The presentation of active TB is influenced by the degree of immunodeficiency. CD4+ count >350 cells/ µ L: HIV/TB clinically resembles TB among HIV-uninfected persons. Extrapulmonary disease is more common regardless of CD4+ counts, although clinical manifestations are not substantially different from those described in HIV-uninfected persons. In advanced HIV disease: , the chest rx findings of pulmonary TB are markedly different compared with those among patients with less severe immunosuppression. Lower lobe, middle lobe, interstitial, and miliary infiltrates are common and cavitation is less common. Marked mediastinal lymphadenopathy also can be found. Even with normal chest radiographs, patients with HIV infection and pulmonary TB might have acid fast bacilli (AFB)-positive sputum smear and culture results. With increasing degrees of immunodeficiency, extrapulmonary TB (e.g., lymphadenitis, pleuritis, pericarditis, and meningitis), with or without pulmonary involvement, is more common, and found in the majority of TB patients with CD4+ counts <200 cells/ µ L. Among such patients, TB can be a severe systemic disease with high fevers, rapid progression, and sepsis syndrome. Histopathologic findings also are affected by the degree of immunodeficiency. Patients with relatively intact immune function have typical granulomatous inflammation associated with TB disease. With progressive immunodeficiency, granulomas become poorly formed or can be completely absent ( 286 ). In severely immunodeficient patients with a high mycobacterial load, TB disease may be subclinical or oligo-symptomatic. After initiation of ART, immune reconstitution might unmask active TB, resulting in pronounced inflammatory reactions at the sites of infection ( 294--298 ). This type of IRIS can manifest as early as 7 days after starting ART. Signs and symptoms include fever; weight loss; and signs of local inflammatory reactions such as lymphadenitis, pulmonary consolidation, infiltrates, nodules, and effusions. Histologically, a vigorous granulomatous reaction, with or without caseation, but with suppuration, necrotising inflammation, and AFB might be evident; cultures of this material are almost invariably positive for M. tuberculosis
The risk of TB among HIV-infected persons not receiving antiretroviral therapy is high, with rates ranging from 720 cases per 100,000 population in the United States  to 8400 cases per 100,000 population in Brazil  and 9700 cases per 100,000 population in South Africa . On a population level, there has been a remarkably consistent 80% decrease in TB risk among persons who receive HAART [40–42]. However, even after several years of HAART, the risk of TB remains higher than that in HIV-uninfected persons, suggesting that immune restoration is not complete [43, 44]. This finding is also an important reminder to clinicians that HIV-infected persons receiving stable HAART remain at increased risk of TB, compared with HIV-uninfected persons.
Among HIV-infected persons who receive a diagnosis of TB and do not receive HAART, the mortality rate is high (as high as 91% among persons with AIDS) [10, 48, 49]. Initiation of HAART is associated with improved survival among all HIVinfected persons, including those with TB [50–54]. It is therefore recommended that HIV-infected patients with TB receive treatment for both diseases, regardless of their CD4+ T lymphocyte count. However, the optimal timing of HAART initiation in relation to the time of anti-TB therapy initiation is unclear. In contrast to the survival benefit provided by HAART, the disadvantages of concomitant treatment of both diseases include a high pill burden, multiple and overlapping drug toxicities, and the possibility of paradoxical worsening of TB in the context of immune reconstitution. In addition, there are drug-drug interactions, particularly between rifamycins and several potent antiretroviral therapy agents. Both the risks and benefits of concomitant therapy are greatest among persons with low CD4+ T lymphocyte counts. The optimum time to initiate antiretroviral therapy (ART) in human immunodeficiency virus (HIV)–1–infected patients with serious opportunistic infections has, until recently, been undefined. Initiation of early ART is associated with the risk of the immune reconstitution inflammatory syndrome (IRIS), complex drug interactions, and a high pill burden, but deferral risks advancing immunosuppression and mortality. A number of recent clinical trials have now better informed this issue. Two studies have shown benefits associated with earlier ART initiation [1, 2]. A study of patients with a range of opportunistic and bacterial infections, not including tuberculosis (TB), demonstrated that early ART initiation (median, 12 days after diagnosis of infection) resulted in fewer events or deaths related to AIDS progression (a combined secondary end point), compared with initiation of ART after acute infection treatment (median, 45 days after diagnosis of infection) . A subanalysis of this study showed that, in patients with fungal infections, there was also a significant reduction in AIDS progression and death associated withearly initiation. In TB, patients who started ART during TB treatment had reduced mortality, compared with those who deferred ART until TB treatment was completed . The pendulum seemed to be swinging in favor of earlier ART initiation in the context of opportunistic infections. However, in a study of patients with TB meningitis, there was no difference in mortality between patients who started ART at the same time as TB treatment and those who deferred ART for 2 months, but there were significantly more severe adverse events in the first 2 months of treatment in the immediate ART arm .
