Three I's to reduce the burden of TB in people with HIV

This article originally appeared in HIV & AIDS treatment in practice, an email newsletter for healthcare workers and community-based organisations in resource-limited settings published by NAM between 2003 and 2014.
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Key activities that are critical to continued success of ART-scale up

This year, approximately 750,000 people with HIV will develop TB, mostly in sub-Saharan Africa. About 230,000 of them will die. Needlessly.

But TB is both a preventable and treatable illness so it does not have to be a death sentence in people with HIV.

There are three essential activities that all HIV programmes should be doing that could protect people with HIV from TB infection, help prevent active disease from developing, and identify active TB disease early and improve the chances of cure — the ‘Three I’s. These are:

  • Intensified case finding (ICF) for active TB: aggressive screening can lead to the early diagnosis of TB — improving the response to treatment and reducing the likelihood of it spreading to others. It also offers an opportunity to protect people with HIV who don’t yet have TB by:
  • Giving them Isoniazid preventive treatment (IPT): an antibiotic that could reduce their risk of developing active TB by 33-62%; and
  • By practicing TB infection control (IC): which involves measures that can reduce the spread of TB to vulnerable people with HIV, health care workers and the community.

Since World AIDS Day last year, HATIP has published special issues supported by the Stop TB Department of WHO that address each of Three I’s [HATIP’s # 96 on IPT, 104 and 105 on intensified case finding, and 109 on infection control]. In those articles, we noted some of the operational challenges involved in implementing these interventions in order to get our readers thinking about how to tackle such issues in their own setting. But challenges should not be seen as barriers — there have also been challenges scaling up HIV care and antiretroviral therapy (ART) in resource-limited settings but now ART is reaching over 3 million people, and HIV care is available for millions of people and families impacted by HIV.


active TB

Active disease caused by Mycobacterium tuberculosis, as evidenced by a confirmatory culture, or, in the absence of culture, suggestive clinical symptoms.

infection control

Infection prevention and control (IPC) aims to prevent or stop the spread of infections in healthcare settings. Standard precautions include hand hygiene, using personal protective equipment, safe handling and disposal of sharp objects (relevant for HIV and other blood-borne viruses), safe handling and disposal of waste, and spillage management.


A healthcare professional’s recommendation that a person sees another medical specialist or service.

drug resistance

A drug-resistant HIV strain is one which is less susceptible to the effects of one or more anti-HIV drugs because of an accumulation of HIV mutations in its genotype. Resistance can be the result of a poor adherence to treatment or of transmission of an already resistant virus.

extensively drug-resistant TB (XDR-TB)

A form of drug-resistant tuberculosis in which bacteria are resistant to isoniazid and rifampicin, the two most powerful anti-TB drugs, plus any fluoroquinolone and at least one injectable second-line drug. 

And yet, HIV programmes have been failing to take advantage of the key strategies to manage TB in people with HIV — and it is undermining those very HIV/AIDS services we have been working so hard to establish.

“The Three I’s need to be viewed as an essential and integral component of ART scale-up, and an integral part of universal access,” said Dr Kevin De Cock, the head of WHO’s HIV/AIDS Department. “You cannot leave these aspects out of all this, any more than you can patient monitoring or dealing with drug resistance for ARVs or some other essential component of the ART scale-up programme.”

He made these comments at the conclusion of a meeting on the Three I’s held in Geneva in early April, where treatment advocates, community representatives, HIV programme managers, HIV caregivers, and international and national policy makers and HIV CBO/NGO representatives from around the world put out a call to action to start implementing the Three I’s now.

This issue of HATIP reviews that three-day meeting, with brief summaries of the presentations made by experts in the field, and some of the challenges to scale-up identified by meeting participants during group discussions. But our primary focus will be on the meeting’s key outcomes, and the participant’s insights about how to speed implementation of the Three I’s, and the proposed concrete steps that can be taken to move this agenda forward on the global and local fronts.

