir boosting.

Although the 8-week results are in the printed abstract submitted to the original ICAAC meeting, the intervening period until the rescheduled conference enabled 24-week results to be analysed and presented.

This was an open label, non-randomised, 48-week study in 25 patients with wild-type virus and six patients with drug resistance. Dual nucleoside backbone was decided by treatment history and resistance profile, with 27/31 using AZT/3TC (Combivir). Tenofovir was not allowed as interaction data at the time of the study were not yet available. The dose studied was brecanavir 300mg with ritonavir 100mg, both twice-daily (Q12H).

The six patients with resistant virus had a median of two primary PI and five NRTI mutations. Median (IQR) CD4 and viral load at baseline was 311 cells/mm³ (203-405) and 4.71 logs (4.3-5.1). Median baseline viral load for the six patients with resistant-HIV was approximately 1 log lower than that of naïve patients (4.2 vs 5.0 logs).

At week 24, 77% patients had viral load <50 copies/mL and 81% had <400 copies/mL by Intent-To-Treat analysis (missing data = failure). Median reductions of -2.2 and –3.3 log in the experienced and naïve patients respectively, was related to different baseline levels and censuring by the lower limit of the test.

There were four discontinuations of the study drug; one due to nausea and vomiting, and a second due to a grade 3 increase in AST, and two due to withdrawal of consent. There were no clinical reports of toxicity greater than Grade 2. Grade 3-4 laboratory abnormalities were CPK (n=3) raised lipids (n-2), AST, GGT, hypoglycemia, total bilirubin and neutropenia (all n=1). Lipid changes included median increases in total cholesterol, HDL and triglycerides of 30.9, 3.9 and 62.3 mg/dL respectively, with no effect on LDL.

The resistance profile of one of the 5/6 treatment experienced patients who achieved <50 copies/mL included broad resistance with mutations associated with protease resistance at positions 10, 24, 33, 46, 48, 53, 54, 62 and 82; associated with RTI resistance at 41, 44, 67, 210, 215 and the K103N conferring resistance to NNRTIs.

COMMENT

Unusually, a single-arm, single-dose study was run in treatment naïve and experienced patients looking at tolerance and efficacy, prior to controlled dose-finding study. Results from such a study have therefore created a higher profile for this compound prior even to Phase 2 dose-finding results.

Given the competitive difficulties sometimes experienced in recruiting treatment-naïve patients, this should help recruitment into future studies. The Phase IIb brecanavir study (HPR20001, STRIVE) will enrol 130 multi-PI experienced patients in the US and Europe and includes sites in the UK.

Ref: Ward D, Lalezari J, Johnson M et al. Preliminary antiviral activity and safety of 640385/ritonavir in HIV-infected patients (Study HPR10006): an 8-week interim analysis. Abstract H-412.

Maturation inhibitor PA-457: safety and efficacy during 10-day monotherapy study

Svilen Konov, HIV i-Base

Beatty and colleagues from Panacos Pharmaceuticals reported results from a double-blind, placebo-controlled, 10 day monotherapy study that looked at the safety and efficacy of PA-457. This is the first in a new class antiretrovirals, called maturation inhibitors. Maturation inhibitors prevent HIV core proteins from maturing, thus making the new viral particles non-infectious.

The study randomised 33 patients (CD4 >200 cells/mm³ and viral load 5000-250,000 copies/mL) who were either treatment-naïve or who were more than 12 months without therapy, to an oral dose of once-daily placebo or 25, 50 100 or 200mg PA-457. The 100 and 200mg doses produced statistically significant median reductions in viral load of –0.48 and –1.03 logs respectively, compared to placebo. At day 11 the participants from the 200mg dose group with baseline viral load <100,000 copies/mL had median viral load reduction of –1.52 log10 copies/mL. The genotypic data obtained at the end of the study (in 21 out of 33 people) demonstrated no evidence of resistance development to PA-457. No grade 3/4 lab abnormalities were seen at any dose, and any adverse events categorised as mild to moderate.

