Dr David Itua Uhuebor

Lecture to the emergency department medical staff at a secondary level

provincial hospital in The northern Free State concerning specific, life
threatening, HIV ARV related medical emergencies that present to the
ED, with reference to presentation, diagnosis and resuscitation.

Introduction

Human Immunodeficiency Virus (HIV) positive patients are initiated on highly

active antiretroviral treatment (HAART) usually based on CD4 count, clinical
features that are AIDS-defining or medical conditions that may be worsened
by not commencing antiretrovirals1.
Currently three classes of drugs are available for use in the public sector in South Africa.
HIV positive patients when initiated on highly active antiretroviral, are commenced on either
a protease inhibitor or non-nucleoside reverse transcriptase inhibitor and two nucleoside
reverse transcriptase inhibitors2.
The commonly available drugs in Public hospitals in South Africa that fit into each of the
mentioned groups are; protease inhibitors which include lopinavir, ritonavir, atazanavir and
saquinavir. Non-nucleoside reverse transcriptase are, Nevirapine and Efavirenz. The
nucleoside reverse transcriptase include abacavir, stavudine,didanosine,

zidovudine,

tenofovir, lamivudine, and emtricitabine2.

There is an increased potential for hepatotoxicity with all antiretroviral whatever the class 1.

Lactic Acidosis

Thymidine analogue nucleoside reverse transcriptase inhibitors (NRTIs) like stavudine and
zidovudine cause mitochondrial toxicity which is a serious side effect of these medications 3.
Mitochondrial

toxicity

can

lead

to

potentially

life

threatening

symptomatic

hyperlactataemia and lactic acidosis 4. The nucleoside reverse transcriptase inhibitor

stavudine and didanosine are the biggest implicator 5. The incidence of hyperlactataemia,
2.5-5mmol, in patients on antiretroviral is about 5-25% in laboratory findings in treated
patients6.
Patients with lactic acidosis may present with feeling of fatigue and malaise, nausea and
vomiting, diarrhoea, abdominal pain, fever and weight loss 7, 8.

Laboratory investigations to diagnose this condition include venous serum lactate levels,
liver function tests and arterial blood gas. Serum lactate level over 5mmol is considered
serious and levels greater than 10mmol could be life threatening. The liver enzymes are
usually elevated to variable degree and the blood gas may show acidosis. That is blood PH
is less than 7.357,8.
Management of lactic acidosis include in addition to stopping antiretroviral drugs, hydration
with intravenous fluid, ventilation, and correction of acidosis with bicarbonates 7, 8. Very
severe cases may require dialysis1.

Immune Reconstitution Inflammatory Syndrome

This clinical condition uniquely results from initiating highly active antiretroviral treatment 9.
There is aggravation of clinically apparent opportunistic infection or activation of dormant
opportunistic pathogens alternatively referred to as paradoxical and unmasking
respectively, usually in HIV nave patients 1, 9. It has an incidence of 10 32% in patients
that started highly active antiretrviral10.
Patients may present with fever, pathologies affecting a range of organ systems. These
include symptoms and signs of meningitis, pneumonitis, lymphadenitis and uveitis 1, 9. The
frequently implicated organisms include Mycobacterium (Avium complex or tuberculosis),
Cryptococcus and cytomegalovirus1, 9.
Immune reconstitution inflammatory syndrome manifest usually within 8 weeks following
commencement of highly active antiretroviral drugs 1. The risk factors are low CD4 T- cell
count (CD4 count less than 200) before initiating highly active antiretroviral, very good
virological response (greater than 2 log drop), high antigen burden from an opportunistic
infection and early initiation after an opportunistic infection 10.
Treatment in patients with severe life threatening symptoms may require temporary
discontinuation of antiretroviral drugs. The treatment of specific pathogen causing illness:
The use of

anti-fungal medication and therapeutic lumber puncture in patients that

developed meningitis from cryptococcal activation, pyrimethamine and sulfonamide for

encephalopathy from toxoplasmosis, needle aspiration for cold abscess, anti-tuberculous

