**8. The treatment of NTB in HIV patients**

(A) (B)

308 Tuberculosis - Current Issues in Diagnosis and Management

(C) (D)

trast uptake and no diffusion restriction.

*6.3.2.Tuberculous abscess*

under 100/mm3

**Figure 3.** Cranio-cerebral *MRI,* showing left pontine tuberculoma in a 16 year-old patient previously diagnosed and undergoing treated for lymph node TB for the past 2 months and recently diagnosed with HIV infection.The patient also associated HBV and CMV infection and oral candidiosis.On admission the patient was in coma. The laboratory data displayed a CD4 count of 24 cells/mm3 and RNA HIV 1064973copies/ml. Final diagnosis was NeuroIRIS TB (tuber‐ culoma).The CSF disclosed no changes.The clinical evolution was favourable. *A:* coronal T1 weighted image demon‐ strating left pontine paramedian nodular lesion of 4 mm surrounded by perilesional edema (discrete hyposignal). *B:* coronal section T1 postcontrast shows hypersignal; C- coronal section T2 and D- axial FLAIR section show intense con‐

The tuberculous abscess represents a purulent collection delineated by a capsule with a granulomatous structure. This is a rare finding in immunocompetent patients as well as in the early stages of AIDS but common in severe immunodeficiency states with CD4+T cell count

[13] or from the necrotic evolution of granulomas in the setting of severe immunodeficiency [98].The necrotic centre is invaded by mycobacteria. The CSF is unchanged. The evolution is more acute than tuberculomas with neurologic deficit, fever and headaches [96, 99-100]. The CT/MRI aspect resembles the images in caseous tuberculomas but the lesion is larger (>3cm), multilobulated, surrounded by a thick capsule and ring enhancement. The perilesional edema and the mass effect are the most important features. The histological and bacteriological exam the cerebral biopsy confirm the diagnosis. The differential diagnosis includes other intracranial

[96]. The tuberculous abscess results from the liquefaction of tuberculomas

The treatment of NTB in HIV patients should be combined, controlled and individualized.


The main antituberculous and antiretroviral classes, their corresponding representative drugs, pharmacologicalinteractions, adverse reactions andtreatment efficacyare shownintable 3.The NTB treatment principles in HIV patients are presented in accordance with the European AIDS Clinical Society guidelines, CDC and American Thoracic Society recomandations [111-113].

### **8.1. The antituberculous treatment**

**Treatment of tuberculous meningitis.** TBM is a curable disease. Response to treatment in patients with NTB and HIV is similar to patients diagnosed with TB only. The elevated mortality is a result of the belated diagnosis, resistant mycobacteria and severe immunodefi‐ ciency

**•** neurological/extraneurological complications

resistance is essential throughout the entire course of therapy.

include rifabutin, fluoroquinolones, kanamycin, ethionamide;

should continue to be closely monitored.

treatment, or even longer;

localizations.

**•** drug resistance.

Monitoring for ensuing complications includes a complete physical examination, laboratory data, CSF aspects and imaging studies. It is important to consider the followings: a) neuro‐ logical complications are more frequent in HIV patients (mostly due to immune exacerbation as tuberculous vasculopathy or IRIS); b) neurological complications may occur during treatment: hydrocephalus and arachnoiditis could sometimes occur even in the presence of a correct treatment; c) complications are frequently associated with other undetected TB

Neurotuberculosis and HIV Infection http://dx.doi.org/10.5772/54631 311

The risk of resistance is increased in non-adherent patients, large bacillary load and patients who start less efficient regimens. The glucocorticoid therapy reestablishes the low permeability of the blood-brain barrier and could therefore decrease the CSF diffusion of antibiotics. Inadequate doses of antituberculous therapy or low CSF antituberculous concentration may induce drug resistance. An unfavourable clinical evolution and decreasing CD4+T cell count require repeated CSF collection for culture and drug resistance. Close surveillance for drug

**3.** *Individualized treatment*. The patient's co-morbidities (like viral hepatitis or other risk factors for hepatotoxicity, ocular diseases, renal failure, allergic reactions,other medica‐ tions and pregnancy) must be investigated before establishing the drug regimen and

**Treatment of tuberculomas.** Cerebral tuberculomas are potentially curable tumor-like masses. There is a low number of tuberculoma cases reported in HIV patients [94- 95, 122-125].

