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HIV, Tuberculosis, and Multidrug Resistance: Implications for HIV-Infected Children

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In a recent supplement to the Journal of Infectious Diseases , Wells et al refer to the coinfection with multidrug-resistant tuberculosis (MDR-TB) and HIV as the "perfect storm."( 1 ) Tuberculosis (TB), an infection that has existed since antiquity but until recently appeared to be on a slow downward epidemiological slope, has coupled with the immunodeficiency associated with HIV infection to become one of the most life-threatening opportunistic infections in HIV-infected individuals.

TB and HIV have several characteristics in common. Both are often associated with poverty, may remain latent for decades between primary infection and recurrence, involve expensive and complex long-term treatment, and require a steady influx of new drugs to overcome resistance. In addition, there is no efficacious vaccine for either infection, and neither can be controlled indefinitely by combination therapy.

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The Joint United Nations Program on HIV/AIDS (UNAIDS) estimated that there were 33 million people living with HIV infection at the end of 2007. Approximately 2.5 million new HIV infections occurred during the same time period, along with an estimated 2.1 million deaths attributable to HIV. As of 2007, there were 2.5 million children with HIV infection.( 2 ) In 2006, UNAIDS estimated that one third of the individuals living with HIV were coinfected with TB.( 3 ) Only 0.9% of 33 million HIV-infected people had been screened for TB in 2006.( 6 )

An Image of a World Map with Estimated HIV Prevalence in New TB cases, 2005
Map from the Public Health Mapping Library, World Health Organization, 2006

TB also has a large global impact. In 2006, there were 14.4 million individuals worldwide living with TB, including a half million cases of MDR-TB. An additional 9.2 million new TB infections occurred that year, of which more than 11% were found in children,( 4 ) and some 1.7 million deaths in 2006 were attributable to TB. Of the new cases worldwide, 8% (709,000 individuals) were infected with both HIV and TB. The prevalence of HIV in TB patients tested in Africa in 2006 was 52%.( 6 ) In countries with high HIV prevalence, as many as 75% of reported TB cases are HIV associated.( 2 )

Data from the United States indicate that HIV and TB comorbidity is increasingly visible and recognized as a synergistic problem, evident in the reporting of HIV infection among TB patients, which increased from 35% in 1993 to 68% in 2003. At least 9% of TB patients were HIV infected in 2005.( 5 ) In the United States, patients with both TB and HIV infection are 5 times more likely to die during treatment of TB than patients who are not infected. HIV is the most important known risk factor for progression from latent TB to active disease. In 2006, based on these observations, the U.S. Centers for Disease Control and Prevention (CDC) recommended routine HIV testing of all TB patients except those who declined testing.( 5 ) Globally, 53% of countries reporting to the World Health Organization (WHO) have adopted a policy of offering HIV testing to TB patients, but HIV testing was reported for only 12% of notified patients.( 6 )

Virtually everything that is known about MDR-TB is obtained from studies involving adults. However, the global burden of TB is often borne by children, who represent 15-20% of the global caseload.( 7 ) As MDR-TB spreads among HIV-infected and HIV-uninfected adults, secondary infection among HIV-infected and HIV-uninfected children will increase and become a major threat to their survival.

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MDR-TB is defined as a strain of Mycobacterium tuberculosis that is resistant to at least isoniazid and rifampin. Extensively drug-resistant TB (XDR-TB) involves resistance to any fluoroquinolone and one of the second-line anti-TB injectable agents (kanamycin, amikacin, or capreomycin), in addition to the basic resistance that defines MDR-TB.( 1 ) In practical terms, XDR-TB may be untreatable unless new anti-TB drugs are discovered. It is estimated that 425,000 cases of MDR-TB are occurring worldwide each year, accounting for approximately 5% of the annual TB burden.( 8,9 ) The percentage of children who are infected with MDR-TB is unknown.

