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

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.

Factors associated with prevalent TB among HIV patients

Lawn, S AIDS 2006

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 TBBlock

Cytokines

Reduce HIV

Replication

TNF-

IL-6 IL-10

TGF- IL-1

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

TB prophylaxis for PLHIV Who? PPD positive

What? INH 300mg daily( WHO

recommendation) 6months

How long? 6/9/12/36 monthslife long

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.

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.

Screen for Tb prophylaxis

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

WHO Recommendation

* based on the CAMELIA, SAPIT and STRIDE trials

Antiretroviral Therapy and TB Treatment

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

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)

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.

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).

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.

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.

1st line Anti TB drugs

2nd line Anti TB

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

ART Coadministration with TB treatment: Drug Interactions

There are substantial overlapping drug toxicities and drug-drug interactions that must be considered when cotreatingHIV and TB.

In particular, the rifamycin derivatives (ie, rifampin, rifabutin, and rifapentine) can induce the hepatic cytochrome P450 enzyme system, resulting in increasedmetabolism 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

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

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.

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 EFVconcentrations, 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.

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.

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

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.

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.

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

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

PREVENTION

References

Ucsf university – HIV insite

Uptodate medicine

Tb and hiv guidelines

Medscape

Katzung clinical phamacology