**•** The perilesional granulomatous vasculitis decreases the penetration of antituberculous drugs; the lesions heal progressively and require 12 to 30 months of antituberculous

**•** The recommended regimen is based on rifampicin, izoniazid and pirazinamide for 4 to 5 months and then rifampicin and izoniazid for 12 to 16 additional months. Other active drugs

**•** Surgical treatment is rarely needed; it is indicated in tuberculomas with mass effect, increased intracranial hypertension and hydrocephalus. The antituberculous treatment

**•** Glucocorticoid therapy is an important part of the treatment regimen as it reduces the edema and improves the clinical manifestations. It should be maintained for at least 4 to 8 weeks.

Treatment monitoring requires the clinical and radiological follow-up on the long term. The evolution of other tuberculous localizations if present should also remain under observation.

should be started before surgery. The recurrence after surgical ablation is unsual.

Response to therapy is favorable despite large lesions or immunodeficiency.

Treatment is based on the same principles as TBM but with the following mentions:

## **• The main characteristics of the antituberculous treatment in HIV patients with NTB**


**•** neurological/extraneurological complications

Monitoring for ensuing complications includes a complete physical examination, laboratory data, CSF aspects and imaging studies. It is important to consider the followings: a) neuro‐ logical complications are more frequent in HIV patients (mostly due to immune exacerbation as tuberculous vasculopathy or IRIS); b) neurological complications may occur during treatment: hydrocephalus and arachnoiditis could sometimes occur even in the presence of a correct treatment; c) complications are frequently associated with other undetected TB localizations.

**•** drug resistance.

**8.1. The antituberculous treatment**

310 Tuberculosis - Current Issues in Diagnosis and Management

ciency

rates.

weeks.

**• Factors to consider**

**•** treatment adherence

tered 3 times per week [121]

**2.** *Controlled treatment* should approach:

patients along with a prolonged treatment.

**Treatment of tuberculous meningitis.** TBM is a curable disease. Response to treatment in patients with NTB and HIV is similar to patients diagnosed with TB only. The elevated mortality is a result of the belated diagnosis, resistant mycobacteria and severe immunodefi‐

**• The main characteristics of the antituberculous treatment in HIV patients with NTB**

**2.** The antituberculous therapy must have increased CSF penetration (table 3) [114-120].

**4.** A long course of therapy for a minimum of 12 months is strong recomended.

**3.** Corticosteroid therapy should be initiated as early as possible and continued for 6–8

**1.** *Combined treatment* must include an *initial phase* of 2 months, with 4 first-line antitubercu‐ lous drugs having high CSF penetration (ussualy isoniazid, rifampicin, pyrazinamide, ethambutol) administered daily; the initial phase is followed by a *second phase* of another 10 months with only 2 first-line antituberculous drugs (isoniazid, rifampicin) adminis‐

**•** drug interactions and toxicities taking into consideration the followings (see table 3):a) the side effects to the antituberculous treatment are three times more frequent in HIV than non HIV patients; b) the interactions between the antituberculous and antiretroviral therapy may impede the administration of the most efficient regimen or a simultaneous therapy; the most important interaction involves the protease inhibitors (important class of antiretrovirals) and rifampicin (first line antituberculous drug). Rifampicin accelerates the hepatic metab‐ olism of protease inhibitors decreasing their blood levels and increasing the risk of HIVdrug resistance. In addition protease inhibitors delay the metabolism of rifampicin increasing its serum concentration and toxicity. Izoniazid and rifampicin also decrease the concentration of fluconazole, an antifungal frequently used in the HIV patients. Additionally there are many other interactions between rifampicin and antiretrovirals, corticosteroids or trimeto‐ prim/sulfamethoxazole (table 3). For this reason rifabutin is preferred to rifampicin in HIV

**1.** Treatment should be urgently started based on clinical and biological data, CSF modifi‐ cations, the history of TB, other tuberculous lesions and imaging studies. The CSF specimens should be collected for culture and for resistance detection before treatment starting. The bacteriological confirmation should not delay the treatment as the treatment delay accounts for a poor prognosis. Advanced stages of the disease with irreversible complications (hydrocephalia, adherences, cerebral infarcts) are related to high mortality