Opportunities for HIV/TB collaboration

Opening the meeting, Dr De Cock stressed that the link between HIV and TB was first noted in the mid-1980s, “and between 1988 and 1993, I was working in West Africa and the association between these diseases just sort of hit you over the head,” he said. But, it took the outbreak of drug-resistant TB in New York in the early 1990’s to renew interest in TB as a global health issue.

Similarly, the outbreak of extensively drug resistant TB (XDR-TB) at an ART clinic in Tugela Ferry, South Africa has brought to the world’s attention the fact that HIV and TB is a particularly dangerous combination — jeopardising TB control efforts worldwide. The risk of XDR-TB to people with HIV is especially grave, as data suggest a greater than 95% mortality rate.

“This issue of XDR-TB and MDR-TB can be interpreted in a couple of ways,” said Dr De Cock. We can either say, ‘this is really quite serious,’ or you could interpret it as one of the most important events in public health in recent times. My own bias is toward that latter interpretation. If there’s one thing that can turn the AIDS epidemic into a pseudo-SARS epidemic, it will be the more visible spread - particularly to the Western industrialised world - of XDR-TB”

Urgent action is thus required to prevent, diagnose and treat TB in PLHIV, their families and communities — and with the ongoing scale-up of HIV services, it should be possible to address HIV/TB in a manner that is convenient for patients with or at risk of both infections.

Clear suggestions for how to better integrate TB and HIV care and treatment are presented in the Policy on Collaborative TB/HIV Activities, released in 2004 by the WHO Stop TB Department and Department of HIV/AIDS.

The policy recommends twelve key activities divided into four “policy-making level” actions required to set up, plan and monitor TB/HIV programme collaboration; five activities that TB programmes can perform to reduce the burden of HIV disease among people with TB (including providing them with HIV testing and counselling, HIV prevention services, and either directly providing or making certain that people with HIV/TB receive adequate and appropriate HIV care including cotrimoxazole prophylaxis and ART, when needed). Recently, national TB programmes (NTPs) have begun to make great strides towards the implementation of activities to reduce the burden of HIV disease in TB patients.

However, national AIDS programmes have not made as much progress adopting the remaining activities that are focused on people accessing HIV care and treatment services: the Three I’s.

The Rwandan example

But several countries have demonstrated that scale-up of these activities is possible. One country that serves as a model is Rwanda, and Dr Greet Vanderbriel of the International Center for AIDS Care and Treatment Programs (ICAP) gave a presentation on that country’s progress on behalf of Dr Jules Mugabo, MD of the Ministry of Health (MoH).

After consultations with key stakeholders, Rwanda’s TB/HIV policy was drafted and approved by the MoH in October 2005. Guidelines, training, TB screening tools and information education and communication materials were soon developed. Importantly, the HIV testing policy was modified to include provider-initiated testing and counselling for TB patients, TB and HIV recording and reporting tools were revised to include information on TB/HIV, and a system for monitoring and evaluation (M&E) of TB screening was developed and implemented.

The programme offers one-stop services so that TB patients who are identified as being HIV-positive can receive all their basic HIV services, including CD4 cell monitoring, cotrimoxazole and ART through their TB clinic while they are on TB treatment. Once the TB treatment is concluded they are referred and/or accompanied to the ART clinic where their care will continue.

Meanwhile, TB screening is offered to all HIV patients at programme entry and at each six-month follow-up visits. TB screening and HIV testing and counselling services are also offered to family members of index patient through home visits by peer educators.

By the end of 2007, 89% of TB patients were being screened for HIV, 61% of those with TB/HIV were receiving cotrimoxazole and 39% ART. TB screening is also high (88% in 25% of the national ART clinics) at enrolment into HIV services, with steady improvement in screening performance at follow-up visits as well.

