As With HIV Treatment, Botswana Leads the Way With TB Prevention
BOTUSA Study Strongly Supports Continuous Preventive IPT for People With HIV
Tuberculosis (TB) remains the leading cause of death among people living with HIV. The World Health Organization's 2009 report Global Tuberculosis Control: Epidemiology, Strategy, Financing reported that in 2007, 1.4 million new cases of TB occurred in people living with with HIV/AIDS (PLWHA), and that it accounted for nearly a quarter of all deaths among the HIV-positive population. The high levels of mortality and the high burden of TB disease among people with HIV clearly points to the urgent need to fully implement interventions that can prevent TB transmission and the progression from TB infection to TB disease in PLWHA.
Among the interventions most clearly proven to be effective in preventing the progression of TB infection to disease are antiretroviral therapy (ART), which strengthens immune control of latent TB infection, and preventive therapy with isoniazid (INH), which directly eliminates the TB bacillus from the body and, while taken, may prevent reinfection. A six- to nine-month course of INH, a first-line TB drug, is one intervention that has been shown to be effective in preventing TB disease in people with HIV. Yet despite the mountain of evidence that shows the efficacy of isoniazid preventive therapy (IPT) in reducing risk for progression to TB -- especially in people with HIV -- the implementation of IPT programs is shamefully low. In 2008, countries reported to the World Health Organization (WHO) that only 4.1% of their estimated HIV-positive patients were screened for TB, and IPT was provided to just 0.2%.
The challenge of being able to rule out the presence of active TB among immune-compromised people with HIV is a significant barrier to the roll-out of IPT, since treatment of active disease with any monotherapy promotes the emergence of drug resistance. Several other issues need to be addressed to clarify how best to implement IPT: determining how best to rule out active TB disease; when to initiate treatment; whether there are important additive drug toxicities with ART; and determining the optimal duration and post treatment protective effect of IPT. In the past five years, new data have emerged that address these challenges. The WHO created an algorithm for the diagnoses of smear-negative and extrapulmonary TB to provide a roadmap to treat the disease among those without smear- or culture-confirmed disease, which includes all children and most people with HIV. Data from Brazil, South Africa, and Thailand have shown that IPT has an additive benefit when given before and alongside ART. Despite valid questions about how to best implement IPT, the lack of political will has been a major impediment to its roll-out. Instead of demonstrating leadership by using best practices to ensure access to IPT, most HIV and TB programs in high-TB/HIV-burden this effective and lifesaving therapy.
Breaking the mold of stagnation and inaction that has limited IPT in most countries, Botswana has carried out both a national scale-up of IPT among its HIV-positive population and a controlled clinical trial comparing 6 months versus 36 months (intended to be a surrogate for lifelong therapy) of IPT among people with HIV. Just as Botswana broke the mold and started providing universal access to ART for its HIV infected people in the early 2000s, in the later part of the decade they moved to implement IPT and study its utility to limit the impact of TB among those with HIV. This study was called BOTUSA. The leadership from the government of Botswana is commendable. Data from the BOTUSA study, conducted in Botswana in partnership with the U.S. Centers for Disease Control and Prevention, were presented at the 40th World Lung Health Conference in December 2009.
The BOTUSA study was conducted from 2004 to 2009 to answer the primary question of whether IPT taken for 36 months was more effective than a 6-month course in reducing risk of TB disease in people with HIV. This study also provided critical information for addressing other IPT-implementation-related issues. The study involved a sample size of 2,000 people, who were randomized to receive either 6 or 36 months of 300 mg of INH daily with 25 mg of vitamin B6. Of these 2,000 people, 821 were assigned to six months of IPT, and 834 to 36 months in the intent-to-treat analysis of the study, which is more likely to reflect the outcomes that can be expected in routine program settings.
The results of the study as reported on December 7, 2009, included:
Thirty-six months of IPT was more effective than 6 months and reduced the risk of TB disease by 56%.
The protective effect of IPT waned 6-7 months after the end of treatment in both the 6-month and the 36-month arms.
Adherence rates of IPT were high, at 78% at 31-36 months.
The rate of INH resistance was lower in the 36-month arm, at 14%, compared with 17% in the 6-month arm, providing additional data to show that IPT does not lead to greater INH resistance.
In people with HIV who had a negative tuberculin skin test (TST), the test commonly used to detect latent TB infection, 36 months of IPT alone reduced the risk of TB disease by 8%, but when given with ART, TB risk declined by 50%.
IPT reduced the risk of TB disease much more dramatically in TST-positive people. Thirty-six months of IPT alone reduced the risk of TB disease by 92% and by 96% when used in combination with ART.
The study results have significant implications for the roll-out of IPT. Findings from the study support treatment with IPT for up to 36 months. IPT should be given continuously, before and during ART, for at least 36 months and probably lifelong, or at least until a patient's CD4 count reaches and stays at 500 CD4 cells or higher, the threshold at which TB rates are roughly the same as those for people not infected with HIV.
IPT is clearly more effective in people with HIV who have a positive TST; thus, a TST would be useful to target IPT to those most likely to benefit. However, the TST is not routine in many program settings; it does not identify TB infection among those with low CD4 counts, it requires refrigeration, it requires the patient to return to the clinic within 72 hours to have the results read, and it could become an additional barrier to scaling up IPT. Therefore, it should be used when available, but when it is not, IPT should be given to all HIV-infected persons without active TB disease.
On January 25-27, 2010, the WHO convened an expert meeting to prepare guidelines for IPT and for intensified case finding. TAG and its activist colleagues participated avidly in the heated discussion to ensure that the strong data supporting the critical need for IPT scale-up were recognized by the global panel, which included several conservative TB progammers who were reluctant to "add to the health worker workload" despite the fact that it is easier for both patient and provider to give a single drug to a healthy person than four drugs for six months to someone who is sick, not to mention that 500,000 people with HIV die each year -- unnecessarily -- of TB, a disease which is clearly both preventable and curable. Now the burden is on various countries' HIV and TB programs to expedite uptake of IPT, along with intensified case finding, infection control, and ART, for TB prevention among people with HIV.
As the BOTUSA study shows, IPT can make a critical contribution toward reducing the burden of TB disease among people with HIV. IPT is a low-cost, relatively simple intervention that can save tens of thousands of lives. The WHO is revising its guidelines for IPT to support its uptake and has also clarified that IPT should be the responsibility of national AIDS programs, which need to work with TB programs and communities of people living with HIV and TB to ensure that IPT is implemented successfully and with high rates of continuation. As Botswana has shown both with ART and with IPT, strong political will at the country level, accompanied by bold action, is urgently needed in order to take full advantage of the protection that IPT offers people with HIV so that they do not continue to die of curable TB.
WHO and Stop TB Partnership. 2009 Tuberculosis Update Facts. Accessed February 7, 2010.
World Health Organization. Global Tuberculosis Control: A Short Update to the 2009 Report. Accessed February 17, 2009.