Primary Care HIV Medicine March 2, 2006

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Primary Care HIV MedicineMarch 2, 2006

• Meg D. Newman, M.D.
• UCSF-PHP
• San Francisco General Hospital

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Adults and children estimated to be living with
HIV/AIDS as of end 2003
Eastern Europe Central Asia 1.2 1.8 million
Western Europe 520 000 680 000
North America 790 000 1.2 million
East Asia Pacific 700 000 1.3 million
North Africa Middle East 470 000 730 000
Caribbean 350 000 590 000
South South-East Asia 4.6 8.2 million
Sub-Saharan Africa 25.0 28.2 million
Latin America 1.3 1.9 million
Australia New Zealand 12 000 18 000
Total 34 46 million
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Changes in life expectancy in selected African
countries with high and low HIV prevalence
1950-2005
65
60
with high HIV prevalence
Zimbabwe
55
South Africa
Botswana
50
Life expectancy (years)
45
with low HIV prevalence
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Madagascar
Senegal
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Mali
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1950 1955
1955- 1960
1960- 1965
1965- 1970
1970- 1975
1975- 1980
1980- 1985
1985- 1990
1990- 1995
2000- 2005
1995- 2000
Source UN Department of Economic and Social
Affairs (2001) World Population Prospects, the
2000 Revision
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U.S. AIDS Cases 12/2002
-
43,158 Cases 2002
816,149 Cases Total
Men 670,687
Men 31,994
(74)
(81)
Women 11,164
Women 145,461
(26)
(18)
Pediatrics 9,074 (1)
Pediatrics 175 (lt1)
Rates in Women, 1981-1987
Men 92
Women 8
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Antiretroviral TherapyWhen Should we Start?

• Old Paradigm Hit early and hit hard.
• VL gt 20K and CD4 lt 500
• New Paradigm Start later and hit hard always
  use maximally suppressive therapy
• CD4 around 200-350. Ideal CD4 TBD
• VL is not a primary criteria for most of us
• Any signs of clinical illness independent of CD4
  and VL are an indication for initiating
  treatment

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Whats New With Antiretrovirals?

• nnRTI regimens with efavirenz (q day) or
  nevirapine (bid) or PI regimen with atazanavir
  (q day) offer low pill burdens
• Common Regimens
• 2 nRTIs a dual or single PI Or
• 2nRTIs a nnRTI
• Boosting with low dose ritonavir has allowed
  PI regimens to be given q day or bid with
  decreased pill burdens

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Basic Pharmacology Principles
Drug Level
Cmax
Area Under the Curve (AUC)
Cmin
IC90
Area of Potential Replication
IC50
Dosing Interval
Time
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Pill Burden 1997 AZT 3TC Crixivan
MORNING
NIGHT
NOON
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Pill Burden 2004. Truvada (FTC tenofovir)
Sustiva
NIGHT
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Republicans understand the importance of bondage
between a mother and child
-Former Vice President Dan Quayle
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Pregnancy and HIV

• Pregnancy is not A/W with progression of
  asymptomatic HIV disease or ? complications
• MTCT can occur in utero (IU), intrapartum (IP)
  and postpartum (PP) through breast feeding
• In breast feeding populations IU transmission
  accounts for 12, IP for 50 and PP for 37.
• Most IP transmission occurs late in the third
  trimester

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HIV and Pregnancy

• Start using prenatal vitamins in all your
  patients who may decide to have children
• Dont use EFV in any woman considering a future
  pregnancy
• Start using prenatal vitamins in all your
  patients who may decide to have children
• Dont use EFV in any woman considering a future
  pregnancy

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European US Registry Independent Role of
Antiretrovirals And Viral Load

• 44 transmissions among 1202 women with viral load
  lt 1000 copies / mL
• Transmission by maternal therapy
• Any antiretrovirals 1.0 (0.4 - 1.9)
• No antiretrovirals 9.8 (7.0 - 13.4)
• Other independent predictors
• Birthweight
• Mode of delivery
• CD4 count

Iannidis JID 2001 183539-545
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Infant HIV Infection Status, by Antiretroviral i
1,183 Infants Born To HIV-infected Women in NY
State 1/96-6/99

• Timing of ARV use N Inf Uninf Indet Effectiveness
  () () ()
• NONE 286 24 51 21 ref
• Prenatal/Intrapartum 558 6 70 24 82 and
  neonatal ZDV
• Prenatal/IP/NN ZDV 280 lt1 76 23 96 with
  other HAART
• Neonatal ZDV only 59 12 61 27 59 within
  24 hrs of birth

