Issues in the Co-management of HIV/AIDS and Tuberculosis

 

Stefanie Woolridge

March 22, 2005

 

 

HIV/AIDS and TB: The Co-Epidemic

 

Tuberculosis

Tuberculosis (TB) is discussed in detail in the chapter devoted exclusively it.  In brief, TB is an infectious disease caused by bacteria called Mycobacterium tuberculosis.  An actively infected patient will pass these bacteria through the air, and left untreated, they can potentially infect 10-15 other people per year.  

 

In the United States, TB infection is at an all time low, with just 14,874 reported cases in 2003.  In addition, 53% of these cases were foreign born, and therefore may have been infected abroad and presented in the United States. 

 

Unfortunately, the US does not represent the global trend in TB infection.  The World Health Organization estimates that one third of the world population is currently infected with TB bacillus, and that a new person is infected every second.[1]  Over 2 million deaths each year are due to TB infection.[2]

 

HIV/AIDS

The Human Immunodeficiency Virus (HIV) is a retrovirus that infects CD4 positive T cells and macrophages of the human immune system.  The infection produces a progressive decline in a patient’s immune response, allowing for other “opportunistic infections” to invade the HIV patient.  Although these infections are often easily treated in immunocompetent people, for individuals with HIV, they are often devastating.[3] 

 

When HIV patients develop higher viral loads (concentrations of virus detectible in their blood) and specific opportunistic infections, they are said to have AIDS, or Acquired Immunodeficiency Syndrome.  This is largely a descriptive term that includes the symptoms and infections immunodeficient patients develop.  The AIDS defining opportunistic infections and neoplasms (tumors) found in patients with HIV infection are[4]:


INFECTIONS

Protozoal and Helminthic Infections

Cryptosporidiosis or isosporidiosis (enteritis)

Pneumocytis (pneumonia or disseminated infection)

Toxoplasmosis (pneumonia or CNS infection)

Fungal Infections

Candidiasis (esophageal, tracheal, or pulmonary)

Cryptococcosis (CNS infection)

Coccidiodomycosis (disseminated)

Histoplasmosis (disseminated)

Bacterial Infections

Mycobacteriosis (atypical, e.g. M. avium-intracellulare, disseminated or extrapulminary; M. tuberculosis, pulmonary or extrapulmonary)

Nocardiosis (pneumonia, meningitis, disseminated)

Salmonella infections, disseminated

Viral Infections

Cytomegalovirus (pulmonary, intestinal, retinitis, or CNS infections)

Herpes simplex virus (localized or disseminated)

Varicella-zoster virus (localized or disseminated)

Progressive multifocal leukoencephalopathy

NEOPLASMS  (tumors)

Kaposi  sarcoma

B-cell non-Hodgkin lymphomas

Primary lymphoma of the brain

Invasive cancer of uterine cervix


 

 

HIV resides in blood, semen, vaginal fluids and breast milk.  Therefore, the modes of transmission include anal or vaginal sex, blood transfusion, reuse of contaminated needles, and between mother and child during pregnancy, birth and breast feeding.[5]

 

The CDC estimates that as of 2003, there were 850,000-950,000 people in the United States living with HIV.  This estimate includes between 180,000-280,000 people who do not know they are infected.  The estimated number of AIDS cases for 2003 were 43,171 adults and 59 children, and deaths attributable to AIDS were estimated at 17,934 adults and 83 children.[6]

 

Sub-Saharan Africa, home to 10% of the world’s population, houses 60% of global HIV cases.[7]  Unlike in the United States, where the majority of HIV infected patients are men between the ages of 35 and 44, Africa’s HIV/AIDS epidemic has most greatly affected young women between the ages of 15 and 24.  It is estimated that there are 36 young African women infected for every 10 young men, and these women make up 75% of the women infected globally.[8]

 

