Part A: Module A2

1
Prophylaxis of Opportunistic Infections

• Part A Module A2
• Session 10

2
Objectives

• Describe the prophylactic use of TMP/SMX and INH
• Describe the WHO recommendations for TMP/SMX and
  INH
• Understand when to prescribe prophylactic
  treatment, to whom and which regimen to use

3
Objectives, continued

• Describe other preventive measures 23-valent
  pneumococcal vaccine, antifungals, and hepatitis
  vaccine
• Understand the purpose of secondary prevention
  and describe the relevant regimens
• Discuss local and national guidelines regarding
  prophylaxis

4
Prophylaxis for Selected OIs Indications and
Treatment Guidelines

• Overview
• Prophylaxis/preventive measures
• Secondary prevention
• Necessary drugs and equipment

5
Overview
6

• OI prevention in resource constrained
  countries occurs in a context that is very
  different than what exists in Europe, North
  America, etc.

• Many HIV/AIDS patients in Africa do not survive
  long enough to develop OIs such as CMV or MAC
• Resources are limited. For the majority of
  patients, no CD4 counts are available, which
  would otherwise enable care providers to monitor
  disease progression
• HIV infection is often not diagnosed until the
  patient is at an advanced stage of disease

7
Common OIs in Resource Constrained Countries

• Tuberculosis widespread
• Pneumococcal disease widespread
• Non-typhoid salmonellosis particularly East and
  West Africa, Thailand, and Cambodia
• Cryptococcosis particularly East and South
  Africa, Thailand and Cambodia
• PCP South Africa and Asia
• Penicilliosis Thailand
• Bacterial infections

8
Some of the prevention measures recommended in
the U.S. are not too expensive and may provide
opportunities to prevent OIs in developing
countries

• TMP/SMX for PCP, cerebral toxoplamosis and
  various bacterial infections
• INH for tuberculosis

Indications for prophylaxis in resource
constrained countries include use of the WHO
clinical stage, and, where possible, CD4 count
and viral load.
9

• General Prevention Measures

• Avoid unpasteurized dairy products, raw or
  undercooked eggs, meat, poultry, or fish (sources
  of salmonella)
• Avoid undercooked or raw meat (source of
  toxoplasmosis)
• If no safe water supply is available, patients
  and family should be advised to boil drinking
  water to avoid diarrheal diseases such as
  cryptosporidiosis
• Moldy sugar cane or bamboo has been suggested as
  possible sources of Penicillium marneffei
  infection (in Thailand)

10
Drugs for OI Prophylaxis
11
Cotrimoxazole (TMP/SMX)

• An effective prophylaxis against
• Various bacterial infections Streptococcus
  pneumoniae, Salmonella species and Nocardia
• Pneumocystis carinii
• Toxoplasmosis
• Isospora belli
• Cyclospora

UNAIDS recommends that Cotrimoxazole be part of a
minimum package of care for adults and children
living with HIV/AIDS in Africa.
12
UNAIDS/WHO Cotrimoxazole Recommendations

• Candidates for cotrimoxazole prophylaxis should
  be
• recruited from all levels of health care
  facilities, AIDS
• service organizations and nongovernmental
• organizations
• Initial prescription of prophylaxis should be
  prescribed
• by trained health care personnel
• Counseling should be provided

13
UNAIDS/WHO Cotrimoxazole Recommendations

• Prophylaxis should be offered to
• HIV positive adults (over age 13) all persons
  with symptomatic HIV (Stage II, III or IV)
  asymptomatic persons with CD4 count of 500 or
  less or total lymphocyte equivalent pregnant
  women after 1st trimester
• HIV exposed infants from 6 weeks of age any
  child born to HIV infected mother any child
  identified as HIV infected during the 1st year of
  life any child older than 15 months who have had
  a PCP event, have symptomatic HIV disease, an
  AIDS defining illness or CD4 less than 15

14
UNAIDS/WHO Cotrimoxazole Recommendations,
continued

• Recommended drug dosages
• Adults 1 DS tablet or 2 SS tablets daily
• (1DSSMX 800 mgTMP 160 mg 1SSSMX
  400 mgTMP 80 mg)
• Children Cotrimoxazole syrup administered
  1/day, daily
• Recommended dose is TMP 10 mg/kg,
• SMX 50 mg/kg
• If syrup is unavailable, may use crushed
  tablets.
• Health professional may switch from syrup to
  tablet to ensure
• ongoing access to medication.