One person had a grade 2 increase in triglycerides that returned to normal by the end of the study. Another participant suffered a lacunar CVA (cerebrovascular accident, minor stroke) but the researchers suggest that this is probably a result of previous poorly-controlled hypertension. The researchers reported that the half-life of PA-457 is close to 60 hours, which is promising for current ARV research focussed on once-daily dosing.

Ref: Beatty G, Lalezari J, Eron J, et al. Safety and antiviral activity of PA-457, the first-in-class maturation inhibitor, in a 10-day monotherapy study in HIV-1 infected patients. 45th Interscience Conference on Antimicrobial Agents and Chemotherapy. December 16-29, 2005. Washington, DC. Abstract H-416d.

Antiviral activity of monoclonal antibody TNX-355 in treatment experienced patients

Svilen Konov, HIV i-Base

TNX-355 is a humanised monoclonal antibody (an antibody that is produced artificially from a single cell clone and, therefore, consists of a single type of immunoglobulin) that binds to CD4 receptors, disrupting viral replication. The compound is aimed at treatment-experienced patients. At ICAAC the 24-week interim assessment of the ongoing 48-week double-blind, placebo-controlled, randomised phase II study showed that TNX-355 in combination with optimised background regimen (OBR) exhibited greater antiviral activity than OBR alone in treatment-experienced HIV-1-infected individuals.

The study randomised 82 three-class experienced patients to either15 mg/kg every 2 weeks or 10mg/kg every week for 8 weeks followed by 10mg/kg every two weeks; or to placebo; with OBR for all groups. The mean RNA log drop was -1.2 (p<0.001), -0.97 (p<0.001), and -0.41 in the 15mg, 10mg and placebo groups respectively. The compound, however, needs to be infused intravenously, which might turn it into a last resort choice. The researchers did not present information on the relative ARV experience of the participants in the study or impact on treatment history on the results.

Another study [2] showed that TNX-355 is active against CCR5-, CXCR4-, and dual/mixed-tropic HIV-1 in vitro. In addition, strong synergistic antiretroviral activity was demonstrated between TNX-355 and T-20 (enfuvirtide) in vitro (CIs of 0.27±0.13 and 0.12±0.11 for single and continuous exposure, respectively). These results suggest that combining 2 entry inhibitors might have a potential of becoming a treatment approach in the future.

References:

1.   Norris D, Morales J, Gathe J et al. TNX-355 in combination with Optimized Background Regimen (OBR) Exhibits Greater Antiviral Activity than OBR Alone in HIV-Treatment Experienced Patients. 45th Interscience Conference on Antimicrobial Agents and Chemotherapy. December 16-29, 2005. Washington, DC. Abstract LB2-26.
2.   Godofsky E, Zhang X, Sorenson M, et al. In vitro antiretroviral activity of the humanized anti-CD4 monoclonal antibody, TNX-355, against CCR5, CXCR4, and dual-tropic isolates and synergy with enfuvirtide. 45th Interscience Conference on Antimicrobial Agents and Chemotherapy. December 16-29, 2005. Washington, DC. Abstract LB-26.

Malawian national guidelines include divided Triomune (fixed combination of d4T, 3TC and nevirapine) tablets to treat paediatric HIV. Children are dosed by weight in 1/4 tablet multiples.

Corbett and colleagues from the University of North Carolina presented findings from a 3-way crossover study comparing pharmacokinetics (PK) of d4T, 3TC and nevirapine in HIV positive children In Lilongwe, Malawi. The children received either divided Triomune 40 (GT), generic liquids (GL) or trade liquids (TL).

The children were divided into three groups by weight: Group 1, 8 to <12kg, dose 1/4 tablet BID; Group 2, 18 to <22kg, 1/2 tablet BID; and Group 3, 28 to <32kg, 3/4 tablet BID and had been taking GT for a minimum of three months. Children were then randomised to receive GT, GL or TL and 6 hour PK was performed after 10 days of receiving each formulation.

