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2. Epidemiology
 The HIV pandemic has resulted in an explosion of TB to epidemic
proportions in many parts of the world, especially in sub-Saharan
Africa, including Tanzania.
 HIV-associated TB has challenged and constrained gains made in
TB care and control, and TB is the leading preventable cause of
death among PLHIV, accounting for 30% of AIDS-related deaths.
 It is estimated that 10-15% of PLHIV are infected with TB globally.
 The lifetime risk of developing active TB among PLHIV co-infected
with TB is 30-50%, compared to a lifetime risk of 5-10% in HIV-
negative individuals.
 About 38% of all TB patients in Tanzania are co-infected with HIV
*NTLP guildeline 2013

3. HIV increases the risk for TB
 HIV is the strongest risk factor for developing
 The risk of developing TB is between 20 and 37 times
 Reactivation of latent TB
 Re- infection with new MTB strains
 Multidrug-resistant TB (MDR-TB) : is defined as TB that
is resistant to at least isoniazid and rifampicin.
 Patients with both HIV and MDR-TB face complicated
clinical management, fewer treatment options and
poorer treatment outcomes.

4. Factors associated with prevalent
TB among HIV patients
Lawn, S AIDS 2006

5. Pathogenesis
 Control of TB infection in the body is dependent on a robust cell-mediated
immunity (T cell) , with which HIV interferes through the systematic killing of
CD4 T-lymphocytes, this increases susceptibility to tb.
TB replication
(reactivation/
persistance)
TB mediated
imm. activation
Increased HIV
replication
Inhibit TB
Block
Cytokines
Reduce HIV
Replication
TNF-
IL-6 IL-10
TGF- IL-1

6. Identification of TB & HIV patients: TB is a
diagnostic challenge among HIV patients
Diagnostic tests
 Offer HIV testing for all TB
patients
 Evaluate all HIV patients for
TB
 Microbiological
 Imaging
 Serological tests
 IGRA
 Cytometry: T cell response
 NAAT
Screening

7. TB prophylaxis for PLHIV
 Who? PPD positive
 What? INH 300mg daily( WHO
recommendation) 6months
 How long? 6/9/12/36 months
life long

8. TB prophylaxis for PLHIV
 Adults and adolescents living with HIV should be screened
for TB with a clinical algorithm; those who report any one
of the symptoms of current cough, fever, weight loss or
night sweats may have active TB and should be evaluated
for TB and other diseases
 Tb patients with known +ve HIV status and TB patients
living in HIV-prevalent settings should receive at least six
months of rifampicin treatment regimen.
 Xpert MTB/RIF should be used as the initial diagnostic test
in individuals suspected of having HIV-associated TB or
multidrug-resistant TB.

9. TB prophylaxis for PLHIV
 Adults and adolescents who are living with HIV, have unknown
or positive tuberculin skin test (TST) status and are unlikely to
have active TB should receive at least six months of IPT
(Children above 1yrs -10mg/kg/day)as part of a comprehensive
package of HIV care.
 IPT should be given to such individuals irrespective of the
degree of immunosuppression, and also to those on ART, those
who have previously been treated for TB and pregnant women
Note: Providing IPT to people living with HIV does not increase the risk of
developing isoniazid-resistant TB. Therefore, concerns regarding the
development of INH resistance should not be a barrier to providing IPT.

10. Screen for Tb prophylaxis

12. Antiretroviral Therapy and TB
 Improved immune responses to TB with HAART
 Reduction in case rates of TB during HAART era
 HAART could reduce risk of primary infection, relapse,
and re-infection

14. WHO Recommendation
* based on the CAMELIA, SAPIT and STRIDE trials

15. Antiretroviral Therapy and TB
Treatment

16. IRIS
IRIS : is a spectrum of clinical features thought to be
ass/ with immune recovery brought about by a
response to ART.
 It is a widely recognized phenomenon that occurs
among 10–30% of the people initiating ART, usually
within the first 4–8 weeks after initiating therapy
 It has been reported for many different infections,
tumours and non-infectious conditions

17. Antiretroviral (ARV)
First Line ARV Combination Regimen for Adults and
Adolescent ART
 The MoHSW recommends the following drugs for first
line treatment:
• Zidovudine (AZT)
• Lamivudine (3TC)
• Tenofovir (TDF)
• Emtricitabine (FTC)
• Nevirapine (NVP)
• Efavirenz (EFV)
• Stavudine (d4T)

18. ARV
 The default first line regimen in Tanzania is:
• Zidovudine (AZT) 300 mg/Lamivudine (3TC) 150 mg twice
daily and Efavirenz (EFV) 600 mg once daily at night.
• For women of child bearing age, Nevirapine (NVP) 200mg
twice a day is given instead of Efavirenz.

