Tuberculosis (TB) is a disease that is caused by a bacterium called Mycobacterium tuberculosis. It is one of the most common deadly infections on earth. One third of planets population is infected by M. tuberculosis. Each year, 8 million people develop active tuberculosis and 2 million succumb to what is essentially a treatable disease.

Natural course of disease

Most exposure to tuberculosis occurs in childhood as a result of breathing in M. tuberculosis transmitted from infected, usually adult, individuals. Once inhaled, the bacteria multiply at the site of infection in the lung and produce an inflamed area. They may then move to the lymph glands in the lungs, which can enlarge. This is known as primary tuberculosis.

In a minority of individuals the bacteria can spread throughout the body leading to serious disease. In most cases, however, the body's immune defences contain the M. tuberculosis organisms by walling them off in scar nodules within the lungs. Here, some of the infection can persist and remain latent for years or even decades. Some people with latent tuberculosis will go on to develop active disease during their lifetime. This is known as reactivation tuberculosis. Most reactivation disease develops during the first few years after infection, but sometimes it occurs decades later.

Symptoms

A chronic productive cough, shortness of breath, weight loss, fever, night sweats and fatigue are the classic symptoms of pulmonary tuberculosis. However, these symptoms can also have several alternative causes in people with HIV.

In people with severe immune damage or in infants, tuberculosis can spread or 'disseminate' from the lungs to other organs. This is often called 'atypical' or 'extrapulmonary' tuberculosis. While symptoms such as fever, fatigue and weight loss are fairly constant, other symptoms depend on where the infection spreads to.

Extrapulmonary conditions include:

• Tuberculous lymph node disease.

• Bone and joint tuberculosis or 'osteitis'. Spine involvement (myelopathy) is particularly dangerous.

• Pericardial tuberculosis: inflammation of soft tissue surrounding the heart. The condition puts great stress on the heart.

• Pleural tuberculosis: infection of the membrane surrounding the lungs.

• Tuberculosis peritonitis: tuberculosis in the abdomen and gut, with swollen lymph nodes and liver. Lymph nodes sometime adhere to the bowel causing obstructions or fistulae (abnormal passages) between the bowel, bladder and abdominal walls.

• Genitourinary tuberculosis: in the kidneys and urinary tract.

• Tuberculosis meningitis: inflammation of the spinal cord or brain. This begins with irritability, sleeplessness, a stiff neck with headache that grows more severe, with increasing drowsiness. It can lead to confusion or delirium, possible convulsions and decreased consciousness leading to coma or death.

• Disseminated or 'miliary' tuberculosis: a generalised systemic disease often with small nodules in affected organs and tissue.

Transmission

Only people with active pulmonary or laryngeal tuberculosis are infectious to other people. People who have latent or extrapulmonary tuberculosis are not infectious. M. tuberculosis is transmitted through the air, usually when someone with active tuberculosis coughs, sneezes, shouts or talks.

In the United Kingdom and the United States, there have been cases in which people have become infected in hospitals due to inadequate infection control procedures. People who are suspected of having active tuberculosis should be nursed in single rooms with negative air pressure, meaning that air is gently sucked out of the room so that any organisms cannot escape into the rest of the hospital.

It is important to avoid contact with people who have active lung tuberculossis until they are no longer infectious. If you are exposed to someone with tuberculosis, see your doctor as soon as possible.

Interactions with HIV

Tuberculosis is one of the most frequent AIDS-defining illnesses and opportunistic infections in the United Kingdom, comprising 27% of all AIDS diagnoses in 2003. The Health Protection Agency estimates that 4% of HIV-positive people in the United Kingdom have tuberculosis, the majority of whom are from Africa (Evans 2004). The incidence of tuberculosis in the general population has risen sharply over the past ten years.

Globally, tuberculosis is the most common serious HIV-related opportunistic infection. Approximately one third of the 40 million people living with HIV or AIDS worldwide are co-infected with tuberculosis. The vast majority live in sub-Saharan Africa and among this population, tuberculosis is leading cause of illness and death. At the same time, countries that have a large HIV-infected population are having difficulty containing the spread of tuberculosis.

The onset of the AIDS epidemic saw a marked increase in the number of cases of tuberculosis worldwide because HIV and tuberculosis interact in a number of dangerous ways. For example, both infections affect the immune system in ways that can alter the natural course of either disease. As a result, HIV changes the symptoms and natural course of tuberculosis, leading to far more extrapulmonary disease. Co-infection complicates the medical management of both diseases, partly because there are interactions between the medications used to treat each disease.

Because of HIVs effect on the immune system, people with HIV are more than seven times more likely than HIV-negative people to develop primary tuberculosis within the first six months of M. tuberculosis infection. Vaccination has little effect on this risk.

People with HIV and latent tuberculosis are also far more likely to develop active disease, with an 8 to 10% chance of developing active disease each year, compared to a total lifetime reactivation risk of about 5% in the HIV-negative population (Goletti 1996). As damage to the immune system worsens, people with HIV are more likely to develop extrapulmonary tuberculosis.

Active tuberculosis has been shown to increase HIV viral load, which might be expected to accelerate loss of CD4 T-cells and disease progression (Michael 1996). However, a more recent study of South African patients has suggested that high viral loads after a tuberculosis event may be due to pre-existing high viral load rather than tuberculosis itself (Day 2004). Viral load may remain elevated if the tuberculosis is not successfully treated, or may remain elevated in some people despite successful treatment.

Although antiretroviral therapy can substantially reduce the incidence of tuberculosis by 70 to 90%, recent studies have shown that most children and adults with HIV continue to have an elevated risk of contracting tuberculosis despite immune reconstitution^[1][2]. Since effective antiretroviral therapy extends life expectancy, it is possible that the lifetime risk of developing tuberculosis may not be substantially reduced by HIV treatment. However, immune reconstitution removes some of the difficulties caused by HIV-related immunosuppression in terms of tuberculosis diagnosis (Lawn 2005).

Diagnosing latent tuberculosis

According to United States guidelines, people with HIV should be tested for tuberculosis when HIV is first diagnosed. This practice is less well supported by doctors in the United Kingdom.

The test most often used is a tuberculin or purified protein derivative (PPD) skin test. This works on the principle of injecting a small amount of purified tuberculosis protein into the skin. After three days, the injection site may show a reddening and hardening reaction, which means that there is an immune response to the protein. An immune response indicates previous or current infection with tuberculosis or vaccination. The larger the size of the reaction, the more likely it is that someone has been infected with M. tuberculosis in the past and has active disease or latent infection.

The absence of a reaction does not prove the absence of infection. HIV disease is one of a number of things that can reduce the immune response so a skin test is negative, despite M. tuberculosis being present in the body. This is termed 'anergy'. Successful treatment of HIV may restore this immune response, leading to a positive skin test without any new infection or exposure. In addition, vaccination sometimes makes interpretation of skin tests difficult. This is one reason why some doctors in the United Kingdom do not favour routine use of these tests in HIV-positive people.