The study included 18 children (11 female and 7 male) with a median age of 7 years (range: 0.08-13.6 years) and a median weight of 19kg (range: 9-30.5kg). Their median CD4 was 383 cells mm³ (range: 13-1415 cells mm³) and viral load 399 copies/mL (range: 261-2,837,779 copies/mL).

The authors reported the following geometric mean ratios (90% CI) for Cmax and AUC:

The authors found that in all dosing groups NVP met the definition for bioequivalence (BEQ) but neither 3TC nor d4T met the definition despite statistically significant differences. They also noted that T-max was delayed for 3TC and d4T compared to both liquid formulations.

Additionally there was clinical difference in 3TC and d4T exposures in children in Group 1 receiving the GT compared to both liquids. In the other two groups, although not BEQ, they reported less clinical difference.

They noted that compared to historical US PK data 3TC and d4T TL concentrations were lower and NVP concentrations higher in Malawian children vs north American children.

They concluded that based on PK, liquid formulations are better for smaller children, but for larger children quartered multiples of fixed dose combinations are a reasonable option.

Ref: Corbett A, Hosseinipour M, Nyirenda J et al. Pharmacokinetics between trade and generic liquid and split tablet formulations of lamivudine, stavudine and nevirapine in HIV infected Malawian children. 45th ICAAC, Washington, 2005. Abstract H-1905

At that point, almost 3 years after randomisation, Cornell University’s Roy Gulick and ACTG colleagues could not sift out a single result suggesting a four-drug efavirenz regimen does better than a three-drug efavirenz regimen [2]. That result confirms a host of earlier studies that found no good reason to start antiretroviral therapy with four drugs instead of three [3-6].

The comparison of the two efavirenz regimens involved 765 people who started therapy with an average viral load of 72,444 copies/mL (57% were below 100,000 copies/mL) and an average CD4 count of 240 cells/mm³. Looking at the primary endpoint-two consecutive viral loads above 200 copies/mL after at least 16 weeks of treatment-Gulick counted 99 failures among 382 people (26%) taking triple therapy and 94 out of 383 (25%) taking quadruple therapy, nowhere close to a statistically significant difference (P = 0.73).

Nor did the three-drug and four-drug groups differ in time to virologic response, time to virologic failure in people with a pretreatment load above 100,000 copies/mL, percentage reaching a load below 50 copies/mL (80% to 85% in each group after 144 weeks), CD4-cell gains, treatment discontinuations, or side effect rates.

Multivariate analysis to track down factors affecting virologic failure found two variables that made failure more likely:

• Coinfection with hepatitis C virus (HCV) raised the failure risk 57% (hazard ratio 1.57, 95% confidence interval 1.02 to 2.40, P = 0.04). HCV coinfected patients had shorter time to viral failure, but they were not found to have shorter time to grade 3/4 adverse events & discontinuation from first regimen.
• Being black instead of white raised the risk 67% (hazard ratio 1.67, 95% confidence interval 1.19 to 2.35, P = 0.003)

The first finding confirms that HIV infection can be more difficult to manage in people also battling HCV. But the racial difference is hard to explain. Gulick stressed that blacks did not differ from whites or Hispanics in overall adherence. About 85% in each ethnic group reported never missing a dose in the 4 days before each self-report.

But poor adherence among blacks at a single point – 12 weeks after treatment began – did correlate with virologic failure when compared with blacks reporting good adherence at that time and with whites or Hispanics reporting good or bad adherence at 12 weeks.

Gulick speculated that genetic differences affecting efavirenz levels could play a part in this higher risk of failure. Genotyping in an earlier ACTG study found that a certain shift in a gene that codes the CYP2B6 efavirenz-metabolizing enzyme turned up more often in blacks (20%) than whites (3%) and correlated with higher efavirenz levels (P < 0.0001) [7].

