Viral suppression improves kidney function in patients with poor baseline kidney function and low CD4 counts

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Suppressing HIV viral load improved kidney function in a large US observational cohort study, but only in those patients who had more advanced stages of chronic kidney disease (stage 2 or greater) and CD4 cell counts below 200 cells/mm3 to begin with. People in this group saw an average GFR increase of 9.2 ml/min/1.73 m3 over a median follow-up of 160 weeks when viral load was suppressed by more than 1 log, regardless of race or sex. The results, which were drawn from 1776 patients, were reported in the journal AIDS.

HIV is widely associated with kidney disease and dysfunction including, but not limited to, HIVAN (HIV-associated nephropathy). Although some antiretrovirals have, themselves, been associated with kidney toxicity, an increasing number of studies have shown improvements in kidney function in HIV-positive people on antiretroviral therapy (ART).

In this study, a group of US researchers analysed retrospective data from 1776 ambulatory patients in the AIDS Clinical Trials Group (ACTG) Longitudinal Linked Randomized Trials (ALLRT) study, a large, multicentre, observational cohort study of patients enrolled in prospective clinical trials. Baseline data was taken from the time of enrollment in ALLRT (between May 1997 and June 2004); follow-up data was collected between October 2002 and November 2004. (Preliminary results were presented at the Fourteenth Conference on Retroviruses and Opportunistic Infections in 2007.)

Glossary

renal

Relating to the kidneys.

replication

The process of viral multiplication or reproduction. Viruses cannot replicate without the machinery and metabolism of cells (human cells, in the case of HIV), which is why viruses infect cells.

observational study

A study design in which patients receive routine clinical care and researchers record the outcome. Observational studies can provide useful information but are considered less reliable than experimental studies such as randomised controlled trials. Some examples of observational studies are cohort studies and case-control studies.

naïve

In HIV, an individual who is ‘treatment naïve’ has never taken anti-HIV treatment before.

exclusion criteria

Defines who cannot take part in a research study. Eligibility criteria may include disease type and stage, other medical conditions, previous treatment history, age, and gender. For example, many trials exclude women who are pregnant, to avoid any possible danger to a baby, or people who are taking a drug that might interact with the treatment being studied.

Overall baseline patient characteristics were as follows: median age 38 years, 82% male, 30% black, 77% ART-naive, 14% hypertensive, 4% diabetic, 9.5% with hepatitis C, and 3.5% with hepatitis B. The median baseline CD4 cell count was 214 cells/mm3, and median HIV viral load 4.8 log10 copies/ml.

For the primary study analyses, glomerular filtration rate (GFR) was calculated by the abbreviated Modification of Diet in Renal Disease (MDRD) equation; values above 200 ml/min per 1.73 m3 were truncated to 200 ml/min per 1.73 m3. Patients were classified according to chronic kidney disease (CKD) guidelines: "normal" was defined as GFR ≥ 60 ml/min per 1.73 m3 without proteinuria (urine protein-to-creatinine ratio > 200 mg/g); stage 1, GFR ≥ 90 ml/min per 1.73 m3 with proteinuria; stage 2, GFR 60-89 ml/min per 1.73 m3 with proteinuria; and stage 3, GFR 3. At baseline, the median GFR was 101 ml/min per 1.73 m3; 11.5% of the participants were at CKD stage 1, and 6.6% were at CKD stage ≥ 2.

Although GFR declined slightly for the cohort as a whole over time (annual decline, 0.3 ml/min per 1.73 m3, p=.04 for nonzero change), changes in GFR differed widely among participant subgroups. Analysis showed an association between viral suppression and GFR improvement, but the association was also linked with baseline kidney function and CD4 cell count.

The most significant change was seen in those who had CKD stage ≥ 2 and CD4 counts 3 at baseline, and whose viral load was suppressed to less than 400 copies/ml or by more than 1 log10. In these patients (n=59), GFR increased by an average of 9.2 ml/min per 1.73 m3 (95% confidence interval [CI], 1.6 – 16.8, p=.02) over the course of the study. Within this group, the most dramatic improvements (32 ml/min per 1.73 m3 (95% CI, 15.6 – 48.3, p<.001 baseline="" ckd="" in="" most="" occurred="" severe="" the="" those="" with="">

These results are consistent with the observations of previous studies including DART and SMART, which also found greater improvements in kidney function in patients who began ART with CD4 cell counts below 200 cells/mm3. In the current study, these improvements were seen regardless of race, sex, previous ART (vs. treatment-naive), or the equation used to determine GFR (MDRD or Cockcroft-Gault). However, in the overall analysis, greater GFR improvements were seen in those with lower baseline GFR (p<.001 art="" c="" co-infection="" hepatitis="" naive="" or="" to="" with="">

GFR improvements that were not associated with viral load suppression were also seen in those who began with higher CD4 counts (≥ 200 cells/mm3), particularly in people with worse baseline kidney function. GFR increases of 9.5 and 1.7 ml/min per 1.73 m3 occurred in those with stage 2 or greater CKD (p<.001 a="" activation="" and="" as="" benefit="" but="" conclusively="" could="" explain="" explanation.="" function="" immune="" in="" kidney="" normal="" not="" or="" possible="" reductions="" researchers="" respectively.="" stage="" suggest="" the="" this="">

The researchers also note that this study cohort likely excluded many individuals with more advanced CKD due to inclusion criteria for the participating clinical trials; and that the abbreviated MDRD equation used tends to underestimate GFR in adults without kidney disease, which may have skewed the results for healthier participants. Nor did the study distinguish between individual ART regimens used.

However, the overall findings demonstrate "a significant association between suppression of plasma HIV-1 viremia and renal function improvement among subjects with both low CD4 cell counts and renal function impairment at the start of therapy, supporting a direct role of … viral replication in the renal dysfunction of advanced HIV infection… independent of race." The improvements seen in those with higher CD4 counts "[suggest] that mechanisms other than … viral replication also may contribute to renal dysfunction in HIV disease."

Reference:

Kalayjian RC et al. Suppression of HIV-1 replication by antiretroviral therapy improves renal function in persons with low CD4 cell counts and chronic kidney disease. AIDS 2008;22:481-487.