The risk of resistance is increased in non-adherent patients, large bacillary load and patients who start less efficient regimens. The glucocorticoid therapy reestablishes the low permeability of the blood-brain barrier and could therefore decrease the CSF diffusion of antibiotics. Inadequate doses of antituberculous therapy or low CSF antituberculous concentration may induce drug resistance. An unfavourable clinical evolution and decreasing CD4+T cell count require repeated CSF collection for culture and drug resistance. Close surveillance for drug resistance is essential throughout the entire course of therapy.

**3.** *Individualized treatment*. The patient's co-morbidities (like viral hepatitis or other risk factors for hepatotoxicity, ocular diseases, renal failure, allergic reactions,other medica‐ tions and pregnancy) must be investigated before establishing the drug regimen and should continue to be closely monitored.

**Treatment of tuberculomas.** Cerebral tuberculomas are potentially curable tumor-like masses. There is a low number of tuberculoma cases reported in HIV patients [94- 95, 122-125]. Treatment is based on the same principles as TBM but with the following mentions:


Treatment monitoring requires the clinical and radiological follow-up on the long term. The evolution of other tuberculous localizations if present should also remain under observation. Response to therapy is favorable despite large lesions or immunodeficiency.

**Treatment of tuberculous abscesses** requires surgical and pharmacological treatment similar to the regimen recommended in tuberculoma but for an interval of 18 months to 2 years. The *prognosis* is unfavourable due to severe imunodeficiency and large lesions [99, 101 ].

**8.2. The antiretroviral therapy**

their adverse reacions.

rifabutin with similar results.

**2.** *Controlled treatment* should approach:

interference. **• Factors to consider**

adverse reactions).

which the CD4+ cell count is below <50 cells /mm3

The antiretroviral (ARV) treatment ought to be started as soon as possible after the antituber‐ culous treatment. The urgency of the ARV therapy increases with the degree of immunodefi‐ ciency. Three important studies (CAMELIA performed in Cambodgia, SAPiT conducted in South Africa and STRIDE a multinational study) established that an earlier start of the ARV therapy significantly decreases the mortality in AIDS patients and especially in patients in

frequent if the ARV treatment is more precocious, the gravity of the IRIS manifestations in the 3 studies above cannot justify a longer delay of the antiretroviral therapy. Most guidelines recommended that HIV patients start the antiretroviral treatment at least 2 weeks after the antituberculous treatment if the CD4+ count is below 50 cells per mm3 ; the antiretroviral

HIV patients could be shadowed by the possible reactivation of other neurotropic agents (cytomegalovirus, toxoplasma, JV virus) or cerebral tumors (cerebral lymphoma, Kaposi sarcoma).The diagnosis in these cases could be difficult and if these associations are not excluded from diagnosis, treatment should also address these conditions with the risk of

**◦** Therapeutic regimens must contain antiretroviral drugs with a high penetration in the CSF. The main ARV drugs used in the co-infection with TB are listed in table 3 along with

**◦** The antiretroviral therapy in NTB is based on reverse transcriptase inhibitors represented by 2 important classes: nucleoside reverse transcriptase inhibitors (NRTI) and nonnucleoside reverse transcriptase inhibitors (NNRTI). The highest drug penetration into the CSF is assigned to zidovudine, abacavir, nevirapine, delavirdine. Although efavirenz (a NNRTI) does not display high levels in the CSF some studies advocate a very good response in the treated adults [131]. Protease inhibitors should not be used due to their interaction with rifampicin and low diffusion in the CSF. If their use is required (as a result of resistance or toxicity to other antiretrovirals) rifampicin is to be replaced with

**◦** The doses of antiretrovirals should be changed according to the antituberculous drug

**1.** *Combined treatment* includes 3 NNRTIs with a preferred option for trizivir (combination of zidovudine, abacavir and lamivudine) or 2 NRTIs + 1 NNRTI (ussualy efavirenz).

