The TB/HIV Syndemic:
Prevention, Detection, and Treatment

Release Date: April 1, 2013

Expiration Date: April 30, 2015

FACULTY:

Adlia Ebeid, PharmD
Clinical Pharmacist, San Jose Clinic
Houston, Texas

Portia Davis, PharmD
Assistant Professor of Pharmacy Practice

Omonike Olaleye, PhD
Associate Professor of Pharmacology

Dominique Guinn
Research Assistant

Emmanuel Aniemeke, CPht, Doctor of
Pharmacy Candidate

Ada Eluwa, Doctoral Candidate,
Pharmaceutics

Sarah Finney, Doctoral Candidate,
Pharmaceutics

Texas Southern University College of Pharmacy
and Health Sciences
Houston, Texas

FACULTY DISCLOSURE STATEMENTS:

Drs. Ebeid, Davis, and Olaleye; Mses. Guinn, Eluwa, and Finney; and Mr. Aniemeke have no actual or potential conflicts of interest in relation to this activity.

Postgraduate Healthcare Education, LLC does not view the existence of relationships as an implication of bias or that the value of the material is decreased. The content of the activity was planned to be balanced, objective, and scientifically rigorous. Occasionally, authors may express opinions that represent their own viewpoint. Conclusions drawn by participants should be derived from objective analysis of scientific data.

ACCREDITATION STATEMENT:

Pharmacy acpe
Postgraduate Healthcare Education, LLC is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.
UAN: 0430-0000-13-006-H02-P
Credits: 2.0 hours (0.20 ceu)
Type of Activity: Knowledge

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Payment of $6.50 required for exam to be graded.

TARGET AUDIENCE:

This accredited activity is targeted to pharmacists. Estimated time to complete this activity is 120 minutes.

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DISCLAIMER:

Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients’ conditions and possible contraindications or dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.

GOAL:

To discuss the evolution of therapy in patients coinfected with tuberculosis (TB) and HIV and give an overview of prevention, detection, and treatment modalities useful for community pharmacists.

OBJECTIVES:

After completing this activity, the participant should be able to:

  1. Understand the public health impact of the TB/HIV syndemic and identify challenges in prevention, detection, and treatment of coinfected patients.
  2. Distinguish between different guidelines and evidence-based medications for treating coinfection and assess the benefits of antiretroviral therapy in coinfected patients.
  3. Recognize, monitor, and avoid drug-drug interactions in an effort to optimize therapy.
  4. Identify emerging therapies and opportunities for research and development.


ABSTRACT: The tuberculosis (TB)/HIV syndemic is a global health threat that is extremely difficult to manage. The CDC recommends that newly diagnosed HIV patients be simultaneously tested for latent TB infection so that proper combination treatment can be pursued without delay. Recent clinical trials indicate that if a coinfection is discovered, antiretroviral therapy must be initiated within the first 2 to 12 weeks of TB treatment, depending upon the patient's CD4 cell count. Because of its pharmacokinetic profile, rifampin should be avoided in patients taking protease inhibitors or nonnucleoside reverse transcriptase inhibitors. Alternatively, rifabutin may be used in these patients, since it is a less potent inducer of CYP3A4. The goal of simultaneous treatment is to prevent HIV progression while effectively treating TB.

Tuberculosis (TB), a preventable and treatable opportunistic infection, is the world's leading cause of HIV-related deaths.1 Individually, TB and HIV are global epidemics that continue to threaten our public health system. The combination of TB and HIV results in costly and often lethal complications, making it difficult to manage and treat this coinfection.1,2

Health organizations such as the CDC and the World Health Organization (WHO) have developed detailed recommendations for the management of HIV and TB, and pharmacotherapy in coinfected patients is complex.3,4 Challenges posed by the TB/HIV syndemic include TB diagnosis in HIV-infected patients, treatment decisions, and therapy adherence. Fortunately, much-needed research is being conducted to address these issues and potentially help bring the communicability of TB to an end.