Peters et al 8th CROI
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Antiretroviral Pregnancy Registry
Phone [phone] Fax
919-315-8981

• PO Box 13398
• Research Triangle
• Park, NC
• 27709-3398

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Potential Side-Effects And Sequalae of AIDS
and or HAART

• Body Habitus Changes
• Extremity and facial fat loss
• Truncal fat accumulation
• Hip and breast fat accumulation-esp. in women
• Dorsocervical fat pads
• The etiology has not been completely elucidated
• NRTIs that have great affinity for human
  mitochondria play a large role (d4T gt ddi gt AZT gt
  3TC gt ABC gt TNF
• Remember body habitus changes antedated PIs

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Potential Side-Effects And Sequalae of
AIDS and or HAART

• Metabolic Changes
• Insulin resistance
• Diabetes mellitus or worsening of pre-existing
  diabetes mellitus
• Abnormal Lipids ( ? HDL, ? Trig, ? Tchol, ? LDL )
  
• Protease Inhibitors as a class have this effect
• Ritonavir / Indinavir / Fortovase / Lopinavir /
  Nelfinavir
• Even when Ritonavir is used as just a booster
• Atazanavir ( Reyataz ) is the PI exception

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Potential Side-Effects And Sequalae
of AIDS and or HAART

• Skin Disease
• Rash associated with many newer ARVs
  (NVP, EFV, ABC) 2-18 of the time
• Nevirapine rash is 11 fold more common in women
• Warts (especially intraoral, facial and anal
  warts)
• More eosinophilic folliculitis
• Peripheral Neuropathy
• Lots of potential Drug Interactions

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Potential Side-Effects And Sequalae Of AIDS and
or HAART

• Mitochondrial Toxicity
• Lactic acidosis and hepatic steatosis
• Onset is often insidious. Patients may present
  with anorexia, weight loss and malaise or more
  focused syndromes with myopathy or peripheral
  neuropathy
• Inhibition of mitochondrial DNA gamma polymerase
  decreases mtDNA and impairs synthesis of mt
  enzymes that generate ATP

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• End Organ Disease.. Bone? Cardiovascular ?
  
  
  
• Renal and
  Neurological Sequalae ?
• 
  Is it so?

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Potential Side-Effects And Sequalae of AIDS
and or HAART ?

• Are these problems really occurring more often ?
• Bone changes appear to be a cohort effect
• Osteopenia ? Osteoporosis
• Avascular Necrosis
• End Organ Cardiovascular / Renal / Neurological
  Sequalae ?
• CAD
• Renal Insufficiency
• HTN
• CVA

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Quick View at Adverse Reactions to ARVs

• d4T / ddi Mt toxicity, peripheral neuropathy,
  pancreatitis
• Abacavir hypersensitivity syndrome
• Tenofovir Renal insufficiency, Fanconis
  Syndrome
• AZT Everything HA, N,V, and anemia
• TMP/SMZ Everything Rash, Stevens-Johnson
  syndrome, Hypotension-Sepsis syndrome, HA, N, IV
  hyperkalemia

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Interesting HIV Cases

• 65 Y/O woman with AIDS, CD4 of 10 / VL of 95 K
  presents to SFGH from LHH with new confusion,
  somnolence, far lateral nytagmus and ataxia
• Your astute MS3 gets the full med list ASA,
  docusate sodium, pravastatin and phenytoin.
  Phenytoin level was 11 just 6 days ago.
• BTW Efavirenz, 3TC/ TNF were started 5 days
  ago

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Interesting HIV Cases

• Phenytoin is a CYP2C9 and 2C19 enzyme inhibitor
  and a CYP1A2, 2B6,2C, 3A3/4 and 3A5-7 enzyme
  inducer
• Metabolism of phenytoin is inhibited or induced
  by efavirenz. In this case it was inhibited and
  phenytoin level was now 48
• Many potential drug interactions exist. How you
  can find out about drug interactions? What tools
  do you have??