Each region and country in Africa has followed its own prevalence trends.  Nine countries have seen their life expectancy rates drop below 40 years, but South Africa remains the worst affected sub-region.  It houses an estimated 5.3 million HIV infected people with no sign of decline in the epidemic.  Uganda, on the other hand, has shown the most substantial drop in prevalence, from 13% in the early 1990s to 4.1% in the end of 2003.  Of course, a drop in prevalence does not mean the infection rate is lower, and it most certainly does not indicate the end of the country’s epidemic.  The need for resources to prevent and treat HIV infections will continue to increase for many years to come.[9]

 

The “Co-Epidemic”

By immunocompromising its carriers, HIV/AIDS facilitates the infection of patients with other opportunistic infections.  Via this mechanism, HIV/AIDS has helped fuel the TB epidemic.  HIV positive individuals are 50 times more likely to be infected by TB, and once infected, are 800 times more likely to develop an active TB infection.[10],[11]  The WHO estimates that one third of the 40 million HIV positive people in the world have TB, and the majority of co-infected cases are in Sub-Saharan Africa, where up to 70% of TB patients are co-infected.[12] 

                                                                                                                         

Without proper treatment, 90% of co-infected patients will die within months.[13]  Unfortunately, drug interactions complicate the situation.  Protease Inhibitors and Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs) are the leading drugs used to inhibit HIV progression.  They are metabolized via a cytochrome P450 system.  Cytochrome P450s are just one type of enzyme to body uses to break down drugs.  There are many different types of cytochrome P450, and each cytochrome P450 has the possibility of interacting with several different drugs.

 

Protease Inhibitors and NNRTIs are inactivated by the cytochrome P450 CYP3A4.  Unfortunately, rifamycins, which are antituberculosis agents, induce the activity of CYP3A4.  This can cause a substantial decrease in the serum concentrations of protease inhibitors and NNRTIs.  Of the three rifamycins available (rifampin, rifapentine, and rifabutin), rifabutin is the least potent inhibitor of CYP3A4, and is usually safe to administer with most protease inhibitors and NNRTIs, although there remain exceptions (saquinavir and delavirdine). 

 

In addition to TB medications affecting the cytochrome P450 metabolism of HIV medications, some HIV medications greatly affect the CYP3A4 system as well.  For instance, ritonavir, an antiretroviral, has the highest potency for inhibiting the CYP3A4 system.  This has the opposite effect as described above, and increases the serum concentration of co-administered protease inhibitors, as well as rifabutin, which can reach toxic levels.[14]  As you can see, there are serious complications in balancing the induction and repression of the CYP3A4 metabolism system.

 

Finally, developing rifamycin resistance has been a problem in HIV infected patients, particularly in the case of highly-intermittent administration of the anti-tuberculosis drug (once- or twice-weekly).  It has also been a noticeable problem with advanced HIV cases.  As such, it is recommended that TB drug administration be more frequent.  It should now be apparent how this, as well as all of the drug specific problems of managing this co-epidemic, could present serious challenges in resource limited areas where access to varieties and quantities of medications is inadequate and/or inappropriate.

 

 

HIV/AIDS Surveillance in TB Patients

 

Objectives and Challenges

The intention of surveillance of any communicable disease is to better understand the magnitude of the diseases effect and to evaluate the efficacy of any plans of action.  Due to the strong relationship between these two epidemics, co-monitoring is a necessity for future efficacious intervention.  In addition, beyond their intrinsic linkage, in many countries, spread of HIV in the general population can be sensitively indicated by the HIV prevalence in TB patients.[15] 

 

There are many challenges to disease surveillance.  In general, surveillance has not been valued enough by health policy makers, so the financing and infrastructure necessary to gather and process the data are not available.  For instance, a common problem is the lack of properly trained epidemiology staff.  Without appropriate training and consistent performance feedback, there is little quality control of the work done.  Specifically in dealing with these two epidemics, there is a problem linking TB information with HIV information, since so much intervention work is done my mutually exclusive groups.  This problem not only impedes surveillance data collection, but also with the clinical management of the diseases, as will be discussed in more detail later.[16]

 