This article will review the testing mechanisms used to diagnose TB, as well as the treatment of latent and active TB infections (ATBIs). It also will discuss controversies surrounding initiation of antiretroviral agents, management of drug-drug interactions, and treatment adherence. To facilitate better patient outcomes in TB and HIV, pharmacists must be well aware of the importance of adherence to treatment and be able to successfully incorporate clinical-study data, reports from health authorities, and information on newly developed drugs.

Epidemiology

TB is estimated to affect one-third of the world's population and approximately 11,000 people in the United States.1 Each year, 9 million new cases of TB are discovered worldwide, with more than 1 million cases occurring in patients with HIV or AIDS.3 Coinfection is the greatest risk factor for progressing from a latent TB infection (LTBI) to active disease.1 The risk of developing TB is 21 to 34 times greater in individuals with HIV than in those without it.5

Nearly 1 in 4 deaths among patients with HIV is due to TB, an AIDS-defining illness that is the world's leading cause of HIV-related mortality.2 A recent study of TB patients in Nigeria revealed a 15.5% mortality rate in HIV-positive patients receiving treatment, compared with 3.1% in HIV-negative patients.6 In 2011, of the 1.4 million patients who died from TB, approximately 430,000 were HIV positive.5 TB and HIV are a lethal combination, each heightening the development of the other and constituting a major health threat.

Pathophysiology

Mycobacterium tuberculosis (MTB) is the causative agent for TB infection, which primarily attacks the lungs but can impact the brain, spine, and kidneys. MTB, an airborne bacterium spread by coughing, sneezing, speaking, or singing, is acquired through inhalation of droplets. Patients infected with MTB who are asymptomatic have LTBI and by definition are noninfectious. Frequently, LTBI patients are treated in order to keep TB from developing. In a weakened immune system, as with HIV, latent TB can be reactivated and rapidly progress to active disease, resulting in the following symptoms: productive cough lasting more than 3 weeks; chest pain; weakness or fatigue; weight loss or loss of appetite; chills, fever, or night sweats; and hemoptysis.4

HIV is a retrovirus that survives in its host by hijacking the host's immune system, thereby rendering the host susceptible to infection by other organisms, such as MTB. Preliminary studies indicate that untreated TB may expedite the course of HIV infection.7 Underlying HIV infection can further disseminate bacteria, giving rise to higher rates of extrapulmonary MTB in HIV-infected patients.8

Diagnosis

The CDC guidelines strongly recommend that all patients be tested for LTBI at the time of HIV diagnosis, and that patients with a positive result undergo a chest x-ray and be evaluated by a clinician to rule out ATBI.4 According to baseline data from the Global Plan to Stop TB, only 25% of HIV patients were tested for TB and only 26% of TB patients were tested for HIV. In the U.S., 10% of TB patients tested for HIV were found to be coinfected.8 The WHO recommends routine HIV testing in patients with established or suspected TB infection, their partners, and their family members.3 Patients with a new TB diagnosis are nearly 19 times more likely than patients without a TB diagnosis to be coinfected with HIV.9

To diagnose LTBI, 0.1 mL of purified protein derivative (PPD) is injected intradermally and examined 48 to 72 hours postinjection. Another method of diagnosing LTBI is the interferon-gamma release assay (IGRA), but the PPD skin test is more popular and cost-effective.4

A chest radiograph that is obtained for reasons not associated with diagnosis of ATBI but is found to contain fibrotic lesions consistent with TB warrants diagnostic testing for LTBI and clinical evaluation for TB. An HIV-infected patient with a CD4 count less than 200 cells/ mm3 should be considered to be infected regardless of the results of LTBI diagnostic tests.4

ATBI can be diagnosed via chest radiograph or sputum samples; however, a normal chest radiograph does not rule out the existence of disease. To diagnose TB by the presence of acid-fast bacilli in a sputum smear or culture, three samples should be obtained on three different mornings. The PPD skin test and IGRA are not recommended for diagnosing ATBI because of the greater potential for false-negative results in HIV-infected patients.4

Prevention

Prevention of ATBI, in essence, starts with effective treatment of LTBI. Given their high risk of TB, coinfected HIV patients should receive appropriate and effective therapy to prevent or treat TB, as well as to prevent drug resistance.

