E-DRUG: NEJM: Pediatric HIV - A Neglected Disease?
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http://www.nejm.org/doi/full/10.1056/NEJMp1107275
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PERSPECTIVE
Global Health
Pediatric HIV A Neglected Disease?
Marc Lallemant, M.D., Shing Chang, Ph.D., Rachel Cohen, M.P.P., and Bernard
Pecoul, M.D., M.P.H.
N Engl J Med 2011; 365:581-583
August 18, 2011
The results of the HIV Prevention Trials Network 052 (ClinicalTrials.gov
number, NCT00074581) study were released this past May, 30 years after the
first publication about U.S. cases of what would come to be called AIDS. The
new study's stunning results earlier treatment of human immunodeficiency
virus (HIV) infection leads to a 96% reduction in the risk of HIV
transmission within sero-discordant couples will influence guidelines in
the direction of even earlier initiation of antiretroviral therapy.1 The
notions of test and treat and treatment as prevention come as no
surprise to anyone who has been involved in the fields of prevention of
mother-to-child transmission of HIV and pediatric HIV care.
Fifteen years after the first study demonstrated the remarkable efficacy of
zidovudine in reducing mother-to-child transmission of HIV, perinatal HIV
has been virtually eliminated in high-income countries. In the countries
most affected by HIV, however, particularly those in sub-Saharan Africa and
Asia, prevention coverage remains appalling. The failure to implement
prevention programs for mother-to-child transmission on an appropriate scale
has resulted in hundreds of thousands of preventable HIV infections among
newborns. Each day, more than 1000 children are newly infected with HIV (see
map Number of New HIV Infections among Children, 2009.), and an alarming 700
die from AIDS-related complications.
In pediatric HIV care, test and treat strategies have been on the research
and implementation agenda for more than 10 years. The Children with HIV
Early Antiretroviral Therapy (CHER) trial in South Africa, which compared
immediate treatment of HIV-infected newborns with treatment initiated on the
basis of immunologic decline or clinical symptoms, demonstrated the survival
benefit of immediate initiation of antiretroviral therapy, which reduced
early mortality by 76%.2 Yet as of the end of 2010, less than one third of
children who needed antiretroviral therapy were receiving it. Without
treatment, one third of children born with HIV die before their first
birthday; 50% die before they turn two.
There are many reasons for this unacceptable state of affairs. One of the
most glaring and yet often overlooked is that treatment options for
children, particularly the youngest and most vulnerable, are insufficient.
Pharmaceutical companies have invested little in ensuring the safety and
efficacy of antiretroviral use in children or in developing
child-appropriate drug formulations. Children with HIVAIDS in low- or
middle-income countries are a largely neglected population.
Vertical transmission of HIV is preventable, and in wealthy countries
effective interventions for preventing mother-to-child transmission have
virtually eliminated HIV infections in newborns. In low- and middle-income
countries, however, there are numerous barriers to prevention: antenatal
care attendance is low, particularly in rural areas; too few pregnant women
have access to HIV testing; access to optimal antiretroviral prophylaxis or
therapy is insufficient; and alternatives to breast-feeding are uncommon. In
its 2010 progress report, the World Health Organization (WHO) indicated that
only one quarter of pregnant women had received an HIV test, and among those
identified as HIV-infected, only half received any antiretroviral
prophylaxis during pregnancy or at delivery.
Diagnosing HIV infection in infants is also a major challenge in
resource-limited settings. WHO guidelines recommend HIV testing of exposed
infants as part of routine care, as early as 6 weeks of age. But in most
HIV-exposed children in resource-limited settings, the infection can be
diagnosed with serologic testing only after 15 to 18 months of age, when
maternal antibodies have disappeared from the child's blood. Waiting until a
child is 18 months old means that as many as half of infected children will
die before their HIV status is even known.
In high-income countries, kits for HIV DNA or RNA polymerase chain reaction
(PCR), considered to be the gold standard for diagnosis of HIV in infants,
are commonly used. In resource-poor areas of Africa and Asia, their
availability is largely limited to clinical research settings because of
prohibitive costs and the need for laboratory infrastructure and trained
personnel.
Researchers have developed alternative virologic tests using real-time PCR
and dried blood spots on filter paper for sample collection, which can be
transported from remote areas to central laboratories. Early diagnosis of
HIV in infants is therefore within reach, although it has yet to be widely
implemented. Still, better-adapted diagnostic tests that can be used at the
point of care are needed to ensure that diagnosis is possible in early
infancy even in the most remote and rural settings.
The WHO recommends immediate antiretroviral therapy for all HIV-infected
children less than 2 years of age.3 But the safety and appropriate dosing of
many of the key antiretroviral agents used in adults have not yet been
established in children, particularly in younger age groups, and appropriate
formulations simply do not exist for children.