There are several unique ethical problems in the surveillance of HIV.  The technique currently utilized for periodic and sentinel surveillance of HIV is unlinked anonymous testing.  In this method, blood is drawn from patients for reasons other than HIV testing.  The left over part of the specimen is stripped of any identifying markers that could be used to identify the individual, and then it is tested for HIV infection without the consent of the patient.  Although there has been controversy over these blinded HIV prevalence surveys, particularly in developed nations, it is generally considered ethical to test for HIV without consent if it is indeed anonymous and unmarked.  The benefit of surveillance in this manner is that it removes participation biases that can occur when testing is voluntary.  Unfortunately, under these circumstances, HIV positive patients can not be offered any counseling or antiretroviral therapy.[17]

 

In the specific circumstance of HIV testing TB patients, the major problem with unlinked anonymous testing, beyond the lack of HIV treatment intervention, is that TB patients do not routinely have blood drawn for evaluation.  Sputum samples are used to evaluate active TB infections.  The WHO is currently in the process of testing the usefulness of sputum testing in HIV surveillance, but as of now, sputum tests lack sensitivity and specificity, and therefore, positive predictive value.  Ethically, if blood is going to be drawn exclusively for the purpose of unlinked anonymous testing, the patient must give consent, which reintroduces the participatory biases that the unlinked anonymous strategy is usually employed to avoid.[18]

 

Assuming that TB patients must agree to be HIV tested, the ethical issue of treatment then arises.  As of now, since most HIV and TB agencies receive separate sources of funding and work independently, TB testing sites may not have resources or relationships to offer treatment options to HIV positive patients.  In order to accommodate these patients, a working relationship between these two organizations is necessary, as will be discussed in more detail later.

 

Methods[19]

There are three methods of HIV surveillance among TB patients that are currently recommended by the WHO: periodic, sentinel, and routine surveys.  Periodic, or special, surveys are cross-sectional HIV surveys among a sample of TB patients.  Ideally, all newly registered TB cases would be monitored, but for ease, countries could focus on specific subsets, like smear positive adults.  This method is ideal for countries with no previous prevalence data to give an initial estimate.  In countries with regular surveillance, it can be used to corroborate current projections.  It can also be used by resource limited countries as a means of monitoring the HIV rate in the general population

 

The sentinel method of surveillance involves a specific number of TB patients being routinely tested at selected sites in a regular, consistent way.  As with the prevalence method, including all TB cases would be ideal, but for ease, focusing on a sub-group such as smear positive adults may be used.  Sentinel methods provide more systematic data, so unlike periodic monitoring, they can be used to design, implement, and monitor public health interventions.  While this is a fairly inexpensive way of gathering good information on trends, lack of representative sentinel sites, selection bias, and inadequate quality control of testing has led to inconsistent data in some countries.

 

The third method of surveillance is routine surveys.  TB patients would voluntarily and confidentially be tested for HIV as part of routine care, the aim being to test all TB patients for HIV.  This system offers the greatest benefit to patients, assuming that treatment options can be made available if HIV infection is detected.  This system also provides the most useful information for public health interventions, including epidemic and burden of disease estimates.  Unfortunately, this system can be costly and time consuming, and it does require a strong information infrastructure.  The data may also reflect access to healthcare services rather than true HIV prevalence.  Hence, as mentioned earlier, periodic surveys are helpful in verifying trends identified.

 

The WHO recommendations for HIV surveillance methods in TB infected patients vary according to the level of HIV epidemic in individual countries.  Generalized HIV epidemics are those in which the HIV prevalence is consistently >1% in pregnant woman.  Concentrated epidemics involve HIV prevalences consistently >5% in at least one defined subpopulation while remaining <1% in pregnant women in urban areas.  Examples of these subpopulations include intravenous drug users, sex workers, and men who have sex with men.  Finally, low level HIV epidemics involve HIV prevalences that consistently do not exceed 5% in any defined subpopulation.

 

The WHO recommends that routine surveillance should be emphasized in all countries with generalized HIV epidemics with periodic surveys to corroborate trend data.  Countries with concentrated epidemics would also fare best using routine surveillance, however, if this system is not in place, periodic or sentinel surveys would be suitable alternatives.  In countries with low-level HIV epidemics, periodic or sentinel screening should be conducted among TB patients. 