Clearly access to ART must be improved, but another finding of the programme was that TB detection through ICF has been lower than expected, indicating a need to strengthen diagnostic capacity at health services and perhaps to adjust the TB screening tool to increase its sensitivity (see ICF below).

Another issue is that, at present, Rwanda is not routinely offering IPT to people who screen negative for TB — something that Dr Vanderbriel said they would have to revisit soon.

ICF— experiences in the field and challenges in the community

“ICF is the gatekeeper for everything else [IPT and IC],” said Dr Wafaa El-Sadr, of ICAP and Columbia University, “what happens next is the problem.” See HATIP 104 & 105). In addition, Dr El-Sadr said, ICF that leads to early diagnosis (and treatment) of TB could help reduce immune response inflammatory syndrome and improve outcomes on ART.

“We have clear reasons to intensify case finding,” agreed Ezio Santos-Filho, member of the Stop TB Coordinating Board and an HIV/TB treatment advocate. “It should be common sense — but it’s not.” The Brazilian activist speaks from experience: he has had TB twice.

Even though ICF is policy in most countries, so far that policy has not been translated into operational guidelines or standard operating procedures. Screening tools have not been standardised and screening is not occurring in all the appropriate settings — wherever people with HIV congregate or come into contact with health services.

According to meeting participants, programmes want more clarity on the best symptom complex to include on a TB screening tool that could be easily administered by trained lay healthcare staff.

One persistent question in some countries is whether chest x-rays should be required to exclude TB — in fact, in some Asian countries, clinicians rely upon them exclusively — although studies suggest that they miss a lot of TB cases. Studies where they have been added to symptom screens have yielded mixed results, some suggesting that they do not greatly improve sensitivity for TB, others suggesting that they do.

But chest-x-rays are rarely possible in most settings.“I find it hard to imagine a chest x-ray as a screening tool —it’s overwhelming if not impossible requiring it in most settings where we work because of the huge numbers of patients involved and because of the lack of availability of chest x-ray even for diagnostic purposes; as well as the need for repeated screening in individuals in HIV care and treatment,” said Dr El-Sadr.

Family contacts also need to be screened since TB can spread in the home. “TB is a family disease,” said Dr El-Sadr. “If you have one person in a household with TB, you’ll have others with TB infection.” However, screening in children is particularly difficult and existing history/symptom scoring systems perform poorly, especially in children who are malnourished or living with HIV. More research is desperately needed to improve TB diagnosis in children.

Another issue is that many programmes have resisted updating their standard TB screening tools that rely on questions about chronic cough (for 3 or more weeks) despite the fact it has been shown to be poorly sensitive as the single gatekeeper symptom for TB in people with HIV.

More sensitive screens that capture up to 90% of the patients with TB would be preferred, but they will dramatically increase the demand on laboratory services to diagnose TB. And, unless diagnostic services are co-located, or specimen transport systems are arranged, patient must be referred to another facility — which isn’t always effective.

“Referral systems are mostly on paper,” said Mr Santos-Filho. “When people have a positive screen, what do we do? If they are referred somewhere else for diagnosis, are they properly encouraged? Do they have the means? People do not have money to go the TB clinic that may be far away. For instance, in Mexico City, the brand new HIV centre doesn’t do microscopy so people have to travel two hours by bus or do a culture.”

And yet there are models where ICF has been scaled up successfully, such as in India’s voluntary testing and counselling clinics, which Dr Puneet Dewan described to the Three I’s participants (a similar presentation was covered in HATIP 105). In addition, Dr Dewan described a more recent collaboration between the national TB programme and Avahan — a Gates Foundation-supported network of NGOs, in which STI clinic staff, outreach staff and peer educators have been trained to perform routine symptom screening.

One of the meeting participants, Dr Kudur Prakash, Deputy Director of the SANKALP Project in Bangalore, works with this network, and said that the outreach workers bring patients into clinics for TB screening, and then there will either be an accompanied referral to the nearest microscopy centre, or the sputum can be collected in the clinic and transported to the lab.