Bacillus Calmette-Guérin (BCG) vaccine, developed nearly a century ago, is a means of preventing TB in developing countries. It is administered to children in parts of the world where the prevalence of TB is extremely high.10 The use of this live vaccine is generally not recommended in the U.S. because of its inconsistent efficacy against the reactivation of latent pulmonary infection in adults; BCG vaccine is administered only in special situations.3,4

Regardless of HIV status, people who spend extended periods in certain congregate environments—including, but not limited to, homeless shelters, correctional facilities, and nursing homes—are at increased risk for acquiring TB. HIV-positive individuals should be physically separated from patients known or presumed to be infected with TB until the patient is determined to be noninfectious.4

Although the U.S. has fairly successfully reduced the incidence of TB, much remains to be done from a global perspective. The WHO strongly advocates the use of pharmacotherapy to prevent TB in patients with HIV. As part of a comprehensive TB-prevention/HIV-care initiative, the WHO guidelines recommend initiating isoniazid preventive therapy (IPT) for at least 6 months in HIV-infected patients regardless of TB status.11 Extensive evidence has demonstrated that IPT is efficacious for reducing TB incidence and preventing LTBI, and that it is beneficial for the survival of HIV patients with positive TB infection.3 Furthermore, at the recommended 300 mg per day, IPT in HIV patients with positive TB infection has not been shown to contribute to the development of isoniazid-resistant TB.3,11

The routine addition of cotrimoxazole preventive therapy (CPT) in coinfected patients reduces hospitalizations, morbidity, and mortality. This inexpensive, broad-spectrum antibiotic is well tolerated and compatible with antiretroviral therapy (ART) and does not increase adverse events (AEs). The WHO recognizes that this agent is a means of helping reduce the burden of HIV in patients with TB, rather than a contributor to the treatment of either infection.12

Drug Resistance

Multidrug-resistant TB (MDRTB) is a consequence of inappropriate pharmacotherapy ranging from prescribing errors to noncompliance. In coinfected patients, prescribing errors are typically due to improper medication selection, dosage, frequency, or duration.2 Noncompliance usually results from the pill burden of TB treatment added to a current HIV regimen, or else from AEs and drug interactions.

In an effort to ensure compliance and limit TB's communicability, local health departments administer TB medications through direct observational therapy (DOT) (the practice of watching a patient take each administered dose of his or her TB drug regimen). Once LTBI or TB disease is identified, the patient undergoes DOT until therapy completion, whenever possible.4 Many local health departments offer cash incentives to encourage adherence to TB medications and to promote prevention and resistance.

The issue of drug resistance has made it difficult to treat TB/HIV coinfection. In 2011, there were an estimated 630,000 cases of MDRTB worldwide.3 The evolution of MTB has outpaced the evolution of its treatment to the extent that some forms of TB are now untreatable.4 The emergence of a totally drug-resistant strain of TB (TDRTB) was recently documented in Mumbai, India. The combination of TDRTB and HIV infection is synergistically lethal. In 2008, the number of deaths from MDRTB was estimated to be 150,000 patients, with 53,000 deaths (35%) occurring in HIV-coinfected patients.9

LTBI Treatment

The CDC currently recommends that HIV-infected patients be tested and treated for LTBI unless there is evidence of ATBI. The test should be repeated at least annually in patients at high risk for contracting TB because of repeated exposure to people with ATBI (e.g., incarcerated individuals, active IV drug abusers, etc.).4

The preferred LTBI regimen in HIV-infected patients who test negative for ATBI is isoniazid (INH) 300 mg daily or 900 mg twice weekly—along with pyroxidine 50 mg daily to reduce the risk of peripheral neuropathy—for 9 months.4,13 For patients needing an alternative treatment because of intolerance or INH resistance, rifampin (RIF) or rifabutin (RBT)—chosen based on potential drug interactions with ART—may be given for 4 months.4 Decisions regarding using multiple drugs to treat patients with INH- or RIF-resistant TB should be made after consultation with public-health officials.4,13 Patients with LTBI should not receive prophylaxis beyond the recommended 4 months (RIF regimen) or 9 months (INH regimen) if they have completed all scheduled doses; there is no evidence that extra doses are beneficial, and extra doses may actually cause harm because of the increased development of drug-resistant TB strains. The CDC also recommends utilizing DOT whenever feasible.4

