Several studies looked at the association between older age and antiretroviral pharmacokinetics (PK).

Tenofovir

Muge Cevik from the Chelsea and Westminster Hospital London reported results from a PK study suggesting that tenofovir clearance is significantly reduced with increasing age and resulting in higher drug levels (AUC and Ctrough). [1]

This included steady-state plasma levels from 52 men and 2 women (12 of whom were on PI/r-based combinations). Median age was 54 years (range 40–81 years) with only two people younger than 50. Samples were drawn randomly and population pharmacokinetics applied to predict values.

Tenofovir median clearance (CL/F), AUC (24hr) and Ctrough (C24) were 110.0 L/r (27.4–248.3). 2.2 mg.hr/L (1.0–9.0), and 0.06 mg/L (0.01–0.3) respectively.

Increasing age was significantly associated with slower clearance (p=0.0012), higher AUC (p=0.0012) and higher Ctrough (p=0.0017). People older than 60 had significantly lower clearances (p=0.0447) and higher AUC (p=0.0457) than those younger than 60.

No PK differences were seen between PI and NNRTI based combinations (p=0.08).

Efavirenz and darunavir/ritonavir

A similar analysis was presented by Ahmed and colleagues from the same group at Chelsea and Westminster on the PK of efavirenz or darunavir/ritonavir used by older patients (median age was 54 years (range 27-77) and 56 years (28-76), respectively). [2]

In 70 men and 7 women taking efavirenz, no differences were seen in any PK parameter when comparisons were made between people older and younger than 50 (all p-values >0.05 for between age comparisons).

In 33 men and one woman taking darunavir/ritonavir (23 using once-daily) oral clearance was significantly lower in people over 50 years old (10.3 vs 13.0 L/h; p=0.027) with higher AUC (80.9 vs 61.6 mg.h/L; p=0.021) and Ctrough levels (1.9 vs 1.2 mg/L; p=0.008) than those younger than 50.

Once-daily vs twice-daily could not be assessed because of unequal age distribution between the two dosing regimens.

References:

1. Cevik M et al. Tenofovir (TFV) pharmacokinetics (PK) in HIV infected individuals over 40 years of age. 13th EACS, 12–15 October 2011, Belgrade. Abstract PS 6/1.
2. Ahmed A et al. Efavirenz and Darunavir Plasma Concentrations in HIV-infected Patients Aged 50 Years or over. 13th EACS, 12–15 October 2011, Belgrade. Abstract PE6.2/1.

Researchers at Makerere University, Kampala and the pharmocology group at Liverpool University reported a significant interaction between high fat meals and ritonavir as a booster in lopinavir/r (Kaletra).

Three meal conditions were studied in an open-label, three part, cross over study in 12 HIV positive people (6 men, 6 women) using lopinavir/r (2 x 400/100 mg tablets) as second-line therapy. Median (IQR) age and weight of patients was 48 (44 – 49) years and 62 (59-68) kgs.

Intensive PK sampling after a moderate (20 g fat) and high (36 g) fat meal (on Day 1 and 8 respectively) were compared to fasted state on Day 15.

Compared to the fasting, administration with a high fat meal resulted in 29% lower ritonavir AUC (geometric mean ratio 0.71; 90%CI 0.61-0.84) and 29% lower Cmax (GM 0.71; 90%CI 0.60-0.84) while C12 increased non-significantly by 12% (GM 1.12 (90%CI 0.94-1.33).

Reference:

Lamorde M et al. – Steady-state exposure of ritonavir is reduced by a high fat meal in Ugandan patients receiving lopinavir plus ritonavir co-formulated tablets. 13th EACS, 12–15 October 2011, Belgrade. Abstract PE6.6/1 (BPD1/1).

Cobicistat is a pharmacokinetic (PK) booster currently in phase 3 studies that unlike ritonavir has no direct antiretroviral activity. This Gilead booster might facilitate a wider range of coformulated boosted medicines: with elvitegravir and Quad (boosted elvitegravir plus Truvada) and with products developed by other companies (darunavir and atazanavir).

An early caution is that cobicistat produces significant reductions in estimated glomerular filtration rate (eGFR). These do not indicate clinically significant changes but will pose a problem for interpretation of routine monitoring tests where clinical changes in eGFR are a concern.

If average actual GFR (aGFR) is used to monitor cobicistat, determined by iohexol clearance (a probe drug excreted almost exclusively by glomerular filtration), no changes are observed.

At ICAAC, Gilead researchers presented results from a placebo controlled study in 36 HIV negative participants with normal renal function (eGFR >80 mL/min) and 18 HV negative participants with mildly impaired renal function (eGFR 50-79 mL/min).

Participants with normal function were randomised (12 per group) to one of three groups: 150 mg cobicistat + placebo; 100 mg ritonavir + placebo; or double placebo for 7 days, with both eGFR and aGFR measured at baseline, day 7 and day 14 (following a 7 day washout). All participants with reduced renal function took cobicistat for seven days with similar monitoring.

Independent of baseline eGFR, volunteers taking cobicistat experienced significant average reductions in eGFR by day seven which resolved seven days after discontinuation, with but showed no significant changes in aGFR (see Table 1). Similar changes were seen using either Cockcroft-Gault or MDRD to calculate eGFR. Participants taking ritonavir or placebo showed no significant changes in either measure.

The researchers interpret these findings to show that true GFR is not affected by cobicistat which affects proximal tubular secretion of creatinine.

While these results are reassuring in terms of clinical impact of cobicistat it is unclear how patients using other medications that affect eGFR would be managed in order not to misinterpret a genuine impact on real GFR.

Source: Mascolini M. Kidney Function Change With Cobicistat Calculated in HIV-Negative Volunteers. NATAP.org
http://www.natap.org/2011/ICAAC/ICAAC_66.htm

Reference:

German P et al. Effect of cobicistat on glomerular filtration rate (GFR) in subjects with normal and impaired renal function. 51st ICAAC, 17-20 September 2011, Chicago. Abstract H2-804.

An article published online ahead of print in JAIDS, November 2011, shows findings from a pharmacokinetic (PK) study to evaluate a lower dose of lopinavir/ritonavir (LPV/r) than that currently approved.

Reshmie A Ramautarsing and HIV-NAT colleagues from Thailand and the Netherlands performed a two-arm crossover study including 20 HIV-positive Thai patients. Participants receiving a PI-containing regimen (virlogically suppressed <50 copies/mL for at least 4 weeks at enrollment) were randomised receive branded or generic LPV/r dosed at 200/50mg twice daily, in addition to an NRTI backbone.

Due to a compulsory license, Abbott only markets the paediatric formulation (100/25 mg) of LPV/r in Thailand. The Indian generic company, Matrix, has developed a 200/50 mg tablet formulation of LPV/r, which is currently used at the standard dose (400/100 mg twice daily).

Following sampling for PK analysis at week 2, all participants crossed over from their initial study arm to the other. A second sampling was performed at week 4. Participants continued with their study regimen until week 12, when they resumed their pre-study regimen.

There were 10 participants in each arm with a median age, weight and CD4 count of 38.6 (IQR 34.4 – 47.5) years, 59.8 (52.9 – 62.0) kg and 578 (476 – 795) cells/mm3, respectively. The majority (n=17) received standard dose LPV/r and the remainder saquinavir containing regimens prior to the study. None were lost or discontinued their medication during follow up.

The investigators reported comparable bioequivalence for the generic and branded formulations, with point estimates and 90% CI of the geometric mean ratios of 1.00 (0.92-1.09), 1.01(0.90-1.07) and 0.87 (0.76-1.31) for the AUC0-12, Cmax and Ctrough respectively.

Overall 10/40 (25%) samples had subtherapeutic (<1.0 mg/L) plasma concentrations of LPV. These were detected in 8 patients: 2 had subtherapeutic levels measured with both branded and generic formulations, 4 with branded and 2 generic. The lowest concentration was 0.25 mg/L. The investigators noted that all participants reported >90% rates of adherence and 7/8 reported 100% at the time that subtherapeutic plasma concentrations were found.

A comparison of PK parameters for different doses and formulations of LPV/r, using historical data from the same research group, revealed decreased concentrations at lower doses. When compared to LPV/r soft gel capsule (SGC) 400/100 mg twice daily, a dose of LPV/r SGC 266/66 twice daily resulted in 44.1%, 36.0% and 49.1% decreases in LPV concentrations for AUC0-12, Cmax and Ctrough respectively. Using LPV/r generic tablets 200/50mg twice daily decreased the same parameters by 63.5%, 56.6% and 70.2% respectively.

At week 12 all participants remained virologically supressed <50 copies/mL.

The researchers noted that LPV plasma concentrations are dependent on the RTV dose to a greater extent than some other PIs and in this study they had reduced both the LPV and RTV dose, which may explain the subtherapeutic LPV concentrations. They wrote that other dose reduction studies suggest that 200 mg of LPV is sufficient if there is a sufficient boosting dose of RTV (100 mg).

The researchers also noted that this bio-equivalence analysis of LPV/r, although not using the approved 400/100 mg twice-daily dose, demonstrated that the generic and branded tablets result in comparable PK parameters. They wrote: “These data are particularly important for clinicians working in settings where the branded tablets are not available due to compulsory licensing or cost. The availability of safe and effective generic alternatives to branded second line treatment will play an important role in the scaling up of second line treatment in low- and middle-income countries.”

comment

That the generic and originator products are bioequivalent is important.

