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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the use of a placebo-controlled clinicaltrial design for research studies in infants.7,8 The criticism was eventually superseded by therealization that the study results could profoundly impact millions of lives of HIV-infectedpregnant women and their noninfected infants and could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: arthur.ammann@globalstrategies.org.
The author received no funding for this article.
No conflict of interest declared.
Copyright Ó 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 3. Chigwedere P, Seage GR, Lee TH, et al. Efficacy of antiretroviral drugs in in children than adults; the mortality in untreated HIV- reducing mother-to-child transmission of HIV in Africa: a meta-analysisof published clinical trials. AIDS Res Hum Retroviruses. 2008;24: infected infants was 50% by 1 year old age; immune recovery after treatment was better in young infants; bacterial infec- 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 deficiency virus programs in less developed settings. Am J Obstet development, are significantly greater when treatment is Gynecol. 2007;197(3 Suppl):S107–S112.
5. Volmink J, Siegfried NL, van der Merwe L, et al. Antiretrovirals for reducing the risk of mother-to-child transmission of HIV infection.
Now that ARV treatment is more accessible in countries Cochrane Database Syst Rev. 2007(1):CD003510.
where research studies for PMTCT and treatment of children 6. Connor EM, Sperling RS, Gelber R, et al. Reduction of maternal-infant are performed, optimal treatment for PMTCT in clinical transmission of human immunodeficiency virus type 1 with zidovudinetreatment. Pediatric AIDS Clinical Trials Group Protocol 076 Study research studies should include early initiation of HAART for Group. N Engl J Med. 1994;331:1173–1180.
all HIV-infected pregnant women, and continuation of 7. Lurie P, Wolfe SM. Unethical trials of interventions to reduce perinatal HAART during and after breastfeeding has ceased. Short transmission of the human immunodeficiency virus in developing courses of HAART, use of 1 or 2 ARVs, and premature countries. N Engl J Med. 1997;337:853–856.
discontinuation of HAART after exposure to HIV should be 8. Bonkovsky FO. Ethical issues in perinatal HIV. Clin Perinatol.
considered suboptimal treatment and prophylaxis. There is 9. Rouse DJ, Owen J, Goldenberg RL, et al. Zidovudine for the prevention of ample evidence at this time to conclude that single drug vertical HIV transmission: a decision analytic approach. J Acquir Immune treatment and prophylaxis consistently results in drug Defic Syndr Hum Retrovirol. 1995;9:401–407.
resistance; delayed initiation of treatment and short duration 10. Brocklehurst P, Volmink J. Antiretrovirals for reducing the risk of mother- to-child transmission of HIV infection. Cochrane Database Syst Rev.
of treatment consistently results in increased HIV trans- mission; and premature cessation of prophylaxis although HIV 11. Jackson JB, Musoke P, Fleming T, et al. Intrapartum and neonatal single- exposure continues results in increased HIV infection.3,16,52–55 dose nevirapine compared with zidovudine for prevention of mother- Clinical research trials, conducted within countries supported to-child transmission of HIV-1 in Kampala, Uganda: 18-month follow-up by international programs that provide HAART for the general of the HIVNET 012 randomised trial. Lancet. 2003;362:859–868.
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for PMTCT and treatment of children has not occurred quickly 14. Baldanti F, Paolucci S, Maga G, et al. Nevirapine-selected mutations enough in clinical research trials, placing too many HIV- Y181I/C of HIV-1 reverse transcriptase confer cross-resistance to infected women and HIV-exposed infants at risk.56 stavudine. AIDS. 2003;17:1568–1570.
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