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Discussion

Introduction

The management of the patient with both HIV infection and active tuberculosis (TB) is complex, particularly in the setting of newly diagnosed HIV and newly diagnosed active TB. Recently published clinical trials data and World Health Organization (WHO) guidelines provide evidence-based recommendations to assist clinicians in managing HIV-infected persons who have active TB [1,2]. In resource-limited settings, for patients newly diagnosed with HIV and active TB, the first management step is to initiate anti-TB therapy. The next priority, as reviewed in this case discussion, is to initiate co-trimoxazole (fixed-dose combination of trimethoprim and sulfamethoxazole) prophylaxis and antiretroviral therapy. The following discussion will address the initiation of co-trimoxazole prophylaxis and antiretroviral therapy in patients with newly diagnosed HIV and newly diagnosed active TB in resource-limited settings. The treatment of the TB, monitoring for treatment response, and management of treatment complications, such as drug toxicities and immune reconstitution inflammatory syndrome (IRIS), will be reviewed in detail in separate case discussions.

Co-trimoxazole Prophylaxis with Active TB

Multiple studies have established that co-trimoxazole prophylactic therapy significantly reduces mortality in HIV-infected persons who have active TB[3,4,5,6,7]. The WHO Guidelines for Treatment of Tuberculosis and the International Standards of Tuberculosis Care therefore recommend people living with HIV who have active TB disease, regardless of CD4 count or HIV disease stage, should receive daily co-trimoxazole prophylaxis, initiated as soon as possible following the initiation of anti-TB therapy[1,8]. The recommended dose of co-trimoxazole for adults and adolescents is one double-strength tablet or two single-strength tablets once daily: the total daily dose is 800 mg of sulfamethoxazole and 160 mg of trimethoprim. The dosing for infants and children is weight based. Individuals with a history of severe (grade 4) adverse reaction to co-trimoxazole or other sulfa drugs should not be prescribed co-trimoxazole prophylaxis. Grading of co-trimoxazole toxicity is summarized in Figure 1[9]. Among adults and adolescents with a previous non-severe (grade 3 or less) reaction to co-trimoxazole or other sulfa drugs, desensitization should be attempted, as outlined in Figure 2.

Indications for Initiating Antiretroviral Therapy with Active TB

The administration of antiretroviral therapy to HIV-infected persons with active TB is associated with significantly reduced mortality, reduced rates of TB treatment failure, and lower TB relapse rates[10,11]. The WHO Guidelines therefore recommend that all HIV-infected persons with active TB initiate antiretroviral therapy, regardless of CD4 count or HIV disease stage[1,2]. The exact timing for initiating of antiretroviral therapy and specific antiretroviral regimens to use concomitantly with anti-TB therapy are discussed below.

Timing of Initiation of Antiretroviral Therapy with Newly Diagnosed TB

The WHO Guidelines recommend initiating antiretroviral therapy as soon as possible (and within the first 8 weeks) after starting anti-TB therapy[1,2]. The guidelines emphasize that patients should be tolerating TB therapy before starting antiretroviral therapy, and ideally they may be able to start antiretroviral therapy as early as 2 weeks after starting TB therapy. The potential for antiretroviral therapy to induce immune reconstitution inflammatory syndrome (IRIS) in antiretroviral therapy-naïve patients with known active TB disease initially led many experts to recommend deferring antiretroviral therapy until the patient had completed at least 2 months of anti-TB therapy. Although concern exists for IRIS in this setting, recent data from three randomized trials – the SAPIT [12,13], CAMELIA [14], and STRIDE[15] studies – have demonstrated that initiation of antiretroviral therapy shortly after initiation of anti-TB therapy is associated with lower mortality, especially among HIV-infected persons with a baseline CD4 count less than 50 cells/mm3. These findings concur with the high mortality rates documented in programs that delayed initiation of antiretroviral therapy until 2 months or longer following initiation of anti-TB therapy[16,17].

