HIV disease and renal function

15 February 2010. Related: Side effects.

Simon Collins, HIV i-Base

Although earlier ARVs including AZT and indinavir were associated with renal toxicity, the focus on routine renal monitoring has increased significantly due to the widespread use of tenofovir.

While there is limited data on the impact of HIV and treatment on renal function, several recent studies contributed new information in this area.

PI-initiated HAART shows eGFR improvement over seven years

Catherine Leport and colleagues from the APROCO-COPILOTE cohort published long-term results of renal function in over 1100 patients who started protease inhibitor (PI) based combinations between 1997 and 1999 in 47 French HIV centres. [1]

Changes in eGFR in this cohort, estimated by MDRD ignoring adjustment for race, increased by +0.72 mL/min/1.73m2/month (95%CI 0.40–1.03) from treatment initiation to month 16 and then remained stable +0.01/month (95% CI, -0.08 to 0.10) for up to 7 years. The proportion of patients with a GFR of <60 or 60–90 were stable over time at approximately 5% and 39%.

This rate increase was lower among men and those with low BMI, AIDS, or who had used indinavir.

The cohort was 77% male; median age was 37 years (IQR 32–43), ethnicity was 10% African/90% Caucasian; 21% had a prior history of AIDS, and median baseline GFR was 93 mL/min/1.73m2 (IQR, 82–107). GFR was estimated using the abbreviated MDRD formula, ignoring adjustment for race.

After a median follow-up of 7.0 years (IQR 3.8–8.4), the median CD4 level increased from 273 cells/mm3 (IQR 126–421) to 524 (IQR 370–737).

The mortality rate was higher for patients with baseline eGFR <60: 4.1 per 100 vs 1.6% among those with baseline GFR of 60–90, and 1.8% among patients with GFR 90 (p=0.21, adjusted for baseline age, CD4 count, HIV RNA level, AIDS stage, and injection drug use). The study also analysed the impact of individual ARVs, although noting that this requires caution in interpreting results from a cohort study.

Indinavir and nelfinavir were the first PI for 40% and 29% patients, respectively. At 7 years, only 13% patients were still receiving their initial PI. Overall, 532 patients were started on indinavir and received it for a median duration of 21 months (IQR 9–42 months), whereas from 2001 onwards, 214 patients received tenofovir for a median duration of 20 months (IQR 8–38 months).

Changes in eGFR over time did not differ between patients who initiated tenofovir, regardless of GFR (<90 vs 90), and those who never used tenofovir, and it did not differ for patients who received indinavir prior to tenofovir, compared with those who never received tenofovir (data not shown). This is a different finding to that reported in the Swiss Cohort Study. [2]

In the multivariate analysis of GFR evolution over time, male sex, AIDS stage, lower baseline BMI, and receipt of indinavir were associated with a poorer evolution of GFR during the first 16 months of treatment. Beyond 16 months, a poorer evolution of GFR was associated with African origin and baseline CD4 cell count 200 cells/mm3 but not receipt of indinavir or tenofovir.

Loss of kidney function despite successful HAART

A paper from Andy Choi and colleagues in the 23 October issue of AIDS reported risk factors associated with reduced kidney function in an HIV-positive cohort of patients both on- and off-HAART, including 7% untreated viral controllers.

They followed 615 patients for a mean of 3.4 (+2.5) years. Mean age was 45 years and 13% were women. Half the group were white, 25% were black and 10% were Hispanic. 15% of the group has risk factors for kidney disease including HCV, hypertension, hyperlipideamia and smoking.

In this study, in contrast to Leport et al, the overall rate of kidney function calculated by changes in eGFR, declined by -2.6 mL/min/1.73m² [95%CI: -3.0 to -2.1] per year. In multivariable adjusted analyses, predictors of eGFR decline included female sex, diabetes, and hyperlipidemia, but not CD4 cell count or viral load.

The impact of HAART, was assessed in a sub group of 82 patients who started HAART during the study. GFR declined an average of -4.7 (95%CI -6.7 to -2.6) per year during the 1.2 years before HAART, and this improved to -1.9 (95% CI -3.7 to -0.1) during a mean 2.9 years of follow-up after starting treatment. In adjusted analysis, HIV treatment was  ssociated with a +2.8 (95% CI 0.8-4.7) per year improvement in eGFR slope. Although these patients benefited from HAART, they continued to lose kidney function at a rate of -1.9 (-3.7 to -0.1) per year.