“There’s beginning to be an effort to try to reach beyond the walls of the facilities to reach people at home,” said Dr El-Sadr. “There’s a lot of potential to use the systems for support, care and treatment for HIV for case finding in households — there are lots of motorcycles and bicycles out there, peer workers going out to the homes, outreach workers trying to ensure that people are brought back in for services. It is potentially possible to layer case-finding within the community using this incredible workforce.”

IPT to prevent active disease and the further spread of TB

IPT is currently recommended by WHO for all people living with HIV (PLHIV) in areas with a prevalence of latent TB infection >30%, and for all PLHIV with documented latent TB infection or exposure to an infectious TB case, regardless of where they live. More recently, evidence has shown that the combined use of isoniazid preventive therapy and antiretroviral therapy among people living with HIV significantly reduces the incidence of TB; and the use of IPT in patients who have successfully completed a course of TB therapy has been shown to markedly reduce the risk of subsequent TB cases.

But when Dr Paul Nunn of the Stop TB Department asked meeting participants whether they thought that IPT was official WHO policy, there was confusion in the crowd — and later many participants said that there are mixed messages coming from within WHO and from other technical advisory groups about IPT. Dr Nunn also noted that currently only 82 countries have IPT policies — and that “there’s clearly a disconnect between policy and implementation, as a result of which implementation is low.”

The only country which has implemented its IPT policy in people with HIV is Botswana, and Ntukunu Makubate, of the BotswanaNational IPT Programme gave a presentation on that country’s experience. As  described in HATIP #96, the large programme had challenges with problems with recording and data entry and high levels of incomplete data. Large numbers of patients never came back for their final clinic visit, so it is impossible to say whether they completed treatment. Makubate believes that many did — it’s just that Botswana’s population is so highly mobile that people are often in a different part of the country at the end of the treatment course. “Batswana often have 4 homes: one in the city, in the ancestral village, the kraal where they keep their cattle, and then at the fields that they plough,” she said.

Her colleague, Dr Ndwapi Ndwapi, Operations Manager of Botswana’s ART programme said that the electronic database and monitoring and evaluation system “should be in place from the start.” He also believes that IPT should be integrated into the HIV treatment guidelines, joint planning and training and supervision “rather than trying to fitting this into an already crowded training field.”

“I’d like to point out that lack of adherence or falling off with prophylaxis is not a disaster for public health, like the lack of adherence to HIV treatment is, because people have latent disease or no disease and so they can’t get resistant or fail,” said Mark Harrington of the Treatment Action Group, who gave a presentation tackling some of the excuses against IPT implementation. But first he talked about his personal experience.

“I look forward to my annual TST because it gives me the opportunity to find out if I need INH. I’ve been on a protease inhibitor-containing regimen since 1996, and if I had gotten active TB, I’d have to switch regimens. So I would much rather be on INH for 9 months or even a year because I wouldn’t have to switch my ART regimen.”

He acknowledged that community activist groups and PWA groups have not done enough to educate their peers about IPT and create demand. But he took TB programmes to task for deriding IPT and said that most of their excuses against IPT implementation had little scientific basis.

“One of the major areas of resistance to adoption of IPT policy, is the fear of drug resistance - particularly by TB programme managers and/or those with control over the INH, but usually it’s the TB programme managers,” Dr Nunn said. “So they’ve got their hands on the INH tap and they don’t want to turn it because of fear of drug resistance - a fear which has never actually been proven to be an issue.”

Mark Harrington pointed out that there was a greater risk of resistance in people with active disease — and “concerns about excluding active disease before using IPT could be addressed by scaling up ICF and WHO’s algorithm for the diagnosis of smear-negative and extrapulmonary TB,” he said.