drugs and antibiotics for tuberculosis and bacterial pneumonia respectively. Non- steroidal
anti-inflammatory drugs may be used in mild to moderate situations and steroids in patients
with respiratory distress and severe conditions11.
Abacavir-related hypersensitivity reaction
The use of the non-nucleoside reverse transcriptase inhibitor abacavir can result in a
serious hypersensitivity reaction in about five percent of HIV positive patients on the drug 12.
The risk of developing hypersensitivity reaction to abacavir is increased in some subclass of
patients12. They include patients who are naive to antiretroviral drugs, patients who are in
acute HIV infection, and patients who are allergic to nevirapine 12.
Patients develop symptoms usually in the first 6 weeks of commencing abacavir 12. The
patients may present with fever, rash, fatigue, malaise, nausea, vomiting, diarrhoea and
abdominal pain. Patient may in addition have respiratory symptoms, including pharyngitis,
cough and tachypnea12.
Diagnosing abacavir hypersensitivity reaction may be dependent on doctors in the
emergency department having a high clinical suspicion 13. Abacavir patch testing can be
used in the process of making specific diagnosis of abacavir related cutaneous
hypersensitivity reaction14.
The treatment of abacavir related hypersensitivity reaction is usually supportive:
Withdrawal of abacavir and other antiretrovirals in use by the patient, rehydration of
patients, the use of antiemetics and analgesia are aimed at symptomatic release 13.
Whether the diagnosis of abacavir related hypersensitivity reaction was confirmed or made
on clinical suspicion, reintroduction of abacavir should never be attempted as it can result
in severe hypersensitivity reaction with hypotension, tachycardia and is potentially fatal 8.

Nevirapine-related adverse drug reaction

Nevirapine can lead to skin rash and liver toxicity. This rash can be seen in 37% of patients
treated with nevirapine. The rash can affect the face, trunk, arms and legs. The risk of
nevirapine related skin rash is increased in patients with higher CD4 cell count 15. The skin

rash ranges from maculopapular erythematous lesions to erythema multiforme. Lifethreatening skin reaction including Steven Johnsons syndrome and toxic epidermal
necrolysis can be seen in HIV patients on nevirapine, occurring within the first fourth to sixth
week of commencing medication8.
Clinical presentations are diffuse rash peeling of large area of the skin 8. There may be
extensive epidermal detachment up to the entire skin surface with involvement of the
mucous membrane: eye (redness of the eyes and conjunctivitis), oropharynx (mouth
blisters), anus, genitalia, gastrointestinal and tracheobronchial epithelium can be affected 8.
Fluid loss is massive with electrolyte imbalance similar to burns. Systemic complications
include impairment of thermo-regulation, excessive energy expenditure, haematological
and immunological derangement16.
Early recognition and prompt intervention is essential to a favourable outcome. The
nevirapine containing antiretroviral drug combination is stopped. Intravenous fluid
resuscitation is initiated. Control of enviromental temperature and

aseptic

handling.

Anticoagulation, prevention of stress ulcer, pain and anxiety control. Tracheobronchial

involvement results in endotracheal intubation and mechanical ventilation. Nasogastric tube
insertion for the initiation of oral feeding. The patient is transferred to burns unit for intensive
care16. Ocular care is necessary to prevent sequelae. Daily examination, eye drops,
physiologic saline or antibiotics. The mouth is sprayed with antiseptic several times a day 16.
Elevation of liver enzymes, aspartate transaminase and alanine transaminase more than
five times the upper limit of normal can be seen in patients on nevirapine based regimen 17.
Early hepatotoxicity can be seen in up to 17% of patients started on nevirapine containing
antiretroviral combination18. Clinical hepatic events in some cases fatal hepatotoxicity,
including hepatic necrosis, fulminant and cholestasis hepatitis, and fulminant hepatic failure
occur in four to five weeks after commencing nevirapine 17.
Increasing risk factors associated with developing nevirapine toxicity include, a higher CD4
count at initiation of treatment (CD4 count greater than 250 for women and greater than 400
for men), baseline liver enzymes elevation, existing hepatitis B and C virus co-infection,
history of drugs and alcohol abuse17.