ATBI Treatment

Upon suspicion or diagnosis of ATBI in HIV patients, a multidrug treatment regimen should be initiated immediately. Current CDC recommendations for anti-ATBI treatment in HIV-infected adults are based on the completed number of ingested doses, rather than on treatment duration.4

Treatment of drug-susceptible TB should include a 6-month course of INH, RIF, and pyrazinamide (PZA) with coadministered ethambutol (EMB) for the first 2 months (initial phase), followed by 4 additional months (continuation phase) of RIF and INH (TABLES 1 and 2).4,13,14 In HIV patients, rifabutin (RBT) may be used instead of RIF to limit drug-drug interactions, and rifapentine (RPT) should not be used in HIV-positive patients. EMB may be discontinued early if absence of resistance to INH, RIF, or PZA has been established. In patients with lung disease and positive TB cultures after the first 2 months of therapy, treatment is extended from 6 to 9 months by adding an additional 3 months of INH or RIF to the continuation phase. The CDC recommends that patients with extrapulmonary disease receive treatment for 6 to 9 months, and that those with central nervous system and bone and joint TB undergo extended treatment for 9 to 12 months.4


table 1


table 2

To facilitate successful DOT and increase compliance, TB treatment doses may be given two or three times per week (intermittent dosing). For the first 2 months, DOT administration may be as frequent as 7 days per week for a total of 56 doses, or as little as twice weekly. For the remainder of the treatment period or continuation phase, DOT should consist of administration of doses either daily or three times per week, to reduce the risk of relapse with drug-resistant TB strains.4

ART Initiation

All guidelines agree that the treatment of TB in HIV-positive patients should be identical to that in patients without HIV, and that a multidrug TB regimen should be initiated immediately. When ART should be initiated in ART-naïve patients has emerged as a particularly controversial issue among clinical practitioners. Initially, the CDC guidelines recommended delaying ART for several weeks or months after TB therapy is initiated.4 However, after the CDC guidelines and other guidelines were published, results from highly reputable, accurate, and applicable clinical trials surfaced and have already impacted cotreatment decisions worldwide.

In the SAPiT trial, patients were randomized to receive ART sequential to TB therapy, but did not complete the trial based on results of an early analysis that showed a 56% mortality reduction with integrated therapy over sequential therapy.15 The researchers concluded that it was more advantageous to initiate ART during TB treatment than to wait until its completion.

The CAMELIA study, which included patients with a CD4 count under 200 cells/mm3, found that earlier ART initiation was associated with a statistically significant reduction in mortality in certain HIV-infected patients. Advanced HIV patients (median entry CD4 count of 25 cells/mm3) were randomized to receive ART at 2 weeks or 8 weeks of TB therapy. There was a 38% reduction in mortality in patients receiving ART at 2 weeks versus those receiving it at 8 weeks.16

STRIDE, a multinational trial, randomized ART-naïve patients to early (<2 weeks) ART and later ART groups. Rates of mortality and AIDS diagnosis were not statistically significant between the groups, which had a median CD4 count of 77 cells/mm3. However, in a subset analysis of patients with CD4 counts under 50 cells/mm3, a significant reduction in AIDS or death was noted in patients receiving early ART.17

The results of these clinical trials confirmed the impact of immunodeficiency on ART initiation and led to the current recommendation to initiate ART within the first 2 weeks of TB treatment in patients with CD4 cell counts under 50 cells/mm3. In patients with CD4 cell counts of 50 cells/mm3 or greater, ART initiation can be delayed until week 8 to 12 of TB therapy. Because these clinical trials did not include patients with CD4 cell counts greater than 500 cells/mm3, however, these data—although sensible considering the probability of a better prognosis—are considered anecdotal.18

Despite obstacles to the therapeutic management of TB/HIV coinfection, the simultaneous treatment of TB and HIV, rather than delayed initiation ART, has proven to be an effective standard of care.19 Overall, the recommendation to initiate ART within the first 8 weeks of TB therapy in all HIV-positive patients was strongly supported by evidence from randomized, controlled trials. Furthermore, conventional ART for HIV also helps reduce rates of MTB infection.7

According to the WHO and baseline data from the Global Plan to Stop TB that were examined in 2009, only 37% of HIV-positive TB patients were receiving ART.3 This percentage is predicted to increase as a result of the most recent recommendations and clinical trials. In patients receiving ART who become infected with TB, considerations regarding alteration or discontinuation of ART and selection of TB agents are contingent upon efficacy, drug interactions, drug resistance, prevention of treatment failure, and patient adherence.

