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  International AIDS Conference
July 13-16, 2003, Paris
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Tenofovir: methadone & ribavirin interaction studies, and renal toxicity in 2 cases
Reported by Jules Levin
Poster 980 at IAS reports on a study of potential drug interactions in vitro (in the test tube) between tenofovir and ribavirin. Ribavirin is used with interferon to treat patients infected with hepatitis C. MT-2 cells were infected with wild-type HIV-1 (HXB2) in the presence of ribavirin (RBV) with either tenofovir, ddI, AZT, 3TC, d4T, abacavir, or nelfinavir. Five concentrations of RBV ranging from 0.75 uM to 12 uM were tested. These concentrations are below the cytotoxicity level for RBV in MT-2 cells (CC50=70uM). For the other compounds, 6 concentrations of drug starting at a meximum drug concentration of at least 4 times the expected IC50 value for each specific drug were tested. RESULTS: Ribavirin on its own did not exhibit any anti-HIV activity, but its presence had en effect on the anti-HIV activity of all the nukecleoside reverse transcriptase inhibitors tested:
--RBV with ddI showed strong enhancement of anti-HIV activity of ddI. The FDA suggests not to combine ddI and RBV because increased ddI toxicity in HIV/HCV
co-infected patients treated with RBV and ddI correlates with this observed strong synergy in vitro and in studies of clinical effects in patients
--RBV with either tenofovir or abacavir resulted in moderate levels of antagonism so this poster concludes that tenofovir did not show synergy with RBV, but low-level antagonism. Although both tenofovir and ddI are both adenosine analogs, their in vitro interactions with RBV are markedly different. The authors conclude: these study results suggest a "low potential for additive toxicity upon co-administration of tenofovir with RBV in patients. They also say "since no clinical significance for the high-level anti-HIV antagonism between AZT & RBV has been reported, the low-level antagonism observed for both tenofovir and abacavir with RBV is unlikely to be clinically signifucant".
METHADONE and Tenofovir
Researchers (P Smith and colleagues, State University of NY at Buffalo) and Gilead Sciences reported an interaction study between methadone and tenofovir in HIV-negative individuals. They found no affect of methadone or tenofovir on each other and recommend it's safe to combine the two. Is there any reason not to follow-up this study with an interaction study in HIV+ individuals on ART in order to confirm these findings?
The purpose of this study presented at the IAS Conference is to evaluate the effect of tenofovir (TDF) co-administration with methadone, on the steady state pharmacokinetics (PK), pharmacokinetics (PD), and safety of methadone. HIV-negative subjects on stable methadone (40-110 mg/day) were enrolled in this 16-day, open-label, drug-drug interaction study. 14 subjects were enrolled, 1 person discontinued for personal reasons. 13 subjects evaluable for PK analysis were 4 men, 9 females, avg age was 43, mean weight 182 lbs, 11 White, 1 Hispanic, 1 Black.
Methadone PK (AUC and Cmax ) were determined by non-compartmental methods, and evaluated for equivalence by generation of 90% confidence intervals about the ratio of geometric means [GMR (90% CI)] for methadone plus TDF, relative to MTH alone. In addition to clinical safety evaluations, a Short Opiate Withdrawal Scale (SOWS) questionnaire and pupillary diameter measurements were performed at baseline and during methadone+TDF co-administration to evaluate methadone PD.
Thirteen subjects (four males, nine females) completed the study. Total MTH systemic exposures were pharmacokinetically PD.. Total methadone systemic exposures were pharmacokinetically equivalent when co-administered with TDF versus alone [total MTH GMR (90% CI) for AUC and Cmax were 1.05 (0.98, 1.13) and 1.05 (0.97, 1.14)]. R-MTH and S-MTH exposures also showed PK equivalence.
Tenofovir PK results were within range of values observed in previous studies in both HIV negative and HIV positive individuals: AUC-SS (ng-hr/mL) 3322, range 2228-5466; Cmax (ng/mL) 353, range 202-762; T-1/2 hr 13.7 (range 10-20).
