<str<strong>on</strong>g>Guidel<strong>in</strong>es</str<strong>on</strong>g> <strong>on</strong> <strong>the</strong> Preventi<strong>on</strong> <strong>and</strong> C<strong>on</strong>trol <strong>of</strong> <strong>Tuberculosis</strong> <strong>in</strong> Irel<strong>and</strong> 2010HSE/HPSC230BFollow up evaluati<strong>on</strong>A cl<strong>in</strong>ical evaluati<strong>on</strong> should be performed m<strong>on</strong>thly to assess medicati<strong>on</strong> <strong>in</strong>tolerance <strong>and</strong> adherence <strong>in</strong> TB/HIV-<strong>in</strong>fected <strong>in</strong>dividuals. Treatment effectiveness should be m<strong>on</strong>itored throughout <strong>the</strong> treatment period. Inpulm<strong>on</strong>ary TB/HIV patients, a m<strong>in</strong>imum <strong>of</strong> <strong>on</strong>e sputum specimen should be exam<strong>in</strong>ed microscopically eachm<strong>on</strong>th, until two c<strong>on</strong>secutive specimens are negative <strong>on</strong> culture. Drug susceptibility should be re-evaluated<strong>in</strong> patients with culture positive specimens after three m<strong>on</strong>ths <strong>of</strong> treatment. The ease <strong>of</strong> m<strong>on</strong>itor<strong>in</strong>gtreatment effectiveness will be determ<strong>in</strong>ed by <strong>the</strong> site <strong>of</strong> <strong>in</strong>fecti<strong>on</strong> <strong>in</strong> extrapulm<strong>on</strong>ary cases. More frequentm<strong>on</strong>itor<strong>in</strong>g is required for patients with underly<strong>in</strong>g liver disease <strong>in</strong>clud<strong>in</strong>g hepatitis C.The risk <strong>of</strong> relapse is believed to be <strong>the</strong> same <strong>in</strong> HIV-<strong>in</strong>fected <strong>and</strong> n<strong>on</strong>-<strong>in</strong>fected TB cases receiv<strong>in</strong>grifampic<strong>in</strong> for a m<strong>in</strong>imum <strong>of</strong> six m<strong>on</strong>ths. HAART has been shown to reduce <strong>the</strong> risk <strong>of</strong> relapse. 370-372Commencement <strong>of</strong> HAARTThe Internati<strong>on</strong>al St<strong>and</strong>ards for TB Care 25 propose that all patients with TB/HIV co-<strong>in</strong>fecti<strong>on</strong> should beevaluated to determ<strong>in</strong>e if antiretroviral <strong>the</strong>rapy is <strong>in</strong>dicated dur<strong>in</strong>g <strong>the</strong> course <strong>of</strong> TB treatment. The use<strong>of</strong> co-trimoxazole <strong>in</strong> TB/HIV-<strong>in</strong>fected <strong>in</strong>dividuals as prophylaxis aga<strong>in</strong>st o<strong>the</strong>r <strong>in</strong>fecti<strong>on</strong>s should also beevaluated.While <strong>in</strong>itiati<strong>on</strong> <strong>of</strong> TB treatment should not be delayed, <strong>the</strong>re is no <strong>in</strong>ternati<strong>on</strong>al agreement <strong>on</strong> <strong>the</strong> optimaltime to start HAART <strong>in</strong> TB/HIV patients. Case-by-case assessments are made <strong>in</strong> an attempt to balance<strong>the</strong> risk <strong>of</strong> progressi<strong>on</strong> <strong>of</strong> HIV aga<strong>in</strong>st that <strong>of</strong> hav<strong>in</strong>g to <strong>in</strong>terrupt/disc<strong>on</strong>t<strong>in</strong>ue <strong>the</strong>rapies due to toxicities,side effects, drug <strong>in</strong>teracti<strong>on</strong>s, etc. Delay<strong>in</strong>g antiretroviral <strong>the</strong>rapy can simplify patient management, limitadverse events, drug <strong>in</strong>teracti<strong>on</strong>s <strong>and</strong> immune restorati<strong>on</strong> reacti<strong>on</strong>s. Fur<strong>the</strong>rmore, studies have showndeaths due to TB are more comm<strong>on</strong> <strong>in</strong> <strong>the</strong> first m<strong>on</strong>th <strong>of</strong> TB treatment, while deaths occurr<strong>in</strong>g later <strong>on</strong>may be due to HIV disease progressi<strong>on</strong>. 