Three studies based in Thailand attempted to elucidate the risks and benefits of concomitant treatment of HIV and TB in coinfected individuals. A retrospective study by Sungkanuparph et al. at a single site in Thailand evaluated 29 adult patients with HIV/TB coinfection, all with CD4 counts less than 200 . Antiretroviral therapy was initiated between 4 and 12 weeks after initiation of antituberculous therapy, based on clinical stability on the TB regimen. A single death in this cohort was attributed to CMV infection, and one case of IRIS was observed. Additional reported adverse events included rash with nevirapine, dizziness with efavirenz, and anemia with d4T. Although this study was limited by the relatively small sample size and lack of a control group, 26 of the 29 patients were able to complete a full course of TB treatment while taking antiretroviral drugs, suggesting the potential tolerability of dual therapy. Manosuthi et al. subsequently performed a larger retrospective cohort study with approximately 1000 adult HIVinfected persons with active TB diagnosed by clinical symptoms and positive sputum acid-fast smear . A uniform anti-TB regimen was administered with the standard initial 2-month regimen comprising isoniazid, rifampin, pyrazinamide, and ethambutol, followed by 4 months of isoniazid and rifampin. There was some variability in the antiretroviral regimen employed with 80% of individuals receiving a nevirapine-based regimen, 16% an efavirenz-based regimen, and the remainder receiving a protease inhibitor-based regimen. Concurrent TB treatment and HAART appeared to confer a significant survival benefit, with a mortality rate of 7.7% in the group receiving both treatments, compared to 67.7% in the group receiving TB treatment alone. Although this study was limited by the greater underlying morbidity in the group not receiving HAART, with more advanced TB and higher rates of drug resistance noted in this group, subgroup analysis demonstrated significantly greater survival among patients receiving HAART within 6 months of TB diagnosis as compared to those receiving HAART beyond 6 months of TB diagnosis. However, patients in whom HAART was started within 2 months of TB treatment initiation did not appear to have improved survival relative to those who began receiving HAART 4 months after initiating TB treatment. A third Thai-based study by Sanguanwongse et al. Also attempted to evaluate the role of HAART on survival of HIV/TB-coinfected individuals . This observational cohort study evaluated 626 HIV/TB-coinfected patients receiving HAART together with TB treatment and 643 HIV/TB-coinfected patients receiving TB treatment alone. A significant decline in mortality was observed in the group receiving concurrent HAART (11%) compared to the group not receiving HAART (46%). Although this study was nonrandomized and precise information on the HAART regimen employed for each patient was lacking, it provided further support for the potential benefit of concomitant HAART and TB treatment.
Five recent studies have attempted to address the appropriate timing of initiation of HAART in HIV/TB-coinfected patients. A small retrospective study in Tehran involving 69 individuals with HIV/TB coinfection was divided into 2 groups . One group, treated from 2002 to 2005, received HAART after 8 weeks of TB treatment if the CD4 count was less than 200. The second group, treated from 2005 to 2006, received HAART after 2 weeks of TB treatment if the CD4 count was less than 100 and after 8 weeks if the CD4 count was between 101 and 200. A lower mortality rate and higher rate of TB cure was observed in the latter group suggesting that early initiation of HAART may be beneficial at lower CD4 counts in HIV-associated TB. No difference in adverse events including IRIS and new opportunistic infections was reported between these 2 groups . A partially retrospective, multicenter study in Madrid, Spain compared HAART initiation within 2 months of TB diagnosis to HAART initiation 3 months subsequent to TB diagnosis .No difference in virological or immunological outcomes was observed between these 2 groups, although the early HAART group had lower mean baseline viral loads. However, early HAART initiation (within 2 months) was associated with improved survival .
0.37; 95% CI 0.17 to 0.66, P = 0.001, Table 3). Interestingly, a dramatic survival advantage was evident in the short term (Fig. 1). At 6 months of follow-up, HR for simultaneous use of TB-HAART was 0.15 (95% CI 0.03 to 0.586, P = 0.007). This survival effect was attenuated at 12 months (HR 0.33; 95% CI 0.14 to 0.78) and was maintained in a similar HR until the end of follow-up.