When comparing 45 untreated to 173 treated viral controllers (defined as having a viral load <500 copies/mL), patients on HAART had greater eGFR declines (adjusted difference -4.4 (-6.7 to -2.1) per year in treated versus untreated controllers).

Intermittent viral blips in the treated group were also associated with more rapid rates of eGFR loss [-6.7 (-11.1 to -2.4) per year. Hypertension and diabetes were both strongly associated with renal decline in treated patients [-4.0 (-7.6 to -0.5) and -5.6 (-10.3 to -0.8) per year, respectively].

Unfortunately this study was underpowered to look at the impact of individual drugs, especially indinavir and tenofovir, and had limited data on other important markers of kidney health or treatment in individual patients.

The study concluded that although HIV treatment appears to help curb kidney function decline, patients who achieved durable viral suppression continue to experience substantial loss of eGFR and that loss of kidney function may be attributable to treatment-related factors, intermittent viremia, and traditional risk factors for kidney disease.

End Stage Renal Failure in HIV-positive patients in the UK

A review of the clinical epidemiology of end-stage renal failure (ESRF) in the UK (defined as starting permanent renal replacement therapy (pRRT), was undertaken by Loveleen Bansi and colleagues from the UK-CHIC study, and published in the 27 November issue of AIDS. [4]

Results were collected from almost 22,000 patients attending seven leading HIV centres between 1998-2007. ESRF occurred in 68 patients (0.31%), 44 (65%) of whom were black. The prevalence increased in black patients from 0.26% in 1998/99 to 0.92% in 2006/07 (p=0.001 for trend) and from 0,03% to 0.11% in non-black patients (p=0.07 for trend). Patients with ESRF were more likely to be female (29 vs. 21%), of black ethnicity (65 vs. 25%), and have lower nadir CD4 cell count (median: 72 vs. 179 cells/mm3).

In multivariable analysis, black ethnicity was associated with a higher risk of ESRF [HR 6.93, 95%CI: 3.56, 13.48], and higher current CD4 cell count with a reduced risk per 50 cells/mm3 higher (HR: 0.83, 95%CI: 0.76, 0.95).

The most common renal diagnosis was HIVAN, (in 53% of all patients and 82% of black patients). All cases of HIVAN were in black patients.

Response to pRRT was generally good with 70% overall 5-year survival. This was significantly better for black patients compared to those of other ethnicities (85% vs. 43%, p=0.001).

The group used data from the HPA and Renal Registry to estimate 231 cases of ESRF occurred in HIV-positive patients in the UK over this period and that this accounted for 0.5% of the 45,500 people who received pRRT.

In summary, this analysis highlighted a prevalence of ESRF of almost 1% in HIV-positive black patients in the UK. The favourable comparison to US incidence rates that are 5-6 times higher and better response to pRRT (98% vs 30-40% 2-year survival) was accounted for by lower rates of IV drug use and HCV coinfection.

The discussion noted that prevalence rates may have been slightly underestimated and treatment responses overestimated given that a minimum of 3 months follow-up was required for this analysis, but that given the strong association with nadir CD4 count, this is another reason to aim for earlier HIV diagnoses in black patients in the UK.

References

1. Leport C et al. Long-term evolution and determinants of renal function in HIV-infected patients who began receiving combination antiretroviral therapy in 1997–1999, ANRS CO8 APROCO-COPILOTE. Clin Infect Dis. 2009 Dec 15;49(12):1950-4. DOI: 10.1086/648445. http://www.ncbi.nlm.nih.gov/pubmed/19911986
2. Fux CA et al. Tenofovir use is associated with a reduction in calculated glomerular ?ltration rates in the Swiss HIV Cohort Study. Antivir Ther 2007; 12:1165–73.
3. Choi A et al. HIV-infected persons continue to lose kidney function despite successful antiretroviral therapy, AIDS. 23(16):2143-2149, October 23, 2009. DOI: 10.1097/QAD.0b013e3283313c91.
4. Bansi L et al on behalf of the UK CHIC/ESRF study group. Clinical epidemiology of HIV-associated end-stage renal failure in the UK AIDS. 23(18):2517-2521, 27 November 2009. doi: 10.1097/QAD.0b013e3283320e12.