Tuberculosis, public health and the need for ARVs

Tuberculosis remains the single greatest public health challenge associated with HIV worldwide. Despite widespread recognition of this fact, and clinical trials showing that interventions can help, for example, through providing isoniazid (INH) prophylaxis, few programmes exist to implement such measures.

The expert view, as presented at the IAS Conference in Paris this week by Dr Kevin De Cock of the US CDC in Kenya, is shifting to the position that only ARVs can be expected to make any fundamental difference to the picture. This was also the message from Dr Peter Mugyenyi of the Joint Clinical Research Centre in Kampala, Uganda, reviewing the state of knowledge on opportunistic infections, which are now a growing epidemic across Africa in the wake of HIV.

Dr De Cock defined "the new tuberculosis" as the epidemic driven by HIV, and distinguished it from the "old tuberculosis" seen in low-resource settings where HIV prevalence remains low, the TB seen in industrialised countries (mainly in ageing populations of foreign-born citizens), and the primary MDR TB epidemics seen in the former Soviet Union.

The new tuberculosis is driven by the increased risk of TB progression at all stages of HIV disease, more severe presentation, frequent recurrence, co-morbidity (TB seen in combination with opportunistic infections). The WHO global response of DOTS, he said, is failing in areas of high HIV prevalence. However, this failure was confined to HIV positive people; good DOTS programmes were still capable of controlling TB in HIV negative people in the same populations.

Among South African gold miners, for example, incidence had risen four-fold from 1993 to 1999 despite a model screening and treatment programme. Incidence among HIV negative workers has not, however, increased at all over the period (once age and silicosis, both risk factors for TB regardless of HIV status, are taken into account).

In Abidjan, Cote d'Ivoire, HIV negative TB has actually declined, but the increasing risk in HIV positive people has meant that overall TB rates have not declined at all. This points to the need for national TB control programmes to monitor their performance separately, for HIV positive and HIV negative people. Only the figures for HIV negative people can give useful information on TB DOTS programme performance.

Paradoxically, in the South African case, although incidence in HIV positive miners is much higher than in HIV negative ones, at any one time, fewer HIV positive people have smear-positive TB (i.e. are infectious). The reason is that HIV positive people with TB either die or come to medical attention much faster than those who are HIV negative. Most HIV transmission therefore occurs from HIV negative people despite the fact that most of the disease is suffered by HIV positive people. So although things are awful "they could have been worse" if HIV had increased the infectiousness of TB as well as its severity for the person suffering from it.

Effective treatment of active cases is still essential, but so is preventive therapy. INH therapy has been used remarkably little and with disappointing results due to lack of commitment, uptake and completion. The likelihood of this changing, given the demands of trying to implement ARV programmes, is low. But the evidence is still there, that it would help.

HAART does reduce death rates from tuberculosis, but with many problems due to drug interactions when HIV and TB need to be treated together. Researchers in the USA, Italy, Brazil and South Africa have all found substantial reductions in TB risk with ARV treatment, by about 80% although this risk remains higher than in HIV negative populations.

The potential exists for bad TB and HAART programmes to worsen rather than improve the TB burden in the longer term, by keeping people with inadequately treated TB alive for longer and giving more opportunities for the disease to spread to an ever growing population of people with moderate levels of damage to their immune system. However, in the near term he concluded that we will not reduce the impact of TB in Africa without the widespread use of HAART.

Unfortunately, present TB services are often understaffed and overstretched. For example, the head of the Kenyan national TB programme had said that in his view, there would not be any realistic possibility of TB services implementing HAART in that country. Control of cross-infection would also be an obvious problem, if TB patients and people with HIV were brought together to an even greater extent than already happened. Responsibility for treatment will have to be decentralised and extended, with aim broadened from control of smear-positive TB (which is the focus of the DOTS strategy) to reduction in illness and death and integration with HIV services.

Nonetheless, many TB treatment services are now virtual AIDS treatment services. Extension of testing for HIV is a critical issue. In 2003, everyone testing positive for TB or HIV should be tested for the other disease. Traditional interventions for TB control have not changed in half a century: these are no longer sufficient. Widespread HIV testing, surveillance by HIV status (only trends in HIV negative population can tell us whether the programme is effective), DOTS expansion, active case finding (household contacts, HIV-positive persons), and preventive therapy in HIV positive people were all justified and needed.

As Dr Mugyenyi observed, there is no sense in creating a separate and parallel medical service to treat HIV, and it will ultimately be necessary to integrate both HIV and TB treatment into a coherent primary care system.

Ultimately, said Dr De Cock, "TB with HIV is AIDS", and will only decline when AIDS is brought under control. Many challenges remain - but "what is needed first of all is a clear definition of our mission and our goals."

Indian researchers reporting on experience in using Cipla's Triomune (fixed dose combination d4T, 3TC, NVP) have found a significant rate of immune reconstitution disease, mostly due to tuberculosis. In a population of 994 people with HIV - mostly male - who are being followed in two clinics in Pune and Ahmedabad - 53 out of 96 "clinical events" recorded were classified as IRD - mostly due to TB (but also with cases of cryptococcal disease and herpes zoster). This was associated with starting treatment at a low CD4 count, which also defines a population in which TB skin tests are often not informative.

A similar pattern has been seen in Brazil (Serro), which confirms and adds to reports from Southern Africa. In Brazil, the usual pattern is that patients who had negative skin tests for tuberculosis before starting on HAART then present with symptoms including severe lymph node enlargement which turns out to be associated with TB. Management with prednisolone was successful, usually taking a month to resolve.

A South African study of hospitalised HIV positive children reported on infection with BCG and disseminated disease associated with it. Of 49 children tested, five showed evidence of BCG infection and two had disease, which was clinically indistinguishable from TB. All five children had been severely immunodeficient, but asymptomatic, at birth (Hesseling).

BCG is a live attenuated vaccine based on M. bovis, which causes TB in cattle. In July 2000 there was a change in BCG strains used in South Africa from Tokyo strain to a Danish strain intradermal vaccine. However, nothing was known about whether this would have an impact on HIV positive children.

In the five cases, only the Danish strain of BCG was found - 3 cases BCG alone, 2 cases combined BCG and TB. All had been infected with HIV around the time of birth. Only one of the five had access to HAART (and has survived), three others died or were lost to follow-up. In all five cases, right axillary adenitis was seen - in other words, the lymph node under the right arm pit swelled up. (BCG injections in South Africa are given into the right arm.) In the baby given HAART the symptoms appeared as an immune reconstitution syndrome, with an ulcer on her right arm.

Discrimination between BCG and TB may be difficult, and BCG does not respond well to standard TB treatment. Despite aggressive treatment, the patients didn't do well. Danish strain may be "more reactogenic" than Tokyo strain.

A limitation of the study was that they didn't do deep tissue biopsies so couldn't confirm disseminated disease in some cases.

While this confirms other previous reports, from Brazil, that disseminated BCG disease can occur among symptomatic HIV positive children, it does not provide a basis for changing the policy of universal immunisation of newborn babies. A population based study is now under way in South Africa in Western Cape to evaluate the extent of the risk, and it is recommended that all live attenuated vaccines used in high HIV prevelance countries should be assessed for the risk they pose to HIV positive children.