Background: Symptomatic hyperlactatemia (SH) is associated with NRTI therapy and is characterized by abdominal complaints, liver abnormalities, and elevated lactate levels.  The purpose of this study was to investigate whether the incidence rate (IR) of this complication varies with the number of NRTIs or with NRTI combinations used in antiretroviral therapy.

Methods: Data were obtained from patients followed longitudinally in the UCSD Owen Clinic Cohort from July 1998 through September 2001.  Cases were adults receiving NRTI(s) with ³1 of the following clinical manifestations: nausea, abdominal pain, abdominal bloating, anorexia, fatigue, or elevated alanine aminotransaminase (ALT), associated with confirmed hyperlactatemia. The IR of SH was estimated for number of NRTIs and different combinations of NRTIs in a regimen.  Poisson regression was used to estimate the incidence rate ratio (IRR) of SH for different number of NRTIs and specific dual and triple NRTI combinations.

Results:  Among the 2144 patients receiving NRTI therapy, 498 had at least 1 symptom of hyperlactatemia and were evaluated with a serum lactate level.  81 met the case definition.  There were 4 patients on 1 NRTI, 65 on 2 NRTIs, and 12 on 3 NRTIs.  The IR was 7.4 cases/1000 person-years for 1 NRTI, 16.8/1000 person-years for 2 NRTIs and 33.9/1000 person-years for 3 NRTIs (p trend = 0.003).  Compared to therapy with 1 NRTI, the IRR of SH increased by 2.1 (95% CI: 1.3, 3.4) for each additional NRTI used in a regimen.  Within the dual NRTI category, the IR of SH was 16.9/1000 person-years for d4T/3TC, 40.0/1000 person-years for d4T/ABC, 59.4/1000 person-years for d4T/ddI, and 3.0/1000 person-years for ZDV/3TC.  Compared to d4T/3TC, the IRR for SH was 2.4 (95% CI: 1.1, 4.9) for d4T/ABC, 3.5 (95% CI: 2.0, 6.2) for d4T/ddI and 0.18 (95% CI: 0.06, 0.51) for ZDV/3TC. Within the triple NRTI category, the IR of SH was 103.4/1000 person-years for d4T/ABC/3TC, 119.0/1000 person-years for d4T/ddI/3TC and 12.7/1000 PY for ZDV/ABC/3TC.  Compared to ZDV/ABC/3TC, the IRR of SH was 8.1 (95% CI: 1.4, 48.6) for d4T/ABC/3TC and 9.3 (95% CI: 1.8, 48.2) for d4T/ddI/3TC. 

Conclusions: In general the risk for SH increases more than 2-fold for each additional NRTI used in a regimen.  Among NRTI pairs, the ascending order of risk for SH is ZDV/3TC, d4T/3TC, followed by d4T/ABC and d4T/ddI, which confer similar risks.  Among triple NRTI combinations, the ascending order of risk for SH is ZDV/ABC/3TC followed by d4T/ABC/3TC and d4T/ddI/3TC, which confer similar risks.