CROI: ART: Helpful or harmful to kidney function?

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The ALLRT Study

In this study, 1,758 HIV-positive individuals beginning either their first or a new ART regimen through an AIDS Clinical Trials Group (ACTG) randomised clinical trial were co-enrolled in the ACTG Longitudinal Linked Randomized Study (ALLRT) - a large, multi-center, observational cohort study.

Glomerular filtration rate (GFR), the standard estimated measure of kidney function impairment, was calculated using the abbreviated MDRD equation (a GFR below 90 ml/minute indicates mild, below 60 indicates moderate, and below 30 severe, renal impairment. Below 15 indicates kidney failure).

The group, at baseline, had a median age of 38 years, CD4 cell count of 214 cells/mm3, and viral load of 4.8 log10 copies/ml; 1439 (82%) were male, 531 (30%) were black, 1,479 (84%) were treatment-naïve, and 529 (30%) had low baseline GFR (<90 ml/minute/1.73 m2). Antiretroviral treatment consisted of three or four antiretrovirals including at least one protease inhibitor or NNRTI.

In the adjusted model, those who began the study with impaired kidney function and low CD4 cell counts (< 200 cells/mm3) and achieved sustained viral load suppression had an average GFR increase of 4.2 ml/minute/1.73 m2 (p<.001).

Glossary

renal

Relating to the kidneys.

matched

In a case-control study, a process to make the cases and the controls comparable with respect to extraneous factors. For example, each case is matched individually with a control subject on variables such as age, sex and HIV status. 

hypertension

When blood pressure (the force of blood pushing against the arteries) is consistently too high. Raises the risk of heart disease, stroke, kidney failure, cognitive impairment, sight problems and erectile dysfunction.

traditional risk factors

Risk factors for a disease which are well established from studies in the general population. For example, traditional risk factors for heart disease include older age, smoking, high blood pressure, cholesterol and diabetes. ‘Traditional’ risk factors may be contrasted with novel or HIV-related risk factors.

clinical trial

A research study involving participants, usually to find out how well a new drug or treatment works in people and how safe it is.

Changes were not statistically significant for higher baseline CD4 cell counts or those with unimpaired baseline GFR. The likelihood of an increase of at least 25% in GFR was 1.74 times higher in those with viral suppression (p=.008), 5.11 times higher in those with baseline GFRs <60 ml/minute/1.73 m2 (p<.001), and 1.49 times higher if baseline CD4s were under 200 (p=.02). History of hypertension or previous antiretroviral treatment reduced the odds of improved GFR; the team did not find that race was a factor (but see the Johns Hopkins study discussed below).

The ALLRT team concluded that “sustained improvement in renal function was apparent with initiation or change in HAART [highly active antiretroviral therapy] among persons with mild to moderate renal impairment at the start of therapy. This improvement was associated with reductions of plasma viremia, supporting a direct relationship between HIV-1 replication and kidney function.”

Investigators from Europe and North America continue to describe a double-edged effect of antiretroviral therapy (ART) on kidney toxicity and kidney disease among people with HIV. While providing a positive effect on kidney function by suppressing the kidney-toxic effects of HIV infection itself, ART continues to exert its own kidney-toxic effects, according to a series of poster presentations at last month's Fourteenth Conference on Retroviruses and Opportunistic Infections in Los Angeles.

Washington cohort

Another US team conducted a cross-sectional study of kidney function among patients at the Washington University HIV Outpatient Clinic during 2005, compared with age-, race- and gender-matched controls from the National Health and Nutrition Examination Study III (NHANES). Data were available for 847 matched pairs: in the HIV-positive group, 63% were men, 34% Caucasian; the mean age was 39.6 years, viral load 3.04 log10 copies/mL and median CD4 cell count 397 cells/mm3. Compared to the controls, HIV-positive participants had lower mean GFR (by simplified MDRD; 95.5 vs. 103.6 mL/minute/1.73 m2, p <0.01) and higher prevalence of chronic kidney disease (defined as GFR <60 ml/minute/1.73 m2: 4% vs. 2%, p <0.01), and those on antiretroviral treatment (63% of the group) had, on average, lower GFR than those who were not (92.0 vs. 101.6, p <0.01).

After controlling for age, race, and gender, the following were found to predict GFR decline: hypertension, hyperlipidemia, proteinuria, use of tenofovir (ever), and lower viral load (all p <0.01). The researchers concluded that “the prevalence of chronic kidney disease is low [in this cohort], but remains higher than that of the general population. Nevertheless, early declines in GFR are prevalent and appear to be attributable not only to traditional risk factors but also to HAART.”

Kidney disease in African-Americans: the Johns Hopkins study

Race is generally known to be a factor in kidney disease. This analysis looked at the rates among African-Americans of “ESRD/RRT”: end-stage renal disease requiring renal replacement therapy (kidney transplant). Participants were taken from two Baltimore-based cohort studies - the (HIV-positive) Johns Hopkins HIV Cohort, and the ALIVE study, a community-based cohort of HIV-negative and HIV-positive injection drug users (IDUs) – and compared to age-matched African Americans in the general population. In the combined cohort of 6,225 individuals, the median age was 37, 32% were female, 70% were IDUs, and 4,509 (72%) were HIV-positive. The median CD4 cell count was 287 cells/mm3 and the median viral load was 4.4 log10 among the HIV-positive group.

Compared to African-Americans in the general population, ESRD/RRT rates were 6.9-fold higher in HIV-positive participants without an AIDS diagnosis, and 16.1-fold higher in those diagnosed with AIDS. Kidney transplants were performed in HIV-positive African Americans at rates of 5.8 per 1,000 person-years before the “HAART era”, and 9.7 per 1,000 p-y since the introduction of highly active antiretroviral therapy in 1996. Researchers concluded that the rate of ESRD/RRT is high in HIV-positive African-Americans, “and has not decreased appreciably in this cohort with the widespread use of HAART. While [chronic kidney disease (CKD)] incidence has declined significantly in the HAART era, CKD prevalence has increased as patients live longer.”

References

Kalayjian R et al. The association between suppression of HIV-1 replication and glomerular filtration rates among subjects on ACTG A5001 (the ALLRT study). Fourteenth Conference on Retroviruses and Opportunistic Infections, Los Angeles, abstract 827, 2007.

Overton E et al. Factors associated with renal dysfunction within an urban cohort in the era of HAART. Fourteenth Conference on Retroviruses and Opportunistic Infections, Los Angeles, abstract 826, 2007.

Lucas G et al. End stage renal disease risk in HIV-infected African-Americans: 12-fold higher than age- and race-adjusted national rate and increasing in the HAART era. Fourteenth Conference on Retroviruses and Opportunistic Infections, Los Angeles, abstract 829, 2007.