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Drug InteractionsThey Rule

• Surrender now with a show of good resources
• Do you use AIDSMEDS.COM or Epocrates?
• aidsmeds.com
• Medscape HIV/AIDS Clinical Drug Calculator and
  Medication Daily Scheduler
• http//www.medscape.com/px/hivscheduler
• Another helpful site is Project Informs drug
  interaction site. http//www.projinf.org

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PRESCRIBER BEWARE

• The common mechanism of action is inhibition or
  induction of the CYP 450 system
• Rifampin with virtually everything
• Ritonavir is a close second
• Rifabutin has many significant interactions
• ddI, clarithromycin, fluconazole, indinavir, INH,
  saquinavir, and antibiotics have many drug
  interactions.
• Prescriber BEWARE

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Interesting HIV Cases

• A 26 Y/O woman is on Day 26 of 3TC, abacavir and
  indinavir/ritonavir. She presents with 2 days of
  fever to 102, malaise and some mild cough. She
  has no rash.
• What are you concerned about in this patient?
• How do you make the diagnosis?

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Description of Hypersensitivity
Reactions to Abacavir

• Observed in approximately 5 of all pts receiving
  abacavir
• Multi-organ system involvement
• Most common signs and symptoms
• Fever
• Rash (may or may not be present) Can be
  urticarial or macpap
• Fatigue
• GI (nausea, vomiting, diarrhea, abdominal pain)
• Other signs and symptoms
• Edema, headache, musculoskeletal, respiratory,
  constitutional symptoms (lethargy, malaise,
  arthralgia, myalgia)

Hetherington S et al. In Abstracts of the 7th
Conference of Retroviruses and Opportunistic
Infections. San Francisco, CA. Jan 30 - Feb 2,
2000, Poster No. 60.
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Description of Hypersensitivity
Reactions to Abacavir

• Symptoms usually worsen during therapy and
  improve within 24-48 hours after discontinuation
• Patients with hypersensitivity reactions must not
  be rechallenged
• Life-threatening hypotension and death have
  occurred in patients who have been rechallenged

Hetherington S et al. In Abstracts of the 7th
Conference of Retroviruses and Opportunistic
Infections. San Francisco, CA. January 30-
February 2, 2000, Poster No. 60.
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Comparison of the Clinical Presentation Initially
and on Rechallenge
Hetherington S et al. In Abstracts of the 7th
Conference of Retroviruses and Opportunistic
Infections. San Francisco, CA. January 30-
February 2, 2000, Poster No. 60.
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Next Case

• 52-year-old male
• First diagnosed April 1998
• Initial VL 36,000 c/ml
• Initial CD4 253 cells/µl
• Wanted to start Rx

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Clinical Case

• Started on d4T 40 mg bid 3TC 150 mg bid
  Indinavir 800 mg tid
• Week 60, complains of mild burning pain in lower
  extremities and increased abdominal Week 16, VL
  lt50 c/mL CD4 448 cells/µl
• Increased abdominal girth
• He also had intermittent nausea, fatigue, some
  SOB with exertion. No CP

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Lab Results (week 60 Fasting)

• VL lt50 c/ml
• CD4 420 cells/µl
• WBC 5,600 normal differential
• PCV 41

• Na 142 K 4.1
• Cl 100 HCO3 20
• Cr 0.9 BUN 21
• Glu 172 AST 36
• ALT 30 Alk phos 134 TAG 487
• Chol 218
• TB 2.2 (1.7 indirect)

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You recommend

• Continue Current Therapy Reevaluate in 2 weeks
• Substitute Tenofovir for d4T
• Reduce d4T dose to 30 mg bid
• Substitute EFV for IND
• Change entire regimen to EFV, ABC, 3TC
• Stop antiretroviral therapy

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Mitochondrial Toxicity, Hyperlactatemia and HAART

• The goal is to diagnose this as early as
  possible to avoid death
• Early symptoms to be aware of include fatigue,
  abdominal pain, weight loss, malaise, nausea,
  vomiting and anorexia. It can be a very
  fulminant picture or a very insidious picture.
• Severe axonal neuropathy can be another
  presentation
• Symptoms can develop after years of tolerating
  NRTIs
• Check the bicarbonate and calculate the anion
  gap
• Obtain a lactate level if you suspect this
  condition

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Mitochondrial Toxicity, Hyperlactatemia and HAART

• Stop all HAART therapy. This is a
  life-threatening complication
• Treatment with stavudine (d4T) appears to be a
  predominant risk factor for the development of
  mitochondrial toxicity. Use of d4T and ddi
  together creates a significant risk.
• HAART with different NRTIs can usually be
  instituted safely at a later time if the patient
  survives

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Mitochondrial Toxicity

• Hepatic steatosis and lactic acidosis are
  secondary to NRTI associated mitochondrial
  toxicity
• Inhibition of mitochondrial DNA gamma polymerase
  decreases mtDNA and impairs synthesis of mt
  enzymes that generate ATP
• Women account for a disproportionate amount of
  cases, especially women with increased BMI
• Have a low threshold to diagnose this disorder
  early in the course. Avoid the ICU.

