TUBERCULOSIS IN HIV INFECTED PERSONS

1
TUBERCULOSIS IN HIV INFECTED PERSONS

• A. Edward Khan, M.D.

2
General

• Worldwide, TB is the leading cause of HIV-related
  deaths
• One third of AIDS deaths are due to TB
• Recent estimates are that 5-6 million people are
  coinfected with HIV and TB
• Although western nations co-epidemic is leveling
  off, developing nations rates are still rapidly
  climbing Africa, S and SE Asia

3
Global TB-HIV Rates

• Of the 8 million annual TB cases worldwide 14
  are HIV-related
• Vast majority in Africa, South and SE Asia
• Marked variation nationally and regionally
• Uganda, Zambia 60 TB cases are HIV positive
• Kenya (Nairobi) 30
• Nigeria 5
• Thailand 25
• India 9
• U.S.A. 3 (median) - 46 (NYC)

4
HIV-TB United States

• In U.S., there was a steady annual decline in TB
  cases until 1986, when steady increase began
  which peaked in 1992
• New epidemic of TB included people at higher risk
  for HIV
• men
• racial and ethnic minorities
• age 25-44
• living in group settings such as prisons, shelters

5
TB in HIV Risks

• Profound increase in development of active TB in
  HIV
• due to both reactivation and primary infection
• In normal hosts, there is a 10 lifetime risk of
  active TB once exposed
• In HIV patients, risk is 10 per year
• This is due to the progressive decline in
  cell-mediated immunity in HIV which is necessary
  to keep quiescent tubercle bacilli in latent state

6
TB in HIV Reactivation vs New Infection

• Initially assumed that in low TB prevalence
  country such as U.S., most new cases were due to
  reactivation of latent infection
• However recent studies using strain
  finger-printing have shown that two thirds of new
  TB cases in HIV were due to recent infection (NYC
  and San Francisco)
• Increased susceptibility in HIV to TB dramatic
• exogenous reinfection with new (MDR) strain
  demonstrated even while patient on therapy

7
TB/HIV Clinical Aspects

• MTB,because of its virulence, is an early
  opportunist in HIV
• active disease while CD4 counts still high
• progressive susceptibility as CD4 lt 500 cells/cc
• Clinical presentation variable reflecting degree
  of immune impairment

8
TB/HIV Clinical Aspects (cont)

• With high CD4 counts, TB presents similar to
  non-HIV hosts (upper lobe disease, cavitation,
  positive PPD)
• In advanced HIV/AIDS, atypical pulmonary
  presentations common, as well as extra-pulmonary
  manifestations
• General symptoms such as cough, fever, night
  sweats, weight loss are similar to non-HIV TB
  patients (may be shorter duration)

9
TB/HIV Clinical Aspects (cont)

• Atypical pulmonary features include
• lack of apical infiltrates
• isolated lower or middle lobe disease
• extensive, diffuse infiltrates
• lack of cavitation
• hilar and/or mediastinal lymphadenopathy
• miliary disease
• Normal chest x-ray (10 of HIV-TB cases)

10
TB/HIV Clinical Aspects (cont)

• Extrapulmonary manifestations especially high
  when CD4 lt 100 sites include
• CNS (meningitis, tuberculomas, abcesses)
• lymph nodes
• bone marrow
• blood (cultures positive in one third of
  patients)
• liver, spleen, kidney
• pericardium and peritoneal
• miliary

11
TB/HIV Infection of Contacts

• Questionable whether HIV-TB patients are more
  infectious to contacts than non-HIV
• Lack of cavitation in HIV-TB results in less
  active discharge of bacilli into airways
• Advanced debilitation and weakness render HIV
  patients less able to generate good cough
• However, lack of immunity allows greater
  multiplication of organisms in host
• Overall, smear positivity rates and skin test
  conversion of contacts appears similar

12
Effect of TB on HIV Infection

• Active tuberculosis accelerates progression of
  HIV virologically, immunologically and clinically
• virologically increased HIV viral load
• immunologically lowered CD4 counts
• clinically more opportunistic infections and
  increased mortality rates
• HIV viral load and CD4 count improve following
  treatment of TB

13
Effect of TB on HIV (cont)

• MTB in macrophages induces production of
  proinflammatory cytokines (IL-1,2,6, TNF) which
  upregulate transcription of HIV
• IL-1 and TNF-alpha enhance replication of HIV via
  enhancer, NF-KB, which binds at the 5 LTR of HIV
  (also act directly)
• TB cell wall antigen, lipoarabinomannan (LAM) can
  directly stimulate HIV through this mechanism

