• PREAMBLE
  
  
• INTRODUCTION
  
  
• IMPACT OF HIV ON TB
  
  
• IMPACT OF TB ON HIV
  
  
• IMPACT OF ANTIRETROVIRAL THERAPY (ART)
  
  
• CLINICAL PRESENTATION
  
  
• DIAGNOSTIC TESTS
  
  
• TREATMENT ISSUES
  
  
• PHARMACOKINETIC INTERACTIONS
  
  
• CURRENT RECOMMENDATIONS
  
  
• WHEN TO INITIATE ANTIRETROVIRAL THERAPY IN HIV-INFECTED PERSONS WITH TB
  
  
• HIV + TB: TREATMENT APPROACHES
  
  
• HIV AND PARADOXICAL WORSENING OF TB
  
  
• CONCLUSION
  
  
• REFERENCES

PREAMBLE

The HIV/AIDS epidemic has led to a rise in the incidence of tuberculosis and an epidemic of co-infection. It is estimated that in developing countries, about half the people living with HIV infection will develop active tuberculosis.

Treatment of TB in patients with HIV infection presents several challenges to the clinician, particularly in resource-poor settings. These include drug-drug interactions between the antiretrovirals and antituberculous drugs, overlapping toxicity profiles and non-adherence to complicated treatment regimens. Another problem is the possibility of paradoxical reactions.

Recently, a significant amount of data has been published in relation to the management of HIV and TB co-infection, which often can be complex and confusing for a practicing physician. This booklet presents a simplified approach and practical guidelines for a physician confronted with the difficult task of treating these patients.

INTRODUCTION

• HIV has had a substantial effect on the incidence, clinical manifestations, treatment and outcome of TB
• Escalating tuberculosis case rates over the past decade are largely attributable to HIV
• Globally, HIV and TB are the 2 leading infectious causes of death.
• Coinfection with these pathogens is particularly devastating in the developing world, where the burden of disease is high.
• India has the greatest number of HIV/TB coinfected individuals worldwide.
• Tuberculosis is the leading cause of death among persons with HIV/AIDS worldwide.
• Globally, TB was estimated to account for 30% of AIDS-related deaths in 1999
  

IMPACT OF HIV ON TB

• HIV infection markedly increases the risk for developing active TB
• Comparison of risks for progressing to active TB in latently infected persons

  HIV-negative persons ...............................................................Lifetime risk of 10%
  HIV-infected persons................................................................ About 10% per year

IMPACT OF TB ON HIV

• Active TB accelerates the course of HIV infection
• The risk for opportunistic infections and death is higher in HIV/TB-coinfected persons than in HIV-infected persons without TB
• The increased mortality is directly attributable to HIV
• TB is associated with a 5- to 160-fold increase in HIV viral replication, which may decrease after successful TB treatment.

IMPACT OF ANTIRETROVIRAL THERAPY (ART)

• ART has decreased the risk for developing active TB
• ART has also decreased the risk for death among HIV-infected persons who develop active TB
• ART has been shown to reduce the incidence of TB among persons with HIV infection

CLINICAL PRESENTATION

• Active tuberculosis can occur at any CD4 cell count but atypical presentations are more likely with advanced HIV disease or AIDS. Thus, the clinical presentation is affected by the degree of immunosuppression.
• Fever, weight loss and constitutional symptoms, commonly accompanied by cough and chest pain may be the presenting features.
• Coinfected patients are slightly less likely to have positive sputum smears than non-HIV-infected individuals.
• Co-infected patients with advanced AIDS commonly have negative tuberculin-skin tests.
• Chest radiographic findings can vary depending on the degree of immunosuppression. Patients with CD4 cell counts greater than 200 are more likely to have classic findings of upper lobe infiltrates with cavitary lesions, while those patients with AIDS may be more likely to have hilar lymphadenopathy and pleural effusions.
• Mycobacteremia and extrapulmonary tuberculosis, especially meningitis and adenopathy, also correlate with diminishing numbers of CD4 cells and degree of immunosuppression.
• TB lymphadenitis is seen most frequently in cervical, supraclavicular and axillary lymph nodes.
• Focal brain lesions are also more common in coinfected patients.

