666 www.japi.org © JAPI • VOL. 52 • AUGUST 2004
Case Report
Lactic Acidosis in HIV-1 Infected  Patients Receiving
Antiretroviral Therapy
AK Patel*, K Patel**, J Patel+
Abstract
Highly active antiretroviral therapy (HAART) has resulted in dramatic declines in morbidity and mortality
in HIV-1 infected patients in the developed world. However, with the availability of generic antiretroviral
treatments (ART) in India, a large number of patients now receive ART. Increase in experience with
ART has led to the detection of drug-related toxicities. We report herein potentially fatal side effects
associated with the use of nucleoside analogues in HIV treatment - hyperlactatemia and lactic acidosis/
hepatic steatosis. ©
lactic acidosis, Falcó and coworkers12 found that among the
30 patients receiving dual therapy, 15 were using d4T plus
3TC and 11 were using d4T plus ddI.
In the management of hyperlactatemia, the lactate level
should be monitored closely, interruption of NRTI therapy is
mandatory if the lactate level increases.12 Pancreatitis,
lipodystrophy/lipoatrophy, and neuropathy can occur in
association with lactic acidosis or separately, requiring careful
clinical evaluation.
CASE 1
A 54 years postmenopausal female patient, weight 72 kg,
presented at the clinic on June 27, 2001 with Pneumocystis
carinii pneumonia (PCP). She had past history of
gynecological surgery and history of two episodes of herpes
zoster eruptions. She was on antihypertensive medications
(Zestril 2.5mg once a day) for the past four years. PCP
responded to treatment with TMP-SMX. She was the started
with HAART consisting of d4T, 3TC, and nevirapine (NVP),
and PCP prophylaxis with TMP-SMX. She developed
maculopapular rash and fever within one week of starting
HAART. NVP was discontinued and substituted with
indinavir. Indinavir was discontinued after two months due
to financial constraints and was replaced by efavirenz. She
tolerated the therapy well without any side effects. She had a
good immunological recovery after starting ART. Her serial
CD4 T cell counts three months apart were 147 (baselines),
232 cells/cmm and 313 cells/cmm.
She presented on March 25, 2002 with complaints of 2-3
loose stools per day, weight loss, weakness, dyspnea on
exertion, nausea and epigastric discomfort. Physical
examination was pertinent for epigastric tenderness and mild
hepatomegaly. Her arterial lactate was 6.5 mmol/L. Serum uric
acid was 6.15 mg%, pH = 7.24, pO2 88 , pCO2: 14, HCO3: 10, Na:
*Chief, **Associate Consultant, Department of Infectious Diseases,
Sterling Hospital, Ahmedabad; +Chief Pathologist, Adit Diagnostic,
Ahmedabad.
Received : 26.8.2003; Accepted : 17.6.2004
INTRODUCTION
Long-term complications with ART like lactic acidosis,
lipoatrophy, neuropathy, lipid abnormalities and hematological
toxicities are serious enough to warrant discontinuation of
treatment and/or changes in ART regimens. Majority of the
long-term toxicities are related to mitochondrial damage
associated with NRTIs by inhibiting mitochondrial DNA
(mtDNA) enzyme polymerase. NRTIs can precipitate the
reduction or mutation of mtDNA and its enzymes leading to
mitochondrial dysfunction.1,2 The relative toxicities of the
NRTIs can be rated: zalcitabine (ddC) >/= didanosine (ddI) >/
= stavudine (d4T) >/= lamivudine (3TC) >/= zidovudine (ZDV)
>/= abacavir (ABC). Combinations of NRTIs have been shown
to have a synergistic or additive effect on mitochondrial
toxicity in vitro.3
The NRTI-associated lactic acidosis is almost always
associated with hepatic steatosis. It is now recognized that
by interfering with lactate production or its clearance in an
organ or tissues, NRTIs can produce a spectrum of
hyperlactatemia syndromes,4 including asymptomatic
hyperlactatemia and symptomatic hyperlactatemia which may
or may not be associated with hepatic steatosis.