 

Community HIV/AIDS and TB Management Collaboration[20]

 

The statistics provided in the co-epidemic portion of this review display how HIV/AIDS is fueling the TB epidemic.  This inextricable linkage raised the question of whether HIV/AIDS and TB services should be integrated so as to reach the co-infected population more readily and effectively.  In order to answer these questions, the WHO started the ProTEST project in 1997 which consisted of six projects in three countries with high burdens of HIV-related TB.  They included:

  1. Lilongwe, Malawi
  2. Bohlabel District, Limpopo Province, South Africa
  3. Ugu District, KwaZulu Natal Province, South Africa
  4. East London District, Eastern Cape Province, South Africa
  5. Cape Town Central District, Western Cape Province, South Africa
  6. Lusaka, Zambia

 

The interventions aimed to more aggressively identify HIV and TB patients, and to employ more proactive measures to prevent further transmission of both.  The protocols by which they hoped to achieve these ends, as listed in the summary report, were:

 

  • Stakeholder and health services collaboration
  • Improved access to high-quality voluntary HIV counseling and testing
  • Intensified case-finding and treatment of active TB for HIV-positive clients to reduce transmission of Mycobacterium tuberculosis
  • Isoniazid preventive therapy (IPT) to treat latent TB infection in HIV-positive clients likely or known to be infected with M. tuberculosis
  • Co-trimoxazole preventative therapy (CPT) to reduce morbidity and mortality due to HIV-related opportunistic infections
  • HIV prevention (including condom promotion, treatment of sexually transmitted infections, prevention of mother-to-child HIV transmission)
  • Improved clinical care for people living with HIV/AIDS

 

 

Each test site was allowed to create their own program according to their self-evaluated needs and resources.  The monitoring and evaluating was also site specific, making cross comparison difficult in quantifying outcomes.  The results of these trials were presented in February, 2003 during the four-day “Lessons Learnt Workshop” in Durban, South Africa. 

 

The Malawi project will be briefly described here, in order to demonstrate the rough architecture of the various site projects, but the WHO report is highly recommended for more detailed explanation of the success and failure of particular interventions across project sites as well as overall future recommendations.

 

The Malawi project took place in the Lilongwe District.  The total population is 1.3 million, one third of which live in the capital city.  Started in August of 1999 and managed by the national tuberculosis control program, the recruited ProTEST staff phased in the following interventions, as listed in the official report:

 

  • Formation of collaboration between stakeholders in TB and HIV/AIDS control at district level, from both public and private sectors
  • Support and expansion of voluntary counseling and testing for HIV services, both stand-alone and health-service-based
  • Creation of a referral system between the various services and partners
  • Involvement of groups of patients living with HIV/AIDS in mobilization and education of the community
  • Introduction of symptomatic screening for STIs and TB among voluntary counseling and testing for HIV clients
  • Training and support of community health volunteer groups in Lilongwe, to provide home based care for patients living with HIV/AIDS, identify ill people with possible TB, and provide community based DOTS
  • Provision of co-trimoxazole preventative therapy to HIV-positive TB patients
  • Provision of Isoniazid preventative therapy to fit and well volunteer counseling and testing for HIV clients showing no symptoms suggestive of TB

 

In late 2001, due to the successes of this district wide program, a National Plan to expand the TB/HIV activities was proposed to the Global Fund to Fight AIDS, Tuberculosis and Malaria.  Funding was approved, and along with contributions from the Ministry of Health and Population, USAID, NORAD (Norwegian Agency for Development Cooperation), and the TB donor basket, will provide the financial resources necessary to expand the TB/HIV activities nationally.

 

During this same time, in early 2002, there was a meeting between partners in the three ProTEST countries (Malawi, South Africa and Zambia) with five other countries that bear the highest combined TB and HIV/AIDS burden.  These included Ethiopia, Kenya, Mozambique, Uganda and the United Republic of Tanzania.  These countries worked together to create program protocols based on the data collected through 2002 in the test sites.  As of the issuing of the Lessons Learnt report, five of the eight countries had approved funding for intervention plans.