15
OI Prophylaxis

• Duration of Treatment
• Prophylaxis should be given life-long for
• adults and children (gt15 months)

16
OI prophylaxis, continued

• For infants lt 15 months
• Prophylaxis should continue until HIV infection
  has been
• reasonably ruled out and there is no further risk
  of
• exposure
• For children gt 15 months
• Prophylaxis should be administered if child has
• had a PCP event
• has symptomatic HIV disease
• has an AIDS-defining illness, or
• has a CD4 percentage less than 15

17
OI prophylaxis, contd.

• Criteria for Stopping Treatment (adults and
  children)
• In the occurrence of severe cutaneous reactions
  such as fixed drug reaction and Stevens Johnson
  syndrome, renal and/or hepatic failure, and
  severe hematological toxicity
• If antiretroviral agents become available and
  when CD4 is greater than 500, prophylaxis can be
  stopped
• Adverse Reactions
• Adverse reactions are common
• Every effort should be made to continue
  prophylaxis
• Lower doses are less effective than the
  recommended daily DS tablet

18
OI prophylaxis, continued

• Alternative Regimens
• Dapsone 50 mg 2 x daily or 100 mg /day
• In patients with CD4lt100 and positive toxoplasma
  antibodies, pyrimethamine 50 mg weekly folinic
  acid 25 mg weekly should be added to regimen
• Pentamidine aerosols 300mg/month are more
  difficult to implement, less effective (PCP),
  effect not entirely understood (toxoplasmosis)
• In cases of non-life threatening adverse
  reactions, treatment should be stopped for 2
  weeks, then the patient should be re-challenged
  with TMP/SMX in a gradually increasing dose

19
OI prophylaxis, continued

• Follow up Prophylaxis should be used where
  regular follow-up of patients is possible
• In adults, follow up should be every month and
  then every 3 months
• Children should be evaluated on monthly basis
• In adults and children, monitoring for toxicity,
  clinical events, and compliance to treatment
  should be undertaken.
• Monitoring of adults should also include
  hemoglobin and white blood counts every 6 months,
  where possible and when clinically indicated

20
OI prophylaxis, continued

• Monitoring Each country should develop an
  implementation and monitoring plan for
  Cotrimoxazole prophylaxis
• Concurrent monitoring for clinical
  effectiveness is important, especially
  in areas where widespread resistance is
  present in addition to prophylaxis
  investigation into new interventions is
  necessary

21
OI prophylaxis, continued

• Evaluation Program evaluation and clinical
  effectiveness indicators will be
  developed by a task force led by UNAIDS.
  Could include surveillance for
• Background rates of OI and antimicrobial
  resistance
• Changes in antimicrobial resistance
• Acute and cumulative toxicities

22
OI prophylaxis, continued

• Research Comparative studies to identify
  affordable alternative therapies
• Further studies on dose and time of
  initiation
• Willingness/ability to pay at the
  household level
• Household income, savings, expenses impact

23
OI prophylaxis, continued

• Cost TMP/SMX in the recommended dose of 1DS
  daily costs US 60/year
• Distribution Cotrimoxazole can be
  Given through community clinics and
  home-care projects
• Integrated into counseling activities,
  favoring the regular follow up of the PLH/A
  by a counselor at the same time as the
  cotrimoxazole prescription is renewed