Previous PK trials have shown that the dose of ritonavir affects LPV levels. In the first dose-ranging trial by Abbott, the dose with the best efficacy and safety profile was 200/100 mg twice daily. If we had 50 mg ritonavir tablets (see below), we could get back to this dose and it may be worth doing more studies.

However, the WHO and Clinton Foundation are more interested in ATV/r and DRV/r, which showed better efficacy and safety profiles than LPV/r (in the CASTLE and ARTEMIS trials, respectively).

Reference:

Ramautarsing RA et al. Neither branded nor generic lopinavir/ritonavir produces adequate lopinavir concentrations at a reduced dose of 200/50mg BID. J Aquir Immune Defic Syndr. Publish ahead of print. DOI: 10.1097/QAI.0b013e3182ba736.

Although not appropriate for LPV (see previous article), a 50mg boosting dose of RTV may be sufficient for selected PIs, argue researchers from the University of Liverpool and Chelsea and Westminster in a letter to the editor published in the December 15 2011 edition of JAIDS.

Lower doses of RTV may be better tolerated, cheaper and easier to co-formulate with PIs than the current dose.

Andrew Hill and colleagues identified four crossover PK studies evaluating 50 vs 100mg of RTV. These included boosting once daily atazanavir (ATV), 300/50 vs 300/100mg and once daily darunavir (DRV) 800/50 vs 800/100mg. The other two studies indentified by the researchers were with saquinavir and amprenavir, which are less commonly used PIs and not preferred options, particularly in resource-limited settings.

These small PK studies – conducted with 13 and 18 participants for ATV and DRV respectively – showed bioequivalent AUC and Cmax concentrations of both drugs using the lower and higher RTV doses. But Cmin concentrations were slightly lower when boosted with the 50 mg dose of RTV. See Table 1: PK parameters of ATV and DRV boosted with 50 and 100mg of RTV.

Mean PKs of boosted PI (SD)

The researchers explained that the clinical significance of the lower Cmin levels was not known and this would need to be investigated in larger studies including efficacy endpoints. They added that small differences in RTV boosting doses might have different consequences in treatment naïve and experienced patients.

They noted that as RTV is only marketed as a 100 mg tablet, these studies were conducted using the liquid formulation. If a 50mg heat stable tablet of RTV could be manufactured or 50 mg coformulated with either PI, new bioequivalence trials would be needed to ensure the boosting effects were similar to those achieved with the liquid.

A 50mg RTV tablet would also be very useful for paediatric dosing, as the liquid is expensive, impractical (particularly for resource limited settings) and tastes dreadful.

They concluded that if lower doses of RTV are able to achieve bioequivalence there is a strong justification for the development of a 50mg tablet and/or coformulations of RTV with these PIs.

comment

Once again, the 50 mg RTV tablet really would be useful in paediatrics.

The generic companies should be able to make 50 mg tablets and get approval by showing that 2 x 50 mg tablets are bioequivalent to an Abbott 100 mg tablet.

Reference:

Hill A et al. Should we switch to a 50mg boosting dose of ritonavir for selected protease inhibitors? J Acquir Immune Defic Syndr. Volume 58. Number 5. December 15, 2011.
http://journals.lww.com/jaids/Citation/2011/12150/Should_We_Switch_to_a_50_mg_Boosting_Dose_of.18.aspx

Artemether-lumefantrine and nevirapine-based antiretroviral therapy (ART) are the most commonly recommended first-line treatments for malaria and HIV respectively in Africa.

However, there is the potential for drug interactions with this combination as artemether and lumefantrine are substrates of CYP3A4 and nevirapine is both a substrate and inducer of CYP3A4.

This parallel-design pharmacokinetic study, obtained concentration-time profiles for lumefantrine, artemether, dihydroartemisinin and nevirapine in two groups of HIV-infected patients: ART-naïve and those stable on nevirapine-based therapy. Both groups (n=18 per group) received the recommended artemether-lumefantrine dose (80/480 mg). The primary outcome was day-7 lumefantrine concentrations, as these are associated with therapeutic response in malaria.

Nevirapine decreased artemether (p<0.0001) and dihydroartemisinin (p=0.01) AUC, but unexpectedly increased lumefantrine exposure. Median (range) day 7 lumefantrine concentrations were 622 ng/mL (185-2040) and 336 ng/mL (29-934) in the nevirapine and ART-naïve groups, respectively (p=0.0002). In the ART-naïve group, 6/18 subjects had day 7 lumefantrine concentrations below target (280 ng/ml) compared with 1/18 in the nevirapine group (Odds Ratio=8.5, 95%CI 0.9 to 80.02, p=0.061). Adverse events were similar between groups, with no difference in electrocardiographic QTcF and PR intervals.

The mechanism of inhibition of lumefantrine remains to be elucidated. Studies investigating the interaction of nevirapine and artemether-lumefantrine in HIV-infected patients with malaria are urgently needed.

Source: hiv-druginteractions.org (16 November 2011).

http://www.hiv-druginteractions.org/LatestArticlesContent.aspx?ID=564

Reference:

Kredo T et al. The interaction between artemether-lumefantrine and nevirapine-based antiretroviral therapy in HIV-1 infected patients. Antimicrob Agents Chemother, 2011, 55(12): 5616-5323.

http://www.ncbi.nlm.nih.gov/pubmed/21947399

The use of traditional/complementary/alternate medicines in HIV/AIDS patients who reside in Southern Africa is quite common. This review looks at the mechanisms of pharmacokinetic interactions and summarises the published clinical studies and case reports of antiretroviral-herbal interactions. In vitro screening studies of several African traditional medicinal plants and extracts are described and details given in a very useful table.

The review highlights the lack of clinical studies – despite a high incidence of HIV/AIDS in the African region, only one clinical study (efavirenz and Hypoxis hemerocallidea) has been conducted. More studies on African traditional medicines are warranted in order for more meaningful data to be generated and the true potential for such interactions to be determined.

Source: hiv-druginteractions.org (24 November 2011).

http://www.hiv-druginteractions.org/LatestArticlesContent.aspx?ID=567

Reference:

Müller AC, Kanfer I. Potential pharmacokinetic interactions between antiretrovirals and medicinal plants used as complementary and African traditional medicines. Biopharm Drug Dispos, 2011, 32(8): 458-470.

http://www.ncbi.nlm.nih.gov/pubmed/22024968

This study aimed to i) evaluate the safety and toxicity of rapamycin (sirolimus) in HIV-infected individuals with KS receiving antiretroviral therapy, ii) investigate rapamycin interactions with both PI-containing and NNRTI-containing regimens, and iii) assess clinical and biological endpoints.

Seven participants, 4 on ritonavir-boosted PIs (2 lopinavir, 2 atazanavir) and 3 on NNRTI-based regimens (2 efavirenz, 1 nevirapine), had rapamycin titrated to achieve trough concentrations of 5-10 ng/mL. Patients were monitored for safety and KS response. Despite pharmacokinetic interactions resulting in >200-fold differences in cumulative weekly rapamycin doses between participants on PI-containing and NNRTI-containing regimens, treatment was well tolerated. Maintenance rapamycin doses in the PI subjects were 0.1 mg and 0.2 mg twice weekly with lopinavir and 0.2 mg twice weekly and 0.3 mg three times weekly for atazanavir; doses in the NNRTI subjects were 2.3 mg and 6.7 mg daily for efavirenz and 2.8 mg daily for nevirapine. There were no significant changes in viral loads or cytokine levels; modest initial decreases in CD4 counts occurred in some patients. Three participants, all on PI-containing regimens and with higher rapamycin exposure, showed partial KS responses.

Rapamycin appears safe in HIV-positive individuals with KS and can, in some cases, induce tumour regression and affect its molecular targets. Significant pharmacokinetic interactions require careful titration to achieve target drug trough concentrations, but may be exploited to achieve therapeutic benefit.

Source: hiv-druginteractions.org (29 November 2011).

http://www.hiv-druginteractions.org/LatestArticlesContent.aspx?ID=566

Reference:

Krown SE et al. Rapamycin with antiretroviral therapy in AIDS-associated Kaposi sarcoma: an AIDS Malignancy Consortium Study. J Acquir Immune Defic Syndr, 2011, epub ahead of print.

http://www.ncbi.nlm.nih.gov/pubmed/22067664

Interactions between rifampicin and protease inhibitors makes treating patients coinfected with HIV and TB more complicated.

Rifabutin is an alternative rifamycin, which can be used in patients receiving a protease inhibitor. Recent findings suggest that the current recommended dose of lopinavir/r (LPV/r) is suboptimal. There are limited data regarding the newer formulation of LPV/r.

Investigators from University of Cape Town, International Union Against Tuberculosis and Lung Disease and WHO evaluated the pharmacokinetics (PK) of rifabutin in co -infected patients on a first line TB regimen before and after the initiation of LPV/r-based ART.

Suhashni Naiker and colleagues showed findings from this study in a poster at CROI 2011.

A group of 16 patients on stable rifabutin-containing TB regimens were initiated on LPV/r-containing HAART. At HAART initiation they were randomised to receive either: rifabutin 150 mg daily for 1 month followed by 150 mg 3 times weekly, or 3 times weekly doses followed by daily doses.

