Tuberculosis

Tuberculosis (TB) is the leading cause of death among people with HIV globally, accounting for almost 25% of all HIV deaths in 2008 (WHO, 2009i). The risk of acquiring TB is 20 to 37 times greater among people living with HIV than in the general population.

In some countries in sub-Saharan Africa, up to 80% of people living with TB are also living with HIV. Sub-Saharan Africa continues to account for the majority of people living with HIV and TB in the world with about 78% of the estimated total people living with HIV and TB in 2008. South East Asia, mainly India, accounts for 13% of the remaining cases.

HIV Infection Fuels TB Epidemics

Rates of HIV and TB co-infection have increased dramatically in a short span of time. There has been a doubling of TB cases associated with the HIV epidemic in sub-Saharan Africa (Heymann et al., 1999). When the HIV epidemic is in an expansive phase, HIV and TB co-infection rates also increase rapidly. For example, HIV seroprevalence among TB cases in Chiang Mai, Thailand increased from 5% in 1989 to 40% in 1992, along with the rapidly growing HIV epidemic (Payanandana et al., 1995 cited in Raviglione et al., 1996; Kharsany et al. 2006). However, at this time, in countries such as India or China where there is a high level of TB, there is less TB/HIV co-infection (WHO, 2009i). “The risk of TB increases with advancing immunodeficiency, so as the HIV epidemic in a community matures, the burden of HIV-associated TB may be expected to increase, even after the prevalence of HIV infection has stabilized” (Lawn et al., 2006: 1046).

TB Is a Serious Risk for Those Living with HIV

Not everyone exposed to TB has active disease.  A person with latent TB infection, or LTBI, has been infected with the TB bacillus but has an immune system sufficiently intact to control the infection and will not permit the bacillus to cause disease. A person with LTBI is not ill and is not infectious. TB becomes a much more serious problem for someone with HIV. When a person infected with the TB bacillus cannot control the infection because of a compromised immune system, the bacillus is able to multiply so that there are millions of TB bacilli that then cause disease. A person with active TB disease becomes sick and is considered infectious to others.

HIV-positive individuals who are latently infected with TB are between 2 to 10 times more likely to progress to active TB disease than their HIV-negative counterparts (Murray, 1990 quoted in Holmes et al, 1998). People whose immune systems have deteriorated due to advanced HIV disease are at greatly increased risk of developing active TB disease from a previously contained latent infection. Some immunocompromised people may not be able to contain a new TB infection and will immediately progress to active disease upon exposure to TB. Additionally people with HIV are more likely to develop extrapulmonary TB (TB outside of the lungs) that may involve multiple organs and is harder to diagnose (Zvandasara et al., 2006).

TB infection also accelerates HIV progression. “HIV-weakened immune systems are at increased risk of TB disease, while active TB disease elevates HIV RNA and accelerates HIV progression” (Marco, 2002).

Treatment Adherence Is Critical to Curing TB and Reducing the Spread of Drug-Resistant Strains

Adherence to the full course of treatment—six months for first-line treatment—is essential to cure TB and avert the development of multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB). MDR-TB (where the disease has developed resistance to the two most common and powerful first-line TB drugs, isoniazid and rifampicin) requires between 18–24 months of often complicated and expensive combination therapy. Of the 9.4 million incident TB cases in 2008, an estimated half a million were multi-drug resistant TB (WHO, 2009i). XDR-TB is resistant to first and second-line drugs and significant efforts are often needed to identify a therapeutic regimen that works and to manage side effects.  By November 2009, 57 countries had reported at least one case of XDR-TB (WHO, 2009i).  The WHO has recently updated the tuberculosis treatment guidelines, confirming its prior recommendation of drug susceptibility testing (DST) at the start of all therapy for previously treated patients in order to find and treat MDR-TB; it also addresses the prevention of acquired MDR-TB, where new TB patients have isoniazid-resistant TB when they begin treatment (WHO, 2010b).

For people who are living with HIV, MDR-TB or XDR-TB co-infection results in high levels of early mortality.  A retrospective observational study in Tugela Ferry, South Africa of 272 MDR-TB and 382 XDR-TB cases, of which 90% and 98% respectively were HIV co-infected, found that mortality at one year was 71% for MDR-TB and 83% for XDR-TB patients. The majority of deaths occurred within the first thirty days of sputum collection, with mortality rates worsening with greater degrees of drug resistance (Gandhi et al, 2009).