24
Isoniazid (INH)

• HIV infection is the strongest known risk factor
  the progression of latent TB infection to active
  TB
• In countries with high TB prevalence, between
  2.4 and 7.5 of HIV-infected adults may develop
  active TB each year
• The mechanisms include reactivation of latent
  infection and/or a re-infection with
  Mycobacterium tuberculosis, characterized by a
  rapid progression towards active disease and a
  rapid progression of primary infection

25
Isoniazid (INH), continued

• Before the AIDS epidemic, preventive therapy for
  tuberculosis was never recommended in developing
  countries except for breast-feeding infants of
  mothers with PTB, or children lt 5 years old
  living with infectious persons
• Preventive therapy as a public health strategy is
  now being reconsidered because of the high
  incidence of TB in HIV-positive patients in
  developing countries
• In the pre-AIDS era, several placebo-controlled
  trials in the USA and Europe demonstrated the
  efficacy of INH prevention in PPD-positive
  persons, which is believed to be at least 60
• The cost of this drug is about US 60 per year

26
Isoniazid (INH), continued

• WHO Recommendations Preventive therapy (PT)
  against tuberculosis in people living with HIV
• Several large randomized controlled trials have
  now demonstrated that PT is effective in
  preventing TB in individuals dually infected with
  HIV and M. tuberculosis
• However, studies of feasibility of PT demonstrate
  that the process required to target appropriate
  individuals, to exclude active TB, to deliver PT,
  and to achieve compliance is complex and
  inefficient

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WHO Isoniazid Recommendations

• Prerequisites The following should be in
  place before a PT service is considered
• Adequate capacity for HIV counseling
• Sufficiently trained health care staff
• Linkage between HIV care and TB control services
• TB treatment services that have a high
  probability of curing cases of TB identified
  through the PT service (defaulter and failure
  rate lt10)

28
WHO Isoniazid Recommendations, continued

• Recommendations to Governments
• 1. Preventive therapy against tuberculosis should
  be part of a package of care for people living
  with HIV/AIDS
• 2. Preventive therapy should only be used in
  settings where it is possible to exclude active
  TB cases and to ensure appropriate monitoring
  and follow-up

29
WHO Isoniazid Recommendations, continued

• Information about tuberculosis, including
  preventive therapy, should be made available to
  people with HIV
• Preventive therapy should be provided from within
  settings that include established voluntary
  counseling and testing (VCT) services for HIV

30
WHO Isoniazid Recommendations, continued

• 5. The priority for TB control programmes
  continues to be the detection and cure of
  infectious tuberculosis cases
• 6. National authorities must regulate the
  procurement and supply of tuberculosis drugs in
  order to prevent the development of drug
  resistance

31
WHO Isoniazid Recommendations, continued

• Those who test positive for HIV should
  receive
• Counseling on tuberculosis
• People living with HIV are at risk of
  developing TB. They should be given health
  education and encouraged to seek early diagnosis
  and treatment of cough and other symptoms
  suggestive of TB.
• 2) Screening for active TB
• PT is inadequate treatment for active TB and
  could lead to the development of drug resistance
  if taken in such cases. Active TB should
  therefore be excluded before PT is started.
• Do chest x-ray before considering PT.

32
WHO Isoniazid Recommendations, continued

• Target those most PT is recommended for
  PPD-positive HIV- likely to benefit infected
  individuals who do not have active TB
• In some settings it may not be feasible to
  perform PPD testing. Under these circumstances
  the following individuals may still be considered
  for preventive therapy if they are infected with
  HIV
• Those living in population with high TB
  prevalence
• Health care workers
• Household contacts of TB patients
• Prisoners
• Miners
• Other groups at high risk of TB

33
WHO Isoniazid Recommendations, continued

• INH alone is the recommended drug regimen for
  preventive therapy to those without active
  tuberculosis
• Trials using combination treatment report higher
• rates of adverse drug reaction

• Isoniazid may be given as a daily,
  self-administered therapy for 6 months at a dose
  of 5 mg/kg to a maximum of 300 mg.
• These individuals should be seen monthly and
  given 1-month supply of medication at each visit.
  