Indeed, Gulick found that black people in his study had a significantly shorter time to virological failure and a shorter time to grade 3 or 4 side effects. But ACTG gene analysts will have to look at blood samples from study participants to see if black people had the critical CYP2B6 gene flips more than other groups, and if those flips correlate with higher efavirenz levels and more efavirenz-induced side effects.

Making that triple correlation – higher rate of critical gene shifts, leading to higher drug levels, leading to more side effects – is not easy. In the earlier ACTG trial, for example, black people had a key CYP2B6 gene change more than white people, and they had higher efavirenz levels, but that gene shift did not correlate with more efavirenz toxicity [7]. An ICAAC study from London’s Chelsea and Westminster Hospital and the University of Liverpool also failed to tie higher efavirenz levels in black people to more efavirenz side effects [8].

Desmond Maitland and colleagues charted efavirenz concentrations in treatment-naive people beginning either 3TC/ddI/efavirenz or tenofovir/ddI/efavirenz in an open-label (non-blinded) trial. Adherence measured by three methods exceeded 99% in both treatment groups. The study ended early when the tenofovir regimen quickly proved virologically inferior, but the London-Liverpool team did measure 4- and 12-week efavirenz levels in 66 people, including 9 women and 13 Africans.

Efavirenz levels proved significantly higher at weeks 4 and 12 in women than in men, and in Africans than in whites. But high efavirenz concentrations did not correlate with neuropsychiatric symptoms assessed at week 12. People with efavirenz readings above 1100 ng/mL at weeks 4 and 12 were more likely to reach a viral load below 50 copies/mL at week 12, a finding confirming a minimum effective concentration of 1000 ng/mL for efavirenz.

Source: www.natap.org

References

1. Gulick R, Ribaudo H, Shikuma C, et al. Triple-nucleoside regimens versus efavirenz-containing regimens for the initial treatment of HIV-1 infection. N Engl J Med 2004;350:1850-1861.
2. Gulick RM, Ribaudo HJ, Shikuma CM, et al. ACTG 5095: zidovudine/lamivudine/abacavir vs. zidovudine/lamivudine + efavirenz vs. zidovudine/lamivudine/abacavir + efavirenz for initial HIV therapy. 45th Interscience Conference on Antimicrobial Agents and Chemotherapy. December 16-29, 2005. Washington, DC. Abstract H.-416a.
3. Moyle G, Pozniak A, Opravil M, et al. The SPICE study: 48-week activity of combinations of saquinavir soft gelatin and nelfinavir with and without nucleoside analogues: Study of Protease Inhibitor Combinations in Europe. JAIDS 2000;23:128-137.
4. Katzenstein TL, Kirk O, Pedersen C, et al. The Danish protease inhibitor study: a randomised study comparing the virological efficacy of 3 protease inhibitor-containing regimens for the treatment of human immunodeficiency virus type 1 infection. J Infect Dis 2000;182:744-450.
5. Shafer RW, Smeaton LM, Robbins GK, et al. Comparison of four-drug regimens and pairs of sequential three-drug regimens as initial therapy for HIV-1 infection. N Engl J Med 2003;349:2304-2315.
6. van Leth F, Phanuphak P, Ruxrungtham K, et al. Comparison of first-line antiretroviral therapy with regimens including nevirapine, efavirenz, or both drugs, plus stavudine and lamivudine: a randomised open-label trial, the 2NN study. Lancet 2004;363:1253-1263.
7. Haas DW, Ribaudo HJ, Kim RB, et al. Pharmacogenetics of efavirenz and central nervous system side effects: an Adult AIDS Clinical Trials Group study. AIDS 2004;18:2391-2400.
8. Maitland D, Boffito M, Mandalia S, et al. Correlation between therapeutic drug monitoring of efavirenz and virological response at week 12 in HIV+ subjects starting once daily antiretroviral therapy. 45th Interscience Conference on Antimicrobial Agents and Chemotherapy. December 16-29, 2005. Washington, DC. Abstract H-1902.