SAPIT: The SAPIT trial randomized 642 South African HIV-infected adults with active TB and a CD4 count less than 500 cells/mm3 to initiate antiretroviral therapy at one of three time intervals following initiation of TB therapy[12]. For the TB therapy, patients were scheduled to take four anti-TB drugs for the initial 2-months (intensive phase), followed by two anti-TB drugs for of 4 months (continuation phase). The "integrated therapy" group initiated antiretroviral therapy during their treatment for TB infection, either within 4 weeks of initiation of TB therapy (the "early integrated therapy" group) or within 4 weeks of completing the initial 2 months of TB therapy (the "late integrated therapy") group. The "sequential therapy" group deferred initiation of antiretroviral therapy until completion of TB therapy. An interim analysis found a significantly higher mortality rate among patients in the sequential therapy group, as compared with patients in the combined early- and late-integrated therapy groups (Figure 3), leading to discontinuation of the sequential therapy arm of the study [12]. Further analysis of patients in the integrated therapy arms (Figure 4Patients with a CD4+ T-cell Count less than 50/mm3Patients with a CD4+ T-cell Count greater than or equal to 50/mm3) found that for patients with initial CD4 counts less than 50 cells/mm3, the early-integrated arm was associated with significantly lower mortality than the late-integrated arm, but this difference was not observed in patients with an initial CD4 count greater than 50 cells/mm3 [13].

CAMELIA: The CAMELIA study (ANRS 1295) was an open label, randomized trial that compared clinical outcomes associated with initiation of antiretroviral therapy at 2 weeks versus 8 weeks following initiation of TB therapy for patients with confirmed TB disease[14]. In this trial, 661 Cambodian HIV-infected patients with an absolute CD4 count less than 200 cells/mm3 initiated standard TB therapy (planned 6 months of treatment) and were randomized to initiate antiretroviral therapy either at week two of TB therapy (the "Early ART" arm) or at week eight of TB therapy (the "Later ART" arm). The key finding was that patients in the later ART arm had a 52% higher mortality rate when compared with patients in the early ART arm, even though patients who received early ART had a higher likelihood of developing TB-associated IRIS (Figure 5).

STRIDE: The STRIDE study (ACTG 5221) trial design and finding were similar to the CAMELIA trial. This open label, randomized trial compared initiation of antiretroviral therapy within 2 weeks after starting anti-TB therapy ("Earlier ART" arm) with initiation of antiretroviral therapy 8 to 12 weeks after starting anti-TB therapy ("Later ART" arm) for 806 HIV-infected patients with an absolute CD4 count less than 250 cells/mm3 and confirmed or suspected TB[15]. Overall, investigators did not observe a significant difference in deaths or AIDS events among patients in the earlier ART versus later ART arms, but among patients with an initial absolute CD4 count less than 50 cells/mm3, earlier initiation of antiretroviral therapy was associated with significantly lower rates of deaths and AIDS events, as compared with later initiation of antiretroviral therapy (Figure 6Data for Entire Study Population Data Related to CD4+ T-cell Count). As in the CAMELIA study, patients in the earlier ART arm experienced higher rates of IRIS than those in the later ART arm, but the increased rates of IRIS did not result in higher mortality.

Selection of Initial Antiretroviral Regimen for Patients with Active TB

A number of important drug-drug interactions can occur between antiretroviral medications and anti-TB agents. Specifically, rifampicin has significant drug-drug interactions with nevirapine and most protease inhibitors, especially ritonavir-boosted protease inhibitors. The drug-drug interactions between efavirenz and rifampicin are not substantial enough to require replacement or dose-adjustment of either medication[1,18,19,20,21]. The 2010 WHO Guidelines[1,2] recommend that HIV-infected persons with active TB receive an efavirenz-based antiretroviral regimen (Figure 7). If use of efavirenz is not an option, a nevirapine- or triple NRTI-based regimen should be used instead. Although pharmacokinetic data suggest that standard dosing of nevirapine with rifampicin could result in sub-therapeutic serum nevirapine levels[22,23], this approach appears to be reasonably effective and well tolerated[21,24]. Use of higher-dose nevirapine (300 mg twice daily) to compensate for lowered nevirapine drug levels is associated with an increased risk of nevirapine hypersensitivity[25] and therefore not recommended. If nevirapine is used, the typical nevirapine 14-day lead-in dosing is not required in the presence of rifampicin[1].

Although not as potent as traditional NNRTI- or PI-based antiretroviral therapy regimens[26,27], a triple NRTI regimen, such as (zidovudine plus lamivudine plus abacavir) or (zidovudine plus lamivudine plus tenfovoir), avoids problematic drug-drug interactions. Use of a raltegravir-based antiretroviral regimen would be ideal in this situation, but raltegravir is not widely available in resource-limited settings. For HIV-infected persons with TB who require a PI-based antiretroviral regimen, rifabutin should be used as a substitute for rifampicin[1], since rifabutin has less severe drug-drug interactions with protease inhibitors. If rifabutin is not available and rifampicin must be included in the anti-TB regimen, adjusted doses of ritonavir-lopinavir or ritonavir-boosted saquinavir may be used (specifically, lopinavir-ritonavir 400 mg/400 mg bid; lopinavir-ritonavir 800 mg/200 mg bid; or saquinavir 400 mg bid plus ritonavir 400 mg bid). These combinations, however, are associated with high levels of drug toxicity and require close clinical and laboratory monitoring[1].

