Safe Use of NRTIs After Symptomatic Hyperlactatemia
Safe Use of NRTIs After Symptomatic Hyperlactatemia
Of 12 patients who experienced NRTI-associated symptomatic hyperlactatemia, only 1 had recurrence of hyperlactatemia after rechallenge with less mitochondrially toxic nucleosides.
NRTIs are the backbone of potent antiretroviral regimens, and patients who have complications of NRTI therapy are left with few well-studied treatment options. NRTIs, by virtue of their activity against human DNA-polymerase (gamma), a uniquely mitochondrial enzyme, all have the potential to be mitochondrial poisons. NRTIs often cause benign and asymptomatic elevations in serum lactate. Less frequently, patients develop symptomatic hyperlactatemia or even frank lactic acidosis, which is associated with substantial morbidity and mortality in this population. Few reports exist regarding the introduction of less mitochondrially toxic NRTIs in the wake of symptomatic hyperlactatemia and discontinuation of the offending agents.
Researchers reviewed charts of patients seen from July 1998 to September 2002 at a university clinic to retrospectively identify patients on NRTI-based regimens with at least 2 elevated serum lactate levels (more than twice the upper normal limit) accompanied by symptoms of nausea/vomiting, abdominal pain, anorexia/weight loss, or fatigue. Lactic acidosis was defined as serum venous lactate >5mmol/L with serum bicarbonate <20 mmol/L. Twelve patients with hyperlactatemia were identified, 2 of whom had lactic acidosis. All patients had been receiving a dual-NRTI regimen that included d4T, and all stopped antiretroviral therapy until symptoms resolved. One patient was coinfected with hepatitis B, and another with hepatitis C; 10 patients were receiving their first antiretroviral regimens. Median time on therapy before discontinuation was approximately 9.5 months.
After a median of 4 months off therapy and resolution of both symptoms and laboratory abnormalities, patients restarted therapy with less mitochondrially toxic NRTIs. Rechallenge nucleoside backbones included at least 2 of the following: AZT, 3TC, and abacavir. Patients were monitored every 4 weeks initially and then every 12 weeks, and recurrent hyperlactatemia was defined more stringently as any serum lactate above the upper limit of normal. With 22 person-years of rechallenge follow-up, 8 patients had normal lactate levels, 3 had mild asymptomatic hyperlactatemia, and 1 had mild symptomatic hyperlactatemia (lactate level, 3.3 mmol/L). Interestingly, this symptomatic patient had been rechallenged with a triple-NRTI regimen; she was subsequently rechallenged with a dual-NRTI triple-drug regimen containing abacavir + 3TC and had not experienced a second recurrence of hyperlactatemia after 9 months of follow-up. No cases of lactic acidosis occurred. The estimated rate of recurrence for symptomatic hyperlactatemia was 45.5 cases per 1000 patient-years of NRTI re-exposure. Reassuringly, each patient's virologic control on the rechallenge regimen was as good as or better than it had been on their previous regimen.
Symptomatic hyperlactatemia and lactic acidosis have become treatment-limiting and highly morbid complications of the mitochondrial DNA-polymerase (gamma)-inhibiting properties of NRTIs. This drawback has prompted interest in nucleoside-sparing regimens such as efavirenz + lopinavir/ritonavir, a combination currently being studied in ACTG 5142. This case series adds to a scant body of literature demonstrating safe rechallenge of patients with mild-to-moderate hyperlactatemia. It is worth noting that only one patient in this series had a lactate level >10 mmol/L: mortality in patients with lactate levels in this range has been estimated at 80%, and the experience with rechallenge of such patients is even more limited. However, given the fact that mitochondrial dysfunction seems to have a cumulative effect, it is somewhat comforting that the successfully rechallenged patients in this study were followed for more than 1 year.
Studies have demonstrated that triple-NRTI regimens are more likely than AZT + 3TC-based regimens to cause hyperlactatemia, making triple-NRTI regimens less attractive for patients who have already experienced symptomatic hyperlactatemia. The authors note that tenofovir, which appears comparable to 3TC and abacavir in the modesty of its mitochondrial offensiveness, is another potentially attractive agent for use in rechallenge of such patients. The role of vitamin supplementation (riboflavin, coenzyme Q, L-carnitine, and other free-radical scavengers) also remains to be defined, both in the therapy of symptomatic hyperlactatemia and in its prevention.