Studying 120 people during their first 48 weeks of antiretroviral therapy, clinicians from Malaga and Seville turned up two baseline predictors of insulin resistance – HCV infection and treatment with indinavir – and two associated factors that evolved during antiretroviral therapy – higher weight and a diagnosis of lipodystrophy [1].

These clinicians tracked 120 people at two HIV clinics who started their first antiretrovirals between June 2002 through June 2003 and stayed with the same regimen for 48 weeks. Everyone had 95% or better antiretroviral adherence, no one had diabetes, and no one took other drugs that could tip a person’s glucose-insulin balance.

Ninety-one cohort members (76%) were men, 69 (66%) smoked, 43 (36%) had HCV infection, and 16 (21%) had a family history of diabetes. Before these people started antiretrovirals their CD4 count averaged 222 cells/mm³ (interquartile range 64 to 313 cells/mm³) and their viral load averaged 5.39 log (about 245,500) copies/mL.

After 48 weeks of therapy, 81% had an undetectable viral load, while the average CD4 count climbed 182 cells/mm³. Most metabolic variables measured strayed significantly in the wrong direction in these 48 weeks. Average total cholesterol climbed from 154 to 191 mg/dL, and menacing low-density lipoprotein cholesterol from 93 to 114 mg/dL (P = 0.0001 for both changes).

The group’s average glucose rose from 90 to 95 mg/dL (P = 0.0001) and insulin from 7.24 to 10.15 microUI/mL (P = 0.002). Average body mass index edged up from 23.1 to a still-normal 24.5 kg/m2. After 48 weeks of antiretroviral therapy, 15 people (13%) had insulin resistance, defined as a HOMA score above 3.8.

Multivariate analysis settled on four factors that independently raised the risk of insulin resistance (Table 1). These researchers did not explain how they defined lipodystrophy, one of the two 48-week variables linked to insulin resistance.

Table 1: Predictors of insulin resistance in multivariate analysis (n=120)

Higher triglycerides correlated with insulin resistance in the univariate analysis, but smoking, family history of diabetes, and baseline glucose did not. People who ended up with insulin resistance had a higher pretreatment insulin reading in the univariate analysis (9.2 versus 6.8 microUI/mL in people who stayed free of insulin resistance, P = 0.01). Insulin resistance developed in none of 19 people who took a nevirapine-based regimen.

Source: www.natap.org

Ref: Palacios R, Merchante N, Macias J, et al. Prospective study of glucose metabolism in antiretroviral naive HIV-infected patients: incidence of insulin resistance at 48 weeks of HAART. 45th Interscience Conference on Antimicrobial Agents and Chemotherapy. December 16-29, 2005. Washington, DC. Abstract H-344.

Two formulas to calculate glomerular filtration rate – a signal of kidney trouble – figured no significant change during 144 weeks of tenofovir therapy in the randomised trial comparing tenofovir with d4T [1]. Development of chronic kidney disease, as defined by the National Kidney Foundation, did not differ between the tenofovir and d4T groups.

With coworkers in Germany and Britain, Joel Gallant from Johns Hopkins University in Baltimore ran this 144-week, double-blind, placebo-controlled trial of tenofovir or d4T plus 3TC and efavirenz in 600 previously untreated people. The trial excluded people with pretreatment portents of kidney problems.

Gallant used the Cockcroft-Gault equation and the Modification of Diet and Renal Disease (MDRD) formula to figure glomerular filtration rates in the two study arms at study week 144. A lower Cockcroft-Gault or MDRD score indicates worse creatinine clearance. Gallant noted that either equation gauges kidney function better than simply measuring serum creatinine, though the MDRD seems more accurate in people without HIV who have chronic kidney disease. However, the MDRD formula has not been validated in people with normal kidney function or in people with HIV. (See note 2 for the equations. Online Cockcroft-Gault and MDRD calculators can be found at http://nephron.com/mdrd/default.html).