The aforementioned studies were primarily observational and retrospective in nature. The need for prospective randomized controlled trials to address the clinically important question of the optimal timing of HAART initiation relative to antituberculous therapy led to the design of several such trials in recent years . The Starting Antiretroviral Therapy at Three Points in Tuberculosis (SAPIT) trial, an open label, randomized controlled trial conducted in a large clinic in Durban, South Africa , enrolled HIV positive adult patients with a CD4 count < 500 and AFB smear-positive TB. The TB regimen consisted of a 2-month standard initial phase with rifampin, isoniazid, ethambutol, and pyrazinamide for TB treatment-na¨ıve individuals, with the addition of streptomycin for treatment-experienced individuals, followed by rifampin and isoniazid during the continuation phase. All patients received the same HAART regimen (didanosine, lamivudine, and efavirenz) and counseling regarding medical adherence. There were 3 main arms of this study: a sequential therapy arm in which patients received HAART subsequent to completion of TB treatment, an early integrated therapy arm in which patients received HAART within 4 weeks after the start of TB treatment, and a late integrated therapy arm in which HAART was administered within 4 weeks after completion of the initial phase of treatment. Patients were randomly assigned to one of these 3 groups and the primary outcome was all-cause mortality. The sequential therapy arm was stopped early by the data and safety monitoring committee upon interim analysis of the data. A significant 56% decline in mortality was observed in the combined integrated arms compared to the sequential arm, with a mortality rate of 5.4 per 100 person-years in the former group as compared to 12.1/100 person-years in the latter group. Similar rates of virological suppression were observed in each of the groups after similarduration of HAART, and no difference was observed in grade 3 and grade 4 events between the groups.
The interval between the completion of tuberculosis therapy and the initiation of antiretroviral therapy is important; a considerable number of deaths in the sequential-therapy group occurred during this time (Fig. 2). Once antiretroviral therapy was initiated, however, it was associated with similarly high levels of viral suppression in the two study
Further elucidation of the precise timing of HAART initiation relative to TB treatment has been provided recently by the Cambodian Early versus Late Introduction of Antiretrovirals (CAMELIA) trial . This study was an open label, prospective, randomized controlled trial enrolling HIV-positive adult patients with a CD4 count < 200/mm3 and AFB smear-positive TB at 5 sites in ruraland urban Cambodia. Patients were treated with a 2-month intensive phase TB regimen consisting of rifampin, isoniazid, pyrazinamide, and ethambutol, followed by a 4 month continuation phase regimen of rifampin and isoniazid. Participants were randomized to 2 arms, an early arm in which HAART was introduced 2 weeks subsequent to the initiation of antituberculous therapy and a late arm in which HAART was introduced 8 weeks subsequent to the initiation of antituberculous therapy. Patients in each arm received a HAART regimen consisting primarily of lamivudine, stavudine, and efavirenz. The preliminary report from this study noted a significant 34% decline in mortality in the early HAART arm compared to the late HAART arm, with amortality rate of 8.28 per 100 person-years in the early arm as compared to 13.77 per 100 person-years in the late arm. Similar rates of virological suppression were observed in both groups.
The AIDS Clinical Trials Group recently completed a study entitled “A Strategy Study of Immediate Versus Deferred Initiation of Antiretroviral Therapy for HIV Infected Persons Treated for Tuberculosis With CD4 Less Than 200 Cells/mm3” . This study was an open-label, randomized controlled trial conducted between August 2006 and July 2010, which enrolled persons aged > 13 years old with CD4 count less than 200 cells/mm3 and confirmed or probable TB. Participants were assigned to early initiationof HAART within 2 weeks after initiating TB treatment, or deferral of HAART until 8 to 12 weeks after initiationof TB treatment. The majority of participants received efavirenz, tenofovir, and emtricitabine and the primary outcome measure was the proportion of participants who have survived without AIDS progression. The analysis of this study is pending.
From this meta-analysis of 27 studies identified from a systematic review, duration of rifamycin therapy of 6 months and daily therapy in the initial intensive phase were associated with lower risk of failure and/or relapse in HIV-positive patients with active TB. However the most important and striking finding of this review is the paucity of well-designed and adequately powered randomized trials of HIV-TB coinfection treatment. Despite the estimated annual incidence of 1.3 million persons with HIV-TB coinfection, of whom almost half a million die , very basic treatment questions remain unresolved. These have important implications for patients, providers, and TB programs. These questions include the optimal dosing schedule and duration of rifamycin, as well as the use and timing of concomitant ART. In conclusion, our review raises important concerns regarding thrice-weekly treatment in the first 2 months of therapy, the optimal duration of rifamycin therapy, and the role of ART therapy in HIV-TB–coinfected patients. Our data suggest that longer duration of rifamycin therapy (at least 8 months) with daily dosing in the initial phase and that concurrent ART might be associated with better outcomes. However, these findings should be viewed with caution, because they are based mostly on observational studies. This reflects the striking paucity of adequately powered, well-designed and -executed, randomized trials on treatment of HIV-TB coinfection. Randomized trials to address the questions raised by this review regarding treatment of active TB in HIV coinfected patients are urgently needed.
