HPI

1
HPI

• 55 y/o AA male
• h/o advanced HIV infection
• Dxd in July 2001 with PCP,
• oral candidiasis (CD4 40, VL 1448)
• Schizophrenia
• Hepatitis (A or B, not C)
• Chronic leg and back pain

2
HPI

• has been in IDSC since August 2001
• Was started on CBV( 3TC AZT) and Efavirenz
• Did not Respond well to therapy but developed
  pancytopenia in 5/02

3
HPI

• Regimen was changed to Tenofovir, Kaletra
  (Lopinavir/ritonavir), and Stavudine
• Responded well to therapy, VL undetectable
• Anemia resolved

4
HPI

• c/o tingling and numbness all extremities after
  19 months of starting new regimen
• Also c/o fatigue, poor appetite, and weight loss
  35 lbs. in 3 months
• No N/V, abdominal pain, F/C, night sweats

5
HPI

• Loose stool sometimes
• No h/o cancer in a family
• smokes marijuana occasionally
• NKDA

6
Physical Examination

• VS T 98.2 F P 97 RR 18 BP 118/68
• BW 128 lb
• GA A O x 3, afebrile, NAD, thin but not
  cachectic, lipodystrophy of both cheeks
• HEENT PERRLA, EOMI, no oral thrush
• LN Small LN at Rt axilla
• Chest CTA bilaterally

7
Physical Examination

• Heart RSR, nl S1, S2, no murmur or
  gallops
• Abd soft, not tender, BS present,
  no organomegaly
• Ext no pitting edema, palpable pulses
• Skin no rash
• Neurological examination decrease vibration
  sense in both arms and feet

8
Diagnostic data

• CBC
• WBC 9 Hb 13.3 Hct 40.5 Platelet 224
• normal differential
• CMP
• CO2 24 AG 17 TB 1.3
• VL lt 50, CD4 340
• Testosterone, TSH, PSA- WNL
• PPD - negative

9
CT Chest, abdomen, and pelvis

• Mild cardiomegaly with left ventricular
  enlargement
• Small hiatal hernia
• Mild atherosclerosis
• Splenule

10
Problem Lists

• Weight loss
• Peripheral Neuropathy

11

• What is the etiology ?

12
Diagnostic data

• Lactic acidosis

• 4.9

13
Diagnostic data

• colonoscopy ordered

14
Clinical Course

• Stavudine was changed to Abacavir
• Still has good response to a new regimen
• Peripheral neuropathy- much improved
• Gained 7 lbs in 3 months after Stavudine was
  stopped
• Lactic acid came down to 4.3 then 3

15
Hyperlactatemia

• Associated with NRTIs
• In the majority of cases
• - transient and occur in the absence of symptoms
  
• Symptomatic hyperlactatemia is an uncommon
  complication
• -nonspecific, predominantly GI symptoms,
  reproducible elevated lactate levels, hepatic
  abnormalities, weight loss, fatigue.

16
Hyperlactatemia

• Slowly resolve over weeks to months upon
  discontinuation of NRTI.
• The proposed mechanism is mitochondrial toxicity
  through inhibition of DNA polymerase gamma
  (enzyme responsible for mitochondrial DNA
  synthesis) .

17
Hyperlactatemia

• In vitro, the ability to cause mitochondrial
  dysfunction is different
• zalcitabine gt didanosine gt stavudine gt
  zidovudine gt abacavir lamivudine tenofovir

Birkus G, Hitchcock JMH, Cihlar T. Assessment of
mitochondrial toxicity in human cells treated
with tenofovir comparison with other nucleoside
reverse transcriptase inhibitors. Antimicrob
Agents Chemother 2002, 46716723
18
Hyperlactatemia

• ? Reintroduce with the less mitochondrial toxic
  NRTIs

19
Peripheral Neuropathy in HIV-infected
patients

• peripheral neuropathy can be
• - a complication of HIV infection
• - a complication of drug therapy
• - or a combination of both
• Most common is a distal, symmetric, predominantly
  sensory polyneuropathy.

