Optimal Versus Suboptimal Treatment for HIV-Infected
Pregnant Women and HIV-Exposed Infants in
Lehman et al1 study in this issue of J Acquir Immune Defic Syndr uses a randomized
trial design to compare the emergence of viral resistance in women receiving highly activeantiretroviral therapy (HAART) compared with zidovudine (ZDV) plus single-dosenevirapine (sdNVP) on the emergence of viral resistance. Treatment was initiated at 34weeks gestation and continued through 6 months of breastfeeding. Women whose CD4counts were greater than 500 cells per cubic millimeter or less than 200 cells per cubicmillimeter were referred elsewhere for additional evaluation. Allele-specific polymerasechain reaction assays identifying K103N and Y181C mutations showed low levels ofresistant virus in 75% of women treated with ZDV/sdNVP and only 8% of women treatedwith HAART. This study, along with other recently published studies, a Cochran Reviewof prevention of mother-to-child transmission of HIV (PMTCT) clinical trials andadditional reports at the 2009 Conference on Retroviruses and Opportunistic Infections,offer an opportunity to comment on the progress of clinical research studies for (PMTCT)especially in relation to how well clinical research studies integrate what is now knownabout optimal prevention and prophylaxis and what should currently be considered optimaltreatment in resource-limited countries to maximize efficacy and reduce the emergenceof HIV resistance.2–5
Historically, 1994 marked the year of one of the most important advances in HIV
prevention efforts. The National Institutes of Health–sponsored clinical research study(ACTG 076) conclusively demonstrated that ZDV, administered to HIV-infected pregnantwomen beginning at 14 to 34 weeks of gestation and given to formula-fed infants for 6weeks after birth, reduced HIV transmission by 66%.6 Criticism of the study after itspublication was based on ethical concerns regarding the use of a placebo-controlled clinicaltrial design for research studies in infants.7,8 The criticism was eventually superseded by therealization that the study results could profoundly impact millions of lives of HIV-infectedpregnant women and their noninfected infants and could accelerate interventions forPMTCT in resource-limited countries.9 Despite optimism, specific obstacles had to beovercome—ZDV was expensive, monotherapy was associated with viral resistance, healthcare infrastructure and prenatal care were inadequate, antiretroviral (ARV) drugs were inshort supply, and the need for breastfeeding resulted in continued infant exposure to HIV.
Additional solutions were required, especially in populations where formula feeding couldnot be safely substituted for breastfeeding. In response, numerous clinical research studieswere planned and executed to address the unique obstacles to prevent mother to child HIVtransmission worldwide.3,5,10
In 1999, a second breakthrough clinical research study for PMTCT brought
encouraging results suggesting that an abbreviated course of antiretroviral therapy (ART)could be used in resource-limited countries. The National Institutes of Health–sponsoredstudy, HIVNET 012, demonstrated that sdNVP, given to HIV-infected pregnant womenduring labor and delivery, and a single dose to their infants shortly after delivery, couldreduce HIV transmission by 50% even when breastfeeding was continued.11 Nevirapine wasinexpensive, stable without refrigeration, and could be easily administered by midlevel
From the University of California San Francisco Medical Center, San Francisco, CA. E-mail: [email protected]
The author received no funding for this article.
No conflict of interest declared.
2009 by Lippincott Williams & Wilkins
J Acquir Immune Defic Syndr Volume 51, Number 5, August 15, 2009
J Acquir Immune Defic Syndr Volume 51, Number 5, August 15, 2009
health care workers, birth attendants, or HIV-infected
the compelling advantages of early treatment approaches.
mothers.12,13 The study results were not without controversy,
Other international organizations have been more aggressive,
however, as it was shown subsequently that sdNVP was
recommending initiation of HAART in asymptomatic indi-
associated with a high rate of drug resistance.14,15
viduals at higher CD4 counts.21 Current recommendations for
Since 1994, more than 45 clinical trials have been
optimal prophylaxis are well defined and consist of HAART
conducted to evaluate maternal HIV treatment and prevention
administered for at least 4 weeks after exposure to HIV.22,23
for PMTCT in resource-limited countries. Due to the
At this point in the epidemic, there is consensus on the
economic and infrastructure constraints of resource-limited
principles that define optimal treatment and prophylaxis of
settings, many trials sought to identify the minimum short-
HIV infection, and it seems appropriate to ask whether
course ARV administration necessary for PMTCT before
participants in clinical trials for PMTCT in resource-limited
efficacy was lost, a curious twist in the history of clinical
countries are being offered the best available treatment.
research considering the magnitude and urgency of the HIVepidemic. One such study included an ultrashort ZDV regimen
1. HAART is the standard of care for the treatment of HIV
despite placing infants at high risk for HIV infection.