Drug Interactions

Drug-drug interactions are a consequence of the recommended HIV/TB integrated therapy. The proper monitoring of therapy could limit the extent of effect on the efficacy and toxicity of accompanying drugs. One of the major setbacks in treating TB/HIV coinfection is the drug-drug interaction with rifamycin antibiotics. Rifamycins, including RIF, RBT, and RPT, bind to mycobacterial RNA polymerase and inhibit RNA synthesis or transcription. They interact with protease inhibitors (PIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) and are also known inducers of CYP450, P-glycoprotein, phase II enzymes, and drug efflux transporter.19,20

RIF therapy is critical because of its bactericidal abilities against slow-growing and intracellular TB, but RIF is also the most potent inducer of the CYP3A4 enzyme.19,20 This induction can reduce the efficacy of PIs and NNRTIs and, in turn, may lead to reduced efficacy of the highly active ART (HAART) regimen.20 For this reason, TB regimens that include RIF should not be used in patients receiving PI and/or NNRTI therapy.

RBT, a less potent inducer of the CYP3A enzyme, is also a substrate of the CYP3A metabolizing enzyme. These characteristics allow RBT to be given concurrently with PIs and NNRTIs, with drug-specific dosage adjustments necessary to prevent drug toxicity or treatment failure (TABLES 3 and 4).21 An increase in RBT concentrations that results in toxicity can lead to neutropenia or uveitis.19 Clinical studies are investigating how to reduce the RBT dosage while avoiding TB treatment failure and drug resistance.


table 3

Efavirenz administered in combination with an RIF TB regimen has proven to be safe, depending upon the patient's pharmacogenetics (TABLE 4). However, combination of an RIF TB regimen with nevirapine leads to decreased efficacy and the eventual failure of HIV therapy.19 Alternatively, since nevirapine is safe in pregnant patients and efavirenz is not, coadministration of nevirapine and RIF may be utilized in pregnant patients when other alternatives are not available. Other dosage adjustments are necessary to ensure proper treatment (TABLE 4).


table 4

RIF seems to have more potent antimycobacterial activity than RMP, according to in vivo studies, but it also induces CYP450 and phase II enzymes, which leads to a high risk of drug-drug interactions. The isolation of resistant strains and treatment failure have led to further studies investigating new drug combinations with moxifloxacin, a fluoroquinolone antibiotic that targets DNA gyrase.19

Emerging Therapies

Significant progress regarding TB has been made since the 1880s—when MTB was discovered to be the causative agent—to the 1990s, when the genome of MTB was annotated.22 In the 1920s, the first vaccine for MTB, Mycobacterium bovis BCG, was administered.22 The development in the 1960s of drug combinations to treat TB marked the beginning of a new era; however, the rise of drug-resistant strains of MTB has rendered these agents ineffective. In the 1980s, there was a decline in the development of new antibacterials.23 Recent research on antibacterials has focused on the structural development of existing antibiotics. While this approach has proven successful in improving efficacy, selectivity, and other pharmacologic profiles, it does not address the problems of drug resistance and latency. As a result, the development of new drugs and new vaccines is under way.