It is important to note that drug-resistant TB can be transmitted. “Overcrowded, poorly ventilated clinics that bring together large numbers of HIV-infected persons, some with active TB, will be a recipe for disaster” (IOM, 2005:107).  Therefore in health care facilities where people with HIV and/or TB access screening, treatment and support, and where TB transmission may be most efficient, measures should be taken to reduce the risk of primary transmission of TB, both drug-resistant and susceptible. Rapid drug susceptibility testing, prompt initiation of effective TB treatment and implementation of infection control measures such as separation of TB suspects, improving patient flow and increasing ventilation may reduce the risk of TB transmission in health care settings.

There Are Gendered Dynamics in TB Prevalence, Detection

Globally, more men than women are affected by tuberculosis disease.  However, the numbers of women co-infected with TB and HIV are increasing (Adhikari, 2009; Gupta, 2009; Druce and Nolan, 2007; Nissapatorn et al., 2006). In countries with HIV prevalence higher than 1%, relatively equal numbers of men and women are diagnosed with TB. 

The World Health Organization’s case notification rates indicate that eight times as many men as women were diagnosed with TB in 2007 (WHO, 2009i). The reasons for the higher global TB notification rates in men are not well understood and could result from a variety of biological or environmental factors such as the likelihood of producing a positive sputum sample, delays in health-seeking behavior, gendered dynamics within the family, stigma and access to care: women are less likely to produce positive sputum samples and more likely to have extrapulmonary TB and/or be co-infected with HIV (Lawson et al., 2008; Karim et al., 2008; Sreeramareddy et al., 2008). 

Preliminary data suggest that the implementation of the revised WHO case definition of smear-positive TB was associated with significant increases in case detection among women in Kenya (Ramsey et al., 2009). The revised guidance lowers the number of bacilli in a sample and reduces the number of smear-positive results from two to one required be classified as a TB case. Evidence from a Vietnamese study also suggests that women are slower to progress to smear-positive disease despite similar time from symptom onset to diagnosis as men (Thorson et al., 2007). Additionally, some studies have shown that physicians are less likely to conduct TB exams on women than men (Begun et al., 2001 cited in Theobald et al., 2006). Further research is needed on differences in testing and disease manifestation in women and men.

Co-Infection is Particularly Deadly for Women During Their Childbearing Years

Women bear the greatest burden of HIV during their childbearing years, and similarly, the greatest burden of TB during those years as well. It is estimated that 15% of maternal deaths are among women co-infected with TB and HIV (Adhikari, 2009; Klotz et al., 2007; Mofenson and Laughton, 2007; Zwang et al., 2007; Ramogale et al., 2007; Gupta, 2009). The development of TB disease is associated with a four-fold increase in AIDS-related deaths among women co-infected with TB and HIV (Lopez-Gatell et al., 2007).  A study in South Africa found young women to be at particular risk. Epidemiologic changes in TB notifications and the prevalence of HIV infection from 1996 to 2004 in a peri-urban community in South Africa of 13,000 found that annual TB notification rates among adolescents increased from zero cases between 1996-1997 to 436 cases per 100,000 in 2003- 2004, with TB cases predominantly among female adolescents (Lawn et al, 2006).

The U.S. CDC states that TB treatment for pregnant women should be the same as for nonpregnant women, but with special considerations for particular medications’ effect on both the woman and the fetus (CDC, 2009a, http://www.aidsinfo.nih.gov/Guidelines/GuidelineDetail.aspx?MenuItem=Guidelines&Search=Off&GuidelineID=211&ClassID=4). “Pregnant women on ART who have a diagnosis of active TB should have their ARV regimens adjusted as needed to accommodate their TB drugs.  For women whose diagnosis includes concurrent active TB and HIV infection during pregnancy, TB therapy should be initiated immediately and ART should be initiated as soon as possible thereafter, usually according to the principles described for nonpregnant adults” (CDC, 2009a).

