Tag: HIV

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HIV and the Kidney

HIV and the Kidney (Keynote, PDF)

 

  • Updated April 2013
  • The lecture was about one hour.
  • The section on APOL1 is rough.
  • I would like a slide describing the transgenic mouse model studies by Klotman that showed that transcription of nef and pol are central to the disease.
  • I need some notes on why I have 2 graphs on slide 16.
  • Add some highlights to table in slide 23.
  • Loved how slide 26 and 27 worked.
  • I think there might be better data on steroids in HIV. Slide 51.
  • Need to flush out IRIS and DILS from slide 67
  • Add comment on adefovir slide mentioning that the hep B dose is a sixth of the anti-HIV dose

 

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Abacavir and methanol poisoning

About a month ago, Nephron Power wrote about a great electrolyte case in AJKD. The case regarded a patient who drank a liter of methanol but was asymptomatic. The reason the patient was apparently resistant to a toxic methanol slug of methanol (The quantity of methanol that produces toxicity ranges from 15 to 500 ml of a 40% solution to 60 to 600 ml of pure methanol) was protective powers of abacavir. Abacavir is a nucleoside reverse transcriptase inhibitor and apparently, is a potant inhibitor of alcohol dehydrogenase, the critical enzyme which converts methanol into formaldehyde. Formaldehyde is then converted into the lethal formic acid by formaldehyde dehydrogenase.

After reading this I started to wonder if abacavir was such an effective inhibitor of alcohol dehydrogenase what happens when patients get exposed to say a more common substrate of alcohol dehydrogenase such as whiskey. Shouldn’t we hear about people on abacavir going on alcohol benders after a single shot of ethanol?

A couple of cracks at PubMed and I sure didn’t find much. Barber, Marrett et al. looked for two types of alcohol reactions from abacavir, either a disulfaram-like reaction or reduced alcohol tolerance. The authors found three cases of in 173 patients starting abacavir. They found one disulfarem reaction (nausea, tachycardia, flushing with a single shock of vodka) and two cases of decreased alcohol tolerance

After three glasses of wine he felt as though he had a bottle and a half, with memory loss.

The only other paper I could find was by McDowell, Chittick, et al. who looked at increased abacavir levels with alcohol intake. The reverse of what I was looking for, but at least it was related. They gave a single dose of abacavir and 0.7 g/kg of ethyl alcohol to 25 HIV positive men. They found a 26% increase in the half life of abacavir with alcohol but…

This study did not demonstrate any alteration in the pharmacokinetic parameters of ethanol by abacavir coadministration; blood ethanol median profiles following ethanol administration in the presence and absence of abacavir were essentially superimposable. There was no evidence that co-administration of abacavir interferes with ethanol metabolism. There were no disulfiram-type reactions in any subject who received coadministration of abacavir and ethanol.

This study tested the effects of a single dose of abacavir, chronic dosing may result in a different effect on alcohol dehydrogenase.

Interesting case nonetheless.

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How to make a cool clinic diagnosis

I had a great case yesterday in clinic.

The patient was a 55 year old woman with HIV and a chief complaint of gradually climbing creatinine. Among her medications were Truvada and Norvir.

Truvada is one of three brand name drugs that contains tenofovir:

  1. Viread: tenofovir
  2. Truvada: emtricitabine-tenofovir
  3. Atripla: efavirenz-emtricitabine-tenofovir
Tenofovir rarely causes renal failure through proximal tubule toxicity. One of its hallmarks is a Fanconi syndrome, though the renal failure can occur without Fanconi’s. Fanconi’ syndrome is generalized dysfunction of the proximal tubule, so metabolites normally reabsorbed in the proximal tubule are wasted in the urine. Patients have amino aciduria, bicarbonaturia (RTA type II), inappropriate phosphaturia and glucosuria. Because of the increased phosphaturia, hypophosphatemia is a surprisingly sensitive indicator of tenofovir toxicity (20/20 cases).
This patient’s creatinine rose from 1.4 in March of ’09 to 1.7 in November. The primary care doctor that handles this patient’s HIV had checked an ultrasound (9 and 10 cm kidneys), and albuminuria (400 mcg/min).
Here are the results of his U/A we did in the clinic:
I focused on the glucosuria and concluded that if her blood sugars are normal then she must have proximal tubular dysfunction and likely tenofovir toxicity.
Her blood sugar was 87. The Tm for glucose is roughly 200, so a serum glucose of 87 should not cause any glucosuria.
The Truvada was stopped. The patient is also on ritonovir (Norvir). Ritonovir is found in 72% of patients with tonofovir induced Fanconi’s syndrome, so it maybe an important co-factor in the development of this condition. We did not stop the Norvir, should we?