19. The recommended first-line ART
regimens for TB patients
 Are those that contain efavirenz (EFV), since interactions with anti-tb
drugs are minimal.
 For those who are unable to tolerate or have contraindications to an
EFV-based regimen, AZT +3TC + NVP or TDF +3TC or FTC + NVP or
a triple NRTI regimen, e.g. AZT+3TC+TDF, is recommended.
 When using Nevirapine based regimen, the patient should be started
on a normal dose (200mg bd). A leading dose is not required.
 In individuals who need TB treatment and require an ART regimen
containing a boosted protease inhibitor (PI), it is recommended to use
Rifampicin and a boosted ARV containing Lopinavir with additional
Ritonavir dosing (LPV/r 400mg/400mg BID).

20. PREFERED ART ON TB
 TDF + 3TC (or FTC) + EFV offers good potential for
harmonizing treatment across different populations:
 TDF/FTC or TDF/3TC are the preferred NRTI backbone for
people coinfected with HIV and TB and among pregnant
women.
 EFV is the preferred NNRTI for people with HIV and TB
(pharmacological compatibility with TB drugs).
 For infants and children infected with HIV younger than three
years, ABC + 3TC + AZT is recommended as an option for
children who develop TB while on an ART regimen containing
NVP or LPV/r.

21.  When people coinfected with TB and HIV are receiving
a boosted PI, rifampicin may need to be substituted
with rifabutin. If rifabutin is not available, LPV/r and
SQV/r can be used for the duration of TB treatment, if
the boosting dose of RTV is increased or double the
standard dose of LPV/r is used.

23. 1st line Anti TB drugs

26. 2nd line Anti TB

27. Safety and Tolerability
 The risk of adverse reactions to TB treatment is higher in
HIV-infected individuals than in HIV-uninfected
individuals, occurring in approximately 25% and 13%,
respectively.

 Hepatotoxicity is common in the Rx of TB in HIV-
infected patients, and may be exacerbated by overlapping
toxicities with ARV and antibiotic medications such as
fluconazole and trimethoprim-sulfamethoxazole, by
coinfection with viral hepatitis, or by preexisting liver
disease

29. ART Coadministration with TB
treatment: Drug Interactions
 There are substantial overlapping drug toxicities and drug-
drug interactions that must be considered when cotreating
HIV and TB.
 In particular, the rifamycin derivatives (ie, rifampin,
rifabutin, and rifapentine) can induce the hepatic
cytochrome P450 enzyme system, resulting in increased
metabolism and decreased serum levels of NNRTIs,PIs,
integrase inhibitors, and the CCR5 antagonist, as well as
other drugs.
 Resulting in bidirectional drug-drug interaction between
many HIV medications and rifamycins

30.  Rifamycins currently are the cornerstone of effective TB Rx and
are recommended for the duration of TB Rx in persons with HIV
coinfection.
 In the HIV-infected popln, regimens that do not include a
rifamycin in the continuation phase have been associated with a
2-3 times higher risk of recurrence.
 The most commonly used rifamycin in TB is rifampin with
drug interactions owing to induction of hepatic metabolism
of many other drugs.
Refamycin

31. Rifamycin
 Rifabutin is another rifamycin that is highly active
against MTB but has less impact on hepatic
microsomal metabolism; it therefore has been the drug
of choice for coadministration with ARVs that are
problematic with rifampin, such as the ritonavir-
boosted PIs.
 When rifampin is changed to rifabutin, the CYP3A4
enzyme induction from rifampin is estimated take up to
2 weeks to dissipate after discontinuation, therefore, a
change from rifampin to rifabutin will need to be
planned in advance of starting an ART regimen that is
negatively impacted by rifampin, to avoid
subtherapeutic ARV levels.