Because of the increased risk of maternal and infant mortality associated with TB and HIV co-infection during pregnancy and postpartum, there is an urgent need to implement TB screening as part of routine antenatal and postpartum care as well as treatment for latent and active TB for women (Mofenson and Laughton, 2007). Maternal and child health and HIV/AIDS prevention programs that include TB education and screening make these services more accessible to women of childbearing age.

Active Case Finding Is Necessary to Increase TB Detection

Only about half of TB suspects seek out TB screening, and it is estimated that about half of these cases are misdiagnosed (Ayles, 2009). “Many of the TB control strategies like passive case finding [as opposed to active case finding where health workers actively screen people for TB symptoms] and directly observed therapy (DOTS), that are used today were developed in the pre-HIV era, and “[do] not take into account the profound impact of HIV on tuberculosis incidence” (Reid et al., 2006: 485).  This situation is compounded by the fact that TB is more difficult to diagnose in people with HIV-related immune suppression.

Active case finding increases TB detection, particularly in sub-Saharan Africa, where HIV is driving the epidemic.  For example, instituting an antiretroviral therapy program in a health center in a mountainous region of Lesotho resulted in a 10-fold increase in the detection of TB among patients with and without HIV (Furin et al., 2007).  In the Thyolo district in Malawi, TB/HIV community volunteers screened for TB symptoms and found that households where someone had a chronic cough had an annual TB incidence rate eight times higher than the general population (Zachariah et al., 2006b). 

However, as noted previously, TB symptoms may be different in people living with HIV, which can complicate diagnosis.  A prospective cohort study with 1,768 HIV-positive patients from eight clinics in Cambodia, Vietnam and Thailand found that TB screening that includes questions about a combination of TB symptoms such as fatigue, fever and weight loss was significantly more effective in ruling out TB than asking about cough alone (Cain et al., 2010).

HAART Can Reduce the Incidence of TB

Highly-active antiretroviral therapy has been shown to reduce the incidence of tuberculosis (Lawn et al., 2005; Wood, 2009). A multi-center cohort study in Spain compared TB incidence in pre-HAART and HAART eras and found that the risk of developing TB was 70% lower in the HAART era than in the pre-HAART era (Muga et al., 2007). Since the initiation of HAART, TB incidence among people on HAART in the Gugulethu township in South Africa has decreased significantly while TB incidence has remained stable among HIV-negative and HIV-positive individuals not on HAART (Wood, 2009). Likewise, TB mortality rates among HIV-positive people have been brought down to comparable levels to HIV-negative individuals (Wood, 2009).  A study in Ethiopia that assessed the effect of HAART on patient mortality and TB incidence rates under routine clinical care conditions in 2003 found that HAART resulted in a 65% decline in mortality and the TB incidence rate was lower in the HAART group (Jerene et al., 2006).  A study in Thailand also found that antiretroviral treatment was significantly associated with reduction in deaths among those on HAART prior to initiating TB treatment (Akksilp et al., 2007).

Isoniazid Preventive Therapy, With or Without HAART, Can Reduce the Incidence of TB

A number of randomized controlled trials have shown that isoniazid preventive therapy (IPT) can reduce the incidence of active TB disease in people living with HIV (Pape et al., 1993; Hawken et al., 1997; Whalen et al., 1997; Mwinga et al., 1998; Halsey et al., 1998; Gordin et al., 2000 cited in Ayles and Muyoyeta, 2006). A Cochrane review of 11 trials involving 8,130 randomized participants showed that IPT reduced the risk of active TB by 33% (Ayles and Muyoyeta, 2006). A recent randomized, double-blind placebo controlled trial in Botswana found that IPT taken for 36 months was more effective than a 6-month course in significantly reducing risk of TB incidence in people with HIV (Samandari, 2009). IPT can also significantly reduce death among people on antiretroviral therapy, compared to those not on IPT.  A retrospective analysis evaluated the impact of IPT on mortality of 3,258 HIV-positive miners in South Africa who initiated IPT and found that the mortality rate was significantly lower, with a 53% reduction in mortality among those on IPT than among those who did not receive IPT (Innes et al., 2010). 