The risk of stavudine substitution in the first 2 months of ART was nearly seven-fold higher in patients initiating stavudine containing ART concurrently with TB treatment than in those not receiving TB treatment . Patients treated concomitantly for both HIV and TB infection require routine pyridoxine supplementation (to prevent isoniazid- related neuropathy), and alternatives to stavudine should be considered when available, particularly in patients with pre-existing neuropathy. Among the first-line TB drugs, pyrazinamide, isoniazid, and rifampicin have all been associated with hepatotoxicity . There are concerns about increased hepatoxicity when NNRTIs, particularly nevirapine, are prescribed with TB treatment. Study results differ. Increased hepatotoxicity was seen when both efavirenz [27,39] and nevirapine  were administered concomitantly with TB treatment. However, in a large South African cohort, there was no increase in drug substitution due to toxicity in patients on TB treatment who were treated with either efavirenz or nevirapine compared with those not on TB treatment, although rates of substitution for toxicity in the cohort were overall higher for nevirapine . Boosted protease inhibitors with rifampicin-based TB treatment may also result in hepatotoxicity (discussed above). Development of deranged liver functions may significantly complicate treatment of co-infected patients and may necessitate interruption of all potentially hepatotoxic antiretrovirals and TB drugs , and inpatient rechallenge. Such interruptions of therapy for TB and HIV, although essential in case of severe drug toxicities, may worsen the prognosis. Other shared side-effects include drug rashes (that may occur due to many of the TB drugs, co-trimoxazole, nevirapine, and, less frequently, efavirenz), gastrointestinal intolerance (especially with zidovudine, didanosine, protease inhibitors, pyrazinamide, ethionamide, and para-aminosalicylic acid), and neuropsychiatric sideeffects (especially with efavirenz, isoniazid, ethionamide, and cycloserine) [5,9]. Use of aminoglycosides (e.g., amikacin and kanamycin) and capreomycin in the treatment of drug-resistant TB may result in nephrotoxicity, and co-administration of tenofovir, which may also result in nephrotoxicity, should be avoided if possible . HIV infection itself results in an increased rate of serious adverse events in patients on TB treatment , and ART may further increase this. A retrospective cohort study in South African patients on rifampicin-based TB treatment found increased serious adverse events, primarily peripheral neuropathy and increased vomiting, in HIV-infected compared with uninfected patients, but no association with concomitant use of ART was found . Isoniazid, stavudine, and didanosine are common causes of neuropathy . In another South African study, patients taking ART together with TB treatment were found to be at increased risk of stavudine discontinuation, primarily due to peripheral neuropathy . The risk of stavudine substitution in the first 2 months of ART was nearly seven-fold higher in patients initiating stavudinecontaining ART concurrently with TB treatment than in those not receiving TB treatment . Patients treated concomitantly for both HIV and TB infection require routine pyridoxine supplementation (to prevent isoniazid- related neuropathy), and alternatives to stavudine should be considered when available, particularly in patients with pre-existing neuropathy. Among the first-line TB drugs, pyrazinamide, isoniazid, and rifampicin have all been associated with hepatotoxicity . There are concerns about increased hepatoxicity when NNRTIs, particularly nevirapine, are prescribed with TB treatment. Study results differ. Increased hepatotoxicity was seen when both efavirenz [27,39] and nevirapine  were administered concomitantly with TB treatment. However, in a large South African cohort, there was no increase in drug substitution due to toxicity in patients on TB treatment who were treated with either efavirenz or nevirapine compared with those not on TB treatment, although rates of substitution for toxicity in the cohort were overall higher for nevirapine . Boosted protease inhibitors with rifampicin-based TB treatment may also result in hepatotoxicity (discussed above). Development of deranged liver functions may significantly complicate treatment of co-infected patients and may necessitate interruption of all potentially hepatotoxic antiretrovirals and TB drugs , and inpatient rechallenge. Such interruptions of therapy for TB and HIV, although essential in case of severe drug toxicities, may worsen the prognosis. Other shared side-effects include drug rashes (that may occur due to many of the TB drugs, co-trimoxazole, nevirapine, and, less frequently, efavirenz), gastrointestinal intolerance (especially with zidovudine, didanosine, protease inhibitors, pyrazinamide, ethionamide, and para-aminosalicylic acid), and neuropsychiatric sideeffects (especially with efavirenz, isoniazid, ethionamide, and cycloserine) [5,9]. Use of aminoglycosides (e.g., amikacin and kanamycin) and capreomycin in the treatment of drug-resistant TB may result in nephrotoxicity, and co-administration of tenofovir, which may also result in nephrotoxicity, should be avoided if possible .