373-375 BHIVA recommend <strong>the</strong> follow<strong>in</strong>g start times <strong>of</strong> antiretroviral<strong>the</strong>rapy <strong>in</strong> TB/HIV-<strong>in</strong>fected patients.Table 10.1: Recommended HAART start<strong>in</strong>g times (adapted from BHIVA guidel<strong>in</strong>es)CD4 cells/μLCommencement <strong>of</strong> HAART200®After complet<strong>in</strong>g 6 m<strong>on</strong>ths <strong>of</strong> TB treatment12F® CD4 count m<strong>on</strong>itor<strong>in</strong>g should be performed every 6-8 weeks. If CD4 count falls, patient may need to start HAART.The <strong>in</strong>itiati<strong>on</strong> <strong>of</strong> HAART with<strong>in</strong> two to four weeks <strong>of</strong> anti-tuberculous <strong>the</strong>rapy has been associated withdecreased HIV-1 progressi<strong>on</strong> (CDC) but a high <strong>in</strong>cidence <strong>of</strong> adverse events <strong>and</strong> paradoxical reacti<strong>on</strong>s (seebelow). By delay<strong>in</strong>g HAART by a m<strong>in</strong>imum <strong>of</strong> four to eight weeks after <strong>in</strong>itiati<strong>on</strong> <strong>of</strong> TB <strong>the</strong>rapy, specificcauses can be assigned to drug side effects <strong>and</strong> <strong>the</strong> severity <strong>of</strong> a paradoxical reacti<strong>on</strong> can be reduced.Optimal tim<strong>in</strong>g for start<strong>in</strong>g HAART should be based <strong>on</strong> an <strong>in</strong>dividual’s <strong>in</strong>itial resp<strong>on</strong>se to treatment, sideeffects <strong>and</strong> acceptance <strong>of</strong> antiretroviral treatment. 342TB treatment should <strong>on</strong>ly be modified when a patient has developed <strong>in</strong>tolerance to, or severe toxicityfrom, HIV drugs or has evidence <strong>of</strong> genotypic resistance to specific HIV drugs thus limit<strong>in</strong>g HAART <strong>the</strong>rapyto agents which are likely to <strong>in</strong>teract with anti-TB <strong>the</strong>rapy. These factors may require <strong>the</strong> durati<strong>on</strong> <strong>of</strong> TBtreatment to be extended. 345Factors complicat<strong>in</strong>g <strong>the</strong> treatment <strong>of</strong> TB/HIV 344;345Adverse pharmacological <strong>in</strong>teracti<strong>on</strong>s occur between rifampic<strong>in</strong> <strong>and</strong> antiretroviral drugs used <strong>in</strong> <strong>the</strong>treatment <strong>of</strong> HIV disease due to shared routes <strong>of</strong> metabolism. Due to <strong>the</strong>se complexities <strong>of</strong> treatment, it isimportant that <strong>the</strong> use <strong>of</strong> both HAART <strong>and</strong> anti-TB treatment is managed by those with relevant expertise.Here we provide an overview <strong>of</strong> <strong>the</strong> complexities <strong>of</strong> c<strong>on</strong>comitant treatment <strong>of</strong> HIV <strong>and</strong> TB.Rifampic<strong>in</strong> <strong>in</strong>duces an enzyme <strong>in</strong> <strong>the</strong> hepatic cytochrome P-450 (CYP) system which is <strong>in</strong>volved <strong>in</strong> <strong>the</strong>metabolism <strong>of</strong> protease <strong>in</strong>hibitors (PIs) <strong>and</strong> n<strong>on</strong>-nucleoside reverse <strong>in</strong>hibitors (NNRTI). Rifampic<strong>in</strong> canaccelerate clearance <strong>of</strong> PIs <strong>and</strong> NNRTIs metabolised by <strong>the</strong> liver, result<strong>in</strong>g <strong>in</strong> sub-<strong>the</strong>rapeutic levels <strong>of</strong> <strong>the</strong>-129-
<str<strong>on</strong>g>Guidel<strong>in</strong>es</str<strong>on</strong>g> <strong>on</strong> <strong>the</strong> Preventi<strong>on</strong> <strong>and</strong> C<strong>on</strong>trol <strong>of</strong> <strong>Tuberculosis</strong> <strong>in</strong> Irel<strong>and</strong> 2010HSE/HPSCdrugs. Cl<strong>in</strong>ically important drug <strong>in</strong>teracti<strong>on</strong>s can become evident after two weeks <strong>of</strong> treatment when <strong>the</strong><strong>in</strong>duc<strong>in</strong>g effect is maximised <strong>and</strong> can persist for two weeks after rifampic<strong>in</strong> has been withdrawn from <strong>the</strong>treatment