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the use of a placebo-controlled clinicaltrial design for research studies in infants.7,8 The criticism was eventually superseded by therealization that the study results could profoundly impact millions of lives of HIV-infectedpregnant women and their noninfected infants and could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@example.com.
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
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.
12. Stringer JS, Chi BH. Extended nevirapine prophylaxis to prevent HIV
population or where optimal treatment of HIV infection is
transmission. Lancet. 2008;372:267–269.
available, should be obligated to provide the best available
13. Welty TK, Bulterys M, Welty ER, et al. Integrating prevention of
treatment within clinical research studies. The transition from
mother-to-child HIV transmission into routine antenatal care: the key
an economically based to an optimal efficacy-based rationale
to program expansion in Cameroon. J Acquir Immune Defic Syndr.
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.
At this juncture in the HIV epidemic, clinical research
15. Church JD, Omer SB, Guay LA, et al. Analysis of nevirapine (NVP)
studies for PMTCT should conform to high ethical standards
resistance in Ugandan infants who were HIV infected despite receivingsingle-dose (SD) NVP versus SD NVP plus daily NVP up to 6 weeks of
defined as the best available care and high efficacy standards
age to prevent HIV vertical transmission. J Infect Dis. 2008;198:1075–
defined as providing optimal treatment and prophylaxis as the
minimal intervention.56 To do less, provides an unintentional
16. Lallemant M, Jourdain G, Le Coeur S, et al. A trial of shortened
signal to international organizations and National Ministries of
zidovudine regimens to prevent mother-to-child transmission of humanimmunodeficiency virus type 1. Perinatal HIV Prevention Trial (Thailand)
Health that HIV-infected pregnant women and their infants
Investigators. N Engl J Med. 2000;343:982–991.
need not receive the same level of treatment and prophylaxis as
17. Working Group on Antiretroviral Therapy and Medical Management of
other HIV-infected or HIV-exposed individuals. Comparison
HIV-Infected Children. Guidelines for the Use of Antiretroviral Agents in
interventions should consist of treatment and prevention
Pediatric HIV Infection. February 23, 2009:1–139. Available at: http://
arms that seek to enhance efficacy beyond current optimal
aidsinfo.nih.gov/contentfiles/PediatricGuidelines.pdf. Washington, DC:DHHS; 2008. Accessed March 10, 2009.
treatment regimens although focusing on short-term and
18. WHO. Antiretroviral drugs for treating pregnant women and preventing
long-term safety evaluation of exposure to ARVs.39 Likewise,
HIV infection in infants: towards universal access. 2008. Available at: http://
international research efforts should focus on improving the
www.who.int/hiv/pub/guidelines/pmtct/en/. Accessed March 10, 2009.
science of implementation and identify ways to improve diag-
19. Granich RM, Gilks CF, Dye C, et al. Universal voluntary HIV testing with
immediate antiretroviral therapy as a strategy for elimination of HIV
nosis, access, adherence, and retention of women and infants
transmission: a mathematical model. Lancet. 2009;373:48–57.
while using the best available treatment and prophylactic
20. De Cock KM, Gilks CF, Lo YR, et al. Can antiretroviral therapy eliminate
regimens to reduce the continued unacceptably high numbers
HIV transmission? Lancet. 2009;373:7–9.
of perinatal HIV-infected infants in resource-poor settings.
21. Hammer SM, Eron JJ Jr, Reiss P, et al. Antiretroviral treatment of adult
HIV infection: 2008 recommendations of the International AIDS Society-USA panel. JAMA. 2008;300:555–570.
22. WHO. Post-exposure prophylaxis to prevent HIV infection. 2007.
1. Lehman DA, Chung MH, Mabuka JM, et al. Lower risk of resistance after
Available at: http://www.who.int/hiv/pub/prophylaxis/pep_guidelines/en/
short-course HAART compared with zidovudine/single-dose nevirapine
used for prevention of HIV-1 mother-to-child transmission. J Acquir
23. CDC releases detailed guidelines for PEP use. Agency focuses on
Immune Defic Syndr. 2009;51:522–529.
nonoccupational exposure. AIDS Alert. 2005;20:42–44.
2. Mofenson L. Overview of periantal intervention trials table. 2008.
24. WHO. Antiretroviral therapy for HIV infection in adults and adolescents.
Available at: http://www.womenchildrenhiv.org/wchiv?page=wx-resource&
2008. http://www.who.int/hiv/pub/guidelines/adult/en/. Accessd March
root=typ&cat=02&subcat=prov&rid=20-7854. Accessed March 10, 2009.
J Acquir Immune Defic Syndr Volume 51, Number 5, August 15, 2009
25. WHO. Antiretroviral therapy of HIV infection in infants and children:
mission of HIV type 1, Ivory Coast, 2003–2006. Clin Infect Dis.
towards universal access. 2006. Available at: http://www.who.int/hiv/pub/
guidelines/art/en/index.html. Accessed May 26, 2009.
42. Tonwe-Gold B, Ekouevi DK, Viho I, et al. Antiretroviral treatment and
26. Dybul M, Fauci AS, Bartlett JG, et al. Guidelines for using antiretroviral
prevention of peripartum and postnatal HIV transmission in West Africa:
agents among HIV-infected adults and adolescents. Recommendations
evaluation of a two-tiered approach. PLoS Med. 2007;4(8):e257.
of the Panel on Clinical Practices for Treatment of HIV. MMWR Recomm
43. Kilewo C, Karlsson K, Massawe A, et al. Prevention of mother-to-child
transmission of HIV-1 through breast-feeding by treating infants
27. Fox Z, Phillips A, Cohen C, et al. Viral resuppression and detection
prophylactically with lamivudine in Dar es Salaam, Tanzania: the Mitra
of drug resistance following interruption of a suppressive non-
Study. J Acquir Immune Defic Syndr. 2008;48:315–323.