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WHO Isoniazid Recommendations, continued

• Compliance may be improved by giving an
  additional 2-week emergency buffer supply to be
  used if the individual has to defer his or her
  monthly review.
• Rifampicin-containing regimens are not
  recommended in order to eliminate the risk of
  promoting rifampicin resistance through
  inadequate screening procedures or by misuse of
  the tablets.

35
WHO Isoniazid Recommendations, continued

• Contraindications Preventive therapy is
  contraindicated in to PT patients with
  active tuberculosis and in patients with
  active (chronic or acute) hepatitis
• Active tuberculosis must be excluded before
  beginning preventive therapy
•  
• Isoniazid should be given with caution to
  individuals who consume alcohol daily

36
Conclusions

• Programs with Cotrimoxazole prevention for PLHA
  must show proof of good patient compliance and
  have strategies in place to follow-up defaulters
• INH prophylaxis is recommended for all known
  HIV-infected persons,without performing a PPD
  test
• Active TB has to be excluded before starting PT
• That is, only asymptomatic PLHA who are in WHO
  clinical stage 1 and 2 and who have a negative
  chest X-ray will be considered for PT
• Patients who have are in clinical stage 3 with
  no other symptoms might also be candidates for
  starting preventive therapy

37
Conclusions, continued

• Dose of INH 5 mg/kg, with a maximum of 300 mg
  daily, for a duration of 6 months. (WHO
  guidelines)
• All projects that face difficulties in the
  control of TB should not start INH preventive
  therapy on a routine basis
• Projects that want to implement PT should have
  close working relationships between HIV and TB
  services. The programmes need qualified staff for
  counseling, a high cure rate for TB and a low
  defaulter rate (lt10) 
• All projects, except pilot projects in HIV/AIDS
  care, should follow the national guidelines
•  Prophylactic Treatment as Recommended in the U.
  S. in appendix C

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Other Preventive Measures

• 23-valent pneumococcal vaccine
• HIV infected at increased risk of invasive
  pneumococcal disease caused by streptococcus
  pneumoniae
• Antifungals
• In some regions with an unusual high incidence of
  cryptococcal meningitis or P. marneffei, primary
  prophylaxis with fluconazole or itraconazole
  might be considered
• Hepatitis B vaccination
• HIV-infected patients have a higher risk of
  hepatitis B because of common risk factors.
  Patients who are HIV-positive are more likely to
  develop chronic hepatitis

39
Secondary Prevention
40

• Tuberculosis

• Tuberculosis
• Until now, secondary prevention for TB has not
  been advocated
• Extended therapy (beyond 6-9 months) has been
  shown to reduce the incidence of relapse, but
  showed no benefit in terms of survival
• Although no firm recommendation can be made, the
  results of a Haiti study favors use of secondary
  INH prophylaxis in patients who had symptomatic
  HIV disease before the initial diagnosis and
  treatment of TB

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• PCP

• PCP
• TMP/SMX 1 DS daily is the recommended dose.
  Tolerance is improved with lower doses

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• Fungal Infections

• Fungal Infections
• P. marneffei Itraconazole 200 mg daily
• Cryptococcus neoformans Fluconazole 200 mg
  daily (1st choice), amphotericin B, IV,
  1/week, or fluconazole 200 mg 3 x
  weekly
• Oral Thrush/ Fluconazole 100-200 mg
  Oesophageal candidiasis daily only if
  recurrences are severe and frequent
• Toxoplasmosis TMP/SMX 1DS daily
• Mucocutaneous Acyclovir 200mg 3 x daily or
• Herpes Simplex acyclovir 400 mg 2 x daily

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Necessary Drugs and Equipment
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