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Discussion

Introduction

In 2010, an estimated 8.8 million new cases of tuberculosis (TB) occurred globally and approximately 1.1 million (12.5%) of these individuals also had HIV infection[1]. In resource-limited settings, the dual and overlapping HIV and TB epidemics have resulted in the common occurrence of simultaneous new diagnosis of both TB and HIV. Accordingly, this discussion will review the initiation of anti-TB therapy in patients newly diagnosed with both HIV and active TB in resource-limited settings, based on the latest World Health Organization (WHO) Guidelines[2,3,4]. The initiation of antiretroviral therapy and co-trimoxazole prophylaxis, monitoring of these patients for treatment response, and management of treatment complications such as drug toxicities and immune reconstitution inflammatory syndrome (IRIS) are reviewed in detail in separate case discussions.

Epidemiology

In 2010, the global tuberculosis incidence was estimated at 128 cases per 100,000 population and the total number of global cases of TB have declined since 2002. Globally, sub-Saharan African and Southeast Asia have the highest incidence rates (cases per 1,000 persons) (Figure 1) [2]. In addition, sub-Saharan Africa has, by far, the highest HIV prevalence rates among persons newly diagnosed with TB (Figure 2) [2]. The HIV epidemic has, in large part, driven the recent increase in TB incidence, especially in sub-Saharan Africa, where the TB and HIV incidence rates have increased in tandem (Figure 3) [1,2,5]. The risk of TB approximately doubles within a year of an individual acquiring HIV infection, and continues to increase as HIV disease advances and the CD4 count declines. Although antiretroviral therapy can reduce the risk developing TB substantially, the risk of TB in an HIV-infected person remains significantly higher than that of someone who is not HIV-infected, even with a robust immunologic response to antiretroviral therapy[6]. Since 1990, the TB-associated death rates have doubled and, in recent years, TB has accounted for roughly one in four deaths among HIV-infected persons worldwide[7,8]. The high mortality rate associated with TB and HIV co-infection results from the enhanced pathogenicity of Mycobacterium tuberculosis in the immunocompromised host: prevention and containment of TB infection depends heavily on acquired T-cell anti-tuberculous immunity, a process severely compromised by HIV infection[9].

Treatment Overview for Patients with HIV and TB Disease

The scenario presented in this case is common in resource-limited settings where many HIV-infected persons are first diagnosed with HIV infection at the time they develop TB. For these patients, the first priority is to initiate anti-TB therapy, ideally accompanied by drug-susceptibility testing to identify patients with drug-resistant strains of TB. Clinical trials have established that patients with TB and HIV also benefit greatly from the timely initiation of antiretroviral therapy and co-trimoxazole prophylaxis[3], as reviewed in Management of the Patient with Newly Diagnosed HIV Infection and Active Tuberculosis: Antiretroviral Therapy and Co-trimoxazole Prophylaxis.