**•** The adherence (especially if a large number of drugs are introduced at the same time) [132]. Nevertheless adherence to trizivir is high (the number of capsules is low, there are few

treatment can be delayed until 4 weeks if the CD4+ count > 50 cells/mm3

multiple drug interactions. Such is the case of cerebral toxoplasmosis.

**• The main characteristics of antiretroviral treatment in HIV patients with NTB**

. Although the development of IRIS is more

Neurotuberculosis and HIV Infection http://dx.doi.org/10.5772/54631 313

. Note that NTB in

**Treatment of NTB with resistant strains of M.tbc.** The risk of resistance is higher in geo‐ graphic areas with high prevalence of resistant mycobacteria and in the case of recent TB improperly treated. Resistance could occur against one or more antituberculous drugs. The association between HIV and multidrug resistance (MDR-TB) or extensive drug resistance (XDR-TB) is not well documented [126,127].The antituberculous treatment should be under‐ taken according to the advice of an experienced specialist only and should include at least 4 antituberculous drugs with an increased diffusion in the CSF [128].

**Treatment of CNS TB with nontuberculous myobacteria.** Data related to infections with nontuberculous mycobacteria is scarce and insufficient for establishing definite treatment guidelines. Therefore treatment regimens are largely undefined and the subsequent outcome remains disappointing. The severity of the evolution appears to be related to the variable sensitivity to the antituberculous antibiotics and the advanced stages of immunodeficiency which predispose to a disseminated disease. Therapeutic regimens should be individualized to include complex drug associations (5-6 drugs) on longer periods of time. A close consultation with an experienced specialist is required. Mycobacteria belonging to the MAC display increased resistance against most antituberculous drugs and therefore a large variety of therapeutic regimens was evaluated. The repeated therapeutic failure is apparently linked to the diverse sensitivity to antituberculous drugs associated with M. avium species. Moreover there is the alternative that some HIV patients could be simultaneously infected with more than one species of M avium. Macrolides proved efficient but cannot penetrate to the CSF. Chlaritromycin is involved in several drug interactions with the antiretroviral therapy. Considering the increased risk for disseminated forms induced by the MAC it is recommended to add azithromycin, ethambutol and rifabutin to therapy. Other drugs that could be associated in such cases include fluoroquinolones, streptomycin, amikacin. Treatment should always be based on the results of susceptibility testing. After 12 months of treatment, prophylaxis with macrolides is recommended until the CD4+ count raises above 100/mm3.M. scrofulaceum, M. simiae, M. malmoense reveal the same sensitivity pattern as MAC. In the case of M. kansasii recommended drugs include: rifabutin, streptomycin, HIN, ethambutol, amikacin.

**Treatment during Pregnancy.** The antituberculous treatment is urgently instituted according to classic treatment regimens. Among prohibited drugs are streptomycin, fluoroquinolones and ethionamide.

**Treatment of NeuroIRIS-TB.** Neurologic TB-IRIS is a rare manifestation of TB-IRIS. It generally occurs within 2-3 months after initiating the combination of antiretroviral and the antituberculous therapy [42].The risk of IRIS increases with the early starting and high efficacy of antiretroviral therapy. Delaying the antiretroviral therapy with a minimum of 2 weeks after antituberculous therapy is recommended to avoid IRIS complication. Usually IRIS is selflimited and requires symptomatic or anti-inflammatory treatment without stopping the antiretroviral treatment. Severe forms benefit from treatment with prednisone or methylpred‐ nisolone 1 mg/g gradually tapered within the 2 following weeks [129,130]

### **8.2. The antiretroviral therapy**

**Treatment of tuberculous abscesses** requires surgical and pharmacological treatment similar to the regimen recommended in tuberculoma but for an interval of 18 months to 2 years. The *prognosis* is unfavourable due to severe imunodeficiency and large lesions [99, 101 ].