The investigators measured serial rifabutin and 25-O-desacetyl rifabutin concentrations during a dose interval after 4 weeks of rifabutin 300 mg daily, after 4 weeks of 150 mg rifabutin daily with LPV/r-based HAART, and after 4 weeks of rifabutin 150 mg 3 times a week with LPV/r-based ART.

At baseline the participants were a mean (SD) of 31.6 (5.5) years, 59.0 (9.4) kg, 160.1 (7.1) cm and 147 (43) CD4 cells/mm3. Ten were men. Two were not included in the analysis due to poor adherence.

The investigators reported median AUC0-24 and Cmax, for participants receiving 300 mg rifabutin daily, 150 mg rifabutin three times a week, and 150 mg rifabutin daily, respectively, of 3026 ng/mL.h and 297ng/mL, 2307 ng/mL.h and 168 ng/mL, and 5010 ng/mL.h and 311ng/mL.

They found that rifabutin was well tolerated at all dosing strategies. There was one case of uveitis that occurred before  LPV/r was initiated, and one grade 2 transaminitis and one grade 2 neutropenia were also reported.

They concluded that rifabutin 150 mg daily used with LPV/r produces Cmax concentrations within the recommended target range of 300 to 900 ng/mL.

Reference

Naiker S et al. Pharmacokinetic evaluation of different rifabutin dosing strategies in African TB patients on lopinavir/ritonavir-based ART. 18th CROI, 27 February–2 March 2011, Boston. Poster abstract 650.

Dolutegravir (S/GSK1349572) is an unboosted, once-daily, next-generation HIV integrase inhibitor. The effects of multivitamins (One-A-Day Maximum, single tablet), antacid (Maalox 20 mL single dose with or 2 hours after dolutegravir) and omeprazole (40 mg once daily for 5 days) on single doses of dolutegravir (50 mg) were studied in HIV-negative subjects.

Coadministration of the multivitamin modestly decreased dolutegravir AUC and Cmax by 33% and 35%, respectively.  Concurrent antacid co-administration reduced dolutegravir AUC and Cmax by 74% and 72%, respectively.  Staggered antacid dosing significantly diminished this interaction, with a reduction in dolutegravir AUC of 26% and Cmax of 18%. Omeprazole did not significantly affect dolutegravir exposure (no change in AUC, 9% decrease in Cmax).

Dolutegravir can be taken with proton pump inhibitors and multivitamins without dose adjustment but should be administered 2 hours before or 6 hours after antacids. The mechanism of the antacid interaction with dolutegravir is likely to result from chelation with metal cations in the antacid rather than an effect of pH and would be consistent with the omeprazole data.

Source: hiv-druginteractions.org (23 June 2011).

Ref: Patel P et al. Pharmacokinetics of the HIV integrase inhibitor S/GSK1349572 co-administered with acid-reducing agents and multivitamins in healthy volunteers. J Antimicrob Chemother, 2011, 66(7): 1567-1572.

http://www.ncbi.nlm.nih.gov/pubmed/21493648

Two cases have been reported recently of patients developing Cushing’s syndrome when treated with atazanavir/ritonavir and corticosteroids.

The first case describes a 75 year old man with a history of HIV for 27 years, hepatitis C, hypothyroidism, recurrent deep venous thrombosis, hypertension, and chronic kidney disease was admitted for treatment of worsening chronic diarrhea and bright red blood per rectum. [1]

His antiretroviral regimen was atazanavir/ritonavir (300/100 mg daily), lamivudine (150 mg daily) and nevirapine (300 mg twice daily). Other medications included atenolol, atropine/diphenoxylate, calcitriol, cholecalciferol, fondaparinux, levothyroxine, lisinopril, loperamide, ranitidine, testosterone patch, trazodone, and vardenafil.  Colonoscopy showed lymphocytic colitis at multiple biopsy sites and oral budesonide (3 mg 3 times a day) was started.

The patient’s diarrhea improved, but he was admitted 12 days later with 10.4 kg weight gain, severe leg and facial swelling, and uncontrolled hypertension.  Physical examination was notable for blood pressure 177/102 mm Hg, cushingoid facies, and 2+ pedal and pretibial edema to the knees.  As the colitis had improved dramatically with budesonide therapy, the plan was to continue it for a full 6-week treatment course, if possible. Amlodipine, hydralazine, and furosemide were added to control the hypertension and edema, but budesonide was discontinued after 3 weeks because of persistent severe edema that was refractory to furosemide.

The patient developed edema, weight gain, uncontrolled hypertension, cushingoid facies, hypokalemia, and metabolic alkalosis shortly  after initiation of budenoside, with resolution of all symptoms  soon after it was stopped.  Congestive heart failure, liver disease, and nephrotic syndrome were ruled out as causes of the edema, which supported the diagnosis of iatrogenic Cushing’s syndrome. Although budesonide concentrations were not measured, the very low serum cortisol level (0.8 µg/dL) in a clinical setting of hypercortisolism provides strong indirect evidence that levels of an exogenous corticosteroid (ie, budesonide) were high.

Budesonide is inactivated through extensive first-pass metabolism by hepatic CYP3A4. The P-glycoprotein (PGP) export pump also limits budesonide serum concentrations by promoting the gastrointestinal excretion of CYP3A4 substrates. By inhibiting CYP3A4 and PGP, protease inhibitors such as ritonavir and atazanavir limit both the first-pass metabolism and gastrointestinal excretion of CYP3A4 substrates and result in increased serum concentrations of steroids.

The second case was of Cushing’s syndrome and adrenal axis suppression in a patient treated with ritonavir and corticosteroid eye drops. [2]

A 51-year-old woman with HIV presented with weight gain and a 1-month history of right hip pain.  Her ART included tenofovir (300 mg once daily), emtricitabine (200 mg once daily), and atazanavir/ritonavir (300/100 mg once daily). Because of previous bilateral cytomegalovirus retinitis, complicated by immune recovery uveitis with severe, chronic, cystoid macular oedema, she was also using dexamethasone 0.1% eye drops six times daily, and betamethasone 0.1% eye ointment at night, in both eyes.

On examination, she was noted to have central adiposity and enlargement of the dorsocervical fat, but no peripheral lipoatrophy. An MRI scan of the hip showed avascular necrosis. A tetracosactide (Synacthen) stimulation test showed marked suppression of the pituitary-adrenal axis, with a baseline cortisol of less than 25 nmol/L rising to only 37 nmol/l 30 min after administration of tetracosactide 250mg (normal response at 30 min, >570 nmol/L). Adrenocorticotropic hormone (ACTH) was undetectable.

The presence of adrenal axis suppression with low ACTH, in the context of Cushingoid features and avascular necrosis of the hip, suggested ongoing exposure to high systemic levels of exogenous corticosteroids. Ritonavir and atazanavir were substituted with efavirenz (600 mg once daily), while continuing the steroid eye drops. Oral hydrocortisone 15 mg daily was added to avoid precipitating crisis due to adrenal insufficiency. Over the following year, the patient’s weight declined, with marked improvement in her adrenal function. Analysis of stored serum samples revealed elevated levels of dexamethasone

at presentation (1.4-1.7 nmol/L) which fell dramatically after discontinuation of protease inhibitor therapy (undetectable to 0.181 nmol/L).

Although prior courses of oral and intravenous corticosteroids may have contributed to adrenal axis suppression, the close temporal correlation between discontinuation of ritonavir, reversal of weight gain and recovery of adrenal function, combined with detectable levels of dexamethasone in the blood, strongly suggests that co-administration of ritonavir was responsible for the accumulation of excessive systemic levels of topical ocular corticosteroids, resulting in adrenal axis suppression and Cushing’s syndrome.

Source: hiv-druginteractions.org (24 June 2011).

References

1. Frankel JK. Cushing’s syndrome due to antiretroviral-budesonide interaction. Ann Pharmacother, 2011, 45(6): 823-824. http://www.ncbi.nlm.nih.gov/pubmed/21558486
2. Molloy A et al. Cushing’s syndrome and adrenal axis suppression in a patient treated with ritonavir and corticosteroid eye drops. AIDS, 2011, 25(10): 1337-1338.http://www.ncbi.nlm.nih.gov/pubmed/21659797

Coadministration of rifampicin dramatically reduces plasma lopinavir (LPV) concentrations. In healthy volunteers, doubling the dose of lopinavir-ritonavir (LPV/r) capsules overcame this interaction, but a subsequent study of double doses of the tablets was stopped early owing to hepatotoxicity. However, healthy-volunteer study findings may not apply to HIV-positive adults.

This study evaluated the steady-state pharmacokinetics of LPV in HIV-infected adults stable on LPV/r tablets (400/100 mg twice daily) who were given rifampicin (600 mg daily), and the dose of the LPV/r gradually increased over a period of two weeks (first to 600/150 twice daily and then to 800/200 mg twice daily). Twenty-one subjects started the study, but two were withdrawn due to grade 3/4 transaminitis.

The median [IQR) pre-dose LPV concentrations were 8.1 (6.2 to 9.8) mg/L at baseline, 1.7 (0.3 to 3.0) mg/L after 7 days of rifampicin, 5.9 (2.1 to 9.9) mg/L with 1.5 times the dose of LPV/r, and 10.8 (7.0 to 13.1) mg/L with double-dose LPV/r. There were no significant differences in the LPV AUC, Cmax, pre-dose concentrations, 12-hour concentration, or half-life between the baseline and double-dose LPV/r time points.