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Of 12 patients who experienced NRTI-associated symptomatic hyperlactatemia, only 1 had recurrence of hyperlactatemia after rechallenge with less mitochondrially toxic nucleosides.
NRTIs are the backbone of potent antiretroviral regimens, and patients who have complications of NRTI therapy are left with few well-studied treatment options. NRTIs, by virtue of their activity against human DNA-polymerase (gamma), a uniquely mitochondrial enzyme, all have the potential to be mitochondrial poisons. NRTIs often cause benign and asymptomatic elevations in serum lactate. Less frequently, patients develop symptomatic hyperlactatemia or even frank lactic acidosis, which is associated with substantial morbidity and mortality in this population. Few reports exist regarding the introduction of less mitochondrially toxic NRTIs in the wake of symptomatic hyperlactatemia and discontinuation of the offending agents.
Researchers reviewed charts of patients seen from July 1998 to September 2002 at a university clinic to retrospectively identify patients on NRTI-based regimens with at least 2 elevated serum lactate levels (more than twice the upper normal limit) accompanied by symptoms of nausea/vomiting, abdominal pain, anorexia/weight loss, or fatigue. Lactic acidosis was defined as serum venous lactate >5mmol/L with serum bicarbonate <20 mmol/L. Twelve patients with hyperlactatemia were identified, 2 of whom had lactic acidosis. All patients had been receiving a dual-NRTI regimen that included d4T, and all stopped antiretroviral therapy until symptoms resolved. One patient was coinfected with hepatitis B, and another with hepatitis C; 10 patients were receiving their first antiretroviral regimens. Median time on therapy before discontinuation was approximately 9.5 months.
After a median of 4 months off therapy and resolution of both symptoms and laboratory abnormalities, patients restarted therapy with less mitochondrially toxic NRTIs. Rechallenge nucleoside backbones included at least 2 of the following: AZT, 3TC, and abacavir. Patients were monitored every 4 weeks initially and then every 12 weeks, and recurrent hyperlactatemia was defined more stringently as any serum lactate above the upper limit of normal. With 22 person-years of rechallenge follow-up, 8 patients had normal lactate levels, 3 had mild asymptomatic hyperlactatemia, and 1 had mild symptomatic hyperlactatemia (lactate level, 3.3 mmol/L). Interestingly, this symptomatic patient had been rechallenged with a triple-NRTI regimen; she was subsequently rechallenged with a dual-NRTI triple-drug regimen containing abacavir + 3TC and had not experienced a second recurrence of hyperlactatemia after 9 months of follow-up. No cases of lactic acidosis occurred. The estimated rate of recurrence for symptomatic hyperlactatemia was 45.5 cases per 1000 patient-years of NRTI re-exposure. Reassuringly, each patient's virologic control on the rechallenge regimen was as good as or better than it had been on their previous regimen.
Symptomatic hyperlactatemia and lactic acidosis have become treatment-limiting and highly morbid complications of the mitochondrial DNA-polymerase (gamma)-inhibiting properties of NRTIs. This drawback has prompted interest in nucleoside-sparing regimens such as efavirenz + lopinavir/ritonavir, a combination currently being studied in ACTG 5142. This case series adds to a scant body of literature demonstrating safe rechallenge of patients with mild-to-moderate hyperlactatemia. It is worth noting that only one patient in this series had a lactate level >10 mmol/L: mortality in patients with lactate levels in this range has been estimated at 80%, and the experience with rechallenge of such patients is even more limited. However, given the fact that mitochondrial dysfunction seems to have a cumulative effect, it is somewhat comforting that the successfully rechallenged patients in this study were followed for more than 1 year.
Studies have demonstrated that triple-NRTI regimens are more likely than AZT + 3TC-based regimens to cause hyperlactatemia, making triple-NRTI regimens less attractive for patients who have already experienced symptomatic hyperlactatemia. The authors note that tenofovir, which appears comparable to 3TC and abacavir in the modesty of its mitochondrial offensiveness, is another potentially attractive agent for use in rechallenge of such patients. The role of vitamin supplementation (riboflavin, coenzyme Q, L-carnitine, and other free-radical scavengers) also remains to be defined, both in the therapy of symptomatic hyperlactatemia and in its prevention.
Click here for AIDS Clinical Care subscription information.
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