Two new blood tests have been developed which provide more accurate identification of people with active or latent infection. The T-SPOT.TB and QuantiFERON-TB Gold tests look for interferon gamma that is produced by T-cells in response to the human form of M. tuberculosis (Ewer 2003). They can tell the difference between tuberculosis exposure and vaccination or exposure to other relatively harmless bacteria. They are also more rapid that the tuberculin skin test, giving results overnight.

A comparative study in 393 patients with suscpected tuberculosis showed that the T-SPOT.TB test gave fewer indeterminate results that the QuantiFERON-TB Gold test, and that it was the only test to diagnose all individuals with extrapulmonary tuberculosis correctly. However, both tests are affected by treatments that affect the immune system, such as cancer chemotherapy or steroid treatment (Ferrara 2006).

Diagnosing pulmonary tuberculosis

The gold standard for tuberculosis diagnosis is being able to grow M. tuberculosis from a sputum sample. However, this takes weeks or months and requires specialised facilities that are not available in every setting. If possible, at least one good specimen should be sent for culturing and drug susceptibility testing, even though treatment of active disease cannot wait for culturing results.

Diagnosis and treatment is normally based upon a combination of other factors, including symptoms, chest X-rays and examination of sputum under the microscope. All of these can be influenced by HIV infection.

Chest X-rays in a person with classic pulmonary tuberculosis usually reveal cavities in the upper lobes of the lung. However in people with HIV, the X-ray might look normal or look similar to the effects of other lung diseases. Importantly, X-rays cannot distinguish between active and treated tuberculosis.

When a patient has classic pulmonary tuberculosis, sputum often contains M. tuberculosis bacteria. These can be seen under the microscope after staining with medical dyes. A diagnosis for pulmonary tuberculosis can be made on the basis of at least one or two positive results out of two or three smears. This test can be performed in most clinic laboratories and plays a pivotal role in most tuberculosis control programmes. However, this method is far less reliable in people with HIV. In some parts of the world, smears from over half the cases of active tuberculosis test negative.

One problem is that it can be very difficult to obtain sputum sample from someone with HIV. Sometimes, in a person who does not have a productive cough, a doctor will try to induce a specimen by spraying saline solution into the back the throat.

If sputum is smear-negative in someone with HIV, samples of the lymph nodes or lung may have to be taken for analysis under the microscope. Often the doctor will give the subject a course of antibiotics to see whether the symptoms resolve.

Extrapulmonary tuberculosis is more difficult to diagnose. It often requires invasive procedures to obtain specimens from whatever organ system is affected.

So far, attempts to develop a fast, simple and accurate blood test for tuberculosis have failed to produce an accurate and reliable test (Letsatsi 2003). However, a number of new techniques are being explored that may help diagnose both latent and active disease in patients coinfected with tuberculosis and HIV (Wilson 2003).

Treating latent tuberculosis

In the developed world, once it is clearly established that there is no active disease, many doctors recommend a course of anti-tuberculosis drugs to try and get rid of the latent infection.

In some settings, preventive treatement or 'prophylaxis' is also given to people with HIV who live or work in situations where exposure to M. tuberculosis is common. Examples include healthcare workers, caregivers and household contacts of people with active tuberculosis, miners and prisoners.

A number of regimens can reduce the risk of developing active tuberculosis in people with HIV. These include:

• A six-month course of isoniazid, a low-cost drug that can be taken at either 5mg/kg daily to a maximum of 300mg or 15 mg/kg twice weekly to a maximum of 900mg twice a week. Pyridoxine (vitamin B₆) is given along with isoniazid to prevent liver toxicity and peripheral neuropathy. Although studies have demonstrated that a nine-month course is superior to six months, there are concerns about decreased adherence with a longer duration of therapy.

• A three- or four-month course of rifampicin (Rifadin / Rimactane), with or without isoniazid. Rifampicin and isoniazid are available in one tablet as Rifater, Rifinah 150, Rifinah 300 and Rimactazid 300.

• A two-month course of pyrazinamide and rifampicin. There have been reports of severe hepatic injury following this combination in HIV-negative patients. However, a recent study claimed that the risk was low in HIV-positive patients and that the difference between the two treatment regimens in terms of risk of liver toxicity was marginal (Gordin 2004).

Isoniazid regimens are by far the most common and widely used, particularly in patients on antiretroviral therapy, as there are interactions between rifamipicin and certain antiretrovirals. However, rifampicin is the most potent anti-tuberculosis medication available so most programmes choose to reserve it for treatment of active disease to reduce the likelihood of resistance developing in a populaton. Although prophylaxis can eliminate latent tuberculosis infection, it does not prevent a new infection. Those in frequent contact with people with tuberculosis may need to repeat prophylaxis every few years.

Careful adherence to the treatment schedule is necessary to prevent the development of resistance. Prophylaxis should therefore only be given to patients who can be relied upon to take their medication correctly.

Treating active tuberculosis

Generally, the standard first-line tuberculosis regimen is the same for HIV-positive and -negative people. However, there are some important considerations when it comes to treating tuberculosis and HIV at the same time, however, as discussed below.

There are two phases to tuberculosis treatment, an intense initial phase, during which more drugs are given to clear the infection, and a longer continuation phase to be certain the infection is gone.

In most settings, for adults with previously untreated tuberculosis, the initial phase consists of two months of daily isoniazid at 4 to 6mg/kg, with 8 to 12mg/kg rifampicin, 20 to 30mg/kg pyrazinamide and 15 to 20mg/kg ethambutol.

In order to make certain that people take all their medication correctly, a health care worker usually observes dosing during this phase. This is called directly observed therapy, short-course (DOTS). This is particularly important as people tend to feel better as the disease comes under control. It is vital to complete the full course of treatment to avoid relapse and drug resistance.

After two months, if new smear results are negative, the patient is no longer deemed to be infectious, and can be switched to a less intensive continuation phase. Different continuation phases are used in different countries because of local and individual drug susceptibility patterns, drug availability and how closely patients can be monitored to ensure adherence.

There are two leading continuation phase regimens:

• Four months of isoniazid and rifampicin. This regimen has been shown to be superior but can only be given with support for adherence, such as directly observed therapy (DOT) to prevent the development of resistance to rifampicin (Jindani 2004). This regimen is usually used in the United Kingdom and the United States.

• Six months of isoniazid and ethambutol, which can be given to patients with monthly follow-up

Some national guidelines recommend a five-month continuation phase with three drugs for some patients. Also tuberculosis programmes in different countries differ on whether the drugs should be given daily, or on three or five days of the week.

People with tuberculosis are often given 25 to 50mg pyridoxine (vitamin B₆) daily to reduce isoniazid's side-effects. If co-infected with HIV, they may also take co-trimoxazole (Septrin / Bactrim), which has been shown to decrease morbidity and mortality.