MDR-TB was discovered and defined in the United States and worldwide during the 1990s.( 9 ) Extensive surveys of the international network of TB laboratories were performed by the WHO and the CDC, which identified 20% of 17,690 TB isolates as MDR-TB and 2% as XDR-TB. Studies of samples from the United States, Latvia, and South Korea indicated that 4%, 19%, and 15%, respectively, of MDR-TB were XDR-TB. The proportion of XDR-TB isolates worldwide increased from 5% of MDR-TB isolates in 2000 to 7% in 2004.( 9 )

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Diagnosis of TB in Children

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There are major challenges in diagnosing TB in children. Sputum analysis, a mainstay of diagnosis in adults, is positive in only 10-15% of children with probable TB. The yield increases to 30-40% using cultures from 2 or 3 gastric aspirates, but both sputum and gastric aspirates are difficult to obtain in children.( 10,11 )

Diagnosis of TB in adults who have not received bacillus Calmette-Guérin (BCG) immunization relies on the use of the standard TB skin test (TST). However, the TST has poor sensitivity when used for diagnosing children. The sensitivity is further diminished in HIV-infected children as a result of their impaired immunity. In addition, among children who have been immunized with BCG, it is not possible to differentiate whether a positive TST result is attributable to infection or immunization.( 4 )

Alternative approaches to diagnosis include nasopharyngeal aspiration, hypertonic saline-induced sputum collection, and string testing. These methods may increase yield but they are difficult to perform in resource-limited settings and under circumstances in which there is a shortage of health care workers.( 10-13 )

Several novel cell assays are in development. These include an early secreted antigen target (ESAT) test, a culture filtrate (CFP-10) test, and an enzyme-linked immunospot (ELISPOT) test.( 10 , 14 , 15 ) These assays may have increased sensitivity but they do not differentiate latent M tuberculosis infection and active disease. In addition, they are costly and therefore not practical for routine use in resource-poor countries.

Without a specific laboratory diagnosis, TB infection in children is suspected on the basis of: 1) close contact with an individual case; 2) a positive TST result; and 3) suggestive signs upon chest X-ray imaging. In TB-endemic areas, the interpretation of a chest X-ray examination may be based on subjective features.( 16 )

HIV coinfection complicates all levels of TB diagnosis in children. Children who live with HIV-infected adults are more likely to acquire TB infection. HIV-TB coinfected adults often test negative for M tuberculosis on sputum analysis.( 17 ) The TST is less sensitive in the presence of immunodeficiency secondary to HIV. Children with HIV may have chronic pulmonary disease from other causes along with weight loss and failure to thrive, which are typical morbidities of both TB and HIV. Lastly, the interpretation of chest X-ray images is complicated by the presence of bacterial pneumonia, bronchiectasis, or atypical manifestations of TB in immunocompromised children.( 18 ) More complex methods of diagnosis may be difficult to perform or may be unavailable in many settings. These include bronchoscopy and computed tomography.

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BCG Immunization

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The efficacy of BCG immunization for preventing TB in children is variable.( 19-22 ) Several recent studies document disseminated BCG infection in HIV-infected children.( 23-25 ) Therefore, BCG immunization of HIV-infected children is no longer recommended. Further, the lack of polymerase chain reaction (PCR) techniques for HIV diagnosis in HIV-exposed infants prevents early diagnosis of HIV infection in resource-poor countries. This means many HIV-infected children may receive BCG immunization before the virus is detected.

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Current guidelines recommend that all children less than 5 years of age who are in close contact with a sputum smear-positive index case should be treated with preventive chemotherapy once active TB has been ruled out.( 26 ) For symptomatic children, further investigation to rule out active TB is required. One situation this recommendation fails to address, however, is the fact that many HIV-TB coinfected adults are sputum negative.( 17 )

Isoniazid has proven efficacy in preventing active disease. Three months of treatment with isoniazid and rifampin has been found equivalent to 6-9 months of treatment with isoniazid alone.( 27-29 ) For HIV-infected children regardless of age or TST result, isoniazid preventive chemotherapy is recommended if they have significant exposure to adults with pulmonary TB once active TB has been ruled out.