14
TB/HIV Diagnosis Caveats

• Similar evaluation as for HIV negative patients
  with suspected TB
• Must maintain high index of suspicion for TB in
  any HIV patient with new symptoms
• Recall that 10 HIV-TB have normal CXR
• Low threshold for respiratory isolation until TB
  ruled out
• Almost any CXR abnormality compatible with TB in
  HIV, especially when HIV advanced

15
TB/HIV Diagnosis (cont)

• Mycobacteremia often present in both local-ized
  and disseminated disease thus should obtain
  mycobacterial blood cultures
• Maintain high index of suspicion for
  extra-pulmonary involvement
• A negative PPD (lt 5mm) should not dissuade
  further evaluation for TB
• Anergy more common as CD4 drops (e.g. 40 if lt
  200, almost all anergic if lt 100)

16
Diagnosis TB vs dMAC

• Major differential diagnosis is disseminated
  Mycobacterium avium complex (dMAC)
• occurs in advanced HIV/AIDS typically when CD4 lt
  50
• presents with fever, sweats, lymphadenopathy,
  hepatosplenomegaly, pancytopenia
• AFB positive organisms present in tissue

17
Diagnosis TB vs dMAC (cont)

• both may have granulomas (note that TB granulomas
  in HIV may not be caseating)
• await culture/specific nucleic acid probe to
  confirm species identification
• helpful clue is frequent/relative lack of
  pulmonary involvement in dMAC
• often need to empirically cover both while
  waiting for culture data

18
TB/HIV Treatment

• Focus on how treatment of TB may differ in HIV
  infected individuals and some unique confounding
  situations
• In HIV negative patients, therapy 1 is IRZ for 2
  months, followed by IR for 4 months
• If primary INH resistance prevalence gt 4, add E
  or S to initial regimen until DST known
• If PZA not part of initial regimen, total
  duration should be 9-12 months

19
TB/HIV Treatment (cont)

• Current debate whether HIV-TB patients require
  longer duration of therapy
• Treatment response rates similar but probable
  higher relapse rates with 6 month regimen
• Zairian study showed 12 months therapy reduced
  relapse rates from 9 to 2
• U.S. (CDC) Guidelines currently favor 9 months of
  total therapy in HIV-TB

20
TB/HIV Treatment (cont)

• In HIV, due to high incidence of peripheral
  neuropathy, all patients should have 50mg
  pyridoxine (B6) added daily to regimen
• Adherence to regimen critical for favorable
  treatment outcome and to avoid resistance
• DOT (Directly Observed Therapy) and combin-ation
  tablets (Rifamate, Rifater, Rifinah) help in this
  regard

21
TB/HIV Treatment (cont)

• May need to empirically treat for both TB and MAC
  until culture results known
• Suggested regimen INH/RFB/PZA/EMB/Clarithro /-
  amikacin
• add parenteral agent if patient very ill

22
TB/HIV Drug Interactions

• Drug interactions may be problematic when patient
  taking medications for both HIV and TB
• Protease inhibitors (PI) and non-nucleoside
  reverse transcriptase inhibitors (NNRTI) both
  significantly interact with rifamycins via
  hepatic cytochrome P450 enzyme system

23
TB/HIV Drug Interactions

• Rifamycins are potent inducers of P450 enzymes,
  which metabolize both PI and NNRTI
• The accelerated degradation of these HIV
  medications results in subtherapeutic levels with
  usual dosing and the subsequent development of
  drug-resistant HIV

24
TB/HIV CDC Old Recommendations

• Prior to March 2000, CDC recommended three
  options to treat TB and HIV
• withholding PI or NNRTI-based therapy for
  duration of rifampin containing regimen
• withholding PI/NNRTI for initial 2 months while
  using RIF, then resume PI/NNRTI and finish TB
  therapy with 16 months INH/EMB
• Using rifabutin at half dose with a PI-based
  regimen with indinivir or saquinivir

25
TB/HIV CDC New Recommendations

• In March 2000, CDC made additional options
• Rifampin can be used with PI-based regimen using
  ritonivir with or without saquinivir
• Rifampin can be used with efavirenz
• Rifabutin (lower dose) can be used with RTV /-
  SQV, or with efavirenz (higher dose RFB)

26
TB/HIV Drug Interactions

• Note that other drugs commonly used in HIV also
  interact with rifamycins (azole antifungals,
  macrolide antibiotics) and may require dose
  adjustments
• Clinicians and pharmacists must be highly
  vigilant to monitor for toxicities and side
  effects of these drugs (e.g. RFB-induced uveitis
  or leukopenia) as well inefficacy of either TB or
  HIV therapy

