Infectious Disease Case Conference

1
Infectious Disease Case Conference

• Asif Zia, MD, MPH
• Wake Forest University
• December 13th 2004

2
History

• 48 year old African American male admitted
  10/13/04 to WFUBMC.
• 5 day history of generalized weakness, fatigue
  and fevers.
• Also had a sore throat with dysphagia and neck
  pain along with a headache.
• Also reported a cough with some yellowish sputum.

3
History 2

• Other symptoms included dysphagia and difficulty
  swallowing.
• One of his house-mates further reported that the
  patient was HIV positive, although the patient
  denied this.
• He was admitted because of concerns for a
  possible pneumonia, and his questionable history
  of HIV.

4
History 3

• PMHx Depression, PTSD, Back pain, Gonnorrhea
  (treated).
• Meds None at home.
• ALL ASA stomach upset
• FHx Mom died during childbirth, otherwise
  unknown.
• SHx Smokes 1 ppd, Hx of cocaine use, and regular
  ETOH use.

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Physical Exam

• In NAD.
• Vitals Tmax-101.4, BP-107/71,RR-16, P-47.
• HEENT Pharyngeal erythema with tonsillar
  enlargement. No exudates. No thrush.
• LUNGS CTA bilaterally.
• CVS RRR, s1 and s2 only.
• ABD Soft, NT, BS positive.
• EXT No edema, few discrete inguinal lymph nodes.
  No penile lesions.

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LABS

• 18
• 2.1 99 HIV Ab Neg for 1 and 2
• 53.5
• N-1300(64), B-300(14), L-400(18) Mono serology
  - Neg
• 139 108 8 Urine tox pos cocaine
• 94
• 3.8 24 1.1 HCV- pos
• Throat swab Group A strep
• CMV IgG pos
• Toxo IgG pos
• HSV 1 and 2 - Neg

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CXR on 10/13/04
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Summary

• Young African American male with acute onset of
  fever, sore throat, fatigue and headache.
• History of drug abuse (cocaine)
• CXR and HIV ab negative, with positive throat
  swab for group A strep and negative Infectious
  mononucleosis serology.

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DDX

• Viral upper respiratory tract infection.
• Streptococcal pharyngitis.
• c) Infectious mononucleosis.
• d) Secondary syphilis.
• e) Acute HIV infection.

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Other Labs

• CD4 160
• HIV Viral load 270,000

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DDX

• Viral upper respiratory tract infection.
• Streptococcal pharyngitis.
• c) Infectious mononucleosis.
• d) Secondary syphilis.
• e) Acute HIV infection.

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Acute HIV Infection

• To treat or not to treat that is the question!

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Acute HIV

• Whether treatment of acute HIV infection results
  in long-term virologic, immunologic, or clinical
  benefit is unknown treatment should be
  considered optional at this time (CIII).
• DHHS Guidelines, Oct 29, 2004

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Acute HIV 2

• IAS-USA guidelines do not comment specifically on
  this although they mention the use of structured
  treatment interruptions (STI) in these patients.
• The British HIV association recommends treatment
  for relief of symptoms of acute retroviral
  syndrome.

15
Early Events

• Infection with HIV 1 typically occurs across
  mucosal surfaces by direct inoculation.
• Virus 1st encounters dendritic cells (DC), which
  subsequently facilitate spread to CD4 T
  lymphocytes.
• An HIV specific DC receptor (DC-SIGN) binds HIV
  at gp 120 domain and transports the HIV to
  lymphoid tissue.
• CID 2004381447-53.

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Early Events 2

• Infected and uninfected cells go to regional
  lymph nodes, where HIV-1 resides and replicates
  within days to weeks.
• DC act as potent antigen-presenting cells,
  enabling rapid infection of naïve T-cells.
• Once HIV infects a cell, it can begin cycles of
  replication or remains inactive, causing latent
  infection in cellular reservoirs.
• CID 2004381447-53.

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Early Events 3

• Rapid viral replication results in widespread
  dissemination.
• Initial viremia can occur as early as 4 11
  days.
• At this time the host response includes
  activation of HIV-1 specific cytotoxic
  T-lymphocytes.
• This then causes a decreased HIV-1 load.
• CID 2004381447-53.

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Early Events 4

• Development of symptoms typically coincides with
  high level viremia.
• Exact mechanism of clinical symptoms are not
  known.
• Could be direct cytopathic effect of the virus
  and/or immune mediated toxicity.
• Formation of HIV-1 specific antibodies marks the
  completion of seroconversion.
• Usually 3-12 weeks, but can take 6-12 months.
• CID 2004381447-53.

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Clinical Presentation

• 40-90 of patients experience an acute retroviral
  syndrome.

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Clinical Presentation 2

• Symptoms usually last 14 days, but can continue
  for up to 10 weeks.
• Diagnosis is difficult due to the non-specific
  nature of symptoms.
• In one study, gt85 of patients sought care, but
  only 25 were correctly diagnosed.