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Novel Therapies Fusion Inhibitors Enfuvirtide
T-20
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Novel TxEntry Inhibitors
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Reverse Transcriptase Inhibitors
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HIV-1 Reverse Transcriptase
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RT Inhibitors NRTI versus NNRTI
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NRTI Mechanism of Action
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Protease Inhibitors
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HIV-1 Protease
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Interesting HIV Cases

• A 47 Y/O woman with a CD4 89/ VL 28,000 has been
  taking her first antiviral regimen for the past 8
  weeks. She is admitted to your service with
  productive cough, sharp chest pain and a fever
  to 102.4. On CXR she has a lobar infiltrate.

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Interesting HIV Cases

• You decide to treat her for this bacterial
  pneumonia
• Should you stop her antiretrovirals ??
• Why or why not ?? If so, how should you stop
  them?
• What if she presents with nausea, vomiting and
  diarrhea ??

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NNRTIs Have Long Half Lives

• Efavirenz (Sustiva) and Nevirapine (Viramune)
  have long half lives
• If a patient is on one of these medications, stop
  the NNRTI and continue the other medications for
  5 days if possible
• If stopping meds for lactic acidosis or other
  acute condition (e.g. Fanconis syndrome), stop
  all the medication immediately regardless of half
  life

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Primary Care

• You are in the ER seeing a 29 y/o Physics Ph.D.
• She presents with a fever to 102, mod myalgias, a
  sore throat, and a rash on her torso.
• Her PMH is benign. Her family history is benign.
• What is your differential diagnosis ??
• How do you make the diagnosis??

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Important Web Sites/Resources

• All you want and more, with links to everything
  HIV HIVinsite www.hivinsite.org
• Drug interactions/side-effects aidsmeds.com
  Epocrates, Project inform
• (AIDS Education and Training Center)
  http//www.aids-etc.org/
• (International AIDS Society-USA) ias-usa.org
• Warmline National HIV Telephone Consultation
• Monday-Friday 8AM- 8PM EST 1-800-933-3413

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Take Home Points

• HAART is essential in most patients. Initiate
  when the benefit exceeds the risk
• Evaluate your patients medication lists for
  potential drug interactions
• Be alert for abacavir hypersensitivity Be alert
  for lactic acidosis syndrome with d4t or ddi
• Be alert for Fanconis syndrome with Tenofovir
• Stop meds when you need to
• HELP is always available! CDC Warmline

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Take Home Points

• AIDS is becoming a disease of women,
  heterosexually transmitted,
  disproportionately affecting women of color
• Have a low threshold for HIV testing and
  counseling
• HIV vertical transmission can be eliminated with
  HAART. Offer optimal antiretrovirals to pregnant
  women

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Sensitivity and Specificity for Diagnostic Tests
for Primary HIV

• 408 Screened (118 infected chronically) 105
  recent HIV Infection Hecht/Kahn et
  al-Options Project
• Fevers 80 / 56
  OR 4.0
• Rash 51 / 82
  OR 3.4
• Pharyngitis 44 / 77 OR
  2.0
• Oral Ulcers 37 / 85
  OR 2.1
• Wt. Loss (5lbs) 32 / 86 NA

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Interesting Cases in HIV Medicine

• A 32 y/o woman with a prior CD4 count of 240
  presents with dry cough for 3 mos a/w DOE, fevers
  and malaise
• What is your differential? What do you want to do
  next?

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PNEUMOCYSTIS Jiroveci PNEUMONIA

• Most commonly presents with DOE, nonproductive
  cough and fatigue
• May present indolently with fever, NS, wt. loss
  and fatigue for days to months before respiratory
  sx occur
• Classic CXR Fine reticular, diffuse, B/L
  interstitial infiltrates

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PNEUMOCYSTIS Jiroveci PNEUMONIA

• Many CXR variations are possible asymmetric
  infiltrates, nodules, and lobar
  consolidation.10 or less can be normal.
• DLco and HRCT may also suggest the diagnosis
• Diagnosis should be confirmed
• Sputum induction is (75) sensitive at SFGH.
• Much less at other centers.
• Bronchoscopy with BAL is greater than 98
  sensitive

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PjP Prophylaxis

• Initiate when CD4 cells are near 200
• Earlier for wasting / thrush / recurrent
  infections
• Primary Prophylaxis
• TMP/SMZ
• Dapsone or Atovoquone. Efficacy is equal
• Secondary Prophylaxis
• TMP/SMZ
• Dapsone / Pyrimethamine or Atovoquone
  Clindamycin/Primaquine or Trim/Dapsone

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Interesting HIV Cases

• Your patient presents with a new onset seizure
  and you obtain a CT scan
• These lesions are pathognomonic for what disease?