 

For a full understanding of the programs one should consult the report as listed in the reference section.  The point most important to recognize here, and what was clearly demonstrated in all of the ProTEST sites, is that HIV/AIDS and TB control programs not only should, but can, work together to improve care and outreach to their patient populations. 

 

Conclusion

 

An estimated 13 million HIV positive people in the world are co-infected with TB.  Due to drug resistance and deleterious drug interactions, clinical co-management of the diseases presents unique complications.  Even so, DOTS and antiretroviral therapies have aided in improving individual outcomes of patients, however many changes are needed in order to control the co-epidemic on a population level.  Constructing effective surveillance infrastructures to monitor the diseases is necessary in order to effectively implement intervention strategies.  In addition, collaboration between TB and HIV/AIDS organizations can greatly improve case discovery, resource distribution, and overall clinical care of populations at risk of co-infection.

 

 

 

 

 

 

 

 


References:

  1. Robbins and Cotran. Pathologic Basis of Disease, 7th Edition. (Philadelphia, PA, Elsevier Saunders: 2005) 255.
  2. WHO. Guidelines for HIV Surveillance among Tuberculosis Patients, Second Edition. (Geneva, 2004).
  3. WHO. Report of the “Lessons Learnt” Workshop on the Six ProTEST Pilot Projects in Malawi, South Africa and Zambia. (Durban, South Africa, 2003).
  4. www.cdc.gov
  5. www.unaids.org
  6. www.who.int

 

 

 

 

Bibliography for Further Reading:

 

The WHO releases new publications on HIV/AIDS-TB co-management throughout the year.  These are listed on the WHO web site at: http://www.who.int/tb/hiv/en/.  Recent WHO TB/HIV publications include:

 

  • Interim policy on collaborative TB/HIV activities
  • Strategic framework to decrease the burden of TB/HIV
  • Guidelines for implementing collaborative TB and HIV programme activities
  • TB/HIV Clinical Manual
  • A guide to monitoring and evaluation for collaborative TB/HIV activities
  • Guidelines for HIV surveillance among tuberculosis patients (Second edition)
  • Report of a "Lessons Learnt" Workshop on the six ProTEST pilot projects in Malawi, South Africa and Zambia, 3-6 February 2004

 

Medical anthropologist and physician Paul Farmer is one of the most prominent authorities in tuberculosis, and has written extensively on the topics of health and human rights.  His writings provide intense perspective on the social milieu that feeds into disease, and he discusses HIV and TB specifically in his book, Infections and Inequalities.

 

Farmer, Paul. Infections and Inequalities. (University of California Press, 2003).



[1] http://www.who.int/tb/hiv/en/

[2] http://www.cdc.gov/nchstp/tb/pubs/TB_HIVcoinfection/default.htm

[3] http://www.unaids.org/en/Resources/faq/faq_general+information+about+hiv+and+aids.asp

[4] Robbins and Cotran, Pathologic Basis of Disease, 7th Edition (Philadelphia, PA, Elsevier Saunders: 2005) 255.

[5] http://www.unaids.org/en/Resources/faq/faq_general+information+about+hiv+and+aids.asp

[6] http://www.cdc.gov/hiv/stats.htm

[7] http://www.unaids.org/NetTools/Misc/DocInfo.aspx?LANG=en&href=http://GVA-DOC-OWL/WEBcontent/Documents/pub/Publications/Fact-Sheets04/FS_SSAfrica_en.pdf

[8] Ibid.

[9] Ibid.

[10] http://www.who.int/tb/hiv/en/

[11] http://www.cdc.gov/nchstp/tb/pubs/TB_HIVcoinfection/default.htm

[12] http://www.who.int/tb/hiv/en/

[13] Ibid.

[14] http://www.cdc.gov/nchstp/tb/tb_hiv_drugs/Mechanisms.htm

[15] WHO, Guidelines for HIV Surveillance among Tuberculosis Patients, Second Edition (Geneva, 2004).

[16] Ibid.

[17] Ibid.

[18] Ibid.

[19] Ibid.

[20] WHO, Report of the “Lessons Learnt” Workshop on the Six ProTEST Pilot Projects in Malawi, South Africa and Zambia (Durban, South Africa, 2003).