Various case reports and cohort studies conclude that
symptomatic hyperlactatemia5,6 and lactic acidosis6-12 is
greater with d4T than with other NRTIs. For example, in the
Swiss HIV cohort study, the risk of hyperlactatemia was
greater with d4T, with or without ddI, than with ZDV (odds
ratio, 2.7).13  In a recent review of 60 cases of NRTI-associated
© JAPI • VOL. 52 • AUGUST 2004 www.japi.org 667
136, K: 4.1, Cl: 97. Ultrasound examination showed
hepatomegaly with Grade II fatty changes. Her renal and liver
functions were normal. Lipid profile was not done. HAART
was withdrawn. Supportive care in the form of niacinamide,
thiamine, carnitine, and Co Q10 supplementation was started.
She was continued with supportive care and her lactate level
came to a baseline after three months. She was started with
indinavir and efavirenz combination without NRTIs. She had
a good immunological recovery with further rise in CD4 T
cells, 147, 232, 313, 273, 492, and 1127 cells/cmm.
CASE 2
A 43 years male, weight 88 kg, known hypertensive, non-
alcoholic, and non-diabetic patient with HIV infection
diagnosed in 1994 was treated for tuberculous meningitis in
1998-99. He was lost to follow up and later presented with
recurrent oral ulcers and odynophagia in September 2000.
His CD4 count was 73 cells/cmm but refused ART and was
lost to follow up again for a period of one year. During this
period he was having recurrent oral and esophageal ulcers,
and recurrent respiratory tract infections. His CD4 count was
27cells/cmm in July 2001. He agreed to start ART. He was
started with d4T, 3TC and NVP. He improved after starting
ART with serial CD4 counts three months apart showing a
steady increase- 27, 174, 164, 132, and 221cells/cmm. He
remained asymptomatic while on ART. In February 2003, he
developed distal sensory neuropathy involving both lower
limbs. As a result, d4T dose was reduced to 30mg bid with
other supportive treatment. He also had facial lipoatrophy.
After one month, he presented with swelling of both lower
limbs and face, weakness, dyspnea on exertion, epigastric
fullness, nausea and vomiting since three days. On
examination he was tachypneic, tachycardia, edema of feet
and anterior abdominal wall, epigastric tenderness, and
massive hepatomegaly. Investigations revealed
hyperlactatemia (arterial lactate level = 9.0mmol/L), serum uric
acid  10mg%, and hypoproteinemia (serum albumin-2.5gm%).
ABG showed pH 7.28, PaO2 80, PCO2 20, HCO3 : 12. His serum
cholesterol and triglyceride levels and RFT and liver function
tests were normal. Ultrasonography of abdomen showed
hepatomegaly with Grade II  fatty infiltration.
He was hospitalized with diagnosis of ART induced lactic
acidosis with hepatic steatosis. He was treated with
withdrawal of ART, IV bicarbonate, niacinamide, carnitine,
co-enzyme Q10, IV albumin and other supportive treatment.
He showed symptomatic improvement and was discharged
from hospital after seven days. He was again hospitalized for
complaint of generalized edema, epigastric discomfort,
anorexia, dry mouth, breathing difficulty, severe pain and
numbness in feet and abdominal distension. He was treated
with IV albumin and other supportive treatment. During
hospitalization, he developed tricyclic antidepressant-
induced hyperthermia, which was treated with oral dantrolene.
After one week of therapy, he showed symptomatic
improvement and reduced arterial lactate level. The patient
was discharged on supportive therapy. On follow up, he was
feeling well, with only the complaint being mild dyspnea and
epigastric discomfort. The arterial lactate level was further
reduced to 4 mmol/L. In follow-up, his edema disappears with
reduction in hepatomegaly with normalization of serum
albumin. He was started with Fortovase + Norvir + Efavirenz.
CASE 3
A 50 years female patient, HBsAg positive, weight 85kg,
was started with ART on in August 2002. She was
asymptomatic with baseline CD4 T cells count of 218/cmm.
Her husband died of advanced HIV with disseminated TB
and pulmonary aspergillosis. She was also hypertensive and
hypothyroid and receiving treatment with an ACE inhibitor
and eltroxin. She remained asymptomatic and did not have
any ADI during the course of illness. She had a good
immunological response- her CD4 T cells count increased
from 218 to 405 cells/cmm within six months.