Patients may present to the emergency department with abdominal pain associated with
nausea and vomiting. Jaundice, fever, malaise and skin rash are clinical signs and
symptoms that may precede the onset of hepatotoxicity 18.
Clinical and biochemical monitoring is essential to early diagnosis of hepatotoxicity. A
greater than three- fold increase which is greater than baseline in aspartate and alanine
transaminase with or without the presence of clinical jaundice is a pointer to
hepatotoxicity17, 18.
There is no optimal treatment for nevirapine related hepatotoxicity. Treatment is essentially
symptomatic management and empiric. A five fold increase in aspartate or transaminase
level will necessitate the withholding of antiretroviral treatment 17, 18.

Pancreatitis

Antiretroviral treatment can be acutely complicated by pancreatitis. A number of

antiretroviral drugs are predominantly implicated. These include; didanosine and stavudine.
It has an incidence of about 7% in patients on stavudine. The incidence is higher in patients
with advanced HIV disease or on higher doses of the drugs. The risk is further enhanced in
concomitant alcohol abuse in HIV infected patients. Patients usually present pancreatitis 35 months after initiation of antiretroviral treatment. A particularly high risk is seen in
combination medication containing didanosine and stavudine or didanosine and tenofovir
19

8,

The spectrum of severity ranges from mild to severe and life threatening. They present to
the emergency department with symptoms of abdominal pain, fever, nausea and vomiting ,
abdominal distention and respiratory distress. Abdominal pain is usually epigastric or
paraumbilical. Pain may radiate to the chest, flank or back. In an effort to relieve the pain
patients bend forward assuming a knee-chest position 8, 19.
In diagnosing acute pancreatitis, biochemical evaluation of amylase and lipase level should
be done20. They are usually elevated in acute pancreatitis. Sonography and computed
tomography of the abdomen may show inflammation in and around the pancrease 19, 20.

Treatment involves immediate suspension of antiretroviral, eliminate oral intake, pain

control, adequate fluid hydration and nutritional support should be considered preferably
parenteral. Severe cases of pancreatitis may require intensive care unit management. It
should be noted that pancreatitis may develop or worsen even after the withdrawal of
antiretroviral treatment, It is thus essential for patients to be continuously monitored even
after antiretroviral drugs have been suspended 19, 20.

Efavirenz Related Neurological Complication

Adverse central nervous system (CNS) symptom is seen with efavirenz. These CNS side
effects are seen within the first few days to weeks. These adverse effects can be seen in
40% of patients on efavirenz. The use of efavirenz containing antiretroviral drugs can result
in a patient developing CNS symptoms such as nightmares and paranoid delusions. Other
CNS related symptoms include: Insomnia, depression, depersonalization, confusion,
suicidal ideation, paranoid delusion and mood flunctuations. The CNS side effects can be
treated with the tranquilliser lorazepam and antipsychotic, haloperidol 8.

Polyneuropathy

Distal sensory polyneuropathy is seen in 34% of patients on stavudine, and didanosine .

The symptoms occur in the first six weeks following the initiation of treatment. The risk
factors includes, a nadir CD4 cell count less than 200, older patients age greater than 50
years and with stavudine, taller patients at the time of

commencing

treatment 21,22.

Nutritional deficiencies including low levels of serum cyanocobalamine and heavy alcohol
consumption can be additional risk factors23.
Patients present at the emergency department with numbness in the feet burning or tingling
sensation, paraesthesia and painful dysesthesia that may affect daily activities 21.

The diagnosis of distal sensory polyneuropathy requires diminished deep ankle reflexes
compared to the knee, in addition to reduction in sensation in the lower extremities
bilaterally21.
Treatment of this condition requires prompt withdrawal of the causative medication and
analgesia usually opiods based. Severe polyneuropathy in addition to stopping the
causative drug, tricyclic antidepressant like amitriptyline or an anticonvulsant agent such as
carbamazepine may be added23.