Two other standard drugs are used less frequently than in the past. These are thioacetazone, which can cause severe life-threatening skin-reactions in HIV-positive patients, and streptomycin, which is not widely used as first line treatment due to toxicity, high rates of resistance and because it must be administered as an injection.

Treating extrapulmonary tuberculosis

Most experts now agree that virtually all forms of extrapulmonary tuberculosis can be treated with the regimens used for pulmonary tuberculosis, although in some cases a longer duration treatment of nine months may be advisable.

Corticosteroids have been shown to benefit patients some patients with extrapulmonary tuberculosis, in particular pericarditis and meningitis. They may also be of use in patients with tuberculosis-related wasting and for airway obstruction due to lymph node compression or endobronchial disease.

Tuberculosis treatment, oral contraception and pregnancy

In pregnant women, co-infection with HIV and tuberculosis has been associated with increased vertical transmission of both infections. Treatment of latent and active disease is therefore important for the health of both the mother and her infant.

Rifampicin interacts with oral contraceptive medications and may reduce their efficacy. The World Health Organization recommends that women taking oral contraceptions who need tuberculosis treatment should either take a contraceptive pill with a higher dose of oestrogen than normal (50µg), or use another form of contraception.

Pregnant women with active tuberculosis should be treated with isoniazid and rifampicin, which are safe during pregnancy. Pyrazinamide, although recommended by many authorities, has not been thoroughly studied in pregnancy, and should be used at the discretion of the treating physician. Ethambutol has not been recommended. Streptomycin should never be used during pregnancy as it might damage the babys hearing.

Tuberculosis treatment and antiretroviral therapy

One of the biggest dilemmas in treating tuberculosis when someone has HIV is whether to treat the tuberculosis first and then consider antiretroviral treatment, or to go ahead with both treatments. Giving both at the same time is complicated by drug interactions and overlapping toxicity.

Given the interactions between protease inhibitors, non-nucleoside reverse transcriptase inhibitors (NNRTIs) and drug rifampicin, previous treatment guidelines recommended delaying treatment with antiretrovirals, if possible. Alternatively, antiretroviral therapy may need to be interrupted for the first stage of tuberculosis treatment.

However, the most recent revision of the Centers for Disease Control and Prevention (CDC) guidelines on treating tuberculosis and HIV moves away from this. It recommends that with the use of rifabutin (Mycobutin) instead of rifampicin. In addition it recommends that with adjustment of dosages in some cases, both antiretroviral and anti-tuberculosis treatment should be given together

Despite this, rifabutin is not available in every country. In addition, United Kingdom doctors have pointed out that rifabutin has not been tested in controlled trials amongst HIV-positive people, and patients given the drug have not been followed up for as long as those given rifampicin. Furthermore, it has not been tested in people who already have isoniazid-resistant tuberculosis. Despite a retrospective cohort study finding similar outcomes in HIV-positive patients treated with rifampicin and rifabutin, a prospective study has shown that rifabutin-based therapy results in high rates of treatment failure and relapse in patients with low CD4 cell counts (Burman 2005; Vargas 2005).

If antiretroviral therapy cannot wait, the antiretroviral regimens may need to be modified to be compatible with rifampicin-based tuberculosis treatment. The following dose adjustments are necessary:

• Efavirenz (Sustiva): while the CDC recommends increasing the efavirenz dose to 800mg daily, there are few published data on efavirenz metabolism in non-Western populations. In some countries experts do not recommend increasing the efavirenz dose when given with rifampicin for fear of increased toxicity.

• Nevirapine (Viramune): nevirapine clearance varies between ethnic groups but no dose adjustments are considered necessary.

• Protease inhibitors: most protease inhibitor levels are significantly reduced when given with rifampicin and should not be used, unless boosted by ritonavir (Norvir). For people taking ritonavir-boosted protease inhibitors, rifabutin is recommended at a substantially reduced dosage.

• When antiretroviral therapy consists of both protease inhibitors and a NNRTI, drug interactions are complex and appropriate dose adjustments are unknown.

The benefits of treating HIV and tuberculosis were demonstrated in a recent retrospective study, which found no differences in treatment outcomes between patients with both diseases, and those with HIV alone. The study also found that the co-infected patients had similar rates of relapse following the end of tuberculosis treatment to a group of HIV-negative patients with tuberculosis^[3].

There is also a risk of additive side-effects and drug toxicity when antiretrovirals are combined with tuberculosis treatment. For example, hepatitis is a common side effect of nevirapine, isoniazid, rifampicin and pyrazinamide. In patients with preexisting liver disease, frequent clinical and laboratory monitoring should be performed to detect drug-induced liver injury. Drinking alcohol increases the risk of liver toxicity.

Multi-drug resistant tuberculosis

Some strains of tuberculosis have become resistant to some of the standard drugs. These multi-drug resistant (MDR) strains have infected both people with HIV and HIV-negative healthcare workers. The likelihood of dying from MDR tuberculosis is high, especially for HIV-positive people, unless treatment can begin very soon after infection with appropriately tailored therapy.

Outbreaks of MDR tuberculosis have been successfully controlled in Cuba, Hong Kong and the United States, but cases of MDR tuberculosis are highest in areas with the fastest growing HIV epidemic, particularly the former Soviet republics, China and South Africa. It seems that the spread of MDR tuberculosis is being fuelled by a high prevalence of tuberculosis in HIV-positive patients, and also by poor adherence to anti-tuberculosis medication (Chengeta 2003; Ngirubiu 2003).

MDR tuberculosis is no more easy to transmit than the more common form of M. tuberculosis. It can be very difficult to determine when HIV-positive people who are undergoing treatment for MDR tuberculosis cease to be infectious, because the M. tuberculosis organisms may disappear from their sputum for a short period, but re-appear a short while later. This makes it very difficult to determine when a patient is truly non-infectious, so affected people may be hospitalised and isolated for many months.

MDR tuberculosis is significantly more difficult to treat and requires extra drugs such as streptomycin, kanamycin, clarithromycin (Klaricid / Klaricid XL), amikacin (Amikin), capreomycin (Capastat) or other antibiotics. These are more expensive, more toxic and less effective and require a longer course of treatment. Drug selection in patients suspected to have MDR tuberculosis should be guided by history and local drug susceptibility patterns whenever possible. Usually, initial treatment is with the four-drug regimen plus at least additional two drugs to which the patient's M. tuberculosis is thought to be susceptible. In people with culture-confirmed MDR tuberculosis, at least three drugs should be used for at least twelve months after the sputum conversion. Most experts recommend that treatment last 18 to 24 months.

Immune reconstitution syndrome

Some people taking antiretroviral therapy develop a syndrome known as immune reconstitution inflammatory syndrome. This is characterised by new or paradoxical worsening of tuberculosis symptoms.