regimen. Fur<strong>the</strong>rmore, rifampic<strong>in</strong> can enhance <strong>the</strong> activity that results <strong>in</strong> <strong>the</strong> elim<strong>in</strong>ati<strong>on</strong> <strong>of</strong> PIsfrom <strong>the</strong> body. Despite <strong>the</strong>se <strong>in</strong>teracti<strong>on</strong>s, rifampic<strong>in</strong> should not normally be excluded from <strong>the</strong> st<strong>and</strong>ardtreatment regimen for TB/HIV cases receiv<strong>in</strong>g antiretroviral <strong>the</strong>rapy.An immune rec<strong>on</strong>stituti<strong>on</strong> <strong>in</strong>flammati<strong>on</strong> syndrome (IRIS) or a paradoxical reacti<strong>on</strong> is a temporaryexacerbati<strong>on</strong> <strong>of</strong> TB symptoms or radiographic f<strong>in</strong>d<strong>in</strong>gs after beg<strong>in</strong>n<strong>in</strong>g anti-TB treatment. It has beendescribed <strong>in</strong> n<strong>on</strong> HIV-<strong>in</strong>fected <strong>in</strong>dividuals but is more comm<strong>on</strong> <strong>in</strong> HIV positive cases. It occurs because <strong>of</strong>rec<strong>on</strong>stituti<strong>on</strong> <strong>of</strong> immune resp<strong>on</strong>siveness due to HIV or TB treatment which leads to an abnormal immuneresp<strong>on</strong>se to TB antigens released by dead/dy<strong>in</strong>g bacilli <strong>and</strong> is accompanied by a high fever, <strong>in</strong>creasedsize <strong>and</strong> <strong>in</strong>flammati<strong>on</strong> <strong>of</strong> lymph nodes, new lymphadenopathy, exp<strong>and</strong><strong>in</strong>g CNS lesi<strong>on</strong>s, worsen<strong>in</strong>g <strong>of</strong>lung parenchymal <strong>in</strong>filtrati<strong>on</strong>s <strong>and</strong> pleural effusi<strong>on</strong>s. Management <strong>of</strong> a n<strong>on</strong>-severe paradoxical reacti<strong>on</strong><strong>in</strong>volves treatment <strong>of</strong> symptoms with n<strong>on</strong>-steroidal anti-<strong>in</strong>flammatory agents. Some studies have shownthat more severe reacti<strong>on</strong>s <strong>in</strong>volv<strong>in</strong>g high fever, airway compromise by enlarg<strong>in</strong>g lymph nodes, enlarg<strong>in</strong>gserosal fluid collecti<strong>on</strong>s <strong>and</strong> sepsis syndrome can be treated with prednis<strong>on</strong>e or methylprednisol<strong>on</strong>e.IRIS can be transient, yet last for many m<strong>on</strong>ths. Most cases experienc<strong>in</strong>g IRIS are at an advanced stage<strong>of</strong> immunodeficiency. Patients commenced <strong>on</strong> HAART with<strong>in</strong> <strong>the</strong> first two m<strong>on</strong>ths <strong>of</strong> TB treatment are atgreater risk <strong>of</strong> IRIS.Overlapp<strong>in</strong>g toxicity pr<strong>of</strong>iles also occur <strong>in</strong> <strong>in</strong>dividuals receiv<strong>in</strong>g c<strong>on</strong>comitant treatment for HIV <strong>and</strong> TB.NNRTIs <strong>and</strong> co-trimoxazole, <strong>and</strong> rifampic<strong>in</strong>, is<strong>on</strong>iazid <strong>and</strong> pyraz<strong>in</strong>amide used to treat TB are all associatedwith side effects <strong>of</strong> fever, rash, peripheral neuropathy <strong>and</strong> o<strong>the</strong>r neurological events, gastro<strong>in</strong>test<strong>in</strong>al<strong>in</strong>tolerance <strong>and</strong> hepatitis. Side effects are most comm<strong>on</strong> <strong>in</strong> <strong>the</strong> first two m<strong>on</strong>ths <strong>of</strong> treatment.Dispens<strong>in</strong>g <strong>of</strong> HIV <strong>and</strong> anti-TB <strong>the</strong>rapyGiven <strong>the</strong> complex drug <strong>in</strong>teracti<strong>on</strong>s that can occur between HIV <strong>and</strong> anti-TB medicati<strong>on</strong>s, <strong>and</strong> <strong>the</strong> needto be able to m<strong>on</strong>itor compliance, patients receiv<strong>in</strong>g <strong>the</strong>rapy for both HIV <strong>and</strong> TB or LTBI should receive<strong>the</strong>ir HIV <strong>and</strong> TB