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  • The following link will open in a new window.
    Figure 1. Co-Trimoxazole Toxicity Grading Scale for Adults and Adolescents

    Source: World Health Organization. Guidelines for co-trimoxazole prophylaxis for HIV-related infections in children, adolescents and adults: recommendations for a public health approach, WHO, Geneva (2006).


    Figure 1
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    Figure 2. Protocol for Co-Trimoxazole Desensitization Among Adults and Adolescents

    Source: World Health Organization. Guidelines for co-trimoxazole prophylaxis for HIV-related infections in children, adolescents and adults: recommendations for a public health approach, WHO, Geneva (2006).


    Figure 2
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    Figure 3. Kaplan-Meier Survival Curves from the SAPIT Study Comparing Mortality among Patients in the Integrated versus the Sequential Therapy Groups.

    There was a reduction in the rate of death among the 429 patients in the combined integrated-therapy groups (5.4 deaths per 100 person-years, or 25 deaths), as compared with the 213 patients in the sequential-therapy group (12.1 per 100 person-years, or 27 deaths); a relative reduction of 56% (hazard ratio in the combined integrated-therapy groups, 0.44; 95% confidence interval, 0.25 to 0.79; P = 0.003). Mortality was lower in the combined integrated-therapy groups in all CD4+ count strata. Rates of adverse events during follow-up were similar in the two study groups.
    Source: Abdool Karim SS, Naidoo K, Grobler A, et al. Timing of initiation of antiretroviral drugs during tuberculosis therapy. N Engl J Med. 2010;362:697-706. Reproduced with permission from the Massachusetts Medical Society. Copyright © 2010 Massachusetts Medical Society. All rights reserved.


    Figure 3
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    Figure 4: Comparison of Earlier versus Later Antiretroviral Therapy in Patients with Newly Diagnosed Tuberculosis: SAPIT Trial. Image 1. Survival without an AIDS-Defining Illness in Patients with a CD4+ T-cell Count less than 50/mm<sup>3</sup><br />
This graph shows comparison data for patients with newly diagnosed TB and a CD4 count less than 50 cells/mm<sup>3</sup> who received either early integrated antiretroviral therapy or late integrated antiretroviral therapy.<br />
<strong>Source:</strong> Abdool Karim SS, Naidoo K, Grobler A, et al. Integration of antiretroviral therapy with tuberculosis treatment. N Engl J Med. 2011;365:1492-1501. Reproduced with permission from the Massachusetts Medical Society. Copyright © 2011 Massachusetts Medical Society. All rights reserved.
    Figure 4 (series)
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    Figure 5. Kaplan-Meier Survival Estimates in Patient with TB who Received Earlier versus Later Antiretroviral Therapy: CAMELIA StudyS

    Patients with active TB were started on standard TB therapy, then randomized to also begin antiretroviral therapy at either 2 weeks or 8 weeks of TB therapy. This graph demonstrates that patients starting earlier antiretroviral therapy (at 2 weeks) had significantly higher probabilities of surviving to 50, 100 and 150 weeks than patients who started later antiretroviral therapy (at 8 weeks).
    Source: Blanc FX, Sok T, Laureillard D, et al. Earlier versus later start of antiretroviral therapy in HIV-infected adults with tuberculosis. N Engl J Med. 2011;365:1471-81. Reproduced with permission from the Massachusetts Medical Society. Copyright © 2011 Massachusetts Medical Society. All rights reserved.


    Figure 5
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    Figure 6: Time to New AIDS-Defining Illness or Death: STRIDE Study. Image 1. Data for Entire Study Population<br />
This graph shows the time to a new AIDS-defining illness or
death for the entire study population based on whether these patients with newly diagnosed tuberculosis received earlier or later antiretroviral therapy.<br />
<strong>Source:</strong> Havlir DV, Kendall MA, Ive P, et al. Timing of antiretroviral therapy for HIV-1 infection and tuberculosis. N Engl J Med. 2011;365:1482-91. Reproduced with permission from the Massachusetts Medical Society. Copyright © 2011 Massachusetts Medical Society. All rights reserved.
    Figure 6 (series)
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    Figure 7. WHO Recommended Antiretroviral Regimens for Persons on TB Therapy

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


    Figure 7