**Treatment of NTB with resistant strains of M.tbc.** The risk of resistance is higher in geo‐ graphic areas with high prevalence of resistant mycobacteria and in the case of recent TB improperly treated. Resistance could occur against one or more antituberculous drugs. The association between HIV and multidrug resistance (MDR-TB) or extensive drug resistance (XDR-TB) is not well documented [126,127].The antituberculous treatment should be under‐ taken according to the advice of an experienced specialist only and should include at least 4

**Treatment of CNS TB with nontuberculous myobacteria.** Data related to infections with nontuberculous mycobacteria is scarce and insufficient for establishing definite treatment guidelines. Therefore treatment regimens are largely undefined and the subsequent outcome remains disappointing. The severity of the evolution appears to be related to the variable sensitivity to the antituberculous antibiotics and the advanced stages of immunodeficiency which predispose to a disseminated disease. Therapeutic regimens should be individualized to include complex drug associations (5-6 drugs) on longer periods of time. A close consultation with an experienced specialist is required. Mycobacteria belonging to the MAC display increased resistance against most antituberculous drugs and therefore a large variety of therapeutic regimens was evaluated. The repeated therapeutic failure is apparently linked to the diverse sensitivity to antituberculous drugs associated with M. avium species. Moreover there is the alternative that some HIV patients could be simultaneously infected with more than one species of M avium. Macrolides proved efficient but cannot penetrate to the CSF. Chlaritromycin is involved in several drug interactions with the antiretroviral therapy. Considering the increased risk for disseminated forms induced by the MAC it is recommended to add azithromycin, ethambutol and rifabutin to therapy. Other drugs that could be associated in such cases include fluoroquinolones, streptomycin, amikacin. Treatment should always be based on the results of susceptibility testing. After 12 months of treatment, prophylaxis with macrolides is recommended until the CD4+ count raises above 100/mm3.M. scrofulaceum, M. simiae, M. malmoense reveal the same sensitivity pattern as MAC. In the case of M. kansasii

recommended drugs include: rifabutin, streptomycin, HIN, ethambutol, amikacin.

nisolone 1 mg/g gradually tapered within the 2 following weeks [129,130]

and ethionamide.

**Treatment during Pregnancy.** The antituberculous treatment is urgently instituted according to classic treatment regimens. Among prohibited drugs are streptomycin, fluoroquinolones

**Treatment of NeuroIRIS-TB.** Neurologic TB-IRIS is a rare manifestation of TB-IRIS. It generally occurs within 2-3 months after initiating the combination of antiretroviral and the antituberculous therapy [42].The risk of IRIS increases with the early starting and high efficacy of antiretroviral therapy. Delaying the antiretroviral therapy with a minimum of 2 weeks after antituberculous therapy is recommended to avoid IRIS complication. Usually IRIS is selflimited and requires symptomatic or anti-inflammatory treatment without stopping the antiretroviral treatment. Severe forms benefit from treatment with prednisone or methylpred‐

antituberculous drugs with an increased diffusion in the CSF [128].

312 Tuberculosis - Current Issues in Diagnosis and Management

The antiretroviral (ARV) treatment ought to be started as soon as possible after the antituber‐ culous treatment. The urgency of the ARV therapy increases with the degree of immunodefi‐ ciency. Three important studies (CAMELIA performed in Cambodgia, SAPiT conducted in South Africa and STRIDE a multinational study) established that an earlier start of the ARV therapy significantly decreases the mortality in AIDS patients and especially in patients in which the CD4+ cell count is below <50 cells /mm3 . Although the development of IRIS is more frequent if the ARV treatment is more precocious, the gravity of the IRIS manifestations in the 3 studies above cannot justify a longer delay of the antiretroviral therapy. Most guidelines recommended that HIV patients start the antiretroviral treatment at least 2 weeks after the antituberculous treatment if the CD4+ count is below 50 cells per mm3 ; the antiretroviral treatment can be delayed until 4 weeks if the CD4+ count > 50 cells/mm3 . Note that NTB in HIV patients could be shadowed by the possible reactivation of other neurotropic agents (cytomegalovirus, toxoplasma, JV virus) or cerebral tumors (cerebral lymphoma, Kaposi sarcoma).The diagnosis in these cases could be difficult and if these associations are not excluded from diagnosis, treatment should also address these conditions with the risk of multiple drug interactions. Such is the case of cerebral toxoplasmosis.

