Managing Drug Interactions in the Treatment of HIV-Related Tuberculosis

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Introduction

Worldwide, tuberculosis is the most common serious opportunistic infection among people with HIV infection. The World Health Organization estimates that of the 8.7 million individuals who developed incident tuberculosis in 2011, 1.1 million, or 13%, were co-infected with HIV.² Further, of those who suffer tuberculosis-related mortality, 31% are HIV-infected. Despite the complexities of simultaneously treating two infections requiring multidrug therapy, antiretroviral therapy is life-saving among patients with tuberculosis and advanced HIV disease.^4-7

Timing of initiation of antiretrovirals among patients with HIV requiring tuberculosis treatment.

There is now clear evidence that providing antiretroviral therapy to HIV-infected adults during tuberculosis treatment, rather than waiting until completion of tuberculosis therapy, reduces mortality, particularly among those with advanced HIV disease. In one randomized controlled clinical trial among HIV-infected adults in South Africa, initiating antiretroviral therapy during tuberculosis therapy rather than waiting until tuberculosis treatment was completed reduced the hazard of all-cause mortality by 56% and was beneficial regardless of CD4 count.³ Subsequent clinical trials evaluating the optimal timing of initiation of antiretroviral therapy during tuberculosis treatment were conducted.^4-7 Results from these trials, all of which were conducted in high prevalence/low resource settings, indicated that earlier initiation of ART significantly reduced mortality in persons with (non-meningitis) HIV-TB and CD4 cell count below 50/mm³. Based on the results of these trials, the Department of Health and Human Services and Infectious Diseases Society of America now recommend that antiretroviral treatment be started two weeks after initiation of tuberculosis treatment for most patients with CD4 counts less than 50 cells/mm³.⁸

Challenges of co-treatment of HIV and tuberculosis.

Concurrent treatment of tuberculosis and HIV is complicated by

• the adherence challenges of polypharmacy,
• overlapping side effect profiles of antituberculosis and antiretroviral drugs,
• immune reconstitution inflammatory syndrome, and
• drug-drug interactions.⁹

The focus of this document is the drug-drug interaction between rifamycin antibiotics (rifampin, rifabutin, and rifapentine) and four classes of antiretroviral drugs: protease inhibitors, non-nucleoside reverse- transcriptase inhibitors (NNRTI), CCR5-receptor antagonists, and integrase inhibitors.¹⁰, ¹¹ Only two of the currently available antiretroviral drug classes, the nucleoside/nucleotide analogues (NRTI) [with the exception of zidovudine ¹², ¹³] and the entry inhibitor enfuvirtide (given parenterally)¹⁴ are free of clinically- significant interactions with the rifamycins. Although serum concentrations of the NRTI zidovudine are diminished by co-administration of rifamycins, no dose adjustment is recommended as the relationship between zidovudine plasma concentrations and efficacy is unclear.

Objectives of these guidelines.

The purpose of these guidelines is to provide the clinician with updated recommendations for managing the drug-drug interactions that occur when using antiretroviral therapy during tuberculosis treatment. (Table 1a) Changes from previous versions of these guidelines include:

• a summary of data from clinical trials regarding timing of initiation of antiretroviral therapy among patients with tuberculosis;
• drug interaction data for new antiretroviral drugs; and
• changes in dosing guidelines
  • for rifabutin when co-administered with protease inhibitors,
  • for nevirapine when co-administered with rifampin, and
  • for raltegravir when co-administered with rifampin.
• more detailed recommendations regarding co-treatment of tuberculosis and HIV among children and pregnant women

We include pharmacokinetic data as well as data about immunologic response and virologic suppression (where available) for antiretroviral drugs that are licensed and available for use in the United States when administered in combination with antituberculosis drugs.