Knowledge of the mechanisms of drug interactions can help predict the likelihood of an interaction, if that specifi c combination of drugs has not been formally evaluated. Th e rifamycin class upregulate (induce) the synthesis of several classes of drug transporting and drug metabolizing enzymes. With increased synthesis, there is increased total activity of the enzyme (or enzyme system), thereby decreasing the serum half-life and serum concentrations of drugs that are metabolized by that system. Th e most common locus of rifamycin interactions is the cytochrome P450 enzyme system, particularly the CYP3A4 and CYP2C8/9 isozymes. To a lesser extent, rifampin induces the activity of the CYP2C19 and CYPD6 isozymes. Th e rifamycins vary in their potential as CYP450 inducers, with rifampin being most potent, rifapentine intermediate, and rifabutin being much less active. Rifampin also upregulates the synthesis of cytosolic drug-metabolizing enzymes, including glucuronosyl transferase, an enzyme involved in the metabolism of zidovudine and raltegravir.
An 8-month isoniazid (INH, H) and ethambutol (EMB, E) based regimen recommended by the World Health Organization (WHO) had never been evaluated in a randomised controlled multicentre trial. OBJECTIVE: To compare, in a non-inferiority study design, two 8-month INH + EMB-based regimens with a standard INH and rifampicin (RMP, R) based regimen. DESIGN: A total of 1355 patients with newly diagnosed smear-positive pulmonary tuberculosis were randomly allocated to receive 1) daily EMB, INH, RMP and pyrazinamide (PZA, Z) for 2 months, followed by EMB + INH for 6 months (2EHRZ/6HE); 2) the same drugs in the intensive phase but given three times weekly, followed by the same continuation phase of daily EMB + INH (2(EHRZ)3/6HE); or 3) a control regimen with the same intensive phase as in regimen 1, followed by 4 months of daily RMP + INH (2EHRZ/4HR). All patients were to be seen and sputum examinations for microscopy and culture carried out at regular intervals up to 30 months after randomisation. RESULTS: At 30 months, failure/relapse rates were 11.7% of 281 2EHRZ/6HE, 15.3% of 301 2(EHRZ)3/ 6HE and 6.0% of 282 2EHRZ/4HR patients ( χ 2, 2 degrees of freedom = 12.8, P = 0.002). CONCLUSION: These results confi rm earlier fi ndings demonstrating the inferiority of the INH + EMB-based regimens to the standard 6-month regimen. The WHO has withdrawn its recommendation of these regimens.
Nel presente studio è stata effettuata la lead-in-dose di nevirapina. A 2-week lead-in period of once daily instead of twice daily dosing is recommended to allow for the autoinduction of the cytochrome P450 enzyme system by nevirapine. In patients taking rifampicin, the system is however already induced. A recent Malawian study30 found that 59% of patients coinfected with HIV and tuberculosis had subtherapeutic nevirapine concentrations during the lead-in dosing phase. The collected experience is suffi cient to make nevirapine an alternative for patients unable to take efavirenz and who do not have access to rifabutin. Conclusion In this cohort study, virological outcomes were inferior when nevirapine based antiretroviral therapy was commenced while taking antitubercular treatment (vs without concurrent tuberculosis) but comparable when starting efavirenz-based antiretroviral therapy (vs without concurrent tuberculosis) or when tuberculosis developed while taking established nevirapine- or efavirenz-based therapies. JAMA. 2008;300(5):530-539
In conclusion, drug C12 levels for efavirenz (600 mg per day) are less compromised by concomitant treatment with rifampicin than are levels for nevirapine (400 mg per day) in patients with concurrent HIV-1 infection and TB who weigh !60 kg. Although efavirenz levels varied across a wide range, almost all patients had drug concentrations greater than the minimal recommended level. Importantly, low NNRTI drug exposure was found to be an important predictive factor for treatment failure after 48 weeks of ART. Therefore, our data suggest that ART that includes efavirenz (600 mg per day) should preferred over that which contains nevirapine (400 mg per day) for eligible patients in a setting where both are available. Nevirapine-based ART remains an acceptable option for pregnant women and for persons with restricted access to efavirenz. For both regimens, the important of strict adherence to medication dosing must be emphasized, to minimize the risk of treatment failure. Nevirapine concentrations are decreased by concomitant rifampicin-based TB treatment, and Thai  and South African  investigators found subtherapeutic nevirapine concentrations in 21–38% of co-infected patients on rifampicin-based TB treatment taking standard nevirapine doses (200mg twice daily). Modeling of data from South African patients indicates that increasing nevirapine doses by 50% to 300mg twice daily would achieve therapeutic concentrations in the majority of patients , but the safety of this strategy has not been adequately explored for recommendation as routine practice, and may result in increased hypersensitivity reactions
Concurrent with the increase in the prevalence of TB IRIS, the emergence of multidrug-resistant (MDR) and extensively drug resistant TB in settings in Southern Africa where HIV infection is prevalent has recently been highlighted [18, 19]. Determining the cause of deterioration in patients with TB during cART in resource-limited settings is important, because adjunctive corticosteroid therapy may worsen an already immunosuppressed patient’s condition if used in the presence of incompletely efficacious TB treatment or other opportunistic infections.