DIAGNOSTIC TESTS

• Clinical suspicion of TB is based on the presence of TB risk factors, signs and symptoms of TB and findings on chest radiographs.
• More than 90% of HIV-infected patients with TB will have an abnormal chest radiograph, but the classic TB findings (e.g. apical infiltrates and cavities) are seen in only one third of coinfected cases.
• Sputum microscopy reveals acid-fast bacilli (AFB) in 31% to 82% of coinfected patients.
• The sensitivity of sputum microscopy is lowest in patients with significant immunosuppression and progressive primary or disseminated disease.
• Ideally, 3 sputum samples should be collected for microscopy, culture and susceptibility testing.
• This may not always be feasible in resource-poor settings. Clinicians may have to rely on their clinical assessment and a sputum AFB smear.
• Subtle and atypical findings - such as lymphadenopathy, pleural effusions, interstitial infiltrates and miliary disease - are seen more commonly.
• A normal chest radiograph can be seen in up to 10% of HIV-infected patients with pulmonary TB.
• Further evaluation for active TB may be conducted with microscopy, culture and molecular methods.

TREATMENT ISSUES

• Anti-TB therapy is equally effective in HIV-negative and HIV-positive patients
• In TB-endemic areas, recurrent TB after completion of a course of therapy is more likely to be due to exogenous reinfection than to relapse
• Compared with HIV-negative TB patients, coinfected patients have a higher risk for recurrent TB, but this is due to reinfection rather than relapse.
• There are complex drug-drug interactions between antiretrovirals and the rifamycins (rifampin, rifabutin and rifapentine).
• Current antiretroviral regimens usually consist of 3 or more drugs from two or three different classes of drugs: nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs) (Table 1).
• Two of these classes, NNRTIs and PIs, have clinically relevant drug interactions with the rifamycins.

PHARMACOKINETIC INTERACTIONS

• The key locus of the drug-drug interactions is the cytochrome P450-3A system in the intestinal wall and the liver.
  
  
• The rifamycins are inducers of CYP3A, thereby decreasing the serum concentrations of drugs metabolized by this enzyme system.
  
  
  • Rifampin is the most potent, rifapentine is intermediate and rifabutin is the least potent inducer
  • Rifapentine is currently not recommended for use in HIV-infected patients
    
    
• The protease inhibitors and the non-nucleoside reverse transcriptase inhibitors are metabolized by CYP3A, and therefore may be affected by the rifamycins. For example, rifampin reduces levels of protease inhibitors (except ritonavir) by 75-95%. This would lead to markedly decreased antiviral activity and more rapid emergence of protease inhibitor resistance. Hence, protease inhibitors (except ritonavir) cannot be used with rifampin.
• The available protease inhibitors are potent inhibitors of CYP3A, thereby increasing the serum concentrations of drugs metabolized by that enzyme system, such as rifabutin, to toxic levels. For example, there are 2- to 4-fold increases in rifabutin concentrations when rifabutin is given with most of the protease inhibitors. This increase in rifabutin concentrations is associated with clinical toxicity (leukopenia, uveitis, arthralgias, skin discolouration) and requires dose modification of rifabutin.

• Some of these drug-drug interactions are so dramatic that there are strong contraindications to the concurrent use of certain rifamycins and antiretroviral drugs.

CURRENT RECOMMENDATIONS

• NRTIs are not significantly affected by TB drugs, including rifampin or rifabutin; no adjustment in dose of NRTIs or anti-TB drugs is required
• Rifampin can be given with efavirenz, ritonavir or ritonavir/saquinavir
  
  
• Rifampin 600 mg + efavirenz (start at 600 mg but consider increasing to 800 mg)
• Rifampin 600 mg + ritonavir 600 mg bid
• Rifampin 600 mg + ritonavir 400 mg bid + saquinavir 400 mg bid
  
  
• Do not give rifampin with nevirapine, indinavir, nelfinavir, amprenavir, lopinavir or delavirdine
• Rifabutin may be given in place of rifampin.
  