This syndrome occurs among people with treated or active but silent M. tuberculosis infection who have had a strong immunological and virological response to antiretroviral therapy. As a result of immune reconstitution, the immune system attacks areas of the body where the bacteria have been lurking (Breton 2004).

Symptoms may be typical, marked by a worsening of fever, coughing, shortness of breath, lymphadenopathy or worsening of signs of tuberculosis on a chest X-ray. They may also be extrapulmonary and atypical, such as unusual lymphoid swelling leading to bursting, open sores or cerebral masses.

This syndrome appears to be more widespread in resource-limited settings, where tuberculosis is most prevalent, and in patients who begin therapy with low CD4 cell counts, especially below 50 cells/mm³. Symptoms may appear within the first couple months on antiretroviral treatment, but later flare-ups have been reported.

Most experts believe antiretroviral therapy should be continued in these patients, unless the reaction is life-theatening. Patients should also receive tuberculosis treatment even though patients may have negative tuberculosis cultures.

Anecdotal data suggest a possible role for corticosteroid therapy to reduce inflammation.

See Immune restoration illnesses in Anti-HIV therapy: Restoring the immune system for further information.

Vaccination

For HIV-negative people there is a live vaccine against tuberculosis known as the Bacille Calmette-Gu鲩n (BCG) vaccine, although its effectiveness appears to vary in different populations. It should not be given to people with HIV, in whom it may cause a disease similar to tuberculosis. The widespread use of BCG in the United Kingdom, but not the United States, means that very few people become infected during childhood.

A tuberculosis vaccine that uses inactivated bacteria is being tested in over 2000 HIV-infected people in Tanzania, after a pilot study in Finland found encouraging results (Vuola 2003).

Research on diagnosis, natural history and epidemiology

Day (2004) carried out an observational cohort study of HIV-infected adults in South Africa. 30 patients developed TB during follow-up: these were compared to 56 control HIV-positive subjects matched for baseline CD4 cell counts and follow-up time. HIV VL was higher at baseline in the TB group (53,700 vs. 17,400 copies/ml, p = 0.003) and after TB (105,000 vs. 21,900 copies/ml, p < 0.001). After adjusting for baseline VL and HIV stage, the difference in final VL was 2 copies/ml (p = 0.06).

van der Sande (2004) conducted a retrospective analysis of TB rates and mortality in 2012 HIV-1 and HIV-2 infected patients in the Gambia. There was no difference in time from HIV diagnosis to TB infection, or the site of TB infection between groups. Incidence was similar in the two groups (3.8 vs. 2.8 per 100 person-years; p = 0.3 after adjusting for baseline CD4 cell count). After stratifying patients on the basis of CD4 cell count, there was no difference in TB incidence between HIV-1 and HIV-2 infected patients (p = 0.2). Mortality and median survival were similar in the 2 groups (43.5 per 100 person-years and 8.9 months respectively).

Results from the CASCADE Collaboration showed that patients who had TB as their first AIDS-defining illness were no more likely to experience accelerated disease progression than AIDS-free patients.

Currie (2003) conducted statistical modelling which showed that boosting the detection and treatment of active TB in resource-poor countries with high rates of HIV infection would have a more significant impact of TB incidence and death and than initiatives to reduce HIV infection, treatment HIV infection and treat latent TB.

Michael reported that levels of serum HIV-1 viral load were higher in patients with active pulmonary TB versus matched HIV-positive controls who did not have TB. The difference became more marked during follow-up, despite evidence for adequate anti-TB therapy, suggesting that M.Tb enhances HIV replication and may permanently accelerate the natural history of HIV disease.

Tetter found that in Houston, Texas TB was the only AIDS-defining illness whose incidence had remained stable since the introduction of HAART. Median CD4 cell count at the time of TB diagnosis being 174 cells/mm³.

Goletti reported that HIV-1 viral load increased between five and 160-fold in seven patients with acute pulmonary TB compared with levels before the onset of disease and after successful treatment. In two people for whom treatment was not successful, viral load levels remained permanently elevated.

Berenguer reported that while tuberculous meningitis occurs more frequently in HIV-infected people, clinical outcomes are similar to those in non-HIV-infected people.

Van Lettow conducted research that showed that TB wasting is more likely to appear in HIV-positive patients who are malnourished. The research involved 298 HIV-positive Malawians. Lower dietary carotenids, vitamin A and selenium were associated with wasting.

Corbett reported that 31% of cases of TB in Africa were due to the HIV epidemic. In South Africa, 50% of TB cases (and 59% of TB deaths) were attributable to HIV and the number of people coinfected with HIV and TB in South Africa was estimated to be 2 million, 8.3% of the adult population. In India, 3.4% of TB cases and 4.8% of TB deaths were due to HIV, with a total of 2 million people in Asia coinfected with HIV and TB.

Van Asten found that the duration of infection with TB increases the risk of injecting drug users developing active TB, independent of CD4 cell count. Compared to the first three years of HIV infection the risk ratio of developing TB was 2.8 for years four to six of HIV infection, 1.2 for years seven to nine, and 4.6 after year nine. As both TB and HIV target the immune system, van Asten speculated that the two conditions might interact causing disease progression, meaning that a patient's risk of developing TB was not solely related to CD4 cell count.

Letsatsi (2003) examined four types of serodiagnostic tests.One type, called the immunochromatographic strip (ICS) is a strip test for TB using blood or serum to determine antibodies unique to TB and the results are available within an hour. The sensitivity of the ICS in previous studies showed a sensitivity of 72% (range 62-100%). A total of 465 patients with coughing for more than two weeks were enrolled in the study. 83% were HIV infected. 175 patients (38%) were diagnosed with confirmed tuberculosis. Of these, 53% had TB diagnosed from sputum; 33% were diagnosed from sputum and blood; and 15% were diagnosed from blood culture only. Characteristics such as weight loss, diarrhoea, fever, chest pains and cough were evaluated but were not significantly different between those with TB and without TB. Abnormal chest x-rays were common to both groups. Patients with TB tended to be younger, were more likely to be infected with HIV and to have a CD4 count of less than 200 cells. Patients with TB were also more likely to be anaemic and had a lower platelet count. Unfortunately, the ICS test did not perform up to expectations. ICS to serum showed a sensitivity of 27% and specificity of 75% while ICS to whole blood had a sensitivity of 11%. Results were similar when stratified by HIV status, CD4>200, sputum status and other factors. All the serodiagnostic tests performed poorly in this population. The relative sensitivities, specificities, positive predictive and negative predictive values for the tests were as follows: for the ICS; 27%, 75%, 39%, and 63%; Osborne Scientific 37%, 63.%, 36%, and 36%; MycoDot 3%, 99%, 55%, 55%; and American Bionostica 0, 99%, 0, and 0. The poor results may have been due to the transportation of samples or to the lack of TB antibodies in the HIV-infected patients.