Lipodystrophy Syndrome

This is one of the disconcerting toxicity associated with long time HIV infection with
antiretroviral use. It results from a disturbance in the way the body produces uses and
distributes fat24. The changes noted in fat distribution results in a psychologically disabling
change in body morphology. The risk of a HIV positive patient developing results from
cumulative toxicity from the use of protease inhibitors and nucleoside reverse transcriptase
inhibitor, particularly stavudine25. Identifiable risk factors includes, age of infection more
than 40 years, low nadir of CD4 count, female sex, advanced stage of HIV infection and
elevated levels of triglycerides24.
Lipdystrophy is most visible on the face. It however is also apparent in the trunk, arms,
buttocks and legs. Lipoaccumulation is associated with an increase in visceral adipose
tissue that enlarges abdominal girth. There is also gynaecomastia which may be unilateral
or bilateral, increased accumulation of dorsocervical fat tissue (buffalo hump) 24.
The type of antiretroviral and the duration of treatment may determine the development of
lipodystrophy syndrome. The use of nucleoside reverse transcriptase inhibitors is
associated with lipodystrophy while lipoaccumulation is seen with protease inhibitors.
Body mass index, size and weight are useful parameters when assessing for lipodystrophy
in HIV infected patients. Waist hip ratio greater than 0.95 in men and 0.85 may be used as
indicators for lipodystrophy26.
lipodystrophy27.

An increase in triglyceride levels is associated with

There is no specific curative treatment for the morphological changes resulting from
lipodystrophy 24.
Treatments switch by substituting a thymidine nucleoside reverse transcriptase analogue
like stavudine for a guanosine analogue abacavir and a non-nucleoside reverse
transcriptase inhibitor to substitute for protease inhibitors. Other measures include ingestion
of high fibre diet and regular exercise in particular, cardiovascular training and
strengthening. In addition liposuction can be used in the treatment of dorsocervical
lipoaccumulation (buffalo hump)24.
Bone Marrow Suppression
The use of the nucleoside reverse transcriptase inhibitor zidovudine by HIV positive
patients can result in marrow suppression after its use for some period, usually two to four
months. It tends to exert this effect after patients must have been on this treatment for
some weeks to month and It is common in patients with advanced disease 29. They present
with anaemia or neutropenia, or a combination of both. Haematologic complication is seen
in two to fourteen percent of patients while one to thirty one percent will present with
anaemia or neutropenia

28,29

. Risk is increased with advanced stage of the HIV disease 28. It

classically causes macrocytic anaemia. Treatment commonly involves blood transfusion,

erythropoietin to stimulate red blood cell production and granulocyte stimulating factor to
stimulate white cell production28.
Renal adverse effect of HAART
The use of highly active antiretroviral drugs can result in renal damage. Patients
presentation may vary from kidney stones, tubular necrosis, acute renal failure and chronic
renal disease28.
With protease inhibitors, ritonavir has been associated with acute renal failure. Incidence
increased in the presence of concomitant administration of nephrotoxic drugs. While
saquinavir although uncommonly, is associated with renal calculi 28.
Patients on nucleotide reverse transcriptase tenofovir may present to the emergency
department in acute renal failure. This may occur a few months into treatment with an
incidence of 17-22% in tenofovir containing regime 29. The risk is increased with advanced
age and HIV infection, higher serum creatinine levels before starting tenofovir containing

treatment, presence of comorbid conditions such as diabetes, diabetes, hepatitis C virus

infection, male sex, low body weight, and co-administration of nephrotoxic drugs and
ritonavir boosted protease inhibitor29.
Patients may present in oliguria. Investigation includes urinalysis which may reveal
proteinuria, 24 hour urine specimens for creatinine clearance calculation, serum creatinine
which may be within limit of normal or elevated29.
Treatment of affected patients involves patient rehydration and early withdrawal of the
offending medication, tenofovir29.

Conclusion
The introduction of highly active antiretroviral drugs in the treatment of HIV/AIDS has
improved dramatically the survival and ensured reasonably good and improved quality of
life of HIV infected individuals. However these have not come without the attendant
consequences some of which may affect treatment compliance, morbidity and is potentially
life threatening. Early recognition and prompt intervention in the emergency department
upon presentation cannot be over emphasied.

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