20
(No Transcript)
21
Peripheral Neuropathy in HIV-infected
patients

• Correlates with the degree of immunocompromise.
• Subclinical neuropathy, detected by
  electrophysiologic or pathologic studies, can
  occur during asymptomatic HIV infection.
• Falling CD4 counts are associated with increasing
  abnormalities of peripheral nerve function.

22
Peripheral Neuropathy in HIV-infected
patients

• Although other factors, i.e., aging, and weight
  loss, likely also contribute.
• Symptomatic neuropathy is uncommon in the early
  stages of HIV infection when CD4 counts are gt400.

23
Distal symmetrical polyneuropathy

• Pathogenesis is unknown and may be
  multifactorial.
• ?Direct infection (HIV in peripheral nerve)
• ?Immunologic reaction to infection
• (macrophage and T cell infiltration of
  peripheral nerves and dorsal root ganglia, and
  activated cytokines are found in the dorsal root
  ganglia)

24
Distal symmetrical polyneuropathy

• Screening blood test
• Liver function tests    Vitamin B 12 and
  folate levels    Thyroid stimulating hormone
  assay    Blood glucose    Blood urea nitrogen
  and creatinine    Serum protein electrophoresis
  and
• immunoelectrophoresis    RPR

25
Drug-induced PN

• Indistinguishable clinically and
  electrophysiologically from HIV-associated distal
  symmetrical neuropathy.
• Although the hands may be affected more often in
  drug-induced cases.
• Dose-dependent.
• Increases with the duration of drug exposure.

26
Drug-induced PN

• The onset is typically 7-9 weeks after beginning
  therapy.
• Associated with nucleoside reverse transcriptase
  inhibitors (NRTIs)
• - stavudine (d4T)
• - zalcitabine (ddC)
• - to a lesser extent, lamivudine (3TC),
• fialuridine (FIAU), and didanosine (ddI).

27
Drug-induced PN

• Zidovudine (ZDV) is not neurotoxic but causes
  myopathy.
• Vincristine, (used to treat Kaposi's sarcoma)
• Dapsone ( treat or prevent PCP)
• Thalidomide, INH, and ethambutol

28
Drug-induced PN

• Asymptomatic distal symmetrical polyneuropathy is
  not a significant predictor of symptomatic
  polyneuropathy.
• Thus, the presence of asymptomatic polyneuropathy
  currently is not a contraindication to the use of
  potentially neurotoxic drugs, if needed.

29
NRTIs-induced PN

• Due to mitochondrial toxicity.
• Phosphorylated NRTIs have azido groups that
  compete with thymidine triphosphate as substrates
  for mtDNA synthesis.

Dalakas MC. Peripheral neuropathy and
antiretroviral drugs. J Peripher Nerv Syst. 2001
Mar6(1)14-20.
30
NRTIs-induced PN

• The following may help to distinguish NRTIs-
  induced PN from HIV-related PN
• a) Temporal association of symptom onset
• or rapid worsening of symptoms.
• b) Improvement of symptoms after cessation or
  reduction of NRTIs dosage.

Dalakas MC. Peripheral neuropathy and
antiretroviral drugs. J Peripher Nerv Syst. 2001
Mar6(1)14-20.
31
NRTIs-induced PN

• c) Coasting- temporary (2-4 wks) worsening of
  symptoms after D/C NRTIs followed by clinical
  improvement.

Dalakas MC. Peripheral neuropathy and
antiretroviral drugs. J Peripher Nerv Syst. 2001
Mar6(1)14-20.
32
Treatment

• Exclude or eliminate other cause of PN
• Lower the dose of NRTIs
• Analgesics- NSAIDs, topical capsaicin, narcotics
• Antidepressants
• Anticonvulsants- Neurontin, Tegretol, etc.

Dalakas MC. Peripheral neuropathy and
antiretroviral drugs. J Peripher Nerv Syst. 2001
Mar6(1)14-20.
33
Treatment

• Riboflavin