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OUTLOOK HIV/AIDS 15 July 2010

Fighting Calmette-Guérin (BCG) TB vaccine can be


lethal in HIV-infected infants.
Many TB patients who were previously

the monster
improving with drugs relapse after starting
a course of immune-boosting antiretroviral
therapy, with a paradoxical reaction called
immune reconstitution inflammatory syn-
drome (IRIS). “It may be that as antiretroviral
Co-infection with HIV and tuberculosis is a potent drugs improve immunity, an inflammatory
reaction is directed at the mycobacterium caus-
combination. Amy Maxmen investigates the impact ing TB, and that reaction gives rise to the IRIS
of this deadly duo. symptoms,” says Graeme Meintjes, senior clini-

S
cal researcher at the University of Cape Town.
ayoki Mfinanga calls it “the monster” TB might be an important reason why HIV IRIS typically occurs two weeks after TB
for the way it wreaks havoc on a body. patients in the developing world suffer higher patients begin taking antiretroviral drugs. The
Co-infection with HIV and tubercu- rates of mortality after beginning antiretroviral lymph nodes in the neck swell, high fevers hit
losis (TB) can be devastating, trigger- therapy, says Steve Lawn, asso- and dry coughing begins. Some
ing rapid weight loss, severe pneumonia and, ciate professor of infectious “We consider patients develop abscesses,
often, a quick death. diseases and HIV medicine at co-morbidity of HIV stomach pain or kidney dam-
Treating both diseases simultaneously does the Desmond Tutu HIV Cen- and TB so prominent age. About one person in every
not improve matters, and in fact can cause fatal tre in Cape Town. Although ten who develop IRIS has men-
that it makes sense to
kidney and brain damage. “We don’t under- the probability of death after ingitis or inflammation of the
stand what happens when you combine TB the first 12 months of antiret- use HIV money for TB brain, and many of these people
and AIDS drugs,” says Mfinanga, director of roviral therapy is about 1.8% research.” die. Because definitions of IRIS
the Muhimbili Medical Center at the National in developed countries1, Lawn vary and there are no diagnostic
Institute for Medical Research in Dar es and colleagues found that the rate is as high as tests, reports of its frequency range from 8% to
Salaam, Tanzania. 26% in sub-Saharan Africa2. 43% of TB patients taking AIDS drugs3.
With weakened immunity, HIV-positive In May 2010, the Center for Global Health IRIS was first described in the mid-1990s,
patients are highly susceptible to TB, and TB Policy drew together leaders in US science but has become more common since. “There’s
makes HIV disease progress quicker. According policy and advocacy to discuss the alarming no question that the large-scale roll-out of
to a 2009 World Health Organization (WHO) increase in TB fuelled by HIV in the develop- antiretroviral therapy has helped millions of
report, there were more than 1.4 million cases ing world. “In 2008, TB killed more people lives, but to be blind to the consequences of
of TB–HIV co-infection worldwide, resulting than anytime in recorded history,” said Peter massive interventions, which are lifelong and
in about 0.5 million deaths in 2008. In sub- Cegielski, team leader for drug-resistant TB at delivered to a large proportion of your popu-
Saharan Africa, home to nearly 80% of those the US Centers for Disease Control and Pre- lation, is not helpful,” says Robert Wilkinson,
infected with both diseases, TB is the leading vention. “In sub-Saharan Africa, that’s purely professor of infectious diseases at the Univer-
cause of death for HIV-infected individuals. because of HIV.” sity of Cape Town.
The deadly fallout of co-infection is forc- In some cases, the immune-suppressing
Graeme Meintjes

ing officials to take notice — and revise their steroid prednisone can mitigate IRIS. Because
priorities. “We consider co-morbidity of HIV of the risk of side effects such as diabetes, high
and TB so prominent that it makes sense to use blood pressure and osteoporosis, however,
HIV money for TB research,” says Anthony prednisone should not be given for more than
Fauci, director of the US National Institute a few months. Worse, if prednisone is given to
of Allergy and Infectious Diseases. “In fact,” people who have drug-resistant TB or another
Fauci says, “what I’m planning to do is to uti- infection that could be mistaken for IRIS, it
lize some of our clinical trial networks that might exacerbate the condition.
were only for HIV to study TB alone and TB
with HIV.” Eye of the monster
One way to prevent IRIS might be in the tim-
Exacting its toll ing of antiretroviral therapy. Some clinicians
In the past few years, access to HIV medi- try to avoid IRIS by delaying antiretroviral
cines in the developing world has improved. drugs until after the patient has completed
As more individuals have begun taking the TB treatment, but a February 2010 report
drugs, however, they have faced unexpected of a controlled clinical trial in South Africa
complications. Interactions between drugs cast doubt on this strategy. The researchers
for HIV and TB can cause nausea, allergic reported that twice as many people died in
reactions and joint pain. Rifampin, which is the group that delayed taking antiretrovirals
the mainstay of TB treatments, weakens the as in the group that treated both diseases at
Many tuberculosis patients on the mend relapse efficacy of antiretroviral drugs such as pro- the same time4.
after taking antiretroviral drugs, developing tease inhibitors and the non-nucleoside inhib- This has stirred some controversy: in June
swollen neck glands and high fevers. itors efavirenz and nevirapine. The Bacillus 2010, other researchers challenged the study
S18 www.nature.com/outlooks
15 July 2010 HIV/AIDS OUTLOOK