No significant changes were observed in SOWS scores or pupillary diameters, and no clinically relevant clinical or laboratory adverse events, including opiate-related toxicity or withdrawal, were observed during the study.
Pharmacodynamic and safety Assessments
--11/14 (79%) of subjects experienced at least 1 treatment-emergent adverse event
--most common adverse events were abdominal pain (43%), asthenia (21%), headache (14%), nausea (14%), dyspepsia (14%), and worsening asthma (21%).
--no clinically significant changes in lab abnormalities were observed
--no subjects exhibited symptoms attributed to opiate-related toxicity or withdrawal
The authors summarized co-administration of TDF with methadone did not affect the steady state PK of methadone, or its R- and S-enantiomers. TDF did not affect methadone PD; symptoms of opiate-related toxicity or withdrawal were not observed. Co-administrstion was safe and well tolerated. TDF PK results when given with methadone were consistent with previously observed values. Dose adjustments are not required for methadone or TDF when these drugs are co-administered.
The study authors concluded that TDF does not affect methadone PK or PD. Therefore, TDF is a viable option for inclusion in HAART regimens in MTH-maintained patients.
In poster 694 French researchers reported on 2 cases they observed of kidney toxicity. I'll stipulate that these are uncommon events as they are reported from large studies. These may be the same 2 cases that were reported in a poster at the Retrovirus Conference in Feb 2003. In the interest of a full discussion, a doctor reader observes "these cases were very unconvincing. Fenofibrate is a well known cause of renal dysfunction. NO evidence of hypophosphatemia, phosphaturia or proteinuria were provided to suggest Fanconi's like syndrome. The second case recovered with rehydration...they were sick with something and got so dry that their renal function went off. No evidence that this was TDF related was given".
Tenofovir disoproxil fumarate (TDF) is an acyclic nucleotide reverse transcriptase inhibitor recently employed as part of HAART. Although this drug's family can induce acute renal failure (ARF) and tubulopathy, human renal toxicity of TDF has been rarely published. We reported here 2 cases of tubulopathy with ARF in patients taking HAART containing TDF.
Patient (pt) 1: a 40-year-old man was known HIV1 positive since 1982. Salvage treatment with TDF, DDC and lopinavir/ritonavir (LPV/r) was started in August 2001 (CD4: 168 cells/mm3, viral load: 4.5 log/ml). Treatment with metformine, fenofibrate and pyrimethamine was maintained. Baseline serum creatinine was 74 ml/mn. On October 30th 2002, he was admitted for asthenia, diarrhoea and oliguria. Laboratory tests: urea nitrogen: 25 mmol/l, creatinine: 1760 µmol/l, bicarbonates: 6 mmol/l, lactates: 7 mmol/l, pH: 7.10. All drugs were stopped and dialysis was required. One month later, creatinine level raised to normal value.
Pt 2: a 35-year-old HIV infected woman (CD4: 0/mm3, VL: 5 log/ml) was treated on January 2002 with TDF, LPV/r, 3TC, cotrimoxazole, itraconazole with a poor treatment adhesion as showed gŽnotype performed in June. On December 2002, she was admitted because of asthenia and diarrhea. At Day 1 (D1) creatinine, urea nitrogen and bicarbonates levels were normal, hypokaliaemia (2.4 mEq/l). Metabolic acidosis was noted at D3 with persistent urine secretion of potassium. Despite treatment withdrawal, on D4 serum creatinine was 443 mmol/l. With parenteral hydratation creatinine raised to normal level at D10. Even in lack of rechallenge test in these observations, TDF can be partly considered as responsible for acute renal failure.
The association with others nephrotoxic drugs or LPV and/or waterloosing may have play a role in acute renal failure onset. Monitoring of serum creatinine and electrolytes levels should be regularly performed in patients taking TDF. So, TDF combination with nephrotoxic drugs must be examined closely.