Doubling the dose of the tablet formulation of LPV/r overcame induction by rifampicin, with less hepatotoxicity occurring in this cohort of HIV-infected participants than reported in healthy-volunteer studies.  The cohort consisted of HIV-infected patients who were virologically suppress with high CD4 counts – the risk of hepatotoxicity may be different in HIV-infected individuals with TB and/or with different CD4 counts.

Source: hiv-druginteractions.org (28 June 2011).

Ref: Decloedt EH et al. Pharmacokinetics of lopinavir in HIV-infected adults receiving rifampin with adjusted doses of lopinavir-ritonavir tablets. Antimicrob Agents Chemother,  2011, 55(7): 3195-3200.

http://www.ncbi.nlm.nih.gov/pubmed/21537021

A placebo-controlled, randomised, two-period crossover study in 19 healthy HIV-seronegative women was conducted to assess the effect of raltegravir (400 mg twice daily) on the pharmacokinetics of an oral contraceptive containing ethinylestradiol and norgestimate.

The geometric mean ratio (GMR) and 90% confidence interval (CI) for ethinylestradiol when co-administrated with raltegravir relative to alone was 0.98 (0.93–1.04) for AUC and 1.06 (0.98–1.14) for Cmax. The GMR (90% CI) for norelgestromin (an active metabolite of norgestimate) when co-administered with raltegravir relative to alone was 1.14 (1.08–1.21) for AUC and 1.29 (1.23–1.37) for Cmax. There were no discontinuations due to a study drug-related adverse experience, nor any serious clinical or laboratory adverse experience.

Raltegravir had no clinically important effect on ethinylestradiol or norgestimate pharmacokinetics and no dose adjustment is required for oral contraceptives containing this combination when co-administered with raltegravir.

Source:

www.HIV-druginteractions.org (24 March 2011).

Reference:

Anderson MS et al. Effect of raltegravir on estradiol and norgestimate plasma pharmacokinetics following oral contraceptive administration in healthy women. Br J Clin Pharmacol, 2011, 71(4): 616-620.
http://www.ncbi.nlm.nih.gov/pubmed/21395656

Lopinavir/ritonavir (LPV/RTV) is first line treatment for young children in South Africa. Concomitant treatment for TB is common in children with HIV. There is a complicated interaction between this boosted protease inhibitor and the first line TB drug, rifampicin (RIF), which reduces the bioavailabilty and Cmin of LPV by approximately 75% and 99% respectively.

Two strategies are possible to increase the LPV levels when it is dosed with RIF – either increasing the dose of RTV to a LPV:RTV 4:4 ratio or doubling the dose to a LPV:RTV ratio 8:2.

Chao Zhang and colleagues from the University of Cape Town showed a population pharmacokinetic (PK) model developed to describe the interactions between LPV, RTV and RIF in children. They used this to look at the effect of various factors (age, BSA, weight, gender, haemaglobin, albumin, ALT) on LPV and RTV PK, and make dosing recommendations for HIV/TB coinfected children receiving these drugs concurrently. [1]

In this study, 39 children with HIV only received the standard dose of LPV/RTV, 4:1, (control group); 15 coinfected children received the super-boosted dose, 4:4; and 20 the double dose, 8:2. Then 11 coinfected children received the standard dose following RIF-based treatment. Repeated sampling was performed (4-6 from each child) up to 12 hours post dose.

The children were a median age of 21 months (range 6 months to 4.5 years) and a medium weight of 10.2kg (range 5-17kg).

Using a one-compartment model with first order absorption for LPV and a one-compartment model with transit absorption for RTV, the investigators modelled the effect of RTV concentration on LPV clearance as direct inhibition with an Emax model.

The investigators found that, during concomitant treatment with RIF, the relative oral bioavailability of LPV was reduced by 79% in children receiving the twice the standard dose of LPV/RTV. RTV clearance was 18 L/h with RIF and 13L/h without.

The estimated baseline clearance of LPV, when there was no detectable RTV was 4.34 L/h. As the concentrations of RTV increased, the clearance of LPV decreased in a sigmoid relationship (EC 50, 0.051 mg/L). They found volume of distribution for LPV and RTV were 11.7 and 102 L respectively.

When the investigators performed simulations for dose optimisation during RIF-based TB treatment with a target of LPV concentrations with Cmin >1mg/L in 95% of children, they predicted doses of LPV/RTV as described in Table 1. They noted that smaller children required higher mg/kg doses of LPV/RTV, in both 4:1 and 1:1 ratios, than larger children.

Table 1: Simulation for dose optimistion of LPV/RTV during RIF-based TB treatment

comment

The same group previously presented data to show that the double dose LPV/r is not sufficient for children when coadministration with rifamipicin. [2]

The current median LPV dose using double dose strategy in this study is 23 mg/kg,

The investigators suggestion for dose adjustment in this study is much higher than double dose. Or they suggest switching to an 8 hourly dose strategy considering the adverse effect slinked to higher doses. [3]

References:

1. Zhang C et al. Population pharmacokinetics of lopinavir and ritonavir in combination with rifampicin-based antitubercular treatment in HIV-infected children. 10th International Congress on Drug Therapy in HIV Infection, November 7-11. Glasgow. Oral abstract O24. Published in Journal of the International AIDS Society 2010 13(Suppl 4). O223.
   http://www.jiasociety.org/content/13/S4/O24
2. McIlleron et al. Double-dose lopinavir/ritonavir provides insufficient lopinavir exposure in children receiving rifampicin-based anti-TB treatment. 16th CROI. February 2009, Montreal. Oral abstract 98.
   http://www.retroconference.org/2009/Abstracts/34615.htm
3. Personal communication with the author.

Several case studies showing the impact of creatinine supplementation on eGFR results, were presented in a poster by Graeme Moyle, from the Chelsea and Westminster Hospital, London. Estimated GFR is now routinely included in renal monitoring using the MDRD calculation, which incorporates serum creatinine, together with age, sex and ethnicity

Six HIV-positive male patients (aged 25- 55) on stable HAART were referred to an HIV/renal clinic due to elevated serum creatinine (range 131-257 umol/L) and low eGFR. All had normal blood pressure and no history of diabetes. Proteinuria levels were normal and confirmed by urinary protein:creatinine ratio. Each patient routinely used protein and creatine supplementation as part of a muscle-building gym routine.

Three months after 5/6 patients discontinued the supplements, serum creatinine levels consistently dropped to between 98 and 118 umol/L and eGFR reported to normalise (eGFR data was not shown).

Although dietary intake of creatine is 1g/day, supplementation can increase this 20-30 fold, and intramuscular concentrations can remain elevated for several weeks. Creatine is converted to creatinine, relative to its concentration, which can increase serum creatinine, despite normal renal function. The poster suggested that ARV exposure may also be involved but also that the association of raised serum creatinine with creatine ingestion has not been published outside of the HIV context.

COMMENT

This study highlights the importance taking a history of supplement use to consider this as a cause for elevated creatinine or low eGRF.

Ref:
Moyle G et al. The pitfalls of the estimated glomerular filtration rate – ‘hitting the gym and creatine supplementation’. 11th Intl Workshop on Adverse Drug Reactions. 26-28 October 2009, Philadelphia. Poster abstract P27. Antiviral therapy 2009; 14 Suppl 2: A49.

Two small studies from the same research group looked at the association between substance use, including alcohol and marijuana, and levels of HIV drugs.

The first study reported that trough concentrations of atazanavir were inversely related to use of tobacco and marijuana in 32 ‘substance using’ (SU) patients from four US sites compared to 35 non-using (non-SU) patients. [1]

Substance use (% of SU patients) followed NIDA criteria and included alcohol (41%), cocaine (19%), marijuana (38%), opioids (22%) and tobacco (91%). 43% of these patients used multiple substances.

During the study period, patients had to complete three clinic visits, for entry, trough and directly observed therapy (DOT), and take scheduled doses of atazanavir at the same time for 4 days before each visit.

Adherence assessment and counseling prior to plasma sampling and each scheduled clinic visit were performed and recorded.

Multiple linear regression models were used to determine factors associated with atazanavir concentrations, immunological and virologic responses while adjusting for covariates. Other demographics including race, gender, ethnicity and BMI were included in the analysis.

Significant reductions in ATV trough concentrations were associated with tobacco and marijuana use (p<0.05) but not with other substances. 36% and 50% of tobacco and marijuana users, respectively had ATV concentrations below the therapeutic range (p<0.05). However, no significant direct effects were linked to viral load or CD4 count.

Table 1. Substance use (SU) and atazanavir trough levels*

* Median, ug/ml (IQR). For HTB, rounded to two decimal points.

The researchers concluded that the underlying mechanism may include enzyme induction, but that further studies were needed for this to be determined.

The second study looked at efavirenz metabolism in relation to the G516T single nucleoside polymorphisms (SNPs) in the CYP2B6 enzyme. Previous studies have demonstrated that GG > GT > TT polymorphisms inhibit efavirenz metabolism resulting in higher plasma concentrations, slower drug clearance, and sometimes increased toxicity.

Based on 516 genotypes, 37 patients (SU n=18; non- SU n=19) were categorised as extensive (GG, n=19), intermediate (GT, n=13), and slow (TT, n=5) metabolisers. These genotypes with were significantly associated with efavirenz trough concentrations (p=0.04). Significantly lower median (IQR) efavirenz concentrations were linked to tobacco use (1.76 ug/ mL; (1.31-2.13) vs 2.29 ug/mL (1.88-4.01), p=0.04) and alcohol use (1.41 ug/mL (0.66-1.88) vs 2.25 ug/mL (1.76-2.48), p=0.02) in the extensive metaboliser group with lower CD4 counts and higher viral loads.