#### **• The main characteristics of antiretroviral treatment in HIV patients with NTB**


#### **• Factors to consider**


**•** Drug interactions and toxicities (see table 3). The clinician should recognize the overlapping toxicities, drug interactions and also the occurrence of IRIS (paradoxical reactions) [133].The interactions between NNRTI or NRTI and antituberculous drugs are few. The risk of toxicity is minimal but adverse reactions are possible with some NRTIs (see table 3). Regarding the toxicity the ARV could interfere not only with antituberculous drugs but also with other drugs used in the prophylaxis or treatment of other opportunistic infections (such as fluconazol for Candida or Criptococcus neoformans or sulphametoxazole/trimethoprim for Penumocystis jirovecii).

ANTITUBERCULOUS DRUGS

Peripheral neuropathy (requires pyridoxine supplementation). Hepatotoxicity (reversible) depending on the dose and association with rifampicin and alcohol consumption. Rare cases of fulminant hepatitis. Rare allergic reactions.

Neurotuberculosis and HIV Infection http://dx.doi.org/10.5772/54631 315

Renal failure. Digestive and allergic reactions. Hepatotoxicity (cholestatic hepatitis) especially

Adverse reactions to rifabutin mirror those of rifampicin; in addition rifabutin could induce uveitis, arthralgias, leucopenia, asymptomatic hepatitis. Rifabutin does not interact with PIs. Because rifabutin is a less potent inducer, it is generally considered a reasonable alternative to rifampicin. Doses should be adjusted in the coadministration with an PI ; underdosing of rifabutin can result in selection of rifamycin resistance, whereas overdosing of rifabutin

Optic neuropathy especially after prolonged treatments. Rarely triggers allergic reactions and hyperuricemia. No hepatotoxicity reactions.

Nephrotoxicity. Neurotoxicity. Ototoxicity. Contraindicated in pregnancy. No recorded

Less toxic than streptomycin.Contraindicated in

hepatotoxic reactions

pregnancy

in drug associations. Hemorrhagic manifestations due to thrombocytopenia. Sulfamethoxazole/ trimethoprim enhances the effect of rifampicin and could increase its toxicity. Corticosteroids decrease the level of rifampicin. Rifampicin could singnificantly reduce the plasma concentrations of most PIs and some NNRTIs; it could be associated with

NRTI and some NNRTIs.

might result in toxicities.

Hepatotoxicity Hypersensitivity reactions

Drug Pharmacologic aspects Drug interactions/Adverse reactions

Interferes with mycolic acids synthesis. Bactericidal to rapidly-dividing extracellular mycobacteria, bacteriostatic against the slow-growing intracellular mycobacteria. CSF peak concentrations exceed 30 times the minimal inhibitory concentration

Rifampicin acts against intra and extracellular bacilli, especially on slow-growing mycobacteria (bactericidal). The metabolism is primarily hepatic; because of its ability to induce certain microsomal hepatic enzymes (CYP3A4) it interferes with the metabolism of other drugs. Poorly penetrates the CSF in the absence of meningeal inflammation. In meningitis CSF level is up to 10-20% of the serum levels. Rapid emergence of resistant mycobacteria. Rifabutin is bactericidal.The level of rifabutin in the serum is 7-10 times lower than the concentration of rifampicin. It easily diffuses through the uninflammed

Active against intracellular bacilli only at acid pH. Bactericidal/bacteriostatic (dose dependent). Is well absorbed and crosses the blood-brain barrier leading to CSF concentrations almost as high as those in the

Bactericidal with low activity. Ethambutol could increase the activity of other antituberculous drugs affecting the cellular permeability of MAC strains and possibly of multiresistant M.tbc strain. Low CSF level (moderate rise above the minimum bactericidal

Belongs to aminoglycosides class. Bactericidal. Active only on replicating extracellular bacilli. Poor CSF level even in patients with meningitis. High rate of

Belongs to the class of aminoglycosides. The same characteristics as streptomycin. Low CSF

Isoniazid (NIH)\*\*\* (first-line agent)

Rifampicin\* (first-line agent) Associations of rifampicin: rifamate, rifater Rifabutin\* Rifapentine

patients)

Pyrazinamide\*\*\* (first-line agent)

Ethambutol\* (first-line agent)

Streptomycin\* (second-line drug)

Amikacin\* (second-line drug)

is a semi-synthetic rifamycin derivate with longer half-time (not recommended in HIV

meninges.

blood

concentration)

resistance

concentrations

