Contributed by guest blogger: Michael McManus ‘12
People undergoing anti-retroviral therapies, which target and interrupt the replicative processes of HIV, are living longer due to the relative success of treatments. Those with HIV are using these drug cocktails for longer periods of time, an important characteristic with results that could not be observed in short-term clinical studies.
Mortality for patients with HIV who are able to undergo highly active antiretroviral therapy (HAART) has shifted from higher rates, during the initial HIV scare, to relatively lower rates. HAART has been incredibly successful, increasing the quality of life for those who have access to it. For some, however, the effects of an HAART regimen, which combines up to four medications, can lead to renal failure within two weeks of regimen administration due to the toxic nature of some of the medications.
Renal failure, or loss of kidney function, can lead to organ failure and eventually death. The kidneys are normally responsible for filtering the blood. They maintain homeostasis by regulating electrolytes, regulating blood pressure, maintaining pH balances, and by removing and diverting waste from the blood into the urinary bladder, producing urine. The kidneys filter many things from the blood in order to retain them in the body, ranging from proteins to glucose. When the kidneys fail, proteins, glucose, and even blood become detectable in the urine. Glycosuria, proteinuria, and hematuria are all biological indicators of a lack of reabsorption and therefore renal failure.
In a recently published paper, Juliette Pavie et al. describe a case of renal failure in an HIV-positive patient after only two weeks of tenofovir therapy. Tenofovir is a nucleotide reverse transcriptase inhibitor associated with low risk of severe renal adverse events in clinical trials. However, tenofovir is in the same class of drugs such as adefovir and cidofovir, which have well-documented nephrotoxicity1,2.
The patient followed was a 46-year-old homosexual male of Scottish descent. His weight, CD4 cell count, plasma HIV RNA level, serum creatine, and urea levels were all taken before HAART regimen, which consisted of tenofovir, emtricitabine, atazanavir, and ritonavir, was started. During treatment, the patient did not take any nonsteroidal anti-inflammatory drugs (NSAIDs), which are known to lead to kidney dysfunction.
Fifteen days after treatment began levels were tested again: serum creatine and urea had increased 3-fold and 2.5-fold respectively. Five days later, the patient became unable to pass urine and levels were immediately measured again: serum creatine showed a 15-fold increase from the original amount, and urea a 12-fold increase. Urinalysis showed glycosuria and proteinuria, indicating loss of kidney function. Renal biopsy indicated necrosis of the kidneys and other abnormalities. After these observations, HAART was halted and hemodialysis was started to rescue lost kidney function. After three months of hemodialysis, HAART was resumed, but tenofovir was excluded from the treatment.
After one year of treatment, the patient showed signs of recovery. CD4 cell count increased to relatively normal levels, and serum creatine and plasma HIV RNA levels dropped. To this day, the patient is still undergoing the same HAART, with serum creatine and plasma HIV RNA levels remaining stable. However, the patient still suffers from moderate glycosuria and proteinuria, indicating that kidney function has not fully recovered.
Although this case only followed one individual undergoing a HAART regimen containing tenofovir, the observations and results are still crucial to studying renal failure resulting from HAART. The novel form of nephrotoxicity observed may serve as a model for other forms of nephrotoxicity caused by reverse transcriptase inhibitors. Although the nephrotoxicity studies1,2 only reported findings in one individual each, their findings should not be discredited, as this is the nature HIV symptom studies. For example, the emergence of Kaposi’s sarcoma as a symptom of HIV began with isolated incidents. The nature of HIV and its rapid mutation also obfuscates the relationship between HAART effectiveness and strain type. From this observation, one question out of many must be addressed: Did the combination of drugs used in the patient’s HAART regimen have an effect on nephrotoxicity?
Despite the emergence of renal failure as a threat, great strides have been made in the fight against HIV. The quality of life for those who are suffering from HIV and who have access to HAART is drastically improved compared to those who are unable to undergo HAART. However, now that HIV patients are living longer, research must switch from just targeting HIV to focusing on HIV and the complications created by decreased mortality. Nephropathy, or disease of the kidney, and subsequent nephrectomy, removal of a kidney, now contribute to the decrease in quality of life associated with the aging HIV population. When developing future treatments, scientists and doctors must analyze the nephrotoxicity of the products they are synthesizing, as renal failure is a clear and present danger for those undergoing HAART.
Article Links:
http://online.liebertpub.com/doi/abs/10.1089/apc.2011.0056
Michael McManus is a senior at Vassar College, majoring in Biochemistry
“Say, you got a nice blog article. Much obliged.”
HBV and HIV both use reverse transcriptase, but their replication cycles are quite different. Im not sure how similar the RT from the two viruses are (obviously different enough that a drug that works on one doesnt work on the other). When HBV replicates, it packages an RNA genome and during maturation and final assembly of the virus, the RT converts it to a partially double stranded DNA while inside the capsid. So the virus that is released from the cell actually has a DNA genome. HIV on the other hand, has an RNA genome in the capsid, which is converted to DNA when it enters the cell.
Im always very cautious with case studies. Being a single case, it is extremely important not to over-interpret the findings. But case studies play an important part in the scientific process. Eventually, enough cases might crop up suggesting that there might be something worth studying. It is a good way to develop a testable hypothesis. A well controlled clinical or epidemiological study would have to be undertaken, to test if the incidence of nephrotoxicity is higher than would be expected. Either way, since the incidence of nephrotoxicity is obviously low if anything, the benefits of the drug strongly outweigh the risks.
I have been trying to read up on how some HAART components lead to renal failure. From what I’ve read it seems that certain drugs are associated with nephrotoxicity. For example, tenofovir is associated with proximal tubular dysfunction and damage within the kidney. This tubular damage leads to swelling and eventually rupture, which allows relatively large compounds, such as proteins, to enter the urine. This is why proteinuria is indicative of renal failure. Unfortunately I have not found the exact mechanism outlining how this damage is caused or how it can be prevented.
Although, the article presented interesting and relevant information it is extremely important, just as Michael mentioned, that the audience recognizes that the article is reporting the results of one single study and thus cannot be taken as a confirmation of a hypothesis. A relevant piece of information to take into consideration because it helps us better understand the scientific method, seeing as to how the results of this study have potentially set the foundations for further research that will investigate the true value (do the pros out weight the cons) of tenofovir as a treatment for patients with HIV. Based on the clinical trial carried out by these researchers other scientist can follow similar procedures on various subjects with different backgrounds to test the nephrotoxicity of tenofovir. Again though it is important that the researchers gather subjects that are truly different from one another, due to the fact that HIV proliferates differently in every individual and the scientist want to be sure that it is truly the drug that is causing the onset of renal failure and not some other underlying cause. These replication studies are essential because they will provide the evidence needed to remove tenofovir as a treatment for HIV if it is causing extremely aversive side effects. A factor that is extremely important not only in the science field but on an ethical one as wel because it might save the lives of individual who are taking the drug as part of their treatment regimen.
While reading this article it was very interesting to see that Adefovir, which treats hepatitis B is unable to combat HIV. This was a very interesting piece of information because both Hepatitis B and HIV use reverse transcriptase to infiltrate their host with their genome, which would mean that they have very similar modes of infection as well as biological mechanism and therefore should respond to antiviral drugs in a similar manner, however it had extremely bad side effects for individuals with HIV, which shows that viruses evolved in a very distinct and complex manner. On a similar note a question that I found myself asking throughout the article was how exactly these drugs impacted the nephron that caused them to stop functioning. All in all, this article I think brings to attention just how well adapted and evolved viruses are, especially HIV because their destruction or dimunition will always in one way or another impact the host somehow