As with the atazanavir study, substance use had no significant relationship to antiviral responses.

References

1. Fehintola FA et al. Tobacco and marijuana uses significantly decrease atazanavir (ATV) trough concentrations in HIV infected individuals. 49th ICAAC, 12-15 September 2009, San Francisco. Poster abstract H-231.
http://www.posters2view.com/icaac/view.php?nu=H-231
2. Brazeau D et al. Effects of CYP2B6 single nucleotide polymorphisms (SNPs) and substance abuse on efavirenz (EFV) pharmacokinetics. 49th ICAAC, 12-15 September 2009, San Francisco. Poster abstract H-228 .
http://www.posters2view.com/icaac/view.php?nu=H-228

Previous reports have shown plasma concentrations of some PIs are reduced in pregnant women.

A late breaker poster authored by Francesca Conradie and coworkers from the A1424182 study showed PK data from women receiving atazanavir/ritonavir (ATV/r) once daily during pregnancy.

This was a multicentre, open label, single arm phase I study with sites in South Africa, Puerto Rico and the USA. Women were enrolled who were between 12 and 32 weeks gestation with CD4 >200 cells/mm³.

This study determined multiple clinical and PK parameters during the second and third trimesters, and post-partum.

ATV was dosed ATV/r 300/100 mg (n=20) or ATV/r 400/100 mg (n=21) in combination with AZT/3TC 300/150 mg twice-daily during the third trimester. Second trimester and post partum dosing was ATV/r 300/100mg.

Third trimester exposures were compared to historical ATV 300/100mg exposures in non-pregnant adults. Foetal:maternal ratio was determined using cord blood samples. Infants were followed up for 6 months.

The investigators reported all mothers had fully suppressed viral load (<50 copies/mL) before or at delivery. At the time of analysis all infants (n=40) were HIV DNA negative. There were no infant deaths.

Maternal drug-related serious adverse events (SAEs) were: hyperbilirubinemia (n=1) and anaemia (n=4). Grades 3-4 hyperbilirubinemia occurred in 6/20 and 13/21 mothers in the 300/100mg and 400/100mg groups, respectively.

Three infants had drug-related SAEs. Infant bilirubins were within normal limits to day 14; 7 had Grade 3 hyperbilirubinemia after day 14 (maximum 8.5 mg/dL at day 15). One infant received 3 days phototherapy from day 3. This infant had other risk factors (low birth weight and prematurity).

For the 300/100mg group, they reported that Cmax and AUC during the third trimester were 27% and 21% lower and C24 was similar to historical data in non-pregnant HIV-positive patients taking ATV/r 300/100 mg once-daily.

For the 400/100mg group they found AUC and Cmax similar to, and C24 39% higher than, historical levels; post partum exposures were also higher than historical. The investigators noted that elevated levels have been observed with other PIs in the post partum period. Levels of ATV appeared to normalise by 16 weeks post partum.

The ATV foetal:maternal ratio was 0.19 and 0.12 for 300/100 and 400/100, respectively. This ratio indicates that ATV, like other PIs, has poor transplacental transfer.

The investigators concluded that this phase I study suggests that no dose modification of ATV 300/100mg once daily is necessary in the third trimester of pregnancy. Clinical outcomes indicate that this dose suppressed HIV viral load effectively in the participating women, and prevented vertical transmission of HIV to their infants, when used in combination with AZT/3TC twice daily. Treatment with ATV/r in the mothers appeared to be well tolerated.

Ref:
Conradie F et al. The safety, efficacy, and steady state pharmacokinetics of atazanavir/ritonavir (ATV/r) once daily given in combination with twice daily AZT/3TC during pregnancy: results of study AI424182. 5th IAS Conference, Cape Town, South Africa.19-22 July 2009. Poster abstract LBPEB06.
http://www.ias2009.org/pag/Abstracts.aspx?AID=3732

Reports from the workshop

The following reports from this meeting have been largely compiled from the abstracts of these studies.

It is disappointing that the abstracts from the virology-education meetings are not published online, and that only a selection of presentations from the meeting are available.
http://www.HIVpresentation.com

A useful summary report of the drug-interaction studies presented at the meeting is available on the Liverpool University website ( in the April 2009 news archive).
http://www.hiv-druginteractions.org/new/Content.asp?ID=431&TDM=

Reports in this issue are:

• Interactions between ARVs and antimalarials atovaquone and proguanil
• Efavirenz-related studies: genetics, smoking and TDM
• Atazanavir: a suitable case for TDM?
• A CYP2B6 haplotype influences nevirapine plasma concentrations following a single dose to reduce mother to child transmission
• Population pharmacokinetic model of nevirapine maternal to infant transfer through breastfeeding
• Phenotypic and genotypic inhibitory quotients and virologic response in treatment experienced children
• Tenofovir pharmacokinetics in three tenofovir-containing regimens in children and adolescents
• Bioavailability of Thai generic lopinavir/ritonavir

Van Luin and colleagues from Nijmegen presented results showing significantly lower levels of the common antimalarials atovaquone and proguanil, commonly used together as prophylaxis, in HIV-positive patients on HAART compared to HIV-negative controls.

Seven-day PK results from HIV-positive patients already on established HAART including efavirenz (n=19), lopinavir/r (n=19) or atazanavir/r (n=19) were compared to levels in 20 HIV-negative volunteers following single-dose atovaquone/proguanil (250/150mg), administered with a fat standardised breakfast. Patients who were negative for CYP2C19 defective *2 and *3 alleles, the key enzyme for proguanil metabolism, were excluded from the proguanil comparisons.

PK parameters were significantly lower in HIV-positive patients (all p<0.05), and are detailed in Table 1. Efavirenz or lopinavir/r resulted in considerably reduced levels suggesting increased dosing may be required. Atazanavir/r considerably lowered proguanil compared to the HIV-negative group, but more modestly lowered atovaquone suggesting that this interaction may be managed with perfect adherence.

Table 1. Mean [range] atovaquone and proguanil levels

COMMENT

An important problem with this study is the use of HIV-negative controls compared to HIV-positive patients, so the differences may have been due to differences in PK of antimalarials in HIV-positive people. These are interesting data, but the results need confirmation and cannot be regarded as definitive.

Ref:
Van Luin M et al. Drug interactions between atovaquone/proguanil and antiretroviral agents. 10th International Workshop on Clinical Pharmacology of HIV Therapy, 15-17 April 2009, Amsterdam. Oral poster O-19.

Several studies presented interesting results on the PK of efavirenz.

In an oral presentation reporting higher rates of antiretroviral switching by patients with pharmacogenetic markers (notably genotype changes in CYP2B6 G516T) associated with an increased risk of side effects, Colombo and colleagues from the Swiss HIV Cohort reported that patients were more likely to switch from efavirenz if they carried these alleles (42% vs. 27%). [1]

Bensemmane and colleagues from a multicentre French study reported on the routine use of therapeutic drug monitoring (TDM) to manage individual patients on efavirenz from 2002-2008. [2]

The target level, based on historical estimates was 1000-4000 ng/mL. Of the 2545 patients (33% women) prescribed efavirenz at 600mg once-daily, with at least one TDM result for Cmin, approximately 5% had levels below the limit of detection for the test (<10ng/mL) suggesting non-adherence. 12% patients had levels below the minimum target, 61% were in the target range and 22% had Cmin levels >4000 ng/mL.

Of the 549 patients with high levels, 41% (n=188) adjusted the efavirenz dose to one of four once-daily doses: 400mg, 300mg, 200mg or 100mg (groups 1 to 4, respectively).

Table 1. Median efavirenz levels in patients with Cmin >4000 ng/mL

Although the poster abstract provided minimal details on the relationship between drug levels and toxicity, it reported that approximately that only 22% of patients making a dose adjustment continued to experience persistent side effects. As the study was unblinded patients who knew they had reduced their dose may have reported side effects differently.

A second poster by Fayet and colleagues from the Swiss Cohort Study reported results from a small prospective study using TDM to individualise efavirenz dosing in 15 patients on stable EFV-based HAART, with levels in the highest quartile. [3]

At baseline, median efavirenz Cmin was 8,409 ng/mL (IQR 6610-10,370). The five patients with levels between 75-95 percentile reduced the efavirenz dose to 400mg QD and then ten patients above the 95th percentile reduced to 200mg QD.

Following dose reductions, ten patients with results achieved the target of 25-75th percentile range (median 2,856, IQR 2192- 3157 ng/mL). Three months after the dose adjustment, all patients remained above the minimum 1000ng/mL lower target level and maintained viral load <40 copies/mL.

Cortes and colleagues presented results from a prospective 215 patients (13 women) in Chile, looking at both drug levels and genetics (CYP2B6: 516G>T and 983 T>C; and contitutive androstane receptor (CAR) rs2307424 polymorphisms). [4]

In the group as a whole, mean (±SD) levels were 3100 ng/mL (±1600), in samples taken a mean 11.9 hours (±1.6) post-dose. Eleven patients (5%) had levels <1000 and 45 (21%) had levels >4000ng/mL. Alleles at CAR, 516G>T and 983 T>C were present in 49%, 35% and 0% respectively, and were related to drug concentations in multivariate analysis (see Table 2).

