114) A 44-year-old HIV-infected man with a CD4 count of 280cell/mm3 presents to your office with complaints of fatigue, body aches, leg cramps and muscle pain. His viral load is undetectable. His HIV medications include tenofovir, lamivudine and Ritonavir for the past one year. The patient was recently seen in the office for lipodystrophy and hyperlipidemia. His LDL cholesterol was 190 during last visit and hence, he was started on Simvastatin about 2 weeks ago. On physical examination, he is afebrile and he has diffuse muscle tenderness. Laboratory studies show a serum creatinine of 3.2 mg/dL ( his baseline = 1.0 mg/dl), serum urea nitrogen = 55 mg/dL , total bilirubin 0.8gm/dl, aspartate aminotransferase (AST) level of 632 U/L and alanine aminotransferase (ALT) level of 140 U/L . Urinalysis was positive for blood on dipstick. Urine microscopy shows no red cells or white cell casts. The most likely reason behind the etiology of this patient’s renal failure :
A) Polymyositis
B) HIV associated Nephropathy
C) Tenofovir induced Nephrotoxicity
D) Interaction between Ritonavir and Simvastatin
E) HIV myopathy
Archer USMLE Step 3 Blog 
interaction simva & rito
D. This seems more reasonable
D,for sure
d
ans C
http://www.medscape.com/viewarticle/470919_3
Elevated statin levels 2/2 rito cyo450 in liver causing rhabdo answre D
HIV drugs! HAART!
Here: Tenofovir is nucleoTIDE reverse transcriptase inhibitor
Lamivudine is nucleoside reverse transcriptase inhibitor
Ritonavir is protease inhibitor
Scenario:
An HIV patient has undetectable viral load while on HAART.
He develops dyslipidemia.
He develops rhabdomyolysis while on Simvastatin for dyslipidemia.
He develops renal failure.
Question:
What is the most likely etiology behind this patients renal failure?
My Answer:
Ritonavir (notoriously) inhibit cytochrome P450.
Simvastatin needs cytochrome P450 for elimination.
Thus Simvastatin accumulates and simulates overdose.
Excess simvastatin leads to myopathy.
Rhabdomyolysis is severe myopathy.
Rhabdomyolysis releases Myoglobin pigment.
Myoglobin pigment colors the urine and causes acute renal failure.
Ritonavir and Simvastatin are interacting adversely & causing rhabdomyolysis and renal failure in this patient.
My Answer is D,
Some facts:
1. HIV/HAART commonly result in significant dyslipidemia
2. HMG coA inhibitors (STATINS) lower cholesterol and harmful lipids
3. Cytochrome P450 eliminates most HMGcoA inhibitors (STATINs).
4. HAART induces or inhibits Cytochrome P450 (CP450)
5. HAART influences elimination of all statins metabolized by CP450.
Goals:
We need statins that are not eliminated by CP450.
We need statins that are not eliminated by the kidneys.
Pravastatin is uniquely suited for this task and it should be used to control HIV dyslipidemia.
Continuing HAART is imperative. (MUST)
Clue:
Notice that current HAART regimen produced undetectable viral load.
A new agent was added before rhabdomyolysis occurred.
The question asks for the most likely cause?
It’s like saying ‘A’ was traveling at top speed and then he was hit by ‘B’ and then ‘A’ crashed. ‘A’ could not have crashed if it was not hit by ‘B’.
Many will argue that ‘A’ could have crashed without ‘B’. But the question asks, what is the MOST LIKELY cause of the crash? It is the fact that ‘A’ was hit by ‘B’. – patho-physiology for dummies – et al. Mua.
Hats off Adnan, for such detailed explanations in many questions. I have been following your comments and responses, and I agree with many of them that you posted!
Just one thing to note. Pravastatin is cleared through the kidneys, and thus avoids the Hepatic pathway. Thats why its useful in patients with Liver dysfunction, or those on drugs that cause P450 inhibition.
excellent answer, however doesnt the rhabdomyolisis and the release of myoglobin result in ATN which is the cause of the acute renal failure form the direct cytotoxic damage of the renal tubules by myoglobin. pravastatin is cleared by the kidneys and therefore useful in patients with abnormal liver function, or those on drugs that cause CYT inhibition such as Ritinovir.
A very generous compliment drqamarahmad. Thank you, I appreciate it. Your additional note was a summary:
1. Pravastatin is cleared by the kidney when the liver is damaged and vice versa. It has effective dual excretion routes (liver and kidney) that compensate each other if one route fails. This is a unique property.
http://www.ncbi.nlm.nih.gov/pubmed/11192473
2. Pravastatin is excreted unchanged in urine but it is also metabolized in the stomach by chemical degradation instead of P450 pathway in the mitochondria in the liver.
3. When P450 is inhibited by drugs, some drugs are not broken down and they reach toxic concentration in the blood.
Simvastatin and Lovastatin need P450 for break down.
Ritonavir is a strong inhibitor of P450.
These drugs can cause myotoxicity and red pigment in urine (blood on dipstick but no red cell cast).
Rule out differentials:
Polymyositis does not present with kidney failure normally
HIVAN cause nephrotic range proteinuria 9not found in his question)
Tenofovir damages proximal convoluted tubules PCT in the kidneys and cause Fanconi syndrome or Type 2 RTA, (there is no proteinuria or alkaline urine here)
HIV myopathy is above presentation minus kidney failure.
http://www.ncbi.nlm.nih.gov/pubmed/18563955
http://www.ncbi.nlm.nih.gov/pubmed/11192473
http://en.wikipedia.org/wiki/Cytochrome_P450