HAART and IPT Used in Conjunction Can Be More Effective Than HAART Alone in Reducing the Incidence of TB

HAART used in conjunction with IPT can significantly reduce the incidence of TB compared with HAART alone or IPT alone. A retrospective medical record review of 11,026 HIV-positive patients who were accessing medical care at 29 public clinics in Rio de Janeiro, Brazil from September 2003 until September 2005 found that isoniazid preventive therapy offered in conjunction with expanded access to HAART may improve TB control among people with HIV in high burden settings. The study was conducted to determine the rates of TB in patients who received no HAART or IPT; only HAART; only IPT; or both HAART and IPT. The overall incidence rate of TB incidence was 2.28 cases/100 person-years. The TB incidence among patients receiving both IPT and HAART was 0.8 cases/100 person years, with a 76% reduction in risk for developing TB in this group (Golub et al., 2007).

Cross-Referral of TB and HIV Screening and More Integrated Treatment and Services Can Increase Uptake for Both

Links between TB and HIV treatment must be strengthened (Makombe et al., 2006; Harries et al., 2009a). Efforts are needed to ensure that those with TB know their HIV status and vice versa. Co-trimoxazole, a broad-spectrum antimicrobial agent that is recommended as primary prevention against opportunistic infections in people living with HIV, can also reduce the mortality of HIV-positive people recently diagnosed with TB (WHO, 2006c). In 2007, only sixteen percent of people with notified TB knew their HIV status, resulting in low rates of access to co-trimoxazole prophylaxis and antiretroviral therapy for people living with HIV and TB (UNAIDS, 2009e).  A pilot cross-referral initiative instituted between VCT centers and treatment facilities in four districts of Maharashtra, India, found that from 2003 to 2004, 3% of VCT patients were diagnosed with TB and 24% of TB patients were found to be HIV-positive (Central TB Division, TB India, 2007 cited in Shetty et al., 2008b). Once a patient has been diagnosed with TB, HIV testing and counseling should be offered if the HIV status is unknown or was previously reported as negative (Harries et al., 2009a: 7). A study of three health care settings in Kinshasa, Democratic Republic of Congo found that provider-initiated HIV counseling and testing among TB patients resulted in greater uptake of HIV testing (Van Rie et al., 2008).  Likewise it is important that people living with HIV be regularly screened for TB and to have access to timely and accurate diagnosis so that the appropriate treatment is administered for TB and HIV.

“Because dual infection with HIV and tuberculosis poses a life-threatening diagnostic and therapeutic dilemma... HIV programs must include capabilities for diagnosis, treatment, and prophylaxis of tuberculosis. Tuberculosis treatment programs should be supported as an important point of entry for HIV testing and consideration for HAART. It is critical to overall treatment success that these coexisting epidemics be addressed in parallel” (IOM, 2005: 6). It is estimated that half a million people with HIV/AIDS could be reached through existing TB programs (Kim, 2004 cited in IOM, 2005: 103).

WHO has developed the Interim Policy on Collaborative TB/HIV Activities (WHO, 2004b, http://whqlibdoc.who.int/hq/2004/who_htm_tb_2004.330.pdf) that recommends twelve activities that can be taken up by the health sector, civil society and governments to address the overlapping epidemics. At a minimum, programs must be scaled up that:

  • Offer HIV testing and counseling to all TB patients;
  • Screen all people living with HIV for TB disease;
  • Provide TB treatment or preventive therapy to all co-infected people;
  • Provide co-trimoxazole and antiretroviral treatment to all TB patients with HIV; and
  • Ensure TB infection control in all health care facilities and high HIV prevalence settings.

Despite overwhelming evidence, many public sector health programs have failed to implement the activities that address reducing the burden of TB and HIV in populations affected by both diseases (Dong et al., 2007; WHO, 2009i). In many countries, the national TB program and the national AIDS control program run as parallel systems without a mechanism to link to one another (Reid et al., 2006; Williams et al., 2008). HIV programs play a vital role in identifying those with TB and interrupting transmission through active TB case finding and implementing infection control measures (Reid et al., 2006). Unfortunately, “delays with the scale-up of antiretroviral treatment have exacerbated the tuberculosis epidemic…and thousands of preventable deaths” (Chopra et al., 2009c: 3).

 

There is very little sex-disaggregated data on TB/HIV that is not pregnancy-related. As a result, there are a number of research and program gaps related to what works for women who are living with both HIV and TB.