JORGEN SCHYTTE/Still Pictures


Co-infection with TB–HIV (as in the woman being examined, above) can be devastating, triggering rapid weight loss, severe pneumonia and, often, a quick death.

design5, and questioned the influence of drug- adults in South Africa. Animal data sug- found that HIV and [multidrug-resistant] TB
resistant TB6 and other factors that contribute gest that it will be safe for infants with HIV, rates are going up, and the two things show a
to IRIS7. Three ongoing large trials are explor- Douglas says. Thus far, there have been no very clear association.”
ing the ideal time for those on TB treatment to serious adverse reactions in adults. David Drug-resistant TB takes longer to treat
begin antiretroviral therapy. McMurray, an immunologist at Texas A&M and requires treatments that are 50 to 200
Other researchers are testing various com- College of Medicine who is not affiliated with times more expensive. According to a 2010
binations of antiretroviral and TB drugs. For Aeras, says the vaccine “ought to be perfectly WHO report, the estimated cost of treatment
instance, Wilkinson’s team is assessing the safe in HIV-positive individuals.” Results are between now and 2015 will reach US$16.2
safety of combining HIV treatments with the expected before 2013. billion. Although new drugs to tackle resist-
TB drug isoniazid. The WHO recommends Clinical trials for HIV vaccines have not yet ant strains are being developed, it will take
isoniazid over rifampin for HIV-positive indi- been designed with TB patients in mind, how- many years for them to be affordable for the
viduals in areas of high TB prevalence who do ever. “A fundamental issue is that if someone majority. “In five years, there will not be new
not show signs of TB, although it has not been has an episode of TB and develops immune anti-TB drugs for use in developing countries
rigorously tested in this setting. dysfunction, will that affect the ability of that because the compounds in the pipeline won’t
Frustrated doctors say they hope that as individual to mount a response when they’re be ready until 2015 — if we’re lucky,” says
each new HIV or TB drug enters the market, given an HIV vaccine?” asks Clive Gray, Paul Nunn, coordinator of the WHO’s Stop
they will not need to scramble to learn how department head of HIV immunology at the TB Partnership.
co-infected patients react. National Institute for Communicable Diseases Perhaps answers will flow from recent
“We quite often sit at meetings where phar- in Johannesburg. “The way to answer that is investments by large organizations and insti-
mas try to convince us to use their [HIV] to do an HIV vaccine trial in people with tutes in rich countries. The Howard Hughes
drugs for South Africa, but unless the drugs immune memory to TB, but it’s not really on Medical Institute, for example, plans to invest
are compatible with pregnancy and TB, unless the agenda now.” US$60 million in its new research centre on
they are compatible with rifampin, they aren’t TB–HIV in South Africa, slated to open by
very useful for us,” says Linda-Gail Bekker, The spectre of drug resistance late 2012.
deputy director of the Desmond Tutu HIV Another looming threat is drug-resistant TB, Those with fewer resources do what they
Center. “They need to be tested in pregnant particularly in crowded hospital wards where can. Mfinanga’s group is trying to determine
women and TB patients — but that rarely hap- susceptible HIV-positive patients provide a res- the ideal timing for antiretroviral therapy in
pens, and often that’s an afterthought.” ervoir for resistant strains. This became appar- people infected with TB, knowing that it is
Some drug developers, however, are finally ent in 2006 at a hospital in Tugela Ferry, South small incremental advances in knowledge —
realizing the importance of developing TB Africa, where 52 of 53 HIV-positive individu- and not a knight in shining armour — that will
solutions that work for HIV-positive patients. als infected with extensively drug-resistant TB help slay the monster.  n
“You can’t use a TB vaccine worldwide on a died within a few months — many before they Amy Maxmen is a freelance writer in New York
massive scale and screen everyone in advance got the results from diagnostic tests. City.
for HIV — that’s impractical,” says Gordon Resistant strains of TB continue to sweep 1. Braitstein, P. et al. Lancet 367, 817–824 (2006).
Douglas, executive chairman of the Aeras through HIV clinics. “We used to think that 2. Lawn, S. D., Harries, A. D. & Wood, R. Curr. Opin. HIV AIDS
5, 18–26 (2010).
Global TB Vaccine Foundation, a non-profit HIV was in Africa and [multidrug-resistant] 3. Meintjes, G. et al. Lancet Infect. Dis. 8, 516–523 (2008).
organization that partners with companies to TB was in Russia — well, not anymore,” says 4. Karim, S. S. A. et al. N. Engl. J. Med. 362, 697–706 (2010).
develop TB vaccines. Gail Cassell, vice president for scientific 5. Wilson, D. & Meintjes, G. N. Engl. J. Med. 362, 2137 (2010).
6. Garcia-Vidal, C., Salvado, M. & Salavert, M. N. Engl. J. Med.
The clinical trial for one of Aeras’ lead can- affairs at Eli Lilly in Indiana. “In 2008, we did 362, 2137–2138 (2010).
didates, AERAS-402, includes HIV-infected big surveys in the Ukraine and in Latvia and 7. Kadhiravan, T. N. Engl. J. Med. 362, 2138 (2010).

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