 I will follow up with the patient in the month. Hopefully she will do well.

Here is a talk I gave on HIV and the Kidney:
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HIV and the Kidney

Gave a lecture to the ID faculty and fellows today. That was the fourth lecture in 2 weeks. Done running the lecture gauntlet.

Excellent website on HIV from the UCSF: HIV InSite Knowledge base

I though my lecture’s section on HIVAN Therapy was little light here is InSite’s monolog on therapy for HIVAN:

Clinical Course and Treatment

In the Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents, the U.S. Department of Health and Human Services now includes a diagnosis of HIVAN as an indication for ART, regardless of CD4 count.(94) Other treatment options that may influence the course of HIVAN include angiotensin-converting enzyme inhibitors (ACEIs) and corticosteroids administered before dialysis or kidney transplantation.

Antiretroviral Therapy

The original case reports of HIVAN described a rapid and inexorable progression to ESRD over a period of weeks to months.(2-4) However, after highly active ART came into use, several dramatic reports of renal recovery among these patients emerged in the medical literature. In one study, a patient with HIVAN and dialysis-dependent renal failure became dialysis free after 15 weeks of ART. Repeat renal biopsy revealed significant histologic recovery from fibrosis with only infrequent glomeruli showing mild collapse and minimal fibrosis.(65) Since then, a growing number of studies has helped establish ART as a first-line treatment for HIVAN.

The effect of ART on kidney disease progression has been characterized primarily by observational studies. A cohort of 53 patients with biopsy-proven HIVAN from the Johns Hopkins renal clinic was found to have better renal survival when treated with ART compared with patients who did not receive ART (adjusted hazard ratio: 0.30; 95% CI: 0.09-0.98).(95) In a retrospective study of 19 patients with a clinical diagnosis of HIVAN, after median follow-up of 16.6 months, the use of protease inhibitors was significantly associated with a slowing of the decline in creatinine clearance.(96)

In the Strategies for Management of Antiretroviral Therapy (SMART) study, 5,472 HIV-infected patients who had a CD4 count of >350 cells/µL were randomly assigned to continuous or episodic use of ART and were followed for a mean period of 16 months. Investigators found that, compared with continuous ART, planned treatment interruptions guided by CD4 counts significantly increased the risk of fatal or nonfatal ESRD (hazard ratio: 4.5; 95% CI: 1.0-20.9) in the treatment interruption arm. Although this study was not statistically powered to detect a difference in renal outcomes, the high incidence of ESRD in the treatment interruption group suggests that continuous therapy with antiretroviral medications is a key factor in preventing and slowing progression of kidney disease.(97)

Angiotensin-Converting Enzyme Inhibitors

Both ACEIs and angiotensin II receptor blockade have inhibited the development and progression of HIVAN in animal models.(98-100) Two prospective studies support the use of ACEI for the treatment of HIVAN. In a case-control study of 18 patients with HIVAN prior to the advent of ART, 9 were treated with captopril, and matched with 9 controls.(101) The captopril-treated group had improved renal survival, defined as time to ESRD, compared with controls (mean renal survival: 156 ± 71 days vs 37 ± 5 days; p < .002). In a single-center, prospective cohort study of 44 patients with HIVAN, 28 patients received fosinopril 10 mg/day, and 16 patients who refused treatment were followed as controls over 5.1 years.(102) The median renal survival of treated patients was 16.0 months, with only 1 patient developing ESRD. All untreated patients rapidly progressed to ESRD over a median period of 4.9 months. Despite the limitations of these studies, they suggest that ACEIs may be beneficial in curbing progression of HIVAN, and this class of drugs is a reasonable first choice as an antihypertensive agent for patients with HIVAN.

Steroids

Evidence supporting the use of steroids for the treatment of HIVAN is also based on observational data.(95,103,104) In a single-center cohort study, 20 patients with HIVAN were prospectively enrolled to receive treatment with corticosteroids. Most patients (17 of 20) manifested improvements in kidney function and significant reductions in 24-hour urinary protein excretion. After steroid therapy, mean rates of protein loss declined from 9.1 ± 1.8 g per day to 3.2 ± 0.6 g per day (p < .005).(105) Another study of steroid therapy employed a control group and found similar results with no increased risk of infection in the steroid group.(104) Although these studies were generally limited by their nonrandomized designs, based on this evidence, steroids are considered second-line therapy for patients with HIVAN. The use of steroids should be considered for patients with a documented rapid deterioration in kidney function despite ART.