Wilson (2003) reported on a new assay called FastPlaqueTB, made by Biotec Laboratories, which requires only basic laboratory facilities, equipment and skills to conduct. Results are produced within 48-72 hours, can be read by eye and are easy to interpret. In a study of 143 HIV-positive people who could not be definitively diagnosed with TB by smear test or X-ray, FastPlaqueTB test detected TB in 64% of the sputum specimens that were culture positive, and produced no false positives. FastPlaqueTB detected only 38% of TB culture positive urine samples, and performed poorly when other bodily fluids (e.g., pleural or ascitic) were investigated. However, the test picked up 63% of the culture positive needle core lymph node biopsy specimens, and 10 out of 10 of the cold abscess aspirates.

Mahomed (2003) reported on his efforts to develop an even faster, more sensitive and specific approach to diagnosing TB. Essentially, the test is a modified PCR technique that utilises a 쌩ght Cyclerevice that can continuously monitor very rapid amplification of TB gene sequences in small volumes. The test can be conducted in several hours and has the potential to assess drug resistance. Unfortunately, unlike the FastPlaqueTB assay, this technology requires expensive, sophisticated laboratory equipment and most importantly, skilled technicians trained to perform it. It will likely be confined to the research laboratory for the time being.

Zachariah's research in Malawi found that 69% of 189 TB cases identified were HIV-positive. The use of sputum testing and chest x-rays significantly increased the number of cases of TB detected amongst household contacts of TB cases. Isoniazid preventative therapy was more likely to be provided when sputum tests and chest X-rays were used. Transport costs associated with attending for a chest X-ray were the main reason for poor take-up of isoniazid therapy.

Research into TB treatment

A recent study of HIV-positive TB patients in New York City has also shown that resistance to rifampicin and relapse are most likely to occur if the drug is taken intermittently (every two to three days) rather than every day during the intensive phase of treatment. This suggests that co-infected patients should not receive the drug intermittently during the intensive phase, in accordance with the CDC's recommendations (Li 2005).

Elliott (2004) conducted a randomised, placebo-controlled trail of prednisolone as an adjunct to TB treatment in adults with HIV-1 and pleural TB. 99 patients were given prednisolone and 98 placebo. Mortality was 21 and 25 deaths per 100 person-years respectively (p = 0.95), but resolution of TB was faster in the prednisolone group, and there was a higher incidence of Kaposi's sarcoma (1.4 vs. 0 cases per 100 person-years, p = 0.02).

Gordin (2004) randomised 1583 HIV-positive patients with latent TB infection to receive a 2-month regimen of rifampicin and pyrazinamide or a 12-month course of isoniazid. At baseline there were no differences between groups in bilirubin or aspartate aminotransferase (AST) levels. 0.6% of the isoniazid group and 1.8% of the rifampicin / pyrazinamide group developed grade III (>2.5mg/dl) bilirubin (p = 0.06). Grade III elevations in AST occurred in 1.6 and 21.% respectively (p = 0.056). The use of rifampicine / pyrazinamide (p = 0.02), non-white race (p = 0.022) and female sex (p = 0.023) were associated with an increase in bilirubin by >0.5mg/dl. Only age above 40 years was associated with an increase in AST by 40u/l (p = 0.026).

Jundani (2004) recruited 1355 patients with two TB smear positive samples in China, Nepal, Benin, Guinea, Tanzania and Mozambique and randomised them to receive daily treatment with isoniazid, rifampicin, ethambutol and pyrazinamide for 2 months followed by 6 months of isoniazid and ethambutol, four-drug treatment for 2 months three times a week followed by 6 months of isoniazis and ethambutol, or daily four-drug treatment for 2 months followed by 4 months of isoniazid and rifampicin. At the end of the 2 month treatment phase, there were fewer negative cultures in the thre times weekly group than those receiving daily treatment (77 vs. 85%, p = 0.001). After 12 months, patients on the 6-month protocols were more likely to have an unfavourable outcome (adjusted odds ratio 2.86). This risk grew with length of follow-up. This effect was also seen in the HIV-positive patients, although it was not significant (5 vs. 27%, p = 0.09).

Thwaites (2004) randomised 545 patients aged over 14 years in Vietnam to receive dexamethasone or placebo. The risk of death was lower in the dexamethasone group (relative risk: 0.69, p = 0.01). The drug did not alter the risk of severe disability (18 vs. 14%, p = 0.27). The effect was similar across patients with different disease severity and by HIV status. Adverse events occurred in fewer patients in the treatment group (9 vs. 17%, p = 0.02).

Gatell reported that in the ENTA 05 study, which enrolled 598 HIV-positive people with suspected tuberculosis, the effectiveness of treatment with isoniazid, rifampicin and pyrazinamide was not enhanced by the addition of ethambutol.

Nettles (2003) conducted retrospective investigation of resistance to anti-TB drugs in the rifamycin (rifampicin and rifabutin) class amongst 109 HIV-positive patients in Baltimore between 1993 and 2001. Data on TB recurrence was gathered and DNA fingerprinting undertaken to identify drug-resistant TB strains. TB recurred in nine patients. Their average CD4 count was 50 cells/mm³. Sputum samples showed that resistance to the rifamycin class of anti-TB drugs was present in three patients, all of whom had received rifampicin.

Korenromp (2003) conducted an analysis of HIV/TB patients and found that recurrence of TB was less likely in people who had taken rifamycin-based treatment for more than 7 months. However, a prospective study of 705 people with HIV and TB infection in Taiwan between 1994-2003, published by Hung (2003b) has found that longer TB therapy or concurrent TB and anti-HIV treatment does not reduce recurrence of TB. 124 people developed active TB, most with CD4 counts below 2000. Despite a mean duration of TB treatment of 9 month, eight people had relapases produces a recurrence rate of 2.5 per 100 patients years.

Yee (2003) reported that the incidence of serious side effects associated with anti-TB drugs was higher than previously estimated. Based on data on 430 TB patients treated between 1990-1999. The incidence of serious side effects per 100 person/months was 1.48 for pyrazinamide, 0.49 for isoniazid, 0.43 for rifampicin, and 0.07 for ethambutol. Risk of any serious side effects was associated with HIV coinfection, female gender and birthplace in Asia. Pyrazinamide side effects were associated with age of 60 years and birthplace in Asia. Rifabutin side effects were associated with age over 60 years and HIV infection. Pyrazinamide-induced liver toxicity and rash was more common than previously thought.

Chaisson concluded that three-times-weekly treatment is equally effective in both HIV-positive and HIV-negative patients with tuberculosis. 427 patients in Haiti were enrolled in the trial, 177 (41%) of whom were HIV-positive. Patients received isoniazid, rifampicin, pyrazinamide, and ethambutol administered three times a week for two months, followed by isoniazid and rifampicin for four months. Improvement in symptoms and sputum conversion occurred equally frequently in both HIV-positive and HIV-negative patients. Mortality was more frequent in the HIV-positive subjects (9% vs. 1%), although most deaths were due to non-tuberculous AIDS-related complications.