In the 9 patients with rifampin-resistant TB, presentation was suggestive of TB IRIS, with improvement while receiving TB treatment before initiation of cART and then deterioration during the weeks after the initiation of cART. The obvious question is whether the condition of the patients with drugresistant TB deteriorated because of suboptimally treated TB, TB IRIS, or both? Our case definitions, which are similar to those used by other researchers [14, 15], classified known rifampin resistance as excluding TB IRIS. However, in light of our observations, we propose that antitubercular drug resistance and TB IRIS are not mutually exclusive and may overlap in the same person. First, given that TB IRIS immunopathology is attributable to restored antigen-specific immunity to M. tuberculosis antigens , it is reasonable to conclude that TBIRIS may occur in response to drug-susceptible or drug-resistant strains, whether the latter are treated or untreated. The antigen stimulus for TB IRIS is unlikely to differ in these scenarios. Second, in the 4 patients with known rifampin-resistant TB, all improved while receiving treatment for MDR TB, and then their conditions deteriorated after cART initiation. The deterioration of their conditions was most likely attributable to TB IRIS, given the timing. These patients may be at higher risk of TB IRIS than patients with rifampin-susceptible TB. M. tuberculosis bacillary load has been suggested as a risk factor for the condition , and even those patients who are effectively treated for MDR TB are likely to have slow bacillary clearance. This may partially account for our observation that these 4 patients developed TB IRIS despite a long interval between initiation of TB therapy and initiation of cART (table 3). Third, 9 patients had undiagnosed rifampin-resistant TB when they presented with suspected TB IRIS. These patients all reported at least partial symptomatic response to standard TB treatment before the initiation of cART. It is possible for patients with MDR TB to initially respond to first-line TB treatment [27–29], either because the organism is sensitive to ethambutol and pyrazinamide or because the patient is dually infected with MDR TB and a susceptible strain . In addition, patients may improve while receiving treatment for drug-susceptible TB and then be reinfected with drug-resistant TB, or the infecting organism may develop rifampin resistance during treatment. Either of these scenarios could have occurred for patient 8 (table 2). For these 9 patients who received a diagnosis of rifampin-resistant TB after presenting with suspected TB IRIS, symptomatic deterioration occurred 3–48 daysafter the initiation of cART—the characteristic timing of TB IRIS.