infection for children and adults.21,24,25
Predictably, the ultrashort arm was found to be inferior to
2. HAART is the standard of care for post exposure
longer treatment and resulted in a higher rate of perinatal HIV
transmission.16 Basically, a spectrum of studies included the
3. Suboptimal treatment (the use of fewer than 3 drugs) does
evaluation of various short-course combinations of ARVs for
not control HIV infection and increases viral resis-
PMTCT, when to initiate treatment during pregnancy, the
preferred duration for treatment during pregnancy, and
4. Interrupted treatment increases the potential for drug
duration of ARVs for women and their infants after delivery
resistance, viral rebound, opportunistic infection, mortality,
and subsequent response to treatment.27–31
Retrospectively, as clinical studies identify the advan-
5. Delayed treatment, either by initiating treatment at low CD4
tages of early uninterrupted treatment, ethical questions arise
counts or waiting until the patient is symptomatic, is
regarding the necessity for extensive clinical trials of various
associated with increased morbidity and mortality which
permutations of PMTCT regimen approaches, especially those
using reduced treatment in resource-limited settings. The
6. Early treatment with HAART and control of HIV infection
failure to apply the lessons learned from other clinical studies
decreases HIV transmission to sexual partners, lowers death
for treatment and prophylaxis for PMTCT and the overly
rates, prevents opportunistic infections, and decreases HIV
cautious approaches of leaders in global health placed too
transmission at the population level.20,32–36
many HIV-infected mothers and their HIV-exposed infants at
7. HAART reduces viral load, which is the major factor in
risk for disease progression including, reduced efficacy of
some ARVs due to viral resistance, continued high rates of
8. Continued use of ART while breastfeeding reduces HIV
viral resistance that may be transmitted to others, mother to
transmission and emergence of viral resistance.1,20,38,39
child transmission rates that did not match those in developed
Clinical research studies for PMTCT have not aggres-
countries, and unnecessarily high mortality rates in infants.
sively incorporated these principles into their study design
Current international HIV treatment and prophylaxis
in resource-limited countries. Initially, implementation of
guidelines recommend the use of HAART to maximize
PMTCT in resource-limited countries was hindered by the
efficacy and prevent the emergence of drug-resistant HIV.17,18
availability and expense of ARVs and inadequate infrastruc-
Guidelines and publications also recommend early initiation of
ture. As a result, clinical studies for PMTCT in breast-feeding
HAART at higher CD4 counts which has been shown in
populations continued to use suboptimal treatment and pro-
pediatric and adult studies to significantly reduce morbidity
phylaxis including the use of fewer than 3 drugs, interrupted
and mortality. Marked decreases in the cost and greater
treatment of mothers, shortened duration of treatment,
availability of ARVs along with persuasive clinical data shifted
shortened duration of prophylaxis, and initiation of treatment
the criteria for initiating optimal ART in resource-limited
at more advanced stages of HIV infection.40–44 Results of these
countries toward earlier treatment at higher CD4 counts.
studies were predictable and confirmed what had been
The change in recommendations was noted by those
previously demonstrated—HIV transmission rates to infants
who perform mathematical modeling to predict what might
increase with the use of suboptimal treatment for PMTCT and
happen if early diagnosis of HIV infection and more
mono or dual prophylaxis results in a higher risk of HIV
aggressive implementation of ART were to be initiated
transmission and drug resistance.16,45–49
simultaneously.19 This model suggested that HIV transmission
The consequences of the use of a suboptimal treatment
could be dramatically decreased and HIV seroprevalence
in clinical trials for the treatment of HIV-infected children was
reduced to ,
1% if HIV testing were coupled with immediate
highlighted when a recent clinical trial was halted because the
initiation of treatment regardless of CD4 count.19,20
mortality in the deferred (suboptimal) treatment arm signif-
Recent publication of guidelines by international
icantly exceeded that of the early treatment arm.50 The study is
organizations such as WHO have slowly shifted away from
an example of a clinical trial design for treatment of HIV-
recommendations to initiate treatment in only the most
infected children, which failed to acknowledge published
advanced cases of HIV infection to recommendations that
evidence that delayed treatment was not the optimal means for
are more consistent with current clinical data demonstrating
controlling HIV disease progression.51 Studies of HIV-infected
J Acquir Immune Defic Syndr Volume 51, Number 5, August 15, 2009
infants had demonstrated that HIV progressed more rapidly
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4. Sripipatana T, Spensley A, Miller A, et al. Site-specific interventions to
tions occurred at higher CD4 counts and are reduced by
improve prevention of mother-to-child transmission of human immuno-
HAART; and growth and development, including neurologic
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EXCEED EXPECTATIONS: “Pathology that Adds Value” Emergence of carbapenem resistant Enterobacteriaceae in South Africa Introduction Treatment A recent article in the Lancet highlighted the emergence of Many NDM-1 producers remain susceptible only to colistin and Enterobacteriaceae with resistance to carbapenems, conferred by tigecycline. A few isolates, mostly E. coli , retain a
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