Table 1: Glomerular filtration rates at 144 weeks in the tenofovir-vs-d4T trial

GFR = Glomular filtration rate * P <0.05

Baseline glomerular filtration rates by either equation and National Kidney Foundation kidney disease stage proved similar in the two treatment arms. After 144 weeks of tenofovir or d4T, glomerular filtration rates did not change significantly in the tenofovir group, though they did rise significantly among people taking d4T (Table 1).

Glomerular filtration rate reckoned by the Cockcroft-Gault equation did not change significantly in either treatment arm among people taking antihypertensives or antidiabetes drugs during the study.

No one in the trial stopped tenofovir because of kidney problems, and study clinicians never diagnosed proximal renal tubular dysfunction or Fanconi syndrome through 144 weeks.

In a separate retrospective look at clinical trial data, Glaxo researchers unearthed no evidence of significant changes in glomerular filtration rate after previously untreated people took efavirenz plus Trizivir (AZT/3TC/abacavir), Combivir (AZT/3TC), or 3TC/abacavir for 48 weeks [3].

Source: www.natap.org

References and notes

1. Gallant J, Staszewski S, Pozniak A, et al. Similar renal safety profile between tenofovir DF and stavudine (d4T) using modification of diet in renal disease and Cockcroft-Gault estimation of glomerular filtration rate in antiretroviral-naive patients through 144 weeks. 45th Interscience Conference on Antimicrobial Agents and Chemotherapy. December 16-29, 2005. Washington, DC. Abstract H-350.
2. Cockcroft-Gault equation: glomerular filtration rate (mL/min) = (140 – age in years) x weight in kg divided by (72 x serum creatinine in mg/dL) x (0.85 if female).
Modification of Diet in Renal Disease equation: glomerular filtration rate (mL/min/1.73 m2)= 186 x serum creatinine in mg/dL(-1.154) x age in years(-0.203) x 0.742 if female x 1.212 if black.
3. Sutherland-Phillips D, Hill-Zabala C, Brothers Q, et al. Regimens containing abacavir, lamivudine, zidovudine, and efavirenz do not affect glomerular filtration rate during long-term treatment of HIV-naive subjects. 45th Interscience Conference on Antimicrobial Agents and Chemotherapy. December 16-29, 2005. Washington, DC. Abstract H-349.

Only 10 of 122 adults (8%) who replaced nevirapine with efavirenz because of rash had the same problem with the second nonnucleoside, Thai clinicians reported [2]. They could tease out no predictors of efavirenz-induced rash after a nevirapine rash.

Weerawat Manosuthi from the Ministry of Public Health in Nonthaburi and coworkers checked records of 122 people, 64 of them (52.5%) men, who had to stop nevirapine because of rash.

These people started their nevirapine regimens with a low median CD4 count of 54 cells/mm³ (interquartile range 20 to 167 cells/mm³). Seventy-six people (62%) dropped nevirapine because of diffuse maculopapular rash or urticaria, and 46 (38%) did so because of rash with constitutional symptoms, angioedema, serum sickness-like reactions, or Stevens Johnson syndrome.

Another rash flared up in 10 people a median of 8 days (interquartile range 2.0 to 12.3 days) after the switch to efavirenz. Stevens Johnson syndrome arose in 1 person with a history of multiple drug allergies, while the other 9 had diffuse maculopapular rash of the trunk and limbs. All rashes cleared after indinavir/ritonavir replaced efavirenz.

Checking a laundry list of variables that may favor a second rash, the Thai team found none. Nonpredictive factors included age, gender, baseline CD4 count, baseline viral load, previous opportunistic infections, severity of nevirapine-induced rash, time between stopping nevirapine and starting efavirenz, and concurrent medications. The 10 people who got a second rash were slightly but not significantly older than those who did not (40.5 versus 36.5 years, P = 0.167).

Source: www.natap.org

Ref: Manosuthi W, Thongyen S, Chumpathat N, et al. Prevalence and risk factors of rash from efavirenz in HIV-infected patients with preceding nevirapine-associated rash. 45th Interscience Conference on Antimicrobial Agents and Chemotherapy. December 16-29, 2005. Washington, DC. Abstract H-343.