medicati<strong>on</strong>s from <strong>the</strong> same pharmacy, from a pharmacist experienced <strong>in</strong> <strong>the</strong> use <strong>of</strong> <strong>the</strong>semedicati<strong>on</strong>s. The pharmacist should keep records <strong>of</strong> TB <strong>and</strong> HIV medicati<strong>on</strong>s dispensed to each patient<strong>and</strong> advise patients <strong>on</strong> <strong>the</strong> importance <strong>of</strong> compliance with <strong>the</strong>ir treatment <strong>and</strong> <strong>on</strong> potential adverse drugreacti<strong>on</strong>s <strong>and</strong> <strong>in</strong>teracti<strong>on</strong>s. Pharmacists should also be part <strong>of</strong> <strong>the</strong> multidiscipl<strong>in</strong>ary team look<strong>in</strong>g afterpatients with TB/HIV <strong>in</strong>fecti<strong>on</strong>. They have an important role <strong>in</strong> <strong>the</strong> provisi<strong>on</strong> <strong>of</strong> advice <strong>on</strong> dosages for anti-TB <strong>and</strong> HIV medicati<strong>on</strong>s, <strong>on</strong> <strong>the</strong>rapeutic drug m<strong>on</strong>itor<strong>in</strong>g for patients who are receiv<strong>in</strong>g treatment withdrugs such as amikac<strong>in</strong> <strong>and</strong> <strong>in</strong> m<strong>on</strong>itor<strong>in</strong>g <strong>the</strong> patient for adverse drug reacti<strong>on</strong>s e.g. hepatotoxicity.10.9 Preventi<strong>on</strong> <strong>and</strong> C<strong>on</strong>trolCases <strong>of</strong> TB <strong>in</strong> HIV positive <strong>in</strong>dividuals should be notified <strong>and</strong> c<strong>on</strong>tact trac<strong>in</strong>g undertaken as recommendedfor n<strong>on</strong>-HIV <strong>in</strong>fected TB cases (chapter 8).HIV positive cases are not c<strong>on</strong>sidered to be more <strong>in</strong>fectious to <strong>the</strong>ir c<strong>on</strong>tacts than HIV negative<strong>in</strong>dividuals. 376;377 On <strong>the</strong> c<strong>on</strong>trary, it has even been suggested that <strong>the</strong> likelihood <strong>of</strong> transmissi<strong>on</strong> is reducedbecause bacillary loads are lower <strong>and</strong> cavitary disease is less comm<strong>on</strong> than <strong>in</strong> n<strong>on</strong>-HIV <strong>in</strong>fected TB cases.However, this has not been proven <strong>on</strong> an <strong>in</strong>dividual case basis, <strong>and</strong> procedures for c<strong>on</strong>tact trac<strong>in</strong>g <strong>and</strong><strong>in</strong>fecti<strong>on</strong> c<strong>on</strong>trol measures should be applied <strong>in</strong> <strong>the</strong> same manner as for n<strong>on</strong>-HIV <strong>in</strong>fectious TB cases.HIV <strong>in</strong>fecti<strong>on</strong> does lead to a greater likelihood <strong>of</strong> TB <strong>in</strong>fecti<strong>on</strong> progress<strong>in</strong>g to active disease <strong>and</strong> a highproporti<strong>on</strong> <strong>of</strong> <strong>in</strong>fecti<strong>on</strong>s <strong>in</strong> this populati<strong>on</strong> result <strong>in</strong> disease with a short time frame between exposure <strong>and</strong><strong>the</strong> development <strong>of</strong> symptoms.BCGThere is <strong>in</strong>ternati<strong>on</strong>al agreement that BCG is c<strong>on</strong>tra<strong>in</strong>dicated <strong>in</strong> HIV positive <strong>in</strong>dividuals. 26;52;369 In countrieswhere <strong>the</strong> risk <strong>of</strong> TB is low, it is recommended that BCG should be withheld from all <strong>in</strong>dividuals known orsuspected to be HIV positive. 26 Infants born to known HIV positive women should have BCG deferred untilafter <strong>the</strong> sec<strong>on</strong>d HIV PCR proves negative (usually at/after 6 weeks <strong>of</strong> age). 332 The benefit <strong>of</strong> vacc<strong>in</strong>at<strong>in</strong>gHIV-<strong>in</strong>fected <strong>in</strong>dividuals to prevent <strong>the</strong> development <strong>of</strong> TB is as yet unproven, 378 <strong>and</strong> adverse events-130-