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					        Questions and responses from the November 19 I-TECH
      presentation of prevention of TB in persons with HIV/AIDS,
                   presented by Dr. Charles Nolan

   Tuberculin Skin Test

    KEMRI/WRP Kericho, Kenya: What is the reliability of TST results
     in persons with severe AIDS?

    Finos Gwanyanya: What is the role of TST in areas with a high
     prevalence of TB?

Response to the two questions above: It is clear that the TST can be
very useful in identifying persons who will benefit from IPT, even in a
region with a high prevalence of TB. To be sure, the TST tends to
become less useful as a marker of latent infection with M. tuberculosis
as the CD4 count diminishes with progressive AIDS. However, even in
that scenario a positive result can still be very helpful, even though a
negative result cannot be trusted as being a true negative. Remember
that in the Cochrane review of IPT (Cochrane Database Syst Rev.
2004;(1):CD000171), presented in my slide #19, the benefit to TST+
persons with HIV infection was twice that of those who did not receive

Using the TST in identifying persons who should receive IPT requires a
commitment to train staff members to read and interpret the test, to
be able to adequately obtain and store the reagent, and to organize so
that persons who receive the test can be accessed two or three days
later for reading the results of the test.

   Isoniazid Preventive Therapy

    I-TECH_INDIA: is there any role of Cotrimoxazole (CTZ) in TB
Response: There is interest at this moment in evaluating
cotrimoxazole as an agent for treatment and preventive treatment of
TB. There is no doubt that CPT prolongs the lives of HIV infected
persons, but that effect has been presumed to be related to the
prevention of opportunistic infections other that TB. Look for further
information on this subject in the near future.

    KIYA: Are there options for preventive therapy other than INH?

Response: At this moment INH and rifampicin are the two agents that
have been shown to be effective as preventive therapy for TB. There
is reluctance to use rifampicin for indications other than active TB in
persons receiving PIs and NNRTIs, so that INH is effectively the only
drug available at the present time. Research continues to identify
additional drugs to prevent TB as well as to treat it.

    I-TECH_INDIA 2: With asymptomatic patients, is it possible to
     have adherence for IPT?

Response: It is very difficult to motivate a person who is not ill from
TB to take medication for 6 to 9 months. Success depends on being
able to see patients regularly, and communicate effectively with them
to explain the benefit that they will experience from taking this
preventive, rather than curative treatment.

    I-TECH_INDIA 2: In TST positive, asymptomatic HIV patients is it
     advisable to start ATT?

Response: I don’t know the abbreviation “ATT.” If the intent was to
write “IPT,” then the answer is clearly yes, it is beneficial to start IPT in
asymptomatic HIV+ patients who are TST+, for reasons given above.

    Otjiwarongo State Hospital- Namibia: How long exactly does
     protection with INH last?
    Kilifi- Kenya: How frequent can we then give IPT to HIV pts since
     it doesnt offer lifetime protection?

Response to the two questions above: Studies have shown that the
protection bestowed by IHN to prevent TB does not last for a lifetime
in persons with HIV infection, particularly in regions where TB is highly
prevalent. The duration of treatment begins to wane after two to
three years, most likely because the person becomes re-exposed,
acquires another latent infection, which may proceed to TB disease.
Because of this observation, with is covered in the Cochrane review
referenced above, there is active research on giving INH for longer
periods of time, or giving several successive course of INH, to provide
more lasting effect. There is current study of giving INH as a single
drug following completion of multi-drug treatment for active TB, to
attempt to prevent relapses which occur more commonly in persons
with HIV infection.

    Itechbotswana: What is the exact mechanism of action in
     preventing TB using monotherapy with INH? How can a 6 month
     IPT course protect a patient up to 2 years?

Response: INH works to prevent TB in persons with latent TB infection
(marked by a positive TST) by eradicating that latent infection. Thus, a
6-9 month course of IPT that has successfully eradicated a latent TB
infection would endure so long as the person does not become
infected again. In low incidence areas, where exposure to TB is rare,
that preventive effect of a course of INH usually lasts a lifetime.
However, in high prevalence areas, there is a greater chance of
becoming re-exposed and re-infected, in which case the patient is
again at risk of progressing from latent to active TB.

    FSinyinza - Rundu, Namibia: Is there any documented evidence
     of INH resistant TB due to IPT?
Response: Studies have repeatedly shown that persons treated with
IPT have a modestly greater chance of having an isoniazid-resistant
strain if they contract TB following IPT, compared with those not so
treated. I showed results of a study from South Africa in which the
frequency of INH-resistant disease was 13.2%, with the rate of INH-
resistant disease in the comparison group 8.2% (slide #24). It is
important to remember that the outcome of treatment of INH-
resistant TB is excellent, using the same drug regimen (rifampicin,
pyrazinamide, and ethambutol, with or without isoniazid) as is used to
treat drug-susceptible TB disease. In other words, you should expect
no decrement in success of treating TB that occurs following IPT, even
if the infecting M.tb isolate is resistant to INH.

    How many of the IPT recipients had tb?