Indeed failure to roll out IPT is directly linked with the failure to implement ICF, and insecurity about the reliability of screening tools and algorithms to exclude active TB at the primary care level — and quite often, whether the use of chest x-rays is required to detect some cases of active TB. There are fears that if cases of active TB are missed, suboptimal treatment could lead to drug resistance. But Mark pointed out quite accurately that most breakthrough cases respond to standard treatment, although that data set is small.

In addition, people have called for more guidance on technical issues such as how to manage toxicity; how to ensure adherence and retain patients in care (particularly well patients that HIV programmes have yet to effectively target).

But Harrington stressed that standard TB treatment is more toxic, and yet it is used, and that ART programmes could adapt ART adherence support mechanisms to help people finish their IPT course.

In general the sense of the meeting participants was that the benefits of IPT far outweigh its potential risks. Also, since IPT is targeted towards ‘well’ patients, who are also frequently given cotrimoxazole, many participants thought that co-formulations or co-packaging the two drugs might be beneficial.

“There is absolutely no reason why cotrimoxazole and isoniazid cannot be co-formulated,” said Dr Charlie Gilks of the HIV Department. “And programmatically, there are a lot of advantages in putting the two together.”

Infection control

TB infection control (IC) measures are essential to prevent the spread of M. tuberculosis tovulnerable patients, health care workers, the community and those living in congregate settings. Fundamentally, TB infection control is about safety — people receiving or offering HIV care should not have to worry about being exposed to TB in the process. In light of the crisis of drug-resistant TB in countries with a high burden of HIV, establishing facilities that are safe from TB has become an emergency situation for health services, prisons and other congregate settings, in general, but especially for HIV programmes.

Guidance on TB IC measures, including administrative controls (good workplace practicing such as triaging coughing patients), environmental (good ventilation) and personal respiratory protection have been produced by WHO and the CDC (see Resources).

However, Phillip Mokoena of the Treatment Action Campaign in South Africa said awareness of TB IC is very low in the community and that treatment literacy efforts were urgently needed to create awareness in the community about the importance of infection control.

The group discussions about TB IC were particularly involved.

“TB IC is a health systems issue that nobody clearly owns; and within public systems there are often multiple or unclear lines of authority to enact and enforce policies and standards. In some settings there may be multiple ministries involved who would be responsible for the healthcare facility,” said Dr Puneet Dewan.

“Most of the engineering solutions are outside of the area of expertise of most people working in healthcare; and there is a short supply of technical experts particularly in resource-limited settings,” said Dr Bess Miller of USAID.

Dr Liz Corbett of the London School of Hygiene and Tropical Medicine noted that “few countries have any concept of TB as an occupational safety hazard” and that the facility-level administrative controls are neglected, without dedicated accountable staff. In addition there is a lack of clear simple operational guidance on basic TB IC for those working in existing health settings, especially small facilities or community based organisations servicing people with HIV/TB. Other technical issues such as commodity/supply chain issues, waste management, and laboratory safety must also be addressed.

Key recommendations of the meeting participants

However, the meeting created new impetus to integrate the Three I’s as part of improved healthcare delivery services for people living with HIV. There was clear consensus on several key outcomes:

As Dr De Cock emphasised, the Three I's (ICF, IPT, IC) need to be promoted and adopted as an essential part of the HIV treatment and care package just like the provision of cotrimoxazole. The WHO 1998 IPT policy should be re-conceptualized and updated by the end of the year to recommend implementation of the Three Is with an emphasis on TB screening with a standardised WHO screening tool as an essential part of HIV care. Whenever people with HIV are screened for TB, they should either be identified as someone needing diagnostic evaluation for TB or other HIV-related conditions, or they should get IPT.

The policy must make it clear that the HIV programme is responsible for the Three I's and in particular IPT and ICF implementation. Policies should also be developed for the Three I's in congregate settings, including households, prisons, mines and the community, and targets should be set for implementation.

The key policy outcomes are described by the official meeting report (see The following section describes more of the meeting participants’ discussions concerning how those outcomes may be put into operation.