As reported in other studies, c516 polymorphisms were related to efavirenz exposure.

This is the first report of the impact of the associations with the contitutive androstane receptor and the group also reported statistically significant lower levels in smokers compared to non-smokers (2.81 vs. 3.32 mg/L, p-0.02).

Table 2. Efavirenz drug exposure (mg/L) in relation to genetic plymorphisms

COMMENT

These posters show the potential for individualising dosing in patients who metabolise efavirenz more slowly (whether due to genetics, hepatitis coinfection etc) and who end up with levels higher than the upper limit of the recommended target range.

The association with smoking status has not previously been reported.

It is unclear if the study adjusted for weight differences and whether this would make a difference to the results. If there is an association with weight, then the association with smoking would be in the opposite direction (ie. smokers tend to weigh less, so levels may be higher rather than lower).

References
1. Colombo S et al. Association of pharmacogenetic markers with premature discontinuation of first-line ART. 10th International Workshop on Clinical Pharmacology of HIV Therapy, 15-17 April 2009, Amsterdam. Oral poster O-03.
2. Bensemmane R et al. Six years of routine therapeutic drug monitoring of efavirenz (EFV) in HIV-infected patients. 10th International Workshop on Clinical Pharmacology of HIV Therapy, 15-17 April 2009, Amsterdam. Poster abstract P-48.
3. Fayet A et al. Successful TDM-guided efavirenz dose reduction in virologically-controlled patients. 10th International Workshop on Clinical Pharmacology of HIV Therapy, 15-17 April 2009, Amsterdam. Poster abstract P-47.
4. Cortes C et al. Correlates of efavirenz exposure in HIV infected patients from Chile reveals novel associations iwith a polymorphism in the contitutive androstane receptor and smoking. 10th International Workshop on Clinical Pharmacology of HIV Therapy, 15-17 April 2009, Amsterdam. Poster abstract P-04.

Numerous studies at this workshop explored the potential for indiviudalised dosing with atazanavir, relating to individual patient absorption, the use of ritonavir boosting ands interations with HIV and TB medications.

Atazanavir is widely used because it is generally well tolerated, has a low pill count and only requires once-daily dosing. Ritonavir boosting is routinely recommended to maximise drug exposure, and to reduce the risk of low trough levels and interpatient variability. However, higher atazanavir exposure is related to risk of hyperbilirubinaemia and the ritonavir boosting negatively impacts on lipid profiles.

As with efavirenz, the study from Columbo and collegues that identified genetic polymorphisms associated with absorption showed a higher rate of discontinuation of atazanavir due to side effects in patients with compared to those without these markers (52% vs. 20%, p=0.008). [1]

Taburet and colleagues reported results from a substudy (n=15) of the INDUMA trial where treatment naive patients were prescribed atazanavir/ritonavir (300mg/100mg QD) plus 2 nukes (not including tenofovir) and then randomised to continue on the same regimen or switch to unboosted atazanavir (400mg), maintaining the nukes. [2]

Atazanavir levels (adjusted geometric mean ratios) for Cmin and AUC dropped by 10% (5.8-19%) and 34% (26-46%) from the switch (week 0) and after 4 weeks on the reduced regimen. As expected, all PK parameters reduced without boosting and interpatient variability increased (see Table 1).

Table 1. Atazanavir levels: geometric mean (CV%) with and without ritonavir boosting

However , despite the reduced atazanavir levels, 14/15 patients maintained viral suppression <50 copies/mL at 48 weeks, with only one patient experiencing a blip (to 113 copies/mL). Regazzi and colleagues presented results from using therapeutic drug monitoring in treatment-experienced patients using atazanavir, with and without ritonavir. [3]

The target range for atazanavir is 150-850 ng/mL.

The group analysed samples from 170 patients (with and without HCV coinfection) using various dosing regimens including ATZ/r 300/100 QD (n=79), ATZ 400 QD (n=57), ATZ 300 QD (n=11), ATZ/r 400/100 (n=5), ATZ 400 BID (n=8) and ATZ/r 200/100 QD (n=10). The main comparison between ATZ/r 300/100 QD and ATZ 400 QD showed lower atazanavir exposure and wider interpatient variability (CV%) without ritonavir (see Table 2).

Although both regimens showed similar levels of viral suppression (~84%), significant differences were seen between patients with or without HCV coinfection.

With the 400mg QD regimen, monoinfected patients experienced significantly lower trough levels (240 [100-400] vs. 600 [400-950] ng/mL, p<0.001). Conversely, coinfected patients using 400mg QD achieved similar trough levels to both mono- and coinfected patients using the 300/100mg dosing.

The authors do not comment on why this may be the case and it is unclear whether this was a real effect directly relating to coinfection or possible confounding with drug use or adherence (if IDUs were less adherent, they would tend to have lower trough levels).

Guillemi and colleagues from British Columbia looked at using TDM to indentify patients with high atazanavir trough levels (>900 ng/mL using ritonavir boosting) and then to confirm unboosted levels were >150 ng/mL prior using 400mg unboosted as a maintenance dose. [4]

They identified 20 patients (14 using tenofovir/FTC and 6 using abacavir/3TC) with baseline median [IQR] trough level of 1369 [1090-1620] ng/mL. Median trough level after 7-10 days on 400mg ATZ (unboosted) was 173 [96-301] ng/mL. CD4 was unchanged and no patient experienced viral rebound, although total bilirubin levels significantly declined (from 52 [28-64] to 18 [12-24] umol/L, p<0.001).

Table 2. Atazanavir exposure with and without ritonavir

The 9/20 patients with Ctrough <150 ng/mL (4 on abacavir, 5 on tenofovir) were switched back to the 300/100 boosting regimen while 11/20 continued on 400mg QD unboosted atazanavir.

A second study from the same group looking at the relationship between tenofovir use and unboosted atazanavir levels and showed that some patients maintained undetectable viral load despite trough level <150 ng/mL. [5]

The mdian atazanavir trough level in 43 patients was 242 (range 106-1100) ng/mL. Four patients with low trough levels (107-131 ng/mL) increased their dose to 600mg QD, resulting in trough increases to 222-294 ng/mL).

Of 31 patients with undetectable viral load at baseline, 30/31 remained <50 copies/mL.

Atazanavir and raltegravir

Two studies looking at the interaction between raltegravir and atazanavir suggest that individual monitoring is likely to be important when considering using these drugs in the same combination.

Molto and colleagues presented results from a study in 15 HIV-positive patients (4 women) who added raltegravir 800mg once-daily for 10 days, to the regimens of patients already using 400mg atazanavir once-daily for at least the previous two weeks. Use of tenofovir or proton pump inhibitors was not permitted. Both drugs were given with a light meal.

Previous studies have shown that atazanavir inhibits raltegravir metabolism by UGT1A1, boosting raltegravir exposure.

The geometric mean ration (95%CI) for Cmax and AUC 0-24 were compared with historical data on 20 HIV-negative individuals receiving raltegravir with a high fat meal.

Mean (IQR) raltegravir values for Cmax, Tmax, AUC0-24h and Ctrough were 5.36 (3.22-8.91 uM/mL, 2.95 (2.09-4.18) hours, 29.04 (20.46-41.22) uM*h/mL and 69.53 (39.58-122.16) nM/mL respectively. Raltegravir Ctough was <33nM in four patients.

Compared to historical controls using a single 400mg dose of raltegravir GMR (95%CI) for Cmax, AUC 0-24h and Ctrough were 2.81 (1.43-5.50) p=0.004; 1.18 (0.74-1.88) p=0.465 NS and 0.15 (0.07-0.32) p<0.001 respectively. The comparisons were not normalised for comparing the 400mg and 800mg dose, so the practical use of information about the almost 3-fold higher Cmax and 85% reduction in Ctrough are unclear. [6]

Ripamonti and colleagues presented what was perhaps a more pharmacologically useful study. This group switched 21 HIV-positive patients to twice-daily atazanavir (200mg without ritonavir-boosted) plus raltegravir (400mg twice-daily), due to either drug resistance or tolerability on their current regimen. [7]

PK results after at least 2 weeks on the new combinatin showed wide interpatient variability for parameters of both durgs. The geometric mean (95%CI) for atazanavir AUC0-12h, Cmax and Cmin were 6257 (4334-8172) ng*h/ML, 1062 ng/mL (676-1448) ng/mL and 227 (122-332) ng/mL respectively. The geometric mean (95%CI) for raltegravir AUC0-12h, Cmax and Cmin were 9085 (6317-11,854) ng*h/ML, 2402 ng/mL (1496-3308) ng/mL and 132 (1-263) ng/mL respectively. Five patients had atazanaivr levels below the minimum target of 150 ng/mL. About 60% of patients entered the study with undetectable viral load, which was achieved by all patients two weeks after the switch, though these results need to show durability before and comment can be made about efficacy of the combination.

Of concern, the investigators concluded that this combination ‘may’ provide adequate plasma concentrations for ‘some’ patients. Clearly the only reliable way to identify thos patinets is through using TDM on an individual basis.

Drug interaction studies with atazanavir and non-HV drugs included an antimalarial study (see article above). [8]

COMMENT

While ritonavir boosting clearly improves atazanavir levels, the results from these studies indicate that for some patients, when supported by TDM, there may be an option to maintain viral suppression on an unboosted regimen.

The wide interpatient variability appears to protect some patients even when druginteractions are known to reduce theraputic levels.