She was brought to the emergency room in May 2003 with
the chief complaint of sudden onset of severe breathlessness
and epigastric discomfort. On physical examination, other
than tachypnea, there was no abnormality. The abdomen was
soft without hepatomegaly. The laboratory investigations
showed: ABG pH: 7.04, PO2 165   PCO2 18, HCO3: 5.0 BE -26
arterial lactate: 21 mmol/lit, S.creatinine: 1.81mg%, K 5.17meq/
L, Na 135.3meq/L, Cl : 99.4 meq/L. Anion gap was 36.07. Hb
11.2gm%, TC 20,280/cmm, DC: P 78, L20, M 1,E1, S.uric acid
11.7mg%, SGPT 33u/L, SGOT 40u/L, S.Proteins: total:
6.09gm%; Albumin 2.39gm%; Globulin: 3.7gm%. Urine
examination showed 130 - 140 pus cells, protein ++. The
abdomen ultrasound showed a normal liver and right upper
ureter dilatation with mild hydronephrosis. Echocardiography
and chest X-rays were normal. Serum triglyceride: 103.9mg%
HDL: 10.3 mg%, cholesterol: 111mg%. She did not evidence
of lipoatrophy/lipodystrophy.
She was treated with bicarbonate replacement, hydration,
and antibiotics. ART was discontinued. Riboflavin 50mg/day,
thiamin and Co Q10 were supplemented. After 18 hours, her
respiratory rate became normal. Her lactate level dropped to
10mmol/L, while the ABG parameters also became normal.
She was discharged from the hospital but was readmitted 11
days later with leg swelling decrease urine output and
breathlessness. Her lactate remained elevated to 11.4 mmol/l,
uric acid was 10.8mg%, serum creatinine was 4.3mg%, Serum
albumin 1.8gm%. Liver enzymes were normal. Urine
examination showed numerous pus cells and grew
enterococci. She was treated with IV antibiotics and
hemodialyzed thrice during hospitalization. She was
discharged home with lactate 5.4 mmol/l, S. creatinine : 1.8mg%
and S uric acid 4.7mg%. She was not restarted on ART.
CASE 4
A 52 years female, weight 93kg, was diagnosed HIV in
1999 with extensive oropharyngeal candidiasis, itchy pruritic
dermatosis, hypertension and coronary artery disease. She
was treated with various combinations ART. Her baseline
CD4 T cell count was 92/cmm. Initially she was started with
AZT and 3TC. She had a good immunological recovery for
668 www.japi.org © JAPI • VOL. 52 • AUGUST 2004
one year her ART was changed to d4T, DDI, and indinavir.
She responded well with CD4 count rise to 480/cmm.
Thereafter, she discontinued ART for 15 months and returned
to the clinic with severe itchy dermatosis. Her CD4 T cell
count had dropped to 46/cmm. She was started with PCP
prophylaxis and d4T, 3TC, and NVP. She again showed
immunological response with clinical recovery. After 6
months, she returned with complaints of weakness, nausea,
vomiting, epigastric discomfort and dyspnea. Laboratory
investigations showed arterial lactate 13.5 mmol/L, serum uric
acid level: 11.8mg%, serum creatinine: 7.4 mg%, SGPT: 104 u/
l, serum bilirubin: 1.12 mg%, ABG showed pH: 7.21, HCO3 7,
PO2 88, PCO2 16. She was started with peritoneal dialysis for
severe acidosis and she died during treatment.
Other clinical cases: Three other cases, two males and one
female, presented with hyperlactatemia without acidosis. All
three were having fatigue, nausea, epigastric discomfort and
leg cramps while receiving d4T, 3TC and NVP. They recovered
with supportive care and subsequently tolerated AZT, 3TC
and NVP without rise in arterial lactate levels.
DISCUSSION
Long-term metabolic complication related to ART is
increasingly recognized with increasing use in HIV infected
patient. Cheaper generic ARTs are available in India. Fix dose
d4T+3TC + nevirapine cost around 30 US$ per month. Many
patients can afford Nevirapine based ART. Patients do adhere
to prescribe ART and have completed two years of follow-up
on ART. We are describing important and fatal if not
recognized early, metabolic side effects due to ART. Six
patients out of seven were receiving fixed dose combination
of d4T+3TC+nevirapine. One patient was receiving
d4T+3TC+Efavirenz. Except one (48kg) all patients were
weighing > 70kg with highest of 93kg. Four patients with
acidosis were hyperurecemic. One patient had facial and limb
lipoatrophy, rest of the patients were free from other long-
term metabolic side effects. Moderate to massive
Hepatomegaly with steatosis was seen in six patients. Only
one patient was hepatitis B co-infected
Small studies show that patients with higher body weight
on d4T and 3TC-based regimen are more susceptible to lactic
acidosis. There is no gender difference, hypertension was
found in four out of seven patients. The median time to the
development of lactic acidosis after ART exposure was 16
months. Hyperurecemia was found in five patients and
impaired renal function test was seen in two patients. Long-
term metabolic side effects were seen in only one patient.
