Differences in Rates of Diarrhea in Patients With Human Immunodeficiency Virus Receiving Lopinavir-Ritonavir or Nelfinavir

Jodie L. Guest, Ph.D. M.P.H.; Charnelda Ruffin, Pharm.D.; Jean M. Tschampa, Pharm.D.; Kathryn E. DeSilva, Pharm.D.; David Rimland, M.D.


Pharmacotherapy. 2004;24(6) 

In This Article

Abstract and Introduction

Study Objective: To determine and compare rates of diarrhea in patients receiving an antiretroviral regimen containing lopinavir-ritonavir versus nelfinavir and in patients who received these drugs sequentially.
Design: Retrospective cohort analysis.
Setting: Hospital-based human immunodeficiency virus (HIV) clinic.
Patients: Four hundred one participants in the HIV Atlanta VA Cohort Study who were prescribed lopinavir-ritonavir or nelfinavir from 1996-2002.
Measurements and Main Results: Chart review identified episodes of diarrhea that potentially were associated with an antiretroviral agent. Data collected included antidiarrheal agents dispensed, baseline viral load and CD4+ cell counts, demographic variables, and previous therapy. Diarrhea associated with an antiretroviral regimen occurred in 175 (49%) of 354 patients receiving nelfinavir and 17 (17%) of 99 patients receiving lopinavir-ritonavir (p<0.001). Treatment for the diarrhea occurred in 118 (33%) of 354 patients receiving nelfinavir and 9 (9%) of 99 receiving lopinavir-ritonavir (p<0.001). Patients in the lopinavir-ritonavir group were more likely to have received highly active antiretroviral therapy and azithromycin than patients receiving nelfinavir, and they had lower baseline CD4+ cell counts (p≤0.01 for each comparison). The average number of months/person-year of diarrhea treatment was 2.0 for the nelfinavir group and 0.13 for the lopinavir-ritonavir group. Of the 10 antiretroviral-naïve patients who received lopinavir-ritonavir, none needed treatment for diarrhea, whereas 78 (36%) of 217 antiretroviral-naïve patients who received nelfinavir required treatment for diarrhea. Of the 52 patients who had been taking nelfinavir and were switched to lopinavir-ritonavir, they were more likely to start antidiarrheal treatment while taking nelfinavir (14 [27%]) than while receiving lopinavir-ritonavir (3 [6%]) (p=0.004).
Conclusions: Patients receiving lopinavir-ritonavir were significantly less likely to have diarrhea or to require treatment for diarrhea than patients receiving nelfinavir. The same results occurred when the drugs were given to the same patients sequentially (nelfinavir followed by lopinavir-ritonavir). The diarrhea associated with lopinavir-ritonavir was less frequent, less severe, and shorter in duration than diarrhea associated with nelfinavir.

Protease inhibitor-based combination antiretroviral therapy has reduced morbidity and mortality dramatically among persons infected with human immunodeficiency virus (HIV).[1] Many patients receiving highly active anti-retroviral therapy (HAART) experience an increase in CD4+ cell counts or stabilization of declining CD4+ cell counts. Before the use of HAART and specifically, protease inhibitors, diarrhea was a significant complication in patients with HIV; it was estimated to affect up to 60% of patients with acquired immunodeficiency syndrome (AIDS).[2,3,4] Studies conducted before the use of HAART found diarrhea to be independently associated with lower CD4+ cell counts.[2,5] With antiretroviral regimens containing protease inhibitors, the frequency of diarrhea due to infectious agents has decreased, likely due to CD4+ cell count improvements.[6] However, non-infectious diarrhea is one of the most common adverse effects of protease inhibitors.[2,5,7,8] Thus, with HAART and the associated improvement in CD4+ cell counts, the frequency of enteric pathogens has decreased while the frequency of diarrhea as a side effect of therapy has increased.

Regardless of the cause of diarrhea, this common symptom affects quality of life, drug adherence, and survival. A study evaluating self-reporting of diarrhea in patients infected with HIV demonstrated an indirect correlation between severity of diarrhea and quality-of-life scores.[9] In this study, diarrhea was an independent predictor of diminished quality of life. Several studies have found an association between drug side effects and adherence.[10,11] Suboptimal adherence to HAART is a significant cause of virologic failure and may lead to development of drug-resistant HIV strains.[12] The Swiss Cohort Study found diarrhea to be an independent predictor of poor survival, with a 47-48% increased risk of death during follow-up for patients with diarrhea.[2] These findings suggest that adverse responses to drugs are important and clinicians should take steps to aggressively manage or prevent them. However, management of symptomatic diarrhea is problematic. The addition of antidiarrheal agents hampers efforts at minimizing regimen complexity while increasing pill burden and cost of care.[4,13]

Nelfinavir (Viracept; Agouron Pharmaceuticals, La Jolla, CA) and lopinavir-ritonavir (Kaletra; Abbott Laboratories, Abbott Park, IL) are protease inhibitors commonly part of HAART regimens. Diarrhea is the most common adverse event associated with either drug.[7,8,14,15] A report published in 2002 compared regimens containing lopinavir-ritonavir with those containing nelfinavir.[8] Though not the focus of this large comparative study, data were collected on adverse events associated with these two protease inhibitors. The study found no significant difference in rates of diarrhea with the two drug regimens. However, that trial did not collect data on treatment of diarrhea.

The objective of our study was to determine and compare reported rates of pathogen-negative diarrhea and corresponding rates of treatment with antidiarrheal agents in patients receiving an antiretroviral regimen containing either lopinavir-ritonavir or nelfinavir. Unique to this study was the ability to capture the use of over-the-counter (OTC) and prescription antidiarrheal agents through the Veterans Affairs (VA) pharmacy database. All patients included in this study were treated in a VA system and were eligible to receive free OTC or prescription products at the time of the analysis.


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