For other combinations, notably with raltegravir, and especially when using novel dosing, TDM seems essential.

References
Unless otherwise stated all references are to the Programme and Abstracts of the 10th International Workshop on Clinical Pharmacology of HIV Therapy, 15-17 April 2009, Amsterdam.
1. Colombo S et al. Association of pharmacogenetic markers with premature discontinuation of first-line ART. Oral poster O-03.
2. Taburet A et al. Pharmacokinetics of atazanavir administered once daily with or without ritonavir in HIV infected patients: INDUMA Study. Poster abstract P-32.
3. Regazzi M et al. Therapeutic monitoring and variability of atazanavir in experienced HIV-infected patients receiving boosted or unboosted regimens. Poster abstract P-35.
4. Guillemi S et al. A short trial of unboosted atazanivir in patients receiving atazanavir/ritonavir with high trough levels to select candidates for unboosted atazanavir maintenance therapy. Poster abstract P-46.
5. Harris M et al. Atazanavir trough levels in patients receiving unboosted atazanavir and tenofovir. Poster abstract P-21.
6. Molto J et al, Pharmacokinetics and safety of once-daily raltegravir (800mg) plus atazanavir (400mg) in HIV-infected patients. Oral abstract O-13.
7. Ripamonti D et al. Steady-state pharmacokinetics of atazanavir (200mg BID) when combinaed with raltegravir (400mg BID) in HIV-infected adults. Oral abstract O-14.
8. Ref: Van Luin M et al. Drug interactions between atovaquone/proguanil and antiretroviral agents. Oral poster O-19.

Tim Cressey from the Program for HIV Prevention and Treatment (PHPT), Chaing Mai, Thailand and Harvard School of Public Health, Boston, USA presented data from an evaluation of the association between single nucleotide polymorphisms (SNP) and haplotypes within CYP2B6, CYP3A4 and ABCB1, and nevirapine (NVP) plasma concentrations in Thai women following single dose NVP as part of HIV mother to child transmission prophylaxis. [1]

Currently, pregnant HIV-positive women that do not reach eligibility criteria for antiretroviral treatment in Thailand receive AZT from 28 weeks gestation and intrapartum single dose NVP to reduce mother to child transmission. Persistence of NVP in plasma following a single dose has been demonstrated to select for NNRTI mutations, which, in turn, can compromise subsequent NNRTI containing HAART.

In this study, investigators from Thailand and the USA, used plasma and DNA samples from 330 women who had received single dose NVP in the PHPT-2 trial. [2] Nine SNPs within CYP2B6, CYP3A4 and ABCB1 were genotyped using real time PCR. Data from 640 plasma samples taken between delivery and 21 days post partum were available.

Nevirapine plasma concentrations were determined by high-performance liquid chromatography and used in a population pharmacokinetic analysis.

For the CYP2B6 516G>T polymorphism, the investigators found, 43.0% (n=142), 46.7% (n=154) and 10.3% (n=34) of women had G/G, G/T and T/T genotypes, respectively. Nevirapine exposure was higher in women carrying the CYP2B6 516G>T polymorphism but this was not statistically significant, p=0.054.

Two tag-SNPs in CYP2B6: g.18492T>C and g.21563C>T, were significantly associated with NVP AUC, p=0.041 p=0.019 respectively.

The mean (SD) NVP AUC was 154.7 (33.7), 160.9 (33.3) and 17.7 (34.4) mcg.hr/mL in women with g.21563C/C C/T and T/T genotypes, respectively, p=0.27.

When they performed a haplotype analysis of CYP2B6 at 5 loci they found that the TGATC haplotype (g.3003T>C, 516G>T, 785A>G, g.18492T.C and g.21563C>T) was significantly associated with NVP AUC, p=0.00061.

The mean (SD) NVP AUC was 164.5 (33.8, n=197), 152.7 (33.9, n=114) and 146.1 (23.9, n=19) mcg.hr/mL for women with non-TGATC, TGATC-heterozygous and TGATC-homozygous genotypes respectively, p=0.0029.

The median time for NVP concentrations to reach 10 ng/mL postpartum was 18 (IQR 14-21) days, 16 (IQR 13-20) days and 14 (IQR 14-19) days for women with non-TGATC, TGATC-heterozygous and TGATC-homozygous genotypes respectively, p=0.02.

No other genetic polymorphisms evaluated in this analysis were significantly associated with NVP AUC.

CYP2B6 516G>T has previously been shown to affect NVP oral clearance during chronic treatment. The investigators observed that CYP2B6 516G>T seems to have a more modest impact on single dose NVP than on NVP used in chronic treatment. They suggest that the physiological changes experienced during pregnancy and/or the minimal autoinduction of CYP3A4 and 2B6 enzymes following a single dose compared to steady state (1.5 to 2-fold increase in NVP CL/F during first two weeks of treatment) may explain this observation.

They concluded that CYP2B6 polymorphisms following single dose NVP may account for some of the interpatient variability observed in post partum NVP concentrations but that the clinical significance of this finding may be relatively small.

Ref:
Chantarangsu S et al. A CYP2B6 haplotype influences nevirapine plasma concentrations postpartum following a single intrapartum dose for the prevention of mother to child transmission of HIV in Thai women. 10th International Workshop on Clinical Pharmacology of HIV Therapy, 15-17 April 2009, Amsterdam. Abstract O_02.

Natella Rakhmanina from the children’s National Medical Center, Infectious Diseases, Special Immunology and Pharmacology, Washington, showed findings from a study to investigate whether the lopinavir (LPV) phenotypic inhibitory quotient (PIQ) and genotypic inhibitory quotient (GIQ) in treatment experienced children correlate with treatment response, when receiving LPV containing HAART, as observed in treatment experienced adults.

In this study the investigators collected 52 weeks prospective data from children and adolescents aged 4-15 years receiving LPV/r as single PI within antiretroviral regimens. 12-hour pharmacokinetic (PK) samples were collected and LPV susceptibility measured within 3 months of enrollment. Treatment histories, including resistance information, were obtained from medical records. Viral load and self reported adherence were measured 3 monthly.

IQ was calculated as the rate of plasma 12-hour trough concentration (Cmin) after observed dose divided by the protein-adjusted IC50 for PIQ and the number of LPV-associated mutations for GIQ.

In this analysis, 45 PI experienced children and adolescents were followed for 52 weeks. Their median age was 11 (5.3-17.8) years; 24 were girls and the majority (n=41) were African American. Of the group 40 (89%) received background regimens of 2 NRTIs, 2 received 3 NRTIs and 3 received NRTI plus NNRTI.

The median length of PI experience was 5.2 (0.7-9.2) years and of previous LPV exposure was 2.2 (0.5-5.0) years. Self reported adherence was a mean of 88% (41-100%). About half, 24/45(53%), of the patients achieved viral load, 400 copies/mL, at least once during the study. The median LPV Cmin was 6.2 (0.1- 16.7) mg/L.

Median PIQ (n=36) was 12.6 (0.03-231.1). The investigators noted that a baseline PIQ cutoff of 15 (as in adults) did not distinguish those achieving a viral load of <400 copies/mL from those that did not, p=0.09.

In multivariate analysis, only baseline PIQ >25 was significantly associated with viral load <400 copies/mL: 11/16 (69%) patients with PIQ >25 achieved viral load <400 copies/mL vs. 5/20 (20%) with PIQ <25, p=0.01.

The geometric mean PIQ in those patients achieving viral load <400 copies/mL was 16.7 vs 2.4 in those who did not, p=0.09.

The investigators found for every increase in baseline PIQ of 10, the probability of achieving viral load <400 copies/ml, when adjusted for prior duration of LPV treatment, increased 9.6-fold (95% CI 9.2-9.9), p=0.02.

They reported a median GIQ (n=22) of 1.0 (0.03-6.5) and a median of 6 (1-13) LPV mutations per patient. The geometric mean GIQ in those achieving viral load <400 copies/mL was 1.0 vs. 0.7 in those who did not, p=0.56.

The investigators concluded that LPV PIQ was associated with viral load <400 copies in PI experienced HIV-positive children and adolescents but GIQ was not. They suggest that a cutoff of LPV PIQ >25 may be a target for maximising efficacy.

Ref:
Rakhmanina N et al. The phenotypic and genotypic susceptibility lopinavir scores and virologic response in treatment experienced children with HIV. 10th International Workshop on Clinical Pharmacology of HIV Therapy, 15-17 April 2009, Amsterdam. Abstract 0_17.

J King and coworkers reported pharmacokinetc (PK) parameters of tenofovir (TDF) tablets received in combination with efavirenz (EFV) or duranavir/ritonavir (DRV/r) or atazanavir/ritonavir (ATV/r) in a group of children and adolescents age 8-18 years.

This study enrolled patients receiving >=2 weeks TDF 300mg in combination with:

Arm 1: EFV 300mg or 600mg once-daily

Arm 2: DRV/ritonavir dosed at 300/100 or 600/100 twice-daily

Arm 3: ATV/ritonavir dosed at 200-400mg/100mg twice-daily

Plasma samples were taken at 0, 1, 2, 4, 6, 8, 12 and 24 hours post dose and plasma concentrations of TDF were measured.

The investigators performed statistical tests to evaluate whether the 90% confidence intervals of the geometric mean (GM) for the PK parameters of TDF were within the target range ie 0.5-2.0 fold of adult values: 2.8 (2.3-3.6) mgxh/L and 0.06 (0.05-0.08) mg/L AUC and Cmin respectively.