Recommendations for the treatment of children with active TB disease are similar whether they are infected or uninfected with HIV( 30-32 ):

Table I: Treatment of Active TB in Children
TB Diagnosis Treatment
Sputum smear negative TB Rifampin + isoniazid + pyrazinamide for 2 months, followed by rifampin + isoniazid for 4 months
Sputum smear positive TB Rifampin + isoniazid + pyrazinamide + ethambutol for 2 months, followed by rifampin + isoniazid for 4 months
Disseminated TB Rifampin + isoniazid + pyrazinamide + ethambutol for 2 months, followed by rifampin + isoniazid for 7-10 months
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Clinical management of patients treated simultaneously for TB and HIV must include a careful review of drug interactions. For instance, rifampin is known to lower the concentrations of nevirapine and other antiretroviral (ARV) medications.( 33,34 ) Buffers contained in formulations of didanosine (ddI) bind to fluoroquinolones and block absorption. Drugs that are associated with adverse neurologic effects may have overlapping toxicities. These include stavudine (d4T), ddI, and ethambutol. Hepatotoxicity is a known adverse effect of pyrazinamide, nevirapine, and efavirenz. Abacavir, amprenavir, nevirapine, efavirenz, fosamprenavir, and pyrazinamide are associated with the frequent occurrence of rash.( 35-38 ) Ocular abnormalities may occur with both ddI and ethambutol. Atazanavir reduces the metabolism of the antimicrobial drug clarithromycin, leading to increased clarithromycin effects. When clarithromycin is combined with atazanavir, the clarithromycin dosage should be reduced by 50% ( 67 ); consultation with an expert is advised.

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The impact of MDR-TB on HIV treatment and care is significant. A high mortality rate is associated with MDR-TB outbreaks among HIV-infected patients, and treatment outcomes are poor even when the WHO recommendations for what is known as DOTS-plus (directly observed treatment--short course, with the addition of second-line anti-TB drugs) are implemented.( 39-43 ) In a study based in New York City, 62% of patients with MDR-TB and HIV died during treatment, compared with 26% of patients with drug-sensitive TB.( 41 ) Similar results were reported from Latvia, where 44% of patients infected with MDR-TB had a poor outcome, and treatment for drug-sensitive TB resulted in a 70-80% success rate.( 43 ) Treatment success in many studies is often linked to the use of fluoroquinolones.( 43 , 45 )

The requirement for multiple drugs to treat MDR-TB and the simultaneous use of antiretroviral therapy for patients who are coinfected with HIV complicates treatment strategies. A minimum of 4 effective drugs is needed to treat MDR-TB, including an injectable drug such as amikacin, kanamycin, or capreomycin, along with a fluoroquinolone and at least 2 drugs from the remaining 3 second-line classes of drugs, which are p -aminosalicylic acid (PAS), cycloserine, and thioamides (ethionamide or protionamide). Treatment also should include first-line drugs beyond isoniazid and rifampin to which M tuberculosis remains sensitive.

The use of intravenous drugs can require extensive hospitalization and frequently causes drug side effects. Without the availability of resistance testing, it is difficult to make informed choices in selecting drugs to treat MDR-TB. Preliminary studies suggest that clarithromycin, clofazimine, linezolid, and metronidazole may be additional treatment options.( 46,47 ) Given the large number of drugs involved in treating MDR-TB, it is understandable that many experts consider XDR-TB almost untreatable.( 1 )

Treatment of patients with MDR-TB is prolonged, usually requiring at least 24 months of therapy, compared with 6-8 months for sensitive strains of M tuberculosis . The requirement for second-line therapy obliges the use of drugs that are considerably more toxic, and it complicates the management of ARV regimens for patients who are coinfected with TB and HIV. In addition, the costs of the drugs used in the treatment of MDR-TB are 10 times greater than the cost of isoniazid or rifampin. Efforts to treat resistant TB are often unsuccessful. Success rates for treatment of drug-susceptible TB reach 90% when treatment programs are well managed. In contrast, in resource-poor countries where the burden of TB is heavy, and where the prevalence of MDR-TB and XDR-TB is rapidly increasing, management of TB is often less than optimal, resulting in dramatic increases in mortality.

