Liver Toxicity

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I have been having liver toxicity which I suspect is due to the cumulative usage of Non Nucleoside Reverse Transcriptase Inhibitors (NNRTIs). Anyone heard of someone having similar problems? Any suggestions will be welcome. Here is what happened:

On September 12, 2005, a routine blood work revealed that my liver enzymes were elevated. Both Alanine aminotranferase (ALT) and Aspartate aminotransfearse (AST) had risen to grade 1 hepatotoxicty and were 1.26 the upper limit of normal (ULN). Alkaline phosphatase (ALP) and bilirubin were within normal limits. At that time I had been on Nevirapine (NVP), Tenofovir (TDF) and 3TC. I had been on NVP for 23 months, on TDF for 16 months, and on 3TC for 38 months. I also was on NVP for 5 years from 3/1997 to 4/2002 without any complication. In addition, I was taking Fluoxetine, Acyclovir and L-Carnitine and had discontinued statin therapy about nine weeks ago. My supplement list included Thymus gland, Vitamins B, C, D and E, Zinc, Calcium, Magnesium, Potassium, Selenium, L-Lysine, N-Acetyl-L-Cystine, Alpha Lipoic Acid, Co-Q Enzymes, Garlic, Ginkgo Biloba, Fish Oils, Acidophilus and a baby Aspirin.

As my ALTs and ASTs continued to increase, I had a hepatitis profile done. I was negative for HCV antibody and the HCV RNA was less than 40 International Units per mL. I had abnormally high antibodies to Hep A and B, consistent with immunity. My Hep B antigen was negative. I had Hep B infection in 1978.

On 9/27/2005, my ALT increased to 3.3 ULN (grade 2 toxicity). Suspecting NVP had caused hepatotoxicity, I stopped it on that day and replaced it with Efavirenz (EFV) on 9/29/2005. I had had a 17-month incident-free experience with EFV in 2002-2003.

But my ALT continued to on increase and was 4.7 ULN on 10/11/2005. On 10/12/2005, my hepatologist ordered Iron Binding Capacity, Alpha-1 Antitrypsin, Mitochondrial AB and CMV IGM AB. Those tests came back normal or negative. On 10/13/2005, I had an ultrasound of the right upper quadrant which did not show any abnormality.

My ALT kept rising and on 10/24/20005 it was 11 ULN reaching a grade 4 toxicity. My Lactic acid dehydrogenase (LDH) and C-Reactive Protein were also high. I decided to stop all ARVs (Anti-retroviral virals) and 10/28/2005 was my first day off of ARVs. I also stopped all my supplements.

I was off of all medications and supplements, except for Fluoxetine, for the next four weeks. As my liver enzymes decreased, I added Zinc, Vitamin B, C and E, Calcium, Magnesium, Potassium, Acidophilus and Fish Oils. On 12/24/2005 (six and a half weeks off of ARVs), my ALT was 1.9 ULN but my HIV RNA had increased from less than 50 copies per mL to 4,676 copies per mL or about 3.7 log10. My CD4 percentage of lymphocytes had decreased from 33% to 26% and the absolute CD4 count went down from 1000 to 645. The CD4/CD8 ratio went down from .78 to .46.

I went back on EFV, TDF and 3TC on 12/14/2005. On 12/22/2005, my ALT increased from 1.9 ULN to 2.7 ULN (grade 2 toxicity). Presuming that TDF and 3TC were not causing hepatotoxicity, it became clear that substituting EFV for NVP did not stop liver damage and in fact, it accelerated it. Once again, I stopped all ARVs.

Questions

1. Most of the hepatotoxicty described in the literature is upon initiation of NNRTI therapy and it manifests as a hyper-sensitive or allergic reaction. My review of the literature failed to show any study documenting hepatotoxicity due to cumulative use of NVP and/or EFV beyond 2 years in patients in whom no toxicity was detected upon initiation of HAART involving NNRTIs. Have you seen hepatotoxicity due to both NVP and EFV two years after initiation of therapy? If so, in what percentage of patients? Are you familiar with any study that shows hepatotoxicity due to both NVP and EFV? Are NNRTIs as a class no longer available to me?

2. Although the incidences of hepatotoxicity due to NVP and EFV as described in the literature are much higher than those due to TDF and 3TC ( 16% with NVP, 8% with EFV and 3% with TDF and 3TC), have you seen liver toxicity due to TDF and/or 3TC in your practice? Theoretically, since I was taking all three drugs, it is conceivable though improbable that TDF and/or 3TC were/was causing my problem.

3. Ideally, I would like to start on three new ARVs. As I had the hypersensitivity reaction to abacavir and want to avoid thymidine drugs due to lipodystrophy and mitochondrial toxicity concerns, it leaves me ddI and FTC. As ddI has been reported with more cases of hepatotoxicity, it does not seem to be a wise choice. And FTC is just a chemical cousin to 3TC. So basically I am left with TDF and 3TC/FTC as my two choices in the Nucleoside/Nucleotide RTIs category. And these are hardly new to me. If I stick with them, how do I eliminate the chance of their causing liver damage?

4. After my ALT comes down to less than 1.5 ULN, I intend to start HAART with boosted atazanavir, TDF and FTC. If ALT does not rise, then great. Otherwise, the culprit might be TDF and/or FTC. If so, how do I come up with a three drug combination as all NRTIs (except ddI) and NNRTIs would then be unavailable to me?

5. So far, I have avoided a liver biposy as the liver enzymes do come down when I go off of drugs. Is there any reason to get one now? Can it show which drug is causing the hapatocellular injury?

Please advise on this course of action. Thank you very much and I really appreciate your input.

Vimal Jairath