They found that among patients receiving EFV (n=15) the TDF GM (90% CI) AUC and Cmin were 2.9 (2.4-3.4) mg.h/L and 0.07 (0.05-0.09) mg/L respectively. AUC and Cmin were 3.1(2.4-4.0) mg.h/L and 0.07 (0.05-0.09) mg/L in patients receiving DRV/r (n=10) and 3.6 (3.0-4.5) mg.h/L and 0.07 (0.06-0.10) mg/L respectively in patients receiving ATZ/r (n=17).

They noted that the TDF Cmin 90% CI included values above the target upper limit of 0.08 mg/L in all three arms and the AUC 90% CI included values above the upper target limit of 3.6 mg.h/L in patients receiving DRV/r or ATV/r.

The investigators concluded: “These data suggest that DRV/r and ATV/r may increase TDF exposure in HIV-infected children and adolescents.”

Ref:
King J et al. A comparison of tenofovir pharmacokinetics across three tenofovir-based antiretroviral regimens in HIV-infected children and adolescents. 10th International Workshop on Clinical Pharmacology of HIV Therapy, 15-17 April 2009, Amsterdam. Abstract P_53

A poster authored by J van der Lugt and coworkers from Thailand and the Netherlands described pharmacokinetic (PK) data and short-term safety of a generic lopinavir/ritonavir (LPV/r) 200/50mg formulation tablet. [1]

In this study, patients receiving PI based therapy with viral load <50 copies/mL were switched to generic LPV/r 400/100mg twice daily. Trough concentrations (Cmin) were measured prior to the switch in 16 patients receiving Kaletra and 4 weeks after the switch in all patients.

Plasma levels of LPV and RTV were measured using high performance liquid chromatography with a lower limit of quantification of 0.1mg/L for LPV and 0.045mg/L for RTV.

A group of 37 patients were evaluated in this study; their mean (SD) weight was 60.3 (11.8) kg and18 were women. Two patients discontinued the study medications due to intolerance.

The investigators reported the mean (SD) Cmin of LPV was 7.3 (1.8) mg/mL. None of the patients evaluated had subtherapeutic levels. They found no difference in LPV Cmin in patients receiving Kaletra before switching to the generic formulation of LPV/r, p=0.21. However, the Cmin of the generic RTV was higher than that reported for Kaletra, p=0.019. They found the coefficient of variation was 25% for the tablet formulation and 54% for the Kaletra. They noted that these values did not appear to be affected by food intake.

They concluded: “These data support the efforts in scaling up access to generic second line treatment in middle and low income countries.”

COMMENT

There are currently limited protease inhibitors available for second line treatment in low and middle-income countries. Although originator LPV/r (Kaletra/Aluvia) is the most common protease inhibitor in industrialised countries, generic LPV/r is not widely used in resource limited settings as there have been concerns about the quality (including studies by the originator company) and limited data. [2]

These data are reassuring, as is the FDA tentative approval in March this year of Indian generic versions of LPV/r manufactured by Aurobindo and Matrix Laboratories. [3]

Studies of a paediatric “sprinkle” formulation from Cipla are underway.

References
1. Van der Lugt J et al. Bioavailability of generic lopinavir/ritonavir in HIV-1 infected individuals. 10th International Workshop on Clinical Pharmacology of HIV Therapy, 15-17 April 2009, Amsterdam. Abstract P_41.
2. Garren KW et al. Bioavailability of Generic Ritonavir and Lopinavir/ritonavir Tablet Products in a Dog Model Abbott Laboratories, Abbott Park, IL. 2nd International Workshop on HIV Treatment, Pathogenesis and Prevention Research in Resource-Poor Settings, 20-23 May 2008, Dakar, Senegal.
3. http://www.fda.gov/InternationalPrograms/FDABeyondOurBordersForeignOffices/AsiaandAfrica/ucm119231.htm

A selection of the latest news and reviews from the Liverpool University pharmacology team at hiv-druginteractions.org are included below.

http://www.hiv-druginteractions.org

Drug interactions with integrase inhibitors

This is an outstanding review on the pharmacology of integrase inhibitors with a substantial section on raltegravir drug-drug interactions and elvitegravir drug-drug interactions. There are four tables summarising all known interactions to date. The authors conclude that overall raltegravir has a low propensity for clinically meaningful drug interactions, whereas elvitegravir (with the presence of ritonavir) has modest potential for interactions.

The review is highly recommended and will appear in 2009. An advance version is available online, but minor changes may still occur before final publication.

Ref: Hazuda DJ et al. Emerging pharmacology: Inhibitors of Human Immunodeficiency Virus integration. Rev Pharmacol Toxicol, [Epub ahead of print]
http://www.ncbi.nlm.nih.gov/pubmed/18928385

Serum bilirubin increases when PEG-interferon and ribavirin are used with atazanavir

This was a retrospective study of 72 HCV/HIV co-infected patients who initiated HCV therapy (peg-IFN weekly and ribavirin 1000-1200 mg/day) and were on either an atazanavir-containing regimen (n=36) or other antiretrovirals (not including indinavir, n=36). Fourteen subjects in the atazanavir group and six in the control group were then excluded from analysis due to poor drug adherence.

The major finding was that on average serum bilirubin increases following initiation of peg-IFN and ribavirin were 1.9-fold higher in patients on atazanavir than in controls. In the atazanavir group, the proportion of patients with grade 3-4 hyperbilirubinaemia increased from 2/22 to 10/22 after beginning hepatitis therapy. No controls developed hyperbilirubinaemia.

The elevation in serum bilirubin levels is directly related to the haemoglobin decline as a result of ribavirin use and haemolysis.

The clearance of the increased bilirubin is compromised by atazanavir.

Ref: Rodriguez-Novoa S et al. Increase in serum bilirubin in HIV/hepatitis-C virus co-infected patients on atazanavir therapy following initiation of pegylated-interferon and ribavirin. AIDS, 2008, 22(18): 2535-2548.
http://www.ncbi.nlm.nih.gov/pubmed/19005277

Drug interactions between efavirenz and itraconazole

This is a case report of the interaction between itraconazole and efavirenz in a woman with  disseminated histoplasmosis and HIV-1 infection. Previous data in healthy volunteers have shown a decrease of about 40% in exposure of itraconazole and its active metabolite (hydroxyitraconazole) and a recommendation to consider alternative antifungal treatment. Here the authors recommend that by the use of therapeutic drug monitoring of both efavirenz and itraconazole individual optimization of dosage can be made so that a change in therapy is not necessary. In this case the patient had a good clinical response and obtained therapeutic concentrations with a regimen including efavirenz 400 mg once daily and itraconazole 800 mg once daily.

Ref: Huet E et al. Therapeutic monitoring is necessary for the association itraconazole and efavirenz in a patient with AIDS and disseminated histoplasmosis. AIDS, 2008, 22(14): 1885-1886.
http://www.hiv-druginteractions.org/frames.asp?new/Content.asp?ID=403

Effect on tacrolimus when switching from nelfinavir to fosamprenavir

This case report outlines the change in tacrolimus trough blood concentrations when 4 HIV-infected orthotopic liver transplant patients were switched from nelfinavir (1250 mg twice daily) to fosamprenavir (1400 mg twice daily without ritonavir) due to the EMEA ruling on nelfinavir in June 2007. After the switch, tacrolimus trough concentrations dropped significantly (>50%) and a marked dosage increase was required to attain the desired target concentration. The cases highlight the need for caution in immunosuppressed patients when switching or starting a protease inhibitor.

Ref: Pea Fet al. Drop in trough blood concentrations of tacrolimus after switching from nelfinavir to fosamprenavir in four HIV-infected liver transplant patients. Antivir Ther, 2008, 739-742.
http://www.hiv-druginteractions.org/frames.asp?new/Content.asp?ID=404

Elvitegravir with tipranavir/ritonavir or darunavir/ritonavir

Two studies are described evaluating potential pharmacokinetic interactions among elvitegravir and ritonavir-boosted tipranavir or darunavir.

In the tipranavir study healthy volunteers received elvitegravir/ritonavir (200/100 mg once daily) alone, or tipranavir/ritonavir (500/200 mg twice daily) alone, or elvitegravir (200 mg once daily) in combination with tipranavir/ritonavir (500/200 mg twice daily). For the darunavir study subjects received elvitegravir/ritonavir (125/100 mg once daily) alone, or darunavir /ritonavir (600/100 mg twice daily) alone, or elvitegravir (125 mg once daily) in combination with darunavir /ritonavir (600/100 mg twice daily). Steady state pharmacokinetics for elvitegravir, tipranavir, darunavir and ritonavir were determined.

No subjects discontinued for adverse events during treatment with elvitegravir/ritonavir alone. On coadministration, AUC and Cmax of elvitegravir/tipranavir and elvitegravir/darunavir were within respecified no-effect boundaries versus treatment alone; trough concentrations were also not substantially altered. The authors concluded that elvitegravir can be added to tipranavir/ritonavir or darunavir/ritonavir regimens without dose adjustment.

Ref: Mathias AA et al. Effect of ritonavir-boosted tipranavir or darunavir on the steady-state pharmacokinetics of elvitegravir. J Acquir Immune Defic Syndr, 2008, 49(2): 156-162.
http://www.hiv-druginteractions.org/frames.asp?new/Content.asp?ID=405