Case presentation:

A 35-year old, HIV-positive, female patient was started on an antiretroviral regimen of tenofovir, lamivudine and efavirenz in 2011. The patient was also on concomitant isoniazid prophylaxis. In November 2013, her viral load was suppressed and CD4 count was 770. She presented to the clinic in November 2013 with a 3 month history of nausea, vomiting and weight loss. A serum lactate was taken and reported to be 5 mmol/l. The blood pH was normal and serum bicarbonate was 21 mmol/l. How should this patient be managed?

Anti-retroviral Therapy (ART) implicated in hyperlactataemia

All nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) may cause hyperlactataemia. This typically occurs within one to 20 months of starting ART. The highest risk for hyperlactataemia has been reported with stavudine (d4T) and didanosine (ddI), followed by zidovudine (AZT). Lamivudine, abacavir and tenofovir have the lowest risk for hyperlactataemia.

The incidence of tenofovir-induced hyperlactataemia is unknown, as most data is limited to case reports. It cannot be ruled out, though. Tenofovir-induced hyperlactataemia often occurs in the presence of other drugs that cause this side effect.

The risk factors associated with hyperlactataemia are female sex, pregnancy, use of NRTIs (ddI & d4T), high body mass index, liver disease, ART use > 6 months and good adherence to treatment.

Hyperlactataemia and Lactic Acidosis

The case definition of hyperlactataemia is a lactate level ≥ 2.5 mmol/l with normal blood pH (≥7.35) and normal standard bicarbonate (> 20mmol/l). Lactic acidosis is a more severe form of hyperlactataemia and is defined as a raised lactate (usually ≥5mmol/l) with pH<7.35 and/or standard bicarbonate < 20 mmol/l. Hyperlactataemia may be asymptomatic or present with symptoms and in both cases lactate levels typically lie in the range of 2.5- 5.0 mmol/l.

The symptoms of hyperlactataemia are usually non-specific and may have been present for weeks and occasionally months with worsening progression. The symptoms may include one or more of the following:  

• Unintentional weight loss (>5%)
• Gastrointestinal symptoms - nausea, vomiting, loss of appetite, abdominal pain, hepatomegaly
• Weakness and fatigue
• Dyspnoea, tachypnoea without respiratory cause
• Unexplained tachycardia
• Myalgia
• Peripheral oedema

Management of hyperlactataemia and lactic acidosis

This is dependent on the lactate level and should be managed as follows:

Mild hyperlactataemia with minimal symptoms (lactate 2.5-5 and standard bicarbonate > 20)

The NRTIs should be switched to agents less likely to cause lactic acidosis (e.g. abacavir, emtricitabine, lamivudine, tenofovir) and the lactate should be monitored closely. If the patient is already on NRTIs less likely to cause lactic acidosis e.g. tenofovir as in this case, an NRTI-sparing regimen consisting of efavirenz and lopinavir/ritonavir should be given.

Moderately severe hyperlactataemia (lactate 5-10 mmol/l and/or standard bicarbonate 15-20)

Stop all NRTIs. Start patient on an NRTI-sparing regimen: lopinavir/ritonavir and efavirenz and refer the patient to doctor. Concomitant drugs that cause hyperlactataemia such as isoniazid, metformin and salicylates should also be stopped. Other causes of hyperlactataemia should be explored e.g. hepatic failure and renal failure.

Severe hyperlacatataemia (lactate > 10 without metabolic acidosis) or significant lactic acidosis (raised lactate and standard bicarbonate <15)

Stop ART and refer to nearest hospital for immediate medical attention.

Our case patient had symptomatic hyperlactataemia (serum lactate 5 mmol/l). The tenofovir and lamivudine were stopped. The patient was kept on efavirenz and lopinavir/ritonavir (Aluvia®) was added. Isoniazid was also stopped. Her GIT symptoms resolved and she regained weight. Her lactate level normalised to 2 mmol/l.

---

 

In Summary

Symptomatic hyperlactataemia should be managed appropriately to prevent deterioration to lactic acidosis.

Hyperlactataemia with tenofovir is uncommon but should be suspected and investigated in patients presenting with a history of non-specific GIT problems and unexplained weight loss.

Patients who develop tenofovir-induced symptomatic hyperlactataemia should be changed to an NRTI sparing regimen: efavirenz and lopinavir/ritonavir. There is the possibility of a mild drug interaction between efavirenz and lopinavir/ritonavir, which is not usually clinically significant, except in pregnancy where dose adjustment of lopinavir/ritonavir may be required. Consult an expert if patient is pregnant or on other concomitant drugs.

---

 

 References

1. South African HIV Clinicians Society. Prevention , diagnosis and management of NRTI-associated symptomatic hyperlactataemia and lactic acidosis. [Online] 2006 [cited 2013, Nov 20]. Available from: http://local host:81/sahivsoc/
2. Wilson,IE, Soentjes,P, Zeier,M, Taljaard,J. Symptomatic hyperlactataemia and lactic acidosis in the era of highly active antiretroviral therapy. SAMJ. 2005; 95(12): 929-930.
3. Tenofovir package insert