PPT Scarpellini "TB and HIV positive people"
Dip Malattie Infettive – Centro San Luigi I.R.C.C.S Osp. San Raffaele, Mi
<ul><li>The HIV pandemic caused a rise in both TB incidence and mortality, with a 40% increase in incident TB cases compared to 20 years ago. </li></ul><ul><li>In the USA, 1/4 of all TB cases occur in HIV-infected persons and worldwide an estimated 1.37 million (14.8%) TB cases occur in HIV-positive persons, resulting in 456,000 TB related deaths in this population. </li></ul><ul><li>HIV/TB coinfection is particularly prevalent in populations with limited resources. (50-80% in sub-Saharan Africa, as compared to 2–15% in other parts of the world). </li></ul><ul><li>HIV/TB coinfected persons have a higher mortality rate than those without either infection alone, regardless of CD4 count. </li></ul><ul><li>TB accounts for 26% of AIDS-related deaths worldwide. </li></ul>Convergence of HIV/TB Pandemics (WHO 2009)
<ul><li>The estimated annual risk for active TB among persons with LTBI: </li></ul><ul><ul><li>general population is 12.9 per 1,000 person-years of observation. </li></ul></ul><ul><ul><li>HIV-infected persons ranged from 35 to 162 per 1,000 person-years of observation. </li></ul></ul><ul><li>Primary disease accounts for one third or more of cases of TB disease in HIV-infected populations </li></ul><ul><li>Unlike other AIDS-related OIs, CD4+ count is not a reliable predictor of increased risk for TB disease </li></ul>Convergence of HIV/TB Pandemics (WHO 2009)
<ul><li>The presentation is influenced by the degree of immunodeficiency: </li></ul><ul><ul><li>CD4+ count >350 cells/ µ L : resembles TB among HIV-uninfected persons. </li></ul></ul><ul><ul><li>In advanced HIV disease : , the chest rx findings of pulmonary TB are markedly different (lower lobe, middle lobe, interstitial, and miliary infiltrates are common and cavitation is less common. Marked mediastinal lymphadenopathy. Normal) </li></ul></ul><ul><ul><li>With increasing degrees of immunodeficiency, extrapulmonary TB , with or without pulmonary involvement, is more common, and found in the majority of TB patients with CD4+ counts <200 cells/ µ L. TB can be a severe systemic disease with high fevers, rapid progression, and sepsis syndrome. </li></ul></ul><ul><ul><li>Histopathologic findings also are affected by the degree of immunodeficiency. </li></ul></ul>HIV/TB Clinical Manifestations (WHO 2009)
<ul><li>Optimal time of HAART initiation relative to TB treatment </li></ul><ul><li>Duration and frequency of dosing of anti-TB drugs </li></ul><ul><li>Concurrent treatment problems </li></ul><ul><ul><li>Overlapping drugs toxicities </li></ul></ul><ul><ul><li>Drug-drug interactions </li></ul></ul><ul><ul><li>Immune reconstitution inflammatory syndrome (IRIS) </li></ul></ul>
Potential risks associated with early versus delayed antiretroviral therapy in patients with HIV-associated tuberculosis
<ul><li>HAART should not be delayed pending completion of TB treatment. </li></ul><ul><li>The most recent WHO guidelines: initiation of HAART between 2 and 8 weeks subsequent to the initiation of TB therapy when CD4 count < 200mm 3 </li></ul><ul><li>The preliminary reported findings from the CAMELIA (HAART initiation early during this intensive phase of TB treatment when CD4 counts <200mm 3 ). </li></ul><ul><li>Further multicountry data on the timing of HAART for coinfected individuals with CD4 counts < 200mm 3 is likely to be provided by the recently concluded ACTG A5221 study. </li></ul>Summary
<ul><li>11 trials were included with a total of 8,130 randomized participants. </li></ul><ul><li>Preventive therapy vs placebo was associated with a lower incidence of active TB (RR 0.64, 95% CI 0.51 to 0.81). This benefit was more pronounced in individuals with a positive TST (RR 0.38, 95% CI 0.25 to 0.57) than in those who had a negative test (RR 0.83, 95% CI 0.58 to 1.18.). </li></ul><ul><li>The initial protective effect may decline over the short to medium term. </li></ul><ul><li>Efficacy was similar for all regimens. </li></ul><ul><li>Overall, there was no evidence that preventive therapy versus placebo reduced all-cause mortality (RR 0.95, 95% CI 0.85 to 1.06), although a favourable trend was found in people with a positive tuberculin test (RR 0.80, 95% CI 0.63 to 1.02). </li></ul>2009
Overlapping drugs toxicities <ul><li>Hepatotoxicity </li></ul><ul><li>INI-induced peripheral neuropathy </li></ul><ul><li>Gastrointestinal distress and high pill burden </li></ul><ul><li>Drug rashes </li></ul><ul><li>Neuropsychiatric side-effects </li></ul><ul><li>Nephrotoxicity </li></ul>
Drug-drug interactions <ul><li>potent inducer of many genes controlling drug metabolism and transport, including cytochrome P450 isoenzymes and the drug efflux pump p-glycoprotein. </li></ul><ul><li>reduce plasma concentrations of NNRTIs and PI, potentially resulting in inadequate ART plasma concentrations and inferior ART outcomes. </li></ul><ul><li>Rifampin also upregulates the synthesis of cytosolic drug-metabolizing enzymes, including glucuronosyl transferase, an enzyme involved in the metabolism of zidovudine and raltegravir. </li></ul>Rifampicin