The lethal synergy of TB and HIV has rendered it imperative to develop new anti-TB and anti-HIV agents. The therapeutic management of TB/HIV coinfection poses great challenges because of the high pill burden, drug-drug interactions, and toxicity. Moreover, the emergence of extensively drug-resistant TB, MDRTB, and TDRTB in HIV patients threatens the efficacy of current drugs. The standard recommended therapy uses medications that were developed about 40 years ago and require an extended treatment duration to be effective, which contributes to the increase in drug-resistant strains. Therefore, novel ways to treat HIV patients coinfected with TB are needed.24

Despite advances in pharmacodynamics, pharmacokinetics, and pharmacogenetics, there remain several pressing needs in the management of TB/HIV coinfection. Patients who have developed resistance to rifamycin antibiotics and those with NNRTI resistance or intolerance need new options and combination regimens. Dooley and colleagues have proposed three alternatives for such patients in clinical trials: 1) Optimize the RBT dosage and use PI-based therapy; 2) keep RMP and give PI-based HAART, but increase the PI dosage; 3) keep RMP and use an integrase inhibitor instead of—or in combination with—a PI.19 Comprehension of the underlying molecular basis for the drug-drug interactions could help guide future pharmacokinetic and pharmacodynamic studies of TB/HIV drug combinations.19

The identification of anti-TB agents that target new pathways is crucial for effective short-term TB therapy that will limit the development of resistance, especially in patients coinfected with HIV.25-27 In an attempt to identify novel inhibitors of TB and validate new targets, scientists have focused on large-scale searches to identify biological markers of disease pathogenesis and on the application of emerging technologies to identify novel drug targets. Such research traditionally has been directed at the discovery of inhibitors of replicating mycobacteria. However, the global clinical significance of latent or persisting TB in the context of HIV coinfection has made the development of new antimycobacterials imperative. Thus, a better understanding of the major pathways involved in the pathogenesis, survival, and dormancy of TB will aid in the identification of new drug targets.24-27

New TB drugs that do not induce CYP450 are being investigated in clinical trials. These agents could be potential candidates for combination with HAART. Drugs currently being examined in clinical trials for the treatment of TB include delamanid, a nitroimidazole; SQ109, an ethylenediamine; and sutezolid, an oxazolidinone.19

New regimens or combinations of novel TB regimens to treat drug-sensitive or drug-resistant TB are advancing in clinical trials and regulatory review. Several vaccines to prevent TB are in the pipeline.3,22 TB/HIV coinfection continues to pose an imminent public health threat, particularly in developing countries. Rising chemotherapy costs, increased toxicity, patient compliance issues, drug-drug interactions, and the emergence of drug-resistant strains make it imperative for scientists to develop novel drugable targets, as well as new therapeutic management strategies.

Sirturo (bedaquiline) is a diarylquinoline-derivative antimycobacterial drug that is approved as part of combination therapy for the treatment of MDRTB in adults when other alternatives are not available. Recently approved through the FDA's accelerated approval program, it is the first new TB therapy in more than 40 years.28 Bedaquiline works by inhibiting mycobacterial adenosine 5´-triphosphate synthase, the bacterial enzyme responsible for the production of energy, and it is indicated to be administered via DOT.28,29 The dosage is 400 mg once daily for 2 weeks, then 200 mg three times weekly for 22 weeks. Bedaquiline carries a black box warning based on its propensity to prolong the QT interval. Caution must be exercised in patients with hepatic dysfunction, because hepatic-related AEs and toxicities have been consistently documented with this agent.14

Conclusion

TB is a disease of global concern, and the commitment to strengthen its prevention, detection, and treatment is paramount to making significant advances in its eradication. MTB is particularly hazardous in HIV-infected patients, and initiation of appropriate drug therapy is critical. When treating the TB/HIV-coinfected patient, the clinician must be mindful of the current ART regimen in order to prevent treatment failure or harm from drug interactions, drug resistance, or treatment nonadherence. Although results from several clinical studies have laid the foundation for treatment guidelines from top health organizations, clinicians and local health authorities alike are often challenged in the provision of best practices for handling this health crisis. Identifying opportunities for TB prevention in patients with HIV and initiating ART early are the most recent recommendations for managing TB/HIV coinfection. Pharmacists can play a key role in educating infected patients and health care providers about the best and least threatening approach to integrated ART and TB regimens. By remaining current with emerging anti-TB therapies and ART, pharmacists are equipped with the knowledge to help bridge the gap between existing literature and current treatment practices.

REFERENCES

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