Nosocomial transmission of both MDR-TB and XDR-TB has been reported, strongly suggesting that hospitalization of HIV-TB coinfected patients is associated with inadequate infection control practices in hospital environments and possibly clinic settings.( 1 , 48-50 ) As delays in the diagnosis and treatment of TB are common, the interval between diagnosis of MDR-TB and death is often as short as 2-8 weeks.( 51 ) Although reports suggest an association between HIV and MDR-TB outbreaks, the data regarding an association of HIV and MDR-TB in general is conflicting.( 8 , 20 , 52 , 53 ) In contrast, HIV is clearly associated with rifampin resistance in patients with TB.( 1 , 27 , 44 , 54-56 )

The high potential for nosocomial rapid spread of MDR-TB and XDR-TB has been documented in reports from hospital settings and prisons in various countries (eg, Russia, Estonia, and Georgia). Transmission incidents are not limited to patients or inmates but are also seen among the health care workers.( 8 , 57,58 ,) In Zambia, only 8 of 1,045 nurses employed at the University Teaching Hospital acquired TB between 1982 and 1984, and all were treated successfully. In contrast, between 1990 and 1996, 114 nurses died of pulmonary TB.( 59 )

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HIV-TB coinfected children have poorer outcomes than HIV-uninfected children. There are several possible causes for that situation. Anti-TB medications may be poorly absorbed in the presence of HIV infection; there is an increased incidence of coinfections with other infectious agents; TB may be misdiagnosed as lymphocytic interstitial pneumonitis (LIP) or other pulmonary conditions; anti-TB drugs may penetrate poorly into chronically infected tissue; adherence may be poor; and HIV infection may be severely advanced, especially if treatment is not provided.( 30 , 60-62 ) The risk of TB is 4 times higher for children with CD4 percentages of <15% and 3 times higher for children with elevated viral loads.( 11 , 19 , 39 , 63 )

HIV is the strongest risk factor for activating TB among patients coinfected with HIV and TB.( 64 ) In areas where the HIV prevalence exceeds 10%, TB is the major cause of death among HIV-infected patients. In addition, HIV-TB coinfection has been associated with outbreaks of MDR-TB.( 8 , 40 , 64-66 )

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Implications for the Future

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The "perfect storm" of a simultaneous HIV epidemic and an emerging MDR-TB epidemic bodes poorly for HIV-infected children. Diagnosing TB in HIV-uninfected children is difficult, and it is further complicated in HIV-infected children by the presence of immunodeficiency and pulmonary disease, which may make X-ray diagnosis of TB even more difficult. The BCG vaccination is only partially effective in preventing TB, but BCG vaccination is no longer recommended for HIV-infected children because of the risk of disseminated BCG infection. Further, a diagnosis of HIV infection in HIV-exposed infants is difficult to make in resource-poor countries without access to HIV PCR diagnostic techniques. The pharmacokinetic and safety profiles of drugs for treating children with MDR-TB are not well studied. Liquid formulations are severely lacking, making the appropriate approach to the treatment of infants uncertain.