Berning, Gordon and Peloquin reported that malabsorption of anti-mycobacterial drugs occurs relatively frequently in AIDS patients with TB. To prevent treatment failure, screening for drug malabsorption may be indicated.

Vernon randomised 71 HIV-infected people with TB to either once weekly isoniazid /rifapentine or isoniazid /rifampicin in the second phase of treatment. Five in the rifapentine group relapsed compared with three in the rifampicin group. Four people on rifapentine developed rifamycin resistant TB compared with no-one on rifampicin.

Chengeta (2003) studied the reasons for patients not completing TB therapy in Botswana. Many had died and been wrongly classified as non-completers. Of 63 non-completers who were interviewed, lack of counselling about TB and TB therapy, and inconsistent delivery of DOTS were commonly reported. Side-effects were the major reason for interruption for 58% of people who stopped during the initial phase of therapy.

Research into multi-drug resistant TB

Several outbreaks of multi-drug resistant tuberculosis (MDR-TB) among HIV-positive people in hospitals and prisons have been reported in the States. Mortality among these patients was initially very high (approximately 80%) and the disease progression was extremely rapid. Turett reported that among 39 HIV-positive people diagnosed with MDR-TB in New York between 1991 and 1994, 54% survived one year after diagnosis, and 51% survived 2 or more years. Response to treatment and survival was associated with initiation of treatment within four weeks of diagnosis, receiving at least two weeks of treatment, and having disease limited to the lungs.

Edlin and Fischl studied outbreaks of MDR-TB in hospitals. They report that nosocomial transmission of MDR-TB bacilli among HIV-infected patients can occur. They caution that acid-fast-bacilli isolation procedures must be strictly enforced in hospitals. Small reported that multi-drug resistance in HIV-infected people can result from re-infection with resistant strains of M. tuberculosis. This re-infection can occur during or after therapy for drug-sensitive tuberculosis.

A new assay is in development which may accelerate the diagnosis of MDR-TB. Jacobs reported that inserting the light-producing luciferase gene into M. tuberculosis in culture allows for the rapid detection of resistant and susceptible strains after treatment with anti-tuberculosis drugs.

Most multi-drug resistant strains are resistant at least to isoniazid and rifampicin. Guidelines drawn up by the US Centers for Disease Control and Prevention (CDC) recommend that susceptibility testing be performed on the initial M. tuberculosis isolates from all patients with TB. Pending results of susceptibility testing, patients with suspected MDR-TB should receive a regimen containing isoniazid, rifampicin and pyrazinamide plus ethambutol or streptomycin. Others have proposed an initial regimen of five or six drugs, including at least two to which the organisms are likely to be susceptible based on local patterns of drug resistance.

Mahmoudi and Iseman reported that inadequate treatment is the primary cause of the development of MDR-TB. Multiple levels of resistance are especially likely to accrete when single drugs are added to a failing regimen.

Cobo found that multi-drug resistant TB was more likely to occur amongst patients with CD4 cell counts below 100 cells/mm³.

Ngirubiu (2003) investigated resistance to TB drugs among 2425 TB patients (60% HIV+) in Botswana. 1124 people were new cases of TB and 10.3% had some drug resistance. This represented a statistically significant increase from previous survey findings (3.7% isolates in 1995-96, and 6.3% in 1999). 4.4% of the new patients had some isoniazid resistance, and 1.9% had some resistance to rifampicin. Resistance to both drugs was observed in 0.8% of the new patients, which represented an increase from 0.2% in previous surveys (not statistically significant: p=0.17). Among 100 previously treated patients, there was a non-significant trend towards an increase in resistance since the previous surveys, from 14% and 22.8% to 24%. Multi-drug resistant TB also rose among previously treated patients, up from 5.8 and 9% in the two previous surveys to 11%.

Research into prophylaxis and vaccination

A recent study has examined the effect of isoniazid prophylaxis in HIV-positive South African mine workers attending a workplace HIV clinic. Patients were invited to attend the clinic and were offered six months' treatment with isoniazid if they had no history of TB. Although this led to an overall reduction in incidence of 38% overall, and 46% in the patients with no history of TB, incidence remained high at 9 per 100 person-years. The investigators warn that further work is required to determine how to use additional interventions most effectively to reduce the incidence of TB in the real-world setting (Grant 2005).

Vuola (2003) studied an old form of vaccine against tuberculosis based on inactivated mycobacteria, a method of vaccination demonstrated to prevent tuberculosis prior to the introduction of the live TB vaccine known as BCG in the 1950s. However, BCG does not work in people with HIV, so researchers decided to test the old method of vaccination to see if it could protect HIV-positive people. The study was done in Finland where BCG vaccine is routinely administered at birth. A cohort of 39 HIV patients, mainly men, were divided into two groups to receive a five-dose course of the killed vaccine, Mycobacterium vaccae, or a control vaccine for Hepatitis B. Parallel studies were also conducted on HIV-negative subjects. Those who received the TB vaccine experienced boosted immunity against TB both in those with HIV and those without TB and no adverse effects were seen in people with HIV.

The above study (Vuola 2003) served as the basis for a large-scale trial Dartmouth researchers have been conducting since 2001 in Dar es Salaam, Tanzania with Muhimbili Hospital Medical Center. The five-year $3 million NIH funded study is the only efficacy trial of a new TB vaccine currently under way in the world. The Tanzania trial will enroll more than 2000 HIV-infected patients to determine if the boosted immunity detected in the Finnish study actually reduces the risk of tuberculosis among HIV infected people in Tanzania at high risk of the disease.

In the USA, where BCG vaccination is not routine, individuals with HIV and a positive skin test for or history of tuberculosis are recommended by the CDC to take preventive isoniazid therapy.

The World Health Organisation currently recommends that all patients with HIV should receive a chest X-ray to rule out the presence of active TB where symptoms are not present. Treatment of TB with a single drug leads to drug resistance, and the WHO protocol is designed to prevent the administration of isoniazid monotherapy to people with active TB. However, physicians in Botswana argue (Chintu 2003) that routine chest X-ray should not be required before administering isoniazid prophylaxis to people with HIV. Mosimaneotsile (2003) assessed 935 individuals with HIV infection referred to a treatment centre from a network of clinics and testing centres, 692 of whom had no signs or symptoms of active tuberculosis. 18% did not return for the X-ray. Of the 560 who completed the process, 96% (536) of chest X-rays were normal. Only one patient could be diagnosed with TB on the basis of a chest X-ray; the remaining 23 had chest X-rays that were interpreted as non-specific pneumonitis (mycobacterial cultures were not carried out to confirm this diagnosis).