Paradoxical: in patients diagnosed with TB and established on TB treatment prior to ART who then manifest with recurrent or new TB symptoms and signs after ART initiation. Unmasking: in patients who are not on TB treatment when they start ART, who then have an unusually inflammatory presentation of TB in the first 3 months of ART. Both forms of TB-IRIS are thought to result from rapid recovery of mycobacterial immune responses resulting in inflammatory reactions to Mycobacterium tuberculosis antigens. Tuberculosis immune reconstitution inflammatory syndrome (TB-IRIS)
Tuberculosis immune reconstitution inflammatory syndrome (TB-IRIS) <ul><li>no diagnostic test for TB IRIS </li></ul><ul><li>differential diagnosis: </li></ul><ul><ul><li>failure of TB treatment attributable to antimicrobial resistance, </li></ul></ul><ul><ul><li>or suboptimal antitubercular drug concentrations, </li></ul></ul><ul><ul><li>drug reactions, </li></ul></ul><ul><ul><li>alternative opportunistic condition. </li></ul></ul>
Paradoxical TB-IRIS A 49 year-old man was diagnosed with pulmonary TB (rif and ini S). Chest radiograph at TB diagnosis (a) right upper lobe infiltrate. His symptoms improved on TB treatment. His CD4 cell count was 29 cells/ml and HIV viral load 191 000 copies/ml. He was started on ART 2 weeks after TB treatment
Paradoxical TB-IRIS 2 weeks after start of ARV therapy he developed recurrent cough, night sweats and dyspnea 2. Chest radiograph (b) showed worsening of the right upper lobe infiltrate and a new right pleural effusion. His CD4 cell count had risen to 51 cells/ml. Repeat TB cultures from sputum and pleural aspirate were negative. His effusion was aspirated and he was treated with prednisone to which he symptomatically responded. His viral load performed 6 months after ART initiation was less than 50 copies/ml.
In 12 published cohort studies from five continents, the incidence of paradoxical TB-IRIS is reported to be 8–43% among patients starting ART while on TB treatment. Major risk factors: low CD4 cell count, disseminated TB, short interval between starting TB treatment and ART The most frequently reported features are: recurrent TB symptoms, fever, enlargement of lymph nodes, worsening radiographic pulmonary infiltrates, enlargement of pleural effusions. Patients typically develop paradoxical TB-IRIS symptoms 2–4 weeks after starting ART Tuberculosis immune reconstitution inflammatory syndrome (TB-IRIS)
Abdominal features of paradoxical TB-IRIS <ul><li>are increasingly recognized. </li></ul><ul><li>hepatic and splenic involvement, intestinal lesions, peritonitis, ascites, intra-abdominal lymphadenopathy, and abscesses. </li></ul><ul><li>Abdominal symptoms are reported in up to 59% of patients (pain, nausea, vomiting, and diarrhea). </li></ul><ul><li>Hepatic involvement (21-56% of TB-IRIS patients), can be difficult to differentiate from drug-induced hepatitis. </li></ul><ul><li>Hepatic TB-IRIS manifests with tender liver enlargement, cholestatic liver function derangement with or without jaundice, and granulomatous hepatitis on liver histology. </li></ul>
Unmasking TB-IRIS: 271 patients without active TB. 16 (5.9%) developed active TB within 6 months (early unmasking) 10 (2.7%) after 6 months (late unmasking). Paradoxical TB-IRIS : 45 patients who started HAART with coexisting active TB, 13/45 (29%) paradoxical TB-IRIS. 9/45 commenced HAART during the intensive phase of TB treatment, of whom 2 (22%) experienced worsening of TB. 36/45 started HAART during the continuation phase of TB treatment of whom 11 (31%), experienced worsening of TB. The median time from initiation of HAART to worsening of TB in patients on concurrent active TB treatment was 5 weeks, and 18 weeks to unmasking of new active tuberculosis. Delaying ART until after 2 months of TB treatment did not appear to prevent paradoxical TB-IRIS
Meintjes G et al. CID 2009 antitubercular drug resistance and TB IRIS are not mutually exclusive and may overlap in the same person Suboptimally treated TB? TB-IRIS? Both?
Meintjes G et al. CID 2009 <ul><li>TB-IRIS may occur in response to drug-S or drug-R strains, whether the latter are treated or untreated. The antigen stimulus for TB IRIS is unlikely to differ in these scenarios. </li></ul><ul><li>M. Tuberculosis bacillary load has been suggested as a risk factor for IRIS, and even those patients who are effectively treated for MDR TB are likely to have slow bacillary clearance. </li></ul><ul><li>partial symptomatic response to standard TB treatment before the initiation of cART (the organism is sensitive to ethambutol and pyrazinamide or because the patient is dually infected with MDR TB and a susceptible strain). In addition, patients may improve while receiving treatment for drug-susceptible TB and then be reinfected with drug-resistant TB, or the infecting organism may develop rifampin resistance during treatment. </li></ul>
1.5 mg/kg per day for 2 weeks then 0.75 mg/kg per day for 2 weeks