32. NNRTI
 EFV(efavirenz) based ART currently is the drug of choice for
patients who are receiving rifampin as part of TB Rx.
 Rifampin co-administration reduces serum EFV
concentrations, raising the question of whether EFV should
be increased to 800 mg when given with rifampin,
particularly those >50 kg weight.
 Patients with a T/T 2B6 polymorphism (genes for
CYP450), which is more common in Sub-saharan African
and African American populations, experience higher levels
of EFV when it is coadministered with rifampin.
 Higher EFV levels have been associated with CNS toxicity.

33. Protease inhibitor (PIs)
 Rifampin greatly reduces plasma concentrations of PIs and
therefore cannot be co-administered safely with PIs given at
standard dosages.
 Two alternative approaches currently are available for giving
rifamycin-based TB treatment with ritonavir-boosted PIs:
 1) using rifabutin rather than rifampin; or
 2) using rifampin with increased dosages of ritonavir or the PI.
 Rifabutin has a complex bidirectional drug interaction with PIs,
“rifabutin increasing PI levels and PIs increasing rifabutin
‘’levels. This has led to a recommendation that the dosage of
rifabutin be reduced.
 If the PI is discontinued, the dosage of rifabutin would need to
be adjusted upward to a standard dosage of 300 mg daily.

34. Nucleoside/Nucleotide Reverse
Transcriptase(NRTI)
 Inhibitors Rifamycin-based TB treatment generally does not
have significant drug-drug interactions with
nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs)
and dosage adjustment of NRTIs is not required.
 INH and the NRTIs - zidovudine (ZDV), stavudine (d4T), and
didanosine (ddI) all can contribute to peripheral neuropathy,
and coadministration particularly of d4T should be avoided, if
feasible.
 Pyridoxine should be given to all HIV-infected patients being
treated for active TB, to reduce the risk of INH-associated
neuropathy

35. Integrase Inhibitors
 Rifampin decreases concentrations of the integrase inhibitor
Raltegravir;Doubling the dosage of raltegravir compensates but does
not normalize raltegravir trough levels.
 It is unclear whether it is necessary to increase raltegravir dosage.
 Until more data are available, the conservative approach would be to
dose raltegravir at 800 mg twice daily when giving it with rifampin.
 Elvitegravir is metabolized by CYP3A4 and therefore its serum
concentration may be reduced by rifampin; coadministration is not
recommended.
 Dolutegravir concentrations also are decreased by coadministration of
rifampin; doubling the dosage of dolutegravir results in plasma
concentrations comparable to those seen without rifampin.

36. CCR5 Antagonists and Fusion Inhibitors
 The CCR5 antagonist maraviroc (MVC) is metabolized by
CYP3A4, and MVC concentrations are reduced by rifampin.
 Owing to limited clinical data, coadministration of MVC and
rifampin is not recommended, but if alternatives are not
available, an increase in MVC dosage to 600 mg twice daily may
be considered.
 There are no data for interactions of rifabutin with MVC; MVC
levels may be slightly decreased but dosage adjustment currently
is not recommended, unless there is another strong CYP3A4
inhibitor or inducer in the regimen.
 The fusion inhibitor enfuvirtide is not affected by
coadministration with rifamycins.

37. Other HIV-Related Medications
Affected by TB Treatment
 Rifamycins also interact with several antifungals commonly
used for treatment or prevention of opportunistic
infections.
 Coadministration of rifampin with ketoconazole or
fluconazole decreases the AUC of the antifungal by
approximately 80% and 20%, respectively
 Therefore, ketoconazole and rifampin should not be given
together.
 Rifampin and fluconazole can be used together, but the
fluconazole dosage may need to be increased

38. Prevention
 Determining which medication is the offending agent can be
challenging. In the setting of TB, this usually involves holding
all medications and restarting sequentially to determine
which medication caused the problem.
 Although this approach works quite well with TB
medications, in the case of HIV infection, sequential addition
of ARV drugs is not advisable because of the risk of
developing ARV resistance.
 When an adverse reaction occurs with ARV medications, the
agent most likely to be responsible usually is deduced based
on known adverse-effect profiles and clinical judgment

39. PREVENTION

41. References
Ucsf university – HIV insite
Uptodate medicine
Tb and hiv guidelines
Medscape
Katzung clinical phamacology