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10 How Can We Protect HIV-Infected Infants Against TB, if BCG is Not Given?

10 How Can We Protect HIV-Infected Infants Against TB, if BCG is Not Given?

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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

possible.

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 [62]. 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 [63]. 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 [64]. Some novel vaccine approaches involve recombinant BCG, such as rBCG

delta ureC hly ỵ [65]. 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.



3.11

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 [27]. No difference was found in specific immunity, as measured by a short-term intracellular cytokine assay, between these two



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68



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 [70]. 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

U-test.



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3.12

Conclusions



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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virus-infected mothers. Clin. Diagn. Lab.

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Kankasa, C., Semrau, K., Scott, N., Tsai, W.

Y., Vermund, S.H., Aldrovandi, G.M. and

Thea, D.M. (2005) Does severity of HIV

disease in HIV-infected mothers affect

mortality and morbidity among their

uninfected infants? Clin. Infect. Dis., 41,

1654–1661.

69 McNally, L.M., Jeena, P.M., Gajee, K.,

Thula, S.A., Sturm, A.W., Cassol, S.,

Tomkins, A.M., Coovadia, H.M. and

Goldblatt, D. (2007) Effect of age,

polymicrobial disease, and maternal HIV

status on treatment response and cause of

severe pneumonia in South African

children: a prospective descriptive study.

Lancet, 369, 1440–1451.

70 Van Rie, A., Madhi, S.A., Heera, J.R.,

Meddows-Taylor, S., Wendelboe, A.M.,



Anthony, F., Violari, A. and Tiemessen, C.

T. (2006) Gamma interferon production

in response to Mycobacterium bovis BCG

and Mycobacterium tuberculosis antigens

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185–195.



Part Two

Drugs



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4

HIV/AIDS Drugs

Roy M. Gulick



4.1

Introduction



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



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