Treatment Interruption Uncovers HIV's Attack on the Kidneys

At the turn of the 21st century, several clinical trials were held to try to assess the impact of treatment interruption in people with HIV/AIDS. The largest and best-designed of these studies was called SMART. Many analyses of SMART appear in TreatmentUpdate 170. In SMART, the risks of specific events among people who interrupted therapy compared to people who remained on HAART were as follows:

• death -- twice as high
• life-threatening infections -- seven times as high
• cancer -- six times as high
• major cardiovascular (heart attack or stroke), kidney or liver damage -- two times as high
• life-threatening reaction(s) as a result of medication-related side effects -- 20% higher

Some of these problems were linked to excessive inflammation. The SMART data set is still being analysed. But what has become clear is that HIV infection transforms the immune system, causing prolonged and high levels of inflammation deep within the body. This inflammation not only affects the immune system but also degrades the heart and circulatory system, the liver and kidneys. This last organ is particularly vulnerable to HIV-related damage because parts of the kidney can be infected by HIV. Because of the relatively high rate of kidney damage seen during SMART, researchers were interested in finding out more about this outcome.

Study Details

Researchers who study the kidneys sometimes use assessments of a protein called cystatin C. This protein is made by most cells and is filtered by the kidneys. Measuring levels of cystatin C in the blood can provide doctors with a fairly accurate picture of kidney health, particularly before serious damage has developed.

An international team of researchers associated with SMART decided to check cystatin C levels in stored blood samples from participants in SMART. The entire SMART study enrolled more than 5,000 HIV positive volunteers between 2002 and 2006. The kidney sub-study used data collected from 249 people who did not interrupt their use of HAART and 250 people who did interrupt therapy.

People who interrupted HAART did so whenever their CD4+ count rose above the 350-cell mark and resumed therapy whenever it fell below 250 cells. This practice continued throughout the study.

The average profile of participants in the kidney sub-study at the time they entered SMART was as follows:

• 30% female, 70% male
• age -- 44 years
• CD4+ count -- 540 cells
• lowest-ever CD4+ count -- 250 cells
• cystatin C levels -- 0.99 mg/dl

SMART participants were randomly assigned to one of the following two groups:

• viral suppression group (continued HAART)
• drug conservation group (treatment interruption according to CD4+ count levels)

Blood samples were regularly collected for analysis. None of the participants in the kidney sub-study had a history of cardiovascular disease (which could affect the kidneys).

The reference range of cystatin C in young, healthy people is between 0.52 and 0.92 mg/dl.

Results

After the first month of SMART, cystatin C levels rose slightly in the drug conservation group and fell slightly in the viral suppression group. Still, the difference between the two groups became statistically significant; that is, not likely due to chance alone. Moreover, in the people interrupting HAART, cystatin C levels remained higher for the rest of the study. And if large increases of cystatin C occurred during the study, they tended to occur in people who had interrupted HAART.

Medicines to lower blood pressure tend to affect the kidneys. In SMART, participants in both groups who used these medications had, on average, a 91% increase in cystatin C levels.

Other factors, such as race/ethnicity or the use of nukes (nucleoside analogues), did not affect cystatin C levels.

Regular Tests

Routine assessments of kidney health to estimate GFR (glomerular filtration rate) using formulae such as the MDRD (modification of diet in renal disease) and Cockcroft-Gault were done. But these tests did not detect kidney damage. Perhaps this is because cystatin C can sometimes detect subtle kidney damage.

The increase in cystatin C levels was also linked to increased levels of D-dimer, suggesting an increased risk for blood clots. And, as cystatin C levels rose, levels of "good" cholesterol (HDL) fell. These changes in cystatin C and D-dimer levels suggest that uncontrolled HIV infection increases inflammation, which leads to kidney damage and an increased risk of serious cardiovascular disease.

The kidney sub-study of SMART suggests the following:

• HIV infection affects the functioning of the kidneys.
• In particular, uncontrolled HIV infection weakens the kidneys and increases the risk for cardiovascular disease.
• Regular assessment of cystatin C levels is an emerging method of determining kidney health.
• Cystatin C levels offer an advantage over other assessments of kidney health because they may be able to detect subtle kidney damage.
• Large clinical trials with HIV positive people are now needed to find out just how useful cystatin C is in this population.

References

1. Mocroft A, Wyatt C, Szczech L, Neuhaus J, El-Sadr W, Tracy R, Kuller L, Shlipak M, Angus B, Klinker H, Ross M; INSIGHT SMART Study Group. Interruption of antiretroviral therapy is associated with increased plasma cystatin C. AIDS. 2009 Jan 2;23(1):71-82.
2. Odden MC, Scherzer R, Bacchetti P, et al. Cystatin C level as a marker of kidney function in human immunodeficiency virus infection: the FRAM study. Archives of Internal Medicine. 2007 Nov 12;167(20):2213-9.

Want to read more articles in the February 2009 issue of Treatment Update? Click here.