HIV-infected people are particularly susceptible to infection by M. tuberculosis, and the course of the disease is accelerated. Daley investigated an outbreak of tuberculosis among residents of a housing facility for HIV-infected people. Among 30 residents exposed, active tuberculosis developed within four months in 11/30 (37%) and newly positive skin tests developed in 4/30 (13%). Jones reported that people with HIV are at increased risk of extra-pulmonary TB, especially at low CD4 counts.

Churchyard (2003) reported that treatment HIV-positive mine workers in South African with isoniazid halves the number of cases of active TB. The protective effect of isoniazid appears to be greatest in men with lower CD4 counts (below 200), where treating 5 people is enough to prevent one case of active TB. When the CD4 count is higher (above 200) it needs 17 people to be treated to prevent one case.

Narita (2002) treated 135 with latent TB as well as HIV infection with directly observed rifamycin/pyrazinamine for 2 months. Completion rate was 92% compared with a 61% completion rate among historical controls taking isoniazid for latent TB. 5 people taking the dual therapy stopped treatment due to severe side effects (allergic skin reaction or hepatitis).

Halsey compared 6 months of isoniazid with 2 months of rifampicin and pyrazinamide for the prevention of TB in HIV-infected people with a positive TB skin tests. Ten months after trial entry, people on isoniazid had a 1% chance of developing TB compared with a 3.7% chance among the rifampicin and pyrazinamide group. Overall follow-up at up to 4 years found that 14 of 370 (3.8%) people on isonaizid and 19 of 380 (5%) people on rifampicin and pyrazinamide developed TB. This result was not statistically significant. The slightly higher occurrence of TB among the rifampicin group was attributed to the shorter duration of treatment. A CD4 count below 20 was associated with the development of TB.

Whalen (1997) conducted a randomised, placebo-controlled trial of three regimens for preventive therapy for tuberculosis among 2736 HIV-infected Ugandans. Participants with positive tuberculin skin tests were randomised to isoniazid for 6 months, isoniazid/rifampicin for 3 months, isoniazid/ rifampicin pyrazinamide for three months, or placebo. TB incidence rates (events per 100 person years) in the four arms were 1.08, 1.32, 1.73 and 3.41 respectively; thus short-term therapy with isoniazid or isoniazid/rifampicin reduced the risk of TB by over 60%, with few adverse effects. Anergic participants were randomised to isoniazid or placebo for 6 months. No significant protective effect of therapy was seen; the rates were 3.06 in the placebo group and 2.53 in the treated group.

Gordin (2000) enrolled 1583 HIV-positive people who had a 5mm of greater PPD skin reaction to receive either 300 mg of isoniazid daily for 12 months or a daily combination of rifampicin (600 mg) and pyrazinamide (30 mg/kg) for 2 months. After a mean follow-up of 37 months, there was no difference between the groups in the rate of TB per 100 patient-years (1.0 versus 1.1 respectively). Adverse events were more common in the two drug group (12.5% versus 0.7%), but this was not statistically significant. 80% of the two-drug group completed the course, versus only 68% of the isoniazid group.

Pape reported that isoniazid prophylaxis significantly reduced the risk of active tuberculosis in PPD-positive HIV-infected people, from 7.5 to 2.2 cases per 100 person years. Wadhawan found that daily isoniazid (600mg) reduced the incidence of tuberculosis from 11.3 to 2.6 cases per 100 patients years of follow-up in a study using a vitamin B complex as the control.

Gordin (1997) enrolled 517 anergic people at high risk of TB in a placebo-controlled study of isoniazid (300 mg) for six months. No significant difference in rates of development of TB was seen, largely because the number of cases was low even in the untreated group (6 vs. 3).

Chin reported that anergy skin testing is both insensitive and non-specific when used to diagnose infection with M.Tb in HIV-positive people.

Horn described the use of ofloxacin (800 mg/day) with pyrazinamide (1500 mg/day) in 16 health-care workers exposed to MDR-TB. The health-care workers were not HIV-infected. 14/16 discontinued prophylaxis before the completion of six months of therapy because of side-effects (arthralgia, GI distress, and others).

Research into TB in the age of HAART

Dheda (2004) compared outcomes in patients starting TB treatment before (n = 36) and after 1996 (n = 60). There was a lower risk of death after 1996 (22 vs. 43%, p = 0.012) and of death or having an AIDS event (43 vs. 69%, p = 0.023). HAART use was asociated with a reduction in the risk of an AIDS event (adjusted hazard ratio 0.38; 95% confidence interval 0.16, 0.91). Event risk was high in patients with CD4 cell counts <100 cells/mm³ (hazard ratio [HR] 3.42) and those who had had an AIDS-defining illness (HR 2.58).

Hung (2003) reported that HIV-positive patients with active TB, who receive anti-TB therapy and highly active antiretroviral therapy (HAART), are just as likely as HAART-treated HIV-positive patients without TB to benefit from antiretroviral therapy. Of 716 HIV-positive patients enrolled in a prospective study between 1994-2003, 125 developed TB. 276 people who had not previously taken anti-HIV treatments began therapy during the study, including 46 with TB. Despite a poorer baseline CD4 count and higher viral load, those with TB had a comparable response to anti-HIV therapy. 43.5% of the TB patients and 46.5% of the non-TB patients achieved viral load below 400 copies/ml at week 4. At 4 months, 38.2% of the TB patients and 25.7% of the non-TB patients were failing therapy - a non-signficant difference (p=0.14). TB patients were at greater risk of developing another AIDS-defining illness or death, especially during the early phase of anti-HIV treatment.

Motasim found that the use of HAART has the potential to reduce the incidence of TB by 80% in HIV-positive people. In a study comparing 294 HAART-treated individuals with 770 non-HAART patients treated at an HIV clinic in Capetown, Motasim found that the HAART-treated patients has an 80% lower incidence of TB despite having lower baseline CD4 cell counts (254 cells/mm³ versus 303 cells/mm³.

Serra found that a paradoxical reaction occurred in 21% of HIV-positive patients with TB treated with HAART. Lymph node enlargement was the most frequent form of TB reactivation (40%), followed by pulmonary TB (30%), lymph node enlargement and pulmonary TB (20%), and disseminated TB (10%). TB occurred a mean of 58 days after HAART initiation. Treatment was with predisone with recovery in a mean of 91 days. There were no deaths.

Research conducted by Marinho found that only 45% of HIV-positive individuals coinfected with TB and treated with an efavirenz-containing regimen achieved a viral load below 80 copies/mL. In addition, only 26% of those treated with a ritonavir/saquinavir-containing regimen achieved a viral load below 80 copies/mL. At baseline mean CD4 cell count was 223 cells/mm³ and mean viral load was 100,000 copies/mL.