Hyperlactatemia may be an independent of other long-term
side effects. All of our patients were treated with supportive
care, and all except one improved. Intensive care is required
to treat acidosis as patients may have serious acid base and
fluid and electrolyte imbalance.
Lactic acidosis rather than infectious causes should be
considered for patients receiving d4T-based ART and whose
CD4 T cell counts are above 350/cmm who present with
weakness, breathlessness and epigastric discomfort. Routine
screening for lactate in a patients receiving NRTI based
therapy is not recommended, as mild hyperlactatemia does
not predict development of lactic acidosis and as the onset
of lactic acidosis can be abrupt, without preceding elevation
of lactate levels.8  Case reports have suggested that vitamins
and cofactors required for oxidative phosphorylation may
help induce recovery from lactic acidosis. These include
riboflavin, thiamine, a vitamin B complex, carnitine, and
coenzyme Q. There is no standardized treatment of NRTI-
induced mitochondrial toxicity, but several authors have
recommended a combination of vitamins with CoQ. Hepatic
steatosis is usually associated with lactic acidosis,
responsible for delayed clearance of lactate from the
circulation.
Spectrum of hyperlactatemia: Symptoms
  Symptoms of lactic acidosis are nonspecific like nausea
and vomiting, abdominal pain, weight loss, malaise,
dyspnea/tachypnea
  Laboratory findings are increased anion gap, increased
lactic acid levels, increased  lactate/pyruvate, metabolic
acidosis (pH < 7.25)
  Lactate level > 9 mmol/L-
  Widespread energy deficits contribute to organ
failure
  Mortality exceeds 75%
Table 1 : Demographic Information
Patients 1 2 3 4 5 6 7
Age/Sex 54/F 43/M 50/F 52/F 32/M 35/M 32/F
Weight (kg) 72 88 85 93 72 68 48
Diagnosis PCP AEU Asymptomatic OPC Genital herpes PCP PUO
Medical dx HBP HBP/CAD HBP/Hypothyroid HBP/CAD — — —
Baseline CD4/cmm 147 27 218 92 479 78 118
ART date July 2001 July 2001 Aug 2002 Oct.1999 Jan.  2001 June 2002 Nov. 2001
Regime D4T+3TC+EFV Triomune Triomune Triomune Triomune Triomune Triomune
Dx of LA March 02 March 03 May  2003 March 02 May 2002 April 03 Feb 02
Metabolic side effect Nil Facial lipoatrophy Nil Nil Nil Nil Nil
Azotemia No No Yes Yes No No No
Uric acid arrowup Yes Yes Yes Yes No No No
Outcome Recovered Recovered Recovered Died Recovered Recovered Recovered
* Triomune = d4T+3TC+Nevirapine, EFV= Efavirenz; Dx = diagnosis, LA = Lactic acidosis
© JAPI • VOL. 52 • AUGUST 2004 www.japi.org 669
Features of hepatic dysfunctions are common which
includes tender hepatomegaly, peripheral edema, ascites, and
encephalopathy. Mild elevation of liver enzymes is common
but jaundice is rare. Hepatic steatosis is frequently observed
on imaging and on biopsy. Lactic acidemia with no or mild
symptoms has been detected in 8% to 21% of patients
receiving at least one NRTI as compared to 0% to 1% of
patients receiving no ART. Hyperuricemia has been found in
up to 60% of patients with lactic acidosis.
In conclusion, increase in experience with HAART in
Indian patients has led to the identification of potentially
fatal lactic acidosis. High index of suspicion is required to
diagnose lactic acidosis, as initial symptoms are nonspecific.
We found lactic acidosis in obese patients who were receiving
d4T-based ART. Hyperuricemia, hypertension and renal
failure were also detected in these patients. Further studies
are required to identify any association between obesity,
hypertension and use of ACE inhibitors with the development
of lactic acidosis.
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