The increased rate of HIV-TB coinfection has placed severe strains on the already overburdened and inadequate worldwide supply of health care workers. It has been conjectured that interaction between health care workers and TB-infected patients may result in poor treatment management and may contribute to increased rates of both MDR-TB and XDR-TB.( 1 ) Numerous medical articles and guidelines developed by international organizations suggest remedies for reducing the number of new cases of HIV-TB coinfection. Among the recommendations are:

transparent gif bullet Make an early and accurate diagnosis of TB.
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transparent gif bullet Improve access to HIV testing and counseling and to ARV therapy for TB patients.
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transparent gif bullet Develop improved diagnostic technology, especially for children and HIV-TB coinfected individuals.
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transparent gif bullet Prioritize the development of new drugs for treating MDR-TB, and especially for treating XDR-TB.
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transparent gif bullet Prioritize pharmacokinetic and safety studies of drugs for the treatment of TB in children.
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transparent gif bullet Develop fixed-dose coformulated drugs as a means to improve adherence.
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transparent gif bullet Maintain aggressive surveillance of anti-TB drug resistance.
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transparent gif bullet Increase TB laboratory capacity.
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transparent gif bullet Implement early infection control measures to reduce nosocomial spread of TB.
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transparent gif bullet Increase capacity in the comanagement of HIV and TB.
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transparent gif bullet Integrate education and training on HIV and TB for health care workers.
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transparent gif bullet Increase collaboration between HIV and TB programs.
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The recommendations for improved HIV and TB control among researchers, clinicians, and international organizations are consistent: They all recognize the need for new, more aggressive and coordinated approaches to controlling the dual epidemics of HIV and TB. The increasing rates of MDR-TB reemphasize some of the most basic paradigms of public health practice. Although having a steady influx of new drugs is an important factor for controlling HIV-TB coinfection, the intertwined nature of the HIV and TB epidemics emphatically indicates that it is impossible to effectively treat HIV without treating other illnesses, maintaining prevention efforts, improving laboratory services, addressing health care inequities, and strengthening basic health care infrastructure. If anything, the realization that HIV treatment is available and thus far sustainable in resource-poor settings should reinforce the conviction that improving treatment for many other diseases is both rational and achievable. MDR-TB can be addressed through classic public health methods such as increasing prevention and diagnostic efforts, contact tracing, infection control, and strengthening basic health care infrastructure and capacity.

ICAP's Guide to TB Screening among HIV-Infected
ICAP's Guide to TB Screening

Although contact tracing is a cornerstone of a sound public health approach to control of TB, it is not discussed in most international recommendations for addressing the dual HIV and MDR-TB epidemics. Contact tracing is particularly important for identifying exposed children of adults who are diagnosed with TB, and the practice has been recommended by the WHO.( 68 ) However, the omission of recommendations for simultaneous universal TB testing for HIV-infected patients and universal HIV testing for TB-infected patients, coupled with the fact that contact tracing rarely occurs in low-resource settings,( 68 ) places family members, sexual partners, community members, and health care workers at risk of acquiring fatal and untreatable, but otherwise preventable, infection with HIV, TB, or both. Such deficiencies in public health policy force clinicians to engage in contradictory medical practices. Clinicians historically have been guided by ethical, legal, and public health principles that include the duty to inform. Typically, this duty involved reporting transmissible infectious diseases, including sexually transmitted diseases, and contact tracing. An acceptable "standard of care" practice should require a clinician caring for patients with TB to perform contact tracing and HIV testing. Any clinician caring for HIV-infected patients should perform contact tracing and TB testing.

Similarly, as part of specific initiatives to reduce coinfection with HIV and MDR-TB in children, it is essential to reexamine basic public health practices and to properly fund efforts to expand prevention programs, improve diagnostic techniques and infection control practices in hospital settings, increase children's access to health care services, and strengthen health care infrastructure. The relative dearth of information available on MDR-TB and HIV coinfected children highlights the need for further research and attention to prevention and control of TB and HIV in this vulnerable subpopulation. Although there has been much verbal support for strengthening health capacity and systems, and for committing forces to work jointly on HIV and TB issues, efforts to cooperate need to be intensified, with emphasis on including children. Without a coordinated, comprehensive approach to the prevention and treatment of both HIV and TB, the dual epidemics of HIV and TB infection, including MDR-TB and XDR-TB, are likely to amplify.

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