The most commonly used regimen in children in resource-limited settings is a
fixed-dose combination of stavudine, lamivudine, and nevirapine. But
stavudine is no longer preferred because of toxicity concerns, and
nevirapine is not recommended for children who have been exposed to
nevirapine for the prevention of mother-to-child transmission, since the
virus may have developed resistance.
The results of two recent studies4,5 generated strong evidence that
protease-inhibitorbased therapies such as zidovudine, lamivudine, and
lopinavir boosted with ritonavir should be used extensively in
HIV-infected infants. However, this combination of three separate liquid
formulations is impractical for caregivers, is unpalatable for children,
requires refrigeration, and owing to drug interactions, is difficult to
manage in cases of coinfection with tuberculosis. Improved first-line
therapies for children are urgently needed.
In 2010, our organization, the Drugs for Neglected Diseases initiative
(DNDi), a not-for-profit research and development organization that develops
new drugs for neglected diseases such as human African trypanosomiasis,
visceral leishmaniasis, Chagas' disease, and malaria, was called on by
various organizations, including Doctors Without Borders (Médecins sans
Frontières) and the international drug-purchase organization UNITAID, to
apply its expertise to the development of pediatric HIV drugs.
In consultation with experts from countries where HIV is endemic (including
South Africa, Ivory Coast, and Thailand), major research institutions, and
international and nongovernmental organizations, DNDi developed ideal and
acceptable specifications for desired formulations or combinations of
pediatric antiretroviral drugs and identified priorities for acceleration of
clinical studies in infants.
There was consensus around the need to develop an improved first-line
regimen for infants, irrespective of prior exposure to antiretrovirals.
Ideally, this new first-line pediatric therapy needs to be easy to
administer and better tolerated by children than current drugs. The ideal
formulation would be palatable, heat-stable, easily dispersible, and
administered once daily or less. It must also carry minimal risk for the
development of resistance and be suitable for infants and young children (<2
months to 3 years of age), with minimum requirements for weight adjustments.
Finally, any new drug must be compatible with tuberculosis drugs and,
especially, affordable.
When it comes to research and development, it is difficult to see HIV
therapeutics as a neglected field. Since HIV was first discovered, more than
20 antiretroviral drugs and several additional antiretroviral combinations
have been approved for the treatment of HIV, and today there remains a
robust pipeline of new products in development.
Yet there is no such pipeline for pediatric HIV. Because it has been
virtually eliminated in wealthy countries, pharmaceutical companies have
little incentive to develop child-appropriate formulations.
Children with HIVAIDS in low- and middle-income countries are not considered in the HIV
research and development agenda because they are poor and voiceless and do
not represent a lucrative market in the traditional sense. Although every
effort should certainly be made to eliminate new HIV infections in children
in low- and middle-income countries, we must not forget the millions of
children already living with HIVAIDS and those who will become infected
in the coming years who urgently need improved, affordable, and
appropriate treatment.
Disclosure forms provided by the authors are available with the full text of
this article at NEJM.org.
SOURCE INFORMATION
From the Drugs for Neglected Diseases initiative, Geneva (M.L., S.C., B.P.)
and New York (R.C.); and the Institut de Recherche pour le Développement
Programs for HIV Prevention and Treatment, Chiang Mai, Thailand (M.L.).
REFERENCES
1. Treating HIV-infected people with antiretrovirals protects partners from
infection: findings result from NIH-funded international study. Bethesda,
MD: National Institute of Allergy and Infectious Disease, May 12, 2011.
(The page you’re looking for isn’t available | NIH: National Institute of Allergy and Infectious Diseases)
2. Violari A, Cotton MF, Gibb DM, et al. Early antiretroviral therapy and
mortality among HIV-infected infants. N Engl J Med 2008;359:2233-2244
Full Text | Web of Science | Medline
3. Antiretroviral therapy of HIV infection in infants and children: towards
universal access: recommendations for a public health approach 2010
revision. Geneva: World Health Organization, 2010.
4. Palumbo P, Violari A, Lindsey J, et al. NVP- vs LPV/r-basedART among HIV+
infants in resource-limited settings: the IMPAACT P1060 Trial. Presented at
the 18th Conference on Retroviruses and Opportunistic Infections, Boston,
February 27March 2, 2011.
5. Coovadia A, Abrams EJ, Stehlau R, et al. Reuse of nevirapine in exposed
HIV-infected children after protease inhibitor-based viral suppression: a
randomized controlled trial. JAMA 2010;304:1082-1090
CrossRef | Web of Science | Medline
--
Rachel M. Cohen
Regional Executive Director
Drugs for Neglected Diseases initiative (DNDi), North America
40 Wall Street, 24th Floor, New York, NY 10005
Mob: +1.646.824.3064
Office: +1.646.616.8683
Email: rcohen@dndi.org
Web: www.dndi.org