  
• Rifabutin 150 mg/day + nelfinavir 1250 mg bid
• Rifabutin 150 mg/day + indinavir 1000 mg q 8 hours
• Rifabutin 150 mg twice or thrice weekly + ritonavir (+ saquinavir)
• Rifabutin 450-600 mg/day + efavirenz 600 mg q D
  
  
• In regimens with any ritonavir (including lopinavir/ritonavir), decrease rifabutin to 150 mg twice or thrice weekly
• Do not give rifabutin with delavirdine or hard-gel saquinavir
  The use of a non-rifamycin-containing regimen avoids drug-drug interactions when ART and anti-TB therapies are given concomitantly. However, rifamycin-containing regimens have been shown to be more effective than non-rifamycin-containing regimens

WHEN TO INITIATE ANTIRETROVIRAL THERAPY IN HIV-INFECTED PERSONS WITH TB

• It is generally agreed that HIV-infected persons receiving antiretroviral therapy at the time of TB diagnosis should continue to receive such therapy.
• Among coinfected patients who have not yet started antiretroviral therapy, the optimal time to initiate such treatment is unknown. Certainly, CD4 cell count and viral load guidelines for the initiation of antiretroviral therapy (regardless of TB status) should be taken into account.
• It is important to balance the increased risk for HIV-related mortality among coinfected patients against the increased risk for paradoxical worsening of TB (described on
  page 11); the risk for paradoxical worsening may be lower if antiretroviral therapy is initiated after several weeks of anti-TB therapy.
• Clinicians must also take into account the high pill burden associated with the treatment of each disease, along with concerns about tolerability and drug interactions.
• Thus, the clinician might consider delaying antiretroviral therapy until the patient has received at least 2 months of anti-TB therapy, particularly if the patient does not have advanced HIV disease
  

HIV + TB: TREATMENT APPROACHES

HIV AND PARADOXICAL WORSENING OF TB

• Paradoxical worsening of TB is the development of new signs or symptoms of TB disease or the exacerbation of existing manifestations of TB in patients receiving appropriate anti-TB therapy.
• It is thought to represent an improvement of the host's immune response to mycobacterial antigens during the course of treatment, leading to more intense inflammation at sites of TB disease. Hence it has also been referred to as "immune restoration syndrome"
• The estimated incidence in HIV-infected patients ranges from 7% to 36%, which is higher than the rate seen in HIV-negative patients.
• Diagnosis requires that other possible explanations be excluded, such as treatment failure, drug resistance, poor compliance, malabsorption, adverse drug reactions and lymphoma.
• It has been associated with the presence of concurrent pulmonary and extrapulmonary TB at the time of initial diagnosis.
• The course can be brief or prolonged, with multiple recurrences and exacerbations.
• Severe episodes can be treated by corticosteroids. This has not been associated with progression of TB disease or failure of anti-TB therapy.
• Patients with less severe symptoms may obtain relief with non-steroidal anti-inflammatory medications.
• Although antiretroviral therapy may be associated with the development or severity of paradoxical worsening, discontinuation of therapy is not generally recommended.

CONCLUSION

• Separately, HIV and TB represent staggering global public-health challenges
• Coinfection with these pathogens threatens to further exacerbate these problems due to the influence of HIV on the incidence, prevalence, clinical presentation, diagnostic yield and treatment options for patients with TB
• The developing world has the highest burden of both diseases but only limited resources
• In the absence of an effective vaccine for either pathogen, more resources for the diagnosis and treatment of both diseases are urgently needed
• In patients who receive treatment for both TB and HIV, careful attention must be paid to pharmacokinetic interactions, to increase the likelihood of a successful outcome

REFERENCES

1. AIDS Clinical Care 2002;14(2): 1-7
2. AIDS 2002; 16:75-83
3. AIDS 2001; 15(Suppl 5): S203-12
4. Am J Respir Crit Care Med 2001;164:7-12
5. MMWR 2000;49:185-7
6. MMWR 1998;47 RR-20:1-58