Anti-TB Therapy for Patients with HIV and TB Disease

  • Drug Susceptibility Testing (DST). Patients with multidrug-resistant (MDR) or extensively drug-resistant (XDR) TB require different treatment regimens than do patients whose strains of TB are susceptible to all commonly available TB drugs[4]. Very high mortality rates, particularly early after the diagnosis, have been documented among HIV-infected patients with co-morbid MDR- or XDR-TB (Figure 4) [10,11]. The WHO recommends that all HIV-infected persons with active TB be tested for drug-resistant TB at the start of anti-TB therapy in order to reduce the risk of death from unrecognized MDR or XDR-TB[4]. If national resources do not permit drug-susceptibility testing for all HIV-infected persons with TB, then those with the highest mortality risk (CD4 counts less than 200 cells/mm3) and those at highest risk of harboring a drug-resistant strain of TB (history of treatment interruption, failure, or relapse) should have priority for drug susceptibility testing[3]. Although drug-susceptibility testing is important, initiation of anti-TB therapy should not be delayed while waiting for results. Empiric treatment with a standard four-drug regimen should begin immediately; the regimen can be modified as needed if susceptibility testing reveals drug resistance.
  • Timing of Initiating Anti-TB Therapy. For HIV-infected persons with newly diagnosed active TB, anti-TB therapy should begin as soon as possible[3]. Coordination between TB and HIV treatment programs and integrated service delivery are critically important in this regard[12].
  • Anti-TB Therapy Regimen Selection. For HIV-infected persons with drug-susceptible pulmonary TB, the treatment course consists of a 2-month, four-drug intensive phase of treatment, followed by a 4-month, two-drug continuation phase of treatment (Figure 5). The four-drug intensive phase regimen consists of isoniazid, rifampicin, pyrazinamide, and ethambutol (commonly abbreviated as HRZE); the two-drug continuation phase typically consists of isoniazid plus rifampicin (HR). The medications should be administered using weight-based dosing (Figure 6). Daily dosing of TB medications is preferred throughout the entire course of therapy for patients with HIV and TB disease, based on evidence of lower efficacy and higher risk of rifampicin resistance when TB therapy is dosed three times weekly[3,13,14].
  • Duration of Anti-TB Therapy. In general, the recommended total duration of anti-TB therapy is 6 months. Some controversy remains regarding whether or not HIV-infected persons should receive a longer course of anti-TB therapy than patients with active TB who are not co-infected with HIV. A systematic literature review concluded that a prolonged (8 months or longer) course of anti-TB therapy for HIV-infected persons was associated with a lower rate of relapse as compared with 6 months of therapy[13]. The WHO, however, does not endorse automatically extending the duration of anti-TB therapy for patients with HIV and TB disease, reasoning that the data quality of the studies included in that review were poor, and that implementing longer treatment protocols for these patients would be operationally difficult[3]. Extension of TB therapy is recommended in the setting of some forms of extrapulmonary TB, regardless of HIV status.
  • Extrapulmonary TB. Extrapulmonary TB should be treated with the same regimens as pulmonary TB, but treatment duration should extend to 9 to 12 months for TB meningitis, and 9 months for bone or joint involvement. Corticosteroids are also recommended in the setting of TB meningitis and pericarditis, unless drug resistance is suspected[3].
  • Drug Interactions with ARVs. Standard anti-TB regimens do not have significant interactions with efavirenz-based antiretroviral therapy regimens. Rifampicin, however, does have significant interactions with nevirapine and most protease inhibitors. Dosing adjustments required for use with these agents are reviewed in detail in the case Management of the Patient with Newly Diagnosed HIV Infection and Active Tuberculosis: Antiretroviral Therapy and Co-trimoxazole Prophylaxis.
  • Drug-resistant TB. The management of drug-resistant TB is beyond the scope of this case. Readers are encouraged to consult the WHO Guidelines for the programmatic management of drug-resistant tuberculosis[4] and to seek out expert consultation, if available, for the management of patients with drug-resistant TB, particularly those patients with MDR-TB or XDR-TB.

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  • The following link will open in a new window.
    Figure 1. Estimated Tuberculosis Incidence Rates 2010.

    Most of the TB cases in 2010 occurred in Asia and Africa. This graph shows the TB incidence rates (new TB cases per 100,000 population), which were highest in Africa and southeast Asia.
    Source: World Health Organization Report 2011. Global tuberculosis control. Geneva: World Health Organization; 2011.


    Figure 1
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    Figure 2. Estimated HIV Prevalence in New TB Cases, 2010.

    This graphic shows the HIV prevalence among new TB cases. Among all of the new TB cases in which the patient was also HIV-positive, 78% of these occurred in the African region and 13% in the South-East Asian region.
    Source: World Health Organization Report 2011. Global tuberculosis control. Geneva: World Health Organization; 2011.


    Figure 2
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    Figure 3. Tuberculosis Incidence and HIV Prevalence in new TB Cases, 2009.

    The HIV epidemic has fueled an increase in new TB cases, especially in sub-Saharan Africa.
    Source: Stop TB Partnership. The Global Plan to Stop TB 2011-2015 : Transforming the Fight – Towards Elimination of Tuberculosis. Geneva : World Health Organization, 2010.


    Figure 3
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    Figure 4. Kaplan-Meier survival plot among multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) patients, 2005 to 2007.

    This retrospective observational study examined survival rates among 272 MDR-TB and 382 XDR-TB cases diagnosed in Tugela Ferry, South Africa, from 2005 to 2007. Ninety percent of MDR-TB patients and 98% of XDR-TB patients were co-infected with HIV. One-year mortality was 71% for MDR- and 83% for XDR-TB patients; 40% of MDR-TB and 51% of XDR- TB cases died within 30 days of sputum collection.
    Source: Gandhi NR, Shah NS, Andrews JR, et al. HIV coinfection in multidrug- and extensively drug-resistant tuberculosis results in high early mortality. Am J Respir Crit Care Med. 2010;181:80-6. Reproduced with permission from American Thoracic Society. Copyright © 2012. American Thoracic Society.


    Figure 4
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    Figure 5. Standard anti-TB Regimens for Patients co-Infected with HIV and TB (with presumed, or known, to have drug-susceptible TB).

    Source: World Health Organization. Treatment of tuberculosis: guidelines–4th edition. Geneva: WHO, 2010.


    Figure 5
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    Figure 6. Recommended Doses of First-Line Antituberculosis Drugs for Adults.

    Source: World Health Organization. Treatment of tuberculosis: guidelines–4th edition. Geneva: WHO, 2010.


    Figure 6