HIV Therapies and Chronic Kidney Disease Risk

With the advent of highly active antiretroviral therapy (HAART), HIV-infected patients are more likely to die of causes other than AIDS. Currently, chronic liver, cardiovascular, and kidney diseases are the predominant causes of morbidity and mortality in these patients.

In particular, health care providers are increasingly recognizing the importance of chronic kidney disease in HIV-positive patients. A recent study found that HIV-positive patients experience 4 times more chronic kidney disease cases than HIV-negative patients do.

The INSIGHT START cohort identified a number of chronic kidney disease risk factors: overweight/obesity (45%), smoking (32%), hypertension (19%), diabetes (3.5%), and proteinuria (5.7%). Of note, nucleoside reverse transcriptase inhibitors, especially tenofovir disoproxil fumarate, and ritonavir-boosted protease inhibitors heighten chronic kidney disease risk.

Now, an article published ahead-of-print in Current HIV/AIDS Reports has analyzed the risk of chronic kidney disease with tenofovir disoproxil fumarate, ritonavir-boosted protease inhibitors, and tenofovir alafenamide therapy. The investigators reviewed prospective longitudinal studies published in the past 2 years that examined HAART (particularly tenofovir disoproxil fumarate and ritonavir-boosted protease inhibitors) to determine whether it induced nephrotoxicity.

Tenofovir disoproxil fumarate is the most commonly used antiretroviral in the United States. It is recommended by the World Health Organization, the European AIDS Clinical Society, and US Department of Health and Human Services guidelines. Tenofovir disoproxil fumarate is also an element of pre-exposure prophylaxis because of its convenient dosing and low adverse effect profile.

Early studies may have overlooked tenofovir disoproxil fumarate’s potential to cause nephrotoxicity because of their short-term follow-up. Two studies addressed tenofovir disoproxil fumarate’s effect on the kidneys, and a meta-analysis found a 4 mL/min excess worsening in glomerular filtration rate (GFR) over 48 weeks.

The Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study, a 7-year international prospective study, found a 14% excess risk accumulating annually. The D:A:D cohort’s risk of developing a GFR <60 mL/min doubled every 5 years, and the researchers probably underestimated this effect because they did not include patients who discontinued the drug.

Clinicians should bear in mind that the overall baseline risk for end-stage renal disease development over 5 years was low (0.3%). Tenofovir disoproxil fumarate-based pre-exposure prophylaxis is associated with clinically insignificant decreases in kidney function.

For comparison, clinicians should know that non-tenofovir disoproxil fumarate regimens containing ritonavir-boosted atazanavir and lopinavir were associated with 22% and 13% increased chronic kidney disease risk annually, respectively. Tenofovir alafenamide selectively concentrates in target immune cells at 10% of the plasma level, thereby reducing nephrotoxicity.

The relative benefit of tenofovir alafenamide over tenofovir disoproxil fumarate is maintained over at least 144 weeks of use. The low nephrotoxicity risk should not outweigh the clear benefits of HAART in the overwhelming majority of patients.

Future studies should incorporate D:A:D risk scoring, eGFR, and proteinuria to determine the relative risk of emerging therapies like tenofovir alafenamide.