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DDX (CID 2004381447-53)
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Rationale To Treat

• HAART during primary HIV infection (PHI) results
  in improvements in markers of disease
  progression.
• Similar to what is seen in chronic infection.
• Also appears to preserve HIV specific immune
  responses.
• Recovery of sub-populations of CD 4 cells occurs
  faster and appears to be more complete with early
  treatment.
• AIDS 2004, 18709-718.

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Rationale To Treat - 2

• The preservation of HIV specific cellular immune
  responses may increase the likelihood that viral
  suppression be maintained even after therapy is
  stopped.
• Primate studies (HIV-2 infected macaques) have
  suggested that even sub-optimal early therapy can
  delay disease progression.
• AIDS 2004, 18709-718.

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Pros and Cons
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Key Questions

• Will early therapy during PHI result in better
  immunological and virologic markers compared with
  treatment initiated later?
• Do long term treatment outcomes improve if
  therapy is initiated during PHI?
• Will transient therapy during PHI alter the viral
  set point?

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AIDS 2004, 18709-718.
27
Study Results-2

• Will early therapy during PHI result in better
  immunological and virologic markers compared with
  treatment initiated later?
• No randomized trials address this question.
• Observational studies (using very sensitive
  assays) suggest that total CD4 cells (but not )
  may be higher in the early treatment patients.

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Study Results - 3

• Malhotra et al in JID, 2000181121-31
  prospectively evaluated T-cell responses in 42
  patients with acute HIV-1 infection.
• 11 patients received open label therapy with
  Indinavir, Zidovudine and Lamivudine.
• These were matched with 30 untreated controls
  with similar demographic features.
• JID, 2000181121-31

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Malhotra Study

• Monitored the viral load and CD4 over 12 months,
  as well as stimulation index to candida,
  tetanus, HIV p-24 and HIV gp-16.
• Stimulation index was basically a measurement of
  lympho-proliferative response.
• Patients were included if within 130 days of
  acute infection.
• JID, 2000181121-31

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SI after 6 12 months of treatment
31
SI after 6-12 months of treatment
32
Malhotra Study - 2

• T helper cell responses to previously exposed
  antigen (candida and tetanus) are restored with
  suppression of viral replication.
• Early treatment was associated with an increase
  in gag-specific T-cell response.
• This was not seen in gp 160 response.
• Early treatment may preserve some antigen
  specific T-helper cell function for up to 12
  months.
• JID, 2000181121-31

33
Study Results - 4

• Do long term treatment outcomes improve if
  therapy is initiated during PHI?
• No randomized studies have been done to try to
  answer this question.
• Berrey et al in the JID 20011831466-75 followed
  the clinical and virologic course of 67 patients
  over 78 weeks.

34
Berrey Study

• 20 were treated immediately (lt30 to gt90 days),
  and 47 had delayed treatment (not all got HAART).
• In treated group
• Decreased minor opportunistic infections.
• Reduced progression to AIDS.
• Reduced mucocutaneous disorders.
• JID 20011831466-75

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Berrey Study - 2

• Conclude by saying that early treatment (within
  90 days) appears to
• Reduce the viral load
• Decreased progression to AIDS
• Decreased opportunistic infections.
• Study is problematic, as the latter group was not
  necessarily on HAART.
• JID 20011831466-75

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HIV Viral Loads
37
CD4 Counts
38
Study Results - 5

• Will transient therapy during PHI alter the viral
  set point?
• Recent studies have suggested that treating PHI
  does not alter viral set points.
• Fidler et al from the UK studied 37 patients with
  short course therapy in PHI (until VLlt50).
• After 48 weeks, their mean viral load was
  comparable to a cohort of untreated patients.
• AIDS 2004, 18709-718

39
Kaufmann Study

• Kaufmann et al in PLoS Medicine, Nov 2004, Vol 1
  report a longitudinal follow up of a single arm
  open-label study.
• To assess the impact of STI in acute HIV
  infection.
• 14 patients at lt31 days of onset of symptoms.
• PLoS Medicine, Nov 2004, Vol 1

40
Kaufmann Study - 2

• Patients achieved viral load lt400 x 2 mos and
  were lt50 at time of study.
• Re-treatment started when viral load gt50,000 or
  gt5,000 for 3 consecutive weeks.
• 79 were able to achieve virologic control
  (lt5,000) for 90 days or more after 3 STIs.
• Durability of this was however not maintained.
• PLoS Medicine, Nov 2004, Vol 1

41
Kaufmann Study - 3

• However the authors note that a majority of
  patients did achieve transient containment of
  viremia.
• They suggest that early treatment should still be
  considered as an important therapeutic option.
• Larger and randomized trials need to be done.
• PLoS Medicine, Nov 2004, Vol 1

42
Treatment Algorithm for PHI
CID 2004381447-53
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Conclusions

• Based on the currently published data, there is
  no clear evidence that there is any long term
  clinical benefit if antiretroviral therapy is
  introduced in acute HIV infection (prior to or
  during seroconversion).
• A randomized clinical trial is needed to
  definitively answer this question.