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10 How Can We Protect HIV-Infected Infants Against TB, if BCG is Not Given?
3.11 BCG Vaccination of HIV-Exposed, Uninfected Infants
protecting HIV-infected infants against TB disease would therefore be to make the
diagnosis of HIV infection as early as possible, and to institute cART as soon as
An alternative approach would be to offer isoniazid prophylaxis to HIV-infected
infants, as this has been shown to signiﬁcantly reduce mortality and the incidence of
TB in HIV-infected infants and children . However, a more recent double-blind,
randomized, placebo-controlled study of primary isoniazid prophylaxis for the
prevention of TB disease and latent infection in 452 young infants with perinatal
HIV-exposure, reported no beneﬁt . Many questions surrounding the proposed
practice remain unanswered, such as the emergence of resistance against this
cornerstone drug for the treatment of TB disease.
The question remains, could BCG be given to HIV-infected infants after commencing cART? If BCG-related disease were to be less severe after early cART, it
might be hypothesized that immune reconstitution would be adequate to allow safe
BCG vaccination, to protect these infants against severe forms of TB. Most experts
agree that testing this approach remains fraught with unacceptable risks, and that
approaches involving new vaccines may hold greater promise. These vaccines, which
contain speciﬁc antigens delivered in specialized viral vectors, or with directed
adjuvants, may prove safer and would constitute the most sustainable intervention . Some novel vaccine approaches involve recombinant BCG, such as rBCG
delta ureC hly ỵ . In animal models of immunodeciency this vaccine has proven
safer than the current BCG, suggesting promise for use in HIV-infected (or HIVexposed) infants (S.H. Kaufmann, personal communication). It should be noted that
BCG-IRIS appears as a signiﬁcant complication after commencing cART in HIVexposed infants. Therefore, the best test for safety would include an assessment of
whether safer, whole, viable mycobacterial vaccines could cause this complication;
however, no such animal models currently exist.
BCG Vaccination of HIV-Exposed, Uninfected Infants
HIV-exposed, uninfected infants may have systemic immune responses that
differ from those of infants born to HIV-uninfected mothers. Typically, the exposed,
uninfected infants demonstrate global T-cell activation and altered immune responses following exposure to multiple microorganisms [66, 67]. These factors may
contribute to the increased mortality and morbidity reported in exposed infants,
although other environmental factors, such as sociological compromise associated
with chronic household disease, are also likely to contribute in poor socioeconomic
environments. In addition, infants of HIV-infected mothers have a higher chance of
being exposed to TB, compared to HIV-unexposed babies [68, 69]. To determine
whether BCG can induce the immunity required by exposed, uninfected infants so as
to protect them against TB, vaccination-induced immunity was compared to that
induced in HIV-unexposed infants . No difference was found in speciﬁc immunity, as measured by a short-term intracellular cytokine assay, between these two
j 3 BCG Vaccination in the HIV ỵ Newborn
infant groups, which suggested that uninfected HIV-exposed infants would beneﬁt
from vaccination (Figures 3.3 and 3.4). These ﬁndings were in agreement with those
from another study, which showed no signiﬁcant differences in BCG-speciﬁc IFN-g
release, as measured by ELISA in seven-day whole-blood assays at the age of six
weeks . However, when these authors used puriﬁed protein derivative (PPD) as
the recall antigen for the same analysis, a lower IFN-g response was observed in
exposed HIV-uninfected infants.
A second important question relating to BCG in HIV-exposed, uninfected infants
is whether the vaccine would still be effective if administration were to be delayed
beyond the immediate newborn period, as recommended in high-resource areas.
The present authors group is currently examining this question in this population,
by investigating induced immunity. However, recent results from a study of HIVunexposed infants have suggested that vaccination-induced immunity may be more
optimal if BCG is delivered at 10 weeks of age rather than at birth. It was shown that, at
one year of age, the frequency of speciﬁc T cells induced by BCG (and particularly
polyfunctional T cells), as measured by a short-term intracellular cytokine assay, was
higher in infants who received their vaccine at 10 weeks of age (Figure 3.5). Thus, it
was hypothesized that BCG would be at least as effective in preventing severe
childhood TB if given to HIV-exposed, uninfected infants after the immediate
neonatal period, as when given at birth.
Figure 3.5 Frequencies of BCG-specific CD4 T
cells induced by vaccination at birth (n ¼ 25), or
at 10 weeks of age (Delayed vaccinated arm,
n ¼ 23), as measured at 50 weeks of age. The
whole-blood intracellular cytokine detection
assay briefly described in Figure 3.1 was used.
Responses >0.01% were considered positive.
The median is represented by the horizontal line,
the interquartile range by the box, and the range
by the whiskers. P-values indicate the statistical
level of significance, using the Mann–Whitney
BCG is a safe vaccine in HIV-uninfected infants, and prevents severe childhood TB.
In HIV-infected infants, the vaccine is associated with unacceptable safety risks, both
in the presence and in the absence of cART; however, public health policies favor
administration of the vaccine to all infants from low-resource settings who are born to
HIV-infected mothers, in order to protect the majority of infants – who will not be
infected by HIV – against severe TB. The risk of BCG disease following this routine
neonatal BCG vaccination would be reduced signiﬁcantly in settings where HIV and
TB are endemic, if programs to prevent the transmission of HIV from mothers to
infants, as well as TB control strategies, could be strengthened. Once an infant has
been diagnosed with HIV infection, the best approach to protect them against TB
might be to initiate cARTas soon as possible. As yet, many questions surrounding the
use of BCG in HIV-exposed and uninfected infants remain unanswered, however.
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Roy M. Gulick
Currently, a total of 25 FDA-approved drugs are available for the treatment of HIV
infection (Table 4.1; Figure 4.1). Approved antiretroviral drugs comprise six
mechanistic classes (in chronologic order of development): nucleoside analogue
reverse transcriptase inhibitors (NRTI); non-nucleoside reverse transcriptase inhibitors (NNRTI); protease inhibitors (PI); fusion inhibitors; chemokine receptor
(CCR5) antagonists; and integrase inhibitors (see Figure 4.2). Following the
successful development of combination antimicrobial treatment regimens for both
tuberculosis (TB) and Gram-negative bacterial infections, strategies for antiretroviral therapy evolved from monotherapy using single-nucleoside analogues during
the late 1980s to early 1990s, to two-drug combination therapy using dual
nucleoside analogues in the early to mid 1990s, and to three-drug combination
therapy using dual nucleoside analogues together with an HIV PI or an NNRTI,
beginning in the mid to late 1990s. The development of three-drug antiretroviral
therapy led to a marked decrease in HIV-related morbidity and mortality, with an
approximate 60% decrease in HIV-related deaths from 1995 to 1997, and a
continued decline thereafter.
Over the past 10 years, effective combination antiretroviral regimens became
more convenient, better tolerated, less toxic, and have demonstrated durable
virologic, immunologic, and clinical responses. The introduction of drugs with
activity against drug-resistant viruses and, in particular, the approval of three new
classes of antiretroviral drugs since 2003 – namely, fusion inhibitors, CCR5
antagonists, and integrase inhibitors – allows the design of effective treatment
regimens even for patients with drug-resistant viral variants, and also challenges the
current standard paradigms of HIV antiretroviral treatment. The development of
effective antiretroviral therapy has reduced HIV-related mortality to rates approaching that seen in the general population in developed countries [1, 2]. Worldwide, the
intersecting epidemics of HIV disease and TB pose challenges for the optimal