Response: I believe this question also refers to the slide from Dr.
Churchyard’s work that I presented in my slide #24. In that study
there were 57 cases of TB among miners who had received IPT; 7
(13.2%) were INH-resistant. In the comparison group, who had
received no preventive therapy, there were 97 TB cases during the
observation period, among whom 8 (8.2%) were INH-resistant. The
slide does not present the number of miners treated with INH, and I
do not have that information.

  Infection Control

   What are isolation requirements for cases of sputum smear-
    negative TB particularly in light of the November 2008 paper in
    CID (that reference is which showed that 13% of TB transmission
    in the Netherlands was due to sputum smear-negative cases?
Response: It is clear that persons who have pulmonary TB yet have
negative sputum smears for AFB may still transmit the infection to
others, as shown by the paper you cite (Clin Infect Dis. 2008 Nov
1;47(9):1135-42), and others. For that reason everyone with a diagnosis of
pulmonary TB should be isolated while in hospital with the same
procedures as for those with sputum smears positive for AFB.

    Derebe: Do infection control principles differ for drug resistant
     TB? if YES HOW?

Response: Patients with known multidrug-resistant TB should be
subject to more extreme infection control measures than others
because they have the possibility of transmitting a fatal infection to
immunocompromised patients and hospital staff. The new WHO
guidelines on infection control, referred to in my slide #27, states that
“Because of the risk of severe morbidity and mortality to HIV-infected
persons from MDRTB, persons with known MDRTB should receive
routine care outside of normal HIV care settings.”

   Intensified Case Finding

    KEMRI/WRP Kericho, Kenya: what proportion of cases of TB in
     HIV-infected persons are sputum positive on ZN stains?

Response: Most studies show that on average, half of cases of
pulmonary TB in persons with HIV infection are sputum AFB+. Persons
in the early stage on HIV infection more often have positive smears for
AFB, and the proportion of AFB+ pulmonary cases decreases as the
CD4+ count falls. In the population without HIV infection, about 70-
75% of cases of pulmonary TB have positive smears.

    Derebe: how feasible are investigations like Chest X-RAY in
     resource limited settings and how sensitive is symptom
     screening only
Response: Studies have been in inconsistent in demonstrating a
positive effect of using Xrays in screening for TB in persons with HIV
infection. In Churchyard’s studies in HIV+ miners, performing Xrays
greatly increased the yield of screening, but in community-based
studies from Zambia Xrays contributed little. My belief is that it is the
screening which is important, with or without Xray. If Xrays are readily
available (with expert readers), I personally favor their use. If they are
not available, I would still conduct symptom screening. There are a
number of studies that address the sensitivity and specificity of
symptom screening. One of the very good screening schemes is found
in the following reference (Rabkin M, El-Sadr W, Abrams E. Care and
treatment of HIV/AIDS in resource-limited settings. The Columbia Clinical
Manual. Available at: http://www.columbia- In
general, algorithms that have a high yield of positives (greater
sensitivity) have a lower specificity, and vice versa.

    Otjiwarongo State Hospital- Namibia: what is the disadvantage
     of delaying early detection of TB in a person with HIV?

Response: Looking at the question from the other point of view, there
are several important advantages of early detection of TB in persons
with HIV infection. (1) By finding the case earlier and starting
treatment sooner, the chances of cure are improved considerably.
(2) Early detection and treatment aborts infectivity sooner and
prevents further spread of the infection, if the patient has pulmonary
TB. (3) Early detection should lead to quicker investigation of
household members, including children, for active TB, latent TB
infection, and HIV infection, and the possibility of even further
preventive interventions in family members.

    Finos Gwanyanya: Would you recommend HIV testing of all
Response: I believe that all household members of HIV+ TB patients
should be offered testing for HIV infection. Excellent data on this issue
are being developed in the Zamstar study in Zambia, under the
leadership of Dr. Helen Ayles and Peter Godfrey-Fausett. Preliminary
results there indicate that among 1490 household contacts of patients
with pulmonary tuberculosis who were tested for HIV infection, 678
(45.5%) were HIV+. Furthermore, a remarkably large proportion (409
or 60%) met criteria for initiation of ART.

   Pathogenesis of TB in HIV-infected persons

    i-tech Addis Abab: among HIV patients which one is more
     common; Reactivation or reinfection.

Response: Both reactivation, the recurrence of disease due to the
same TB strain that caused the original episode of disease, and re-
infection, the development of disease due to acquisition of another
strain after cure of a previous infection, occur commonly in areas of
high TB prevalence. Good supervision of TB treatment should limit
recurrences, but so long as TB circulates widely in a community, all
persons from that community are subject to exposure and re-
infection. This is another reason to support programs for early
detection of TB.

    MoHSS-Katutura: In which countries were those reviews carried
     out, those with a high tb prevalence or no?

Response: I believe that question relates to slide #11, the review by
Steven Lawn et al covering studies that show a reduction in TB
incidence during ART. The slide gives the locations of the studies:
USA, Italy, two from Brazil, two from South Africa, and three from
Spain. Consequently, the effect of ART to reduce the incidence of TB
has been shown in both low TB incidence and high TB incidence
regions of the world.

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