Rolla's research established that patients receiving HAART and anti-TB therapy at the same time were no more likely to experience side-effects. The study included 147 patients with TB, 53% of whom were HIV-positive. The relative risk of side-effects occuring in HIV-positive patients was similar to that for HIV-negative individuals (0.96 versus 1.04, p=0.13). Amongst the HIV-positive patients, 37% of those treated with HAART experienced side-effects compared to 28.6% of HAART-naÔ¶e patients. The difference was not significant (p=0.93).

Souza Carvalho found that HIV-positive individuals with TB were no more likely to interrupt anti-TB therapy than HIV-negative patients.

Clarke's research in Rwanda/Zambia demonstrated with TB can be diagnosed in 90% of cases on the basis of symptoms including presentation with cough, chronic cough, night sweats and fever.

Cuellar found that NNRTI-containing regimens are safe and effective when used with anti-TB therapy including rifampin. After one year of anti-TB therapy and HAART 75% of patients treated with an NNRTI had a viral load below 400 copies versus 88% of controls (p=0.3).

Lopez-Cortes's research involving 63 HIV-positive patients with active TB found that a HAART regimen including a once-daily 800mg dose of efavirenz was safe and effective when administered at the same time as anti-TB therapy including rifampin. At baseline median CD4 cell count was 54 cells/mm³ and median viral load was 160,000 copies/mL. A total of 21 patients completed nine months of anti-TB therapy with a viral load below 50 copies/mL and a median increase in CD4 cell count of 220 cells/mm³. Virological failure was noted in five patients, four of whom had adherence below 75%. Treatment was withdrawn from six patients, attributable to efavirenz in two patients and anti-TB therapy in four.

Burman (2003) found that in a trial involving 169 HIV/TB coinfected patients, with low CD4 counts (average 90 cells/mm³) and high viral loads (average 5.3 log), HAART was successful at improving immune function and decreasing HIV replication when administered at the same time as anti-TB therapy consisting of rifabutin and isoniazid (with pyrazinamide and ethambutol for the first two months). Average CD4 count increased by 61 cells and viral load fell by an average of 1.6 log. TB therapy had a cure rate of 95%. When the investigators compared their findings with a pre-HAART study into TB treatment in HIV patients (CPCRA 019/ACTG 222), they found that although baseline CD4 counts were similar in both studies, survival was significantly better in TB treated patients post-HAART (85% versus 95%) after twelve months of TB treatment.

Patel (2003) conducted a study in the HIV care clinic in Ahmedabad, India, comparing CD4 counts in two groups of HIV patients. 99 patients were also coinfected with TB and received anti-TB therapy based on rifampicin, and 98 were just HIV-infected. Anti-HIV therapy consisted of efavirenz and either AZT/3TC or d4T/3TC. At baseline, CD4 counts were lower in TB patients (104 cells/mm³), but after six months of HAART and anti-TB treatment CD4 counts were approximately 280 in both groups. By month nine of the study, CD4 counts were higher in the patients receiving TB therapy (306 vs 270).

Redral-Samapio (2003) treated 44 HIV/TB coinfected patients with TB therapy (rifampicin and isoniazid for 9 months, with pyrazinamide for the first 2 months). HAART consisted of two nucleoside analogues plus efavirenz at 600mg daily. At baseline patients had an average CD4 count of 106 cells/mm³, a 6 log viral load and weighed 51 kg. After two years, average CD4 count had increased to 341 cells/mm³, viral load had fallen to 1.4 log and weight increased by 21 kg. 3 patients died in the first month of therapy, 2 due to an infection and one with treatment-related renal failure. Over 80% had resolution of TB and responded to HAART. Of the 9 treatment failures, 6 abandoned their therapy within 6 months.

Hollender (2003) tested pharmacokinetic drug levels were tested in 20 HIV-positive TB patients treated with rifabutin and efavirenz-containing regimens in an HIV clinic in Florida between June 2000 and September 2002. The dose of rifabutin was 300mg or 450mg twice weekly, with the efavirenz dose 600mg daily. Six patients were treated with a 300mg dose of rifabutin and 16 the 450mg dose. Blood levels of rifabutin were 0.17 and 0.50 at two and six hours pre-HAART on the 450mg dose and 0.16 and 0.21 at the same intervals two weeks after starting HAART. For the 300mg dose, two and six hour levels were 0.12 and 0.15 pre-HAART and 0.14 and 0.11 two weeks after starting anti-HIV therapy. Efavirenz levels at four and 24 hours were within expected ranges.

Navas conducted a retrospective chart review of all AIDS patients at the Ramon y Cajal Hospital with TB 1996-1998.139 people with HIV plus TB were identified and the study investigated 82 of these cases. 23% were treated with HAART, 44% with dual nucleosides and 33% did not take anti-HIV drugs during TB treatment. Four people on HAART had their first TB diagnosis while on treatment. Six people, who all began HAART during the first two months of TB treatment, had TB reactivation. Of these 10 cases, 8 had CD4 counts below 100. Of the remaining 9 cases of TB in people receiving HAART, no reactivation was seen and 8 had CD4 counts below 100. However, all began HAART after the third month of TB treatment.

Duval reviewed case charts of 6 antiretroviral naive men who were started on TB therapy and later on HAART. At diagnosis of TB, mean viral load was 5.3 log and mean CD4 count was 130. HAART was commenced approximately one month later. Four had a worsening of symptoms including increased fever and lymphadenopathy within 32 days of starting treatment. HAART was briefly discontinued in 3 people and steroid treatment was used in 2 cases. Among the 4, mean CD4 increase was 110 and their viral loads were below 500. The 2 who did not develop symptoms did not achieve undetectable viral load.

Narita compared 33 HIV-infected people treated with anti-TB and anti-HIV therapy (group 1), with 55 HIV-negative people treated for TB (group2) and 28 HIV infected people treated for TB but not on antiretroviral therapy (group3). The incidence of transient worsening of TB symptoms was 36% (12 of 33) in group 1 compared with 2% in group 2 and 7% in group 3. In people who experienced these paradoxical responses, tuberculin skin tests often converted from negative to strongly positive.

Dean found that amongst HIV-positive patients with TB in London, 39% of those presenting with TB and a CD4 cell count below 100 cells/mm³ would develop another AIDS-defining illness. Anyone with a CD4 cell count below 100 cells/mm³ at the time of TB diagnosis was recommended to start HAART immediately. However, patients taking HAART and TB therapy at the same time were found to be 90% more likely to develop side effects, with women twice as likely as men to experience adverse-events. 21% of HIV-positive patients receiving anti-TB therapy developed peripheral neuropathy, of whom 56% were taking HAART.

Martinez conducted research involving 50 patients who received NNRTIs as HIV therapy whilst on TB treatment. These patients had significantly better viral load control than patients who received a protease inhibitor, but the control of viral load exerted by the HAART regimen had no impact on the rate of TB cure.

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