27
TB/HIV Response to Treatment

• HIV patients with TB generally respond well to
  standard regimens
• Similar rates to HIV negative comparing
• time to sputum conversion
• clinical / radiographic improvement
• overall rates of cure
• Question as to whether relapse rate higher in
  HIV-TB (would support longer treatment duration)

28
TB/HIV Response to Treatment

• Despite similar responses, higher mortality rates
  in HIV associated TB
• 5 to 14 increased mortality during therapy
• also increased mortality following completion of
  six month regimens, however deaths largely due to
  progression of HIV and not TB relapse

29
TB/HIV Adverse Drug Reactions

• Adverse reactions to TB drugs initially reported
  as higher in HIV patients (18), but subsequent
  studies have not confirmed this
• Thiacetazone, commonly used worldwide but not in
  U.S., strongly associated with severe cutaneous
  reactions in HIV-TB with high fatality rate
  (Stevens-Johnson, TEN)

30
HIV/TB Response to Therapy

• Low serum drug levels frequently reported in
  HIV-TB patients (RIF, EMB), however routine
  monitoring not indicated unless patient not
  responding to therapy
• Evaluate patient monthly for clinical status,
  sputum evaluation, assessment of adherence to
  therapy and adverse events

31
HIV/TB Slow Responders

• If sputum still positive after 2-3 months on
  therapy, need to consider evaluation of
• adherence
• drug resistance (may need to repeat DST)
• repeat chest x-ray
• serum drug levels
• possible impaired blood flow to diseased lung
  (perfusion scan)

32
Paradoxical Responses

• Prior to HIV, well known phenomenon of
  paradoxical response while on appropriate
  therapy for TB
• Typically manifested as
• worsening of infiltrate on chest x-ray
• new areas of infiltrate developing on therapy
• enlargement of pleural effusion
• enlarging lymph nodes often with rupture and
  drainage if close to skin

33
Paradoxical Response (cont)

• These phenomena are not due to bacteriologic
  progression of disease, but to restoration of
  anti-TB immune responses and subsequent increased
  inflammation
• Main consideration is distinguishing between true
  worsening of disease or treatment failure

34
Immune Reconstitution Syndrome

• Similar to paradoxical response, a perhaps even
  more exaggerated phenomenon has been observed
  during HIV therapy as immunity is restored
  against clinically silent opportunistic pathogens
• enlargement/drainage of MAC lymphadenitis
• worsening of CMV retinitis
• worsening of chronic active hepatitis B
• development of active sarcoidosis

35
Immune Reconstitution HIV/TB

• In patients receiving treatment for both HIV and
  TB, a marked and rapid enhancement of immune
  response may occur, resulting in
• worsening infiltrates and development of acute
  respiratory failure
• enlarging hilar/mediastinal lymphadenopathy
• cerebral tuberculomas
• numerous focal syndromes due to enhanced
  inflammation at extrapulmonary TB sites

36
Immune Reconstitution HIV/TB Treatment

• When reaction is severe, steroids are often used
  in conjunction with TB and HIV therapy
• Typically at prednisone dose of 60mg daily
  followed by a slow taper over two months
• Alternative is to defer HIV therapy until TB
  infection is controlled

37
Latent TB Infection in HIV

• Previously referred to as preventative therapy
  or prophylaxis
• LTBI defined by a positive PPD skin test but no
  evidence of active TB disease
• Because of high incidence of active TB developing
  in HIV patients exposed to TB, it is important to
  recognize and treat
• Recall that in HIV patient exposed to TB, risk of
  active disease is 10 per year

38
LTBI in HIV (cont)

• Screening for TB is with PPD skin test
• 0.1ml of 5 tuberculin units
• For HIV, gt 5mm induration is positive
• HIV patients should get PPD annually
• Anergy is common in HIV, especially as the CD4
  count falls

39
LTBI in HIV (cont)

• Treatment of LTBI in HIV has been shown to reduce
  active TB rates by 3-5 fold
• Treatment of LTBI recommended for any HIV patient
  with
• a positive PPD
• high risk exposure to an active case regardless
  of skin test status (due to high risk of anergy)
• Empiric therapy of LTBI in anergic HIV no benefit
  despite high local prevalence (10)

40
LTBI in HIV Treatment

• Several regimens available for treatment of LTBI
  in HIV
• INH x 9 months (can also be given as 900mg
  biweekly directly observed (DOPT) but efficacy
  not proven)
• Rifampin (or rifabutin) x 6 months
• RIF PZA daily for 2 months
• EMB (either PZA or oflox) for 12 months
• Tailor therapy if drug resistant case contact