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Toxoplasmosis

• If the Toxo IgG titer were negative would you be
  comfortable waiting 10-14 days with just Toxo
  treatment?
• Please say NO!
• Time for additional diagnostic testing

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TOXOPLASMOSIS ENCEPHALITIS (TE)

• Occurs due to reactivation and disseminationof
  latent organisms
• 97 - 98 of patients are Toxoplasmosis gondii
  IgG antibody
• Common presentations may include focal
  neurological deficits, hemiparesis,
  seizures,fever and HA
• Less common Behavioral changes, lethargy,
  visual, speech and cerebellar abnormalities

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TOXOPLASMOSIS ENCEPHALITIS

• Diagnosis 2 or more hypodense, contrast
  enhancing lesions on CT are supportive of the dx
• More lesions are common on MRI but single lesions
  can also be TE
• Differential Diagnosis lymphoma, or abscess
  dueto a fungal or bacterial infection (including
  Tb)
• Toxo may also cause ocular, pulmonary and other
  neurological diseases including transverse
  myelitis
• Prophylaxis TMP/SMZ or Dapsone Pyrimeth or
  Atovoquone

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DISSEMINATED CRYPTOCOCCUS

• Portal of entry is the lungs. 70-80 of infection
  in the lungs is asymptomatic.
• Common presentations include fever and malaise
• Extraneural involvement can occur in the lungs,
  GU tract, skin, mediastinum, pericardium,
  myocardium and oral cavity
• Pulmonary disease has an acute phasemortality of
  40

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DISSEMINATED CRYPTOCOCCUS

• Diagnosis Serum Cryptococcal antigen testing
  (CRAG)
• Sensitivity is 93 - 99
• All positive serum CRAGs requires an LP to
  assess the CSF for involvement
• All positive serum CRAGs requires an LP to
  assess the CSF for involvement

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CRYPTOCOCCAL MENINGITIS

• Common in patients with CD4 cells lt 100
• Common presentations include fever, HA and
  malaise. The absence of focal neurologicaldeficit
  s is typical
• Diagnosis is confirmed by CSF-CRAG
• 99 of patients show short and long term benefit
  from 14 days of IV Amphotericin and then
  suppression with PO Fluconazole

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DISSEMINATED MYCOBACTERIUM AVIUM COMPLEX (MAC)

• Exclusively in patients with lt 50 CD4 cells
• Common presentations include fever(frequently
  102-104 F) malaise, fatigue,GI sx and wt. loss
• High fevers occur without the appearance of
  septicemia. GI sx chronic diarrhea, abdominal
  pain, malabsorption and biliary obstruction
• Prophy Azithro 1200 mg q wk or Clari 500 mg bid

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CMV RETINITIS

• Usually occurs in patients with lt 50 CD4 cells
• Classic presentation Floaters. Findings on
  exam are hemorrhage and exudate
• Will lead to progressive disease (blindness)
  without treatment and immune restoration
• Tx will often prevent progression of disease but
  will never restore vision in affected areas
• Prophylaxis HAART and more HAART

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Interesting HIV Cases

• This patient did have toxo in 1996 when she had
  11 CD4 cells. She also had PCP. She now has 1265
  CD4 cells.
• When can we stop her PCP prophylaxis?
• Can we ever stop her Toxo suppressive treatment?

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Prophylaxis of OIs- Whats New

• Discontinuation of primary and secondary
  prophylaxis for PCP, Toxo, MAC, Crypto is safe
• PjP 10 and 20 if gt 200 for at least 3-6 mos.
  Restart if lt or near 200.
• Toxo 10 stop if gt 100 for 3-6 mos. 20 gt 200.
  Restart tx if lt 200
• MAC 10 stop gt 50 for 3-6 mos. 20 Complete 12
  mos. of tx and if gt 100 stop
• Crypto 20 gt 100-200 for at least 6 mos. Restart
  if lt 100. ( MMWR Dec 2004
  54(rr15) 1-112)

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Common Problems in
HIV Medicine

• A 41 y/o woman presented with 600 CD4 cells and a
  VL of 32,000 copies per/ ml
• She asked you if she should start HAART?
• What if she were pregnant?