44. Kumwenda NI, Hoover DR, Mofenson LM, et al. Extended antiretroviral
prophylaxis to reduce breast-milk HIV-1 transmission. N Engl J Med.
28. Eron JJ. Managing antiretroviral therapy: changing regimens, resistance
testing, and the risks from structured treatment interruptions. J Infect Dis.
45. Leroy V, Sakarovitch C, Cortina-Borja M, et al. Is there a difference in the
efficacy of peripartum antiretroviral regimens in reducing mother-to-child
29. Benson CA, Vaida F, Havlir DV, et al. A randomized trial of treatment
transmission of HIV in Africa? AIDS. 2005;19:1865–1875.
interruption before optimized antiretroviral therapy for persons with drug-
46. Phanuphak P. Ethical issues in studies in Thailand of the vertical
resistant HIV: 48-week virologic results of ACTG A5086. J Infect Dis.
transmission of HIV. N Engl J Med. 1998;338:834–835.
47. Shaffer N, Chuachoowong R, Mock PA, et al. Short-course zidovudine for
30. Danel C, Moh R, Minga A, et al. CD4-guided structured antiretroviral
perinatal HIV-1 transmission in Bangkok, Thailand: a randomised
treatment interruption strategy in HIV-infected adults in west Africa (Trivacan
controlled trial. Bangkok Collaborative Perinatal HIV Transmission
ANRS 1269 trial): a randomised trial. Lancet. 2006;367:1981–1989.
Study Group. Lancet. 1999;353:773–780.
31. Holkmann Olsen C, Mocroft A, Kirk O, et al. Interruption of combination
48. Taha TE, Kumwenda NI, Hoover DR, et al. Nevirapine and zidovudine at
antiretroviral therapy and risk of clinical disease progression to AIDS or
birth to reduce perinatal transmission of HIV in an African setting:
a randomized controlled trial. JAMA. 2004;292:202–209.
32. Lawn SD, Harries AD, Anglaret X, et al. Early mortality among adults
49. Wade NA, Birkhead GS, Warren BL, et al. Abbreviated regimens of
accessing antiretroviral treatment programmes in sub-Saharan Africa.
zidovudine prophylaxis and perinatal transmission of the human
immunodeficiency virus. N Engl J Med. 1998;339:1409–1414.
33. Williams BG, Dye C. Antiretroviral drugs for tuberculosis control in the
50. Violari A, Cotton M, Gibb D. Antiretroviral therapy initiated before 12
era of HIV/AIDS. Science. 2003;301:1535–1537.
weeks of age reduces early mortality in young HIV-infected infants:
34. Lawn SD, Myer L, Bekker LG, et al. Burden of tuberculosis in an
evidence from the Children with HIV Early Antiretroviral Therapy
antiretroviral treatment programme in sub-Saharan Africa: impact on
(CHER) study. Abstract WESS103. Presented at: Fourth International
treatment outcomes and implications for tuberculosis control. AIDS.
AIDS Society Conference on HIV Treatment and Pathogenesis; July 22–27,
35. Corbett EL, Marston B, Churchyard GJ, et al. Tuberculosis in sub-Saharan
51. Welch SB, Gibb D. When should children with HIV infection be started on
Africa: opportunities, challenges, and change in the era of antiretroviral
antiretroviral therapy? PLoS Med. 2008;5(3):e73.
treatment. Lancet. 2006;367:926–937.
52. Dabis F, Bequet L, Ekouevi DK, et al. Field efficacy of zidovudine,
36. De Cock KM, Fowler MG, Mercier E, et al. Prevention of mother-to-child
lamivudine and single-dose nevirapine to prevent peripartum HIV
HIV transmission in resource-poor countries: translating research into
transmission. AIDS. 2005;19:309–318.
policy and practice. JAMA. 2000;283:1175–1182.
53. Eshleman SH, Mracna M, Guay LA, et al. Selection and fading of
37. Janssen RS, Holtgrave DR, Valdiserri RO, et al. The serostatus approach
resistance mutations in women and infants receiving nevirapine to
to fighting the HIV epidemic: prevention strategies for infected
prevent HIV-1 vertical transmission (HIVNET 012). AIDS. 2001;15:
individuals. Am J Public Health. 2001;91:1019–1024.
38. Perez H, Vignoles M, Laufer N, et al. Low rate of emergence of nevirapine
54. Faye A, Le Chenadec J, Dollfus C, et al. Early versus deferred
and lamivudine resistance after post-partum interruption of a triple-drug
antiretroviral multidrug therapy in infants infected with HIV type 1. Clin
regimen. Antivir Ther. 2008;13:135–139.
39. Gray GE, Saloojee H. Breast-feeding, antiretroviral prophylaxis, and HIV.
55. Suksomboon N, Poolsup N, Ket-Aim S. Systematic review of the
efficacy of antiretroviral therapies for reducing the risk of mother-
40. Chi BH, Chintu N, Cantrell RA, et al. Addition of single-dose tenofovir
to-child transmission of HIV infection. J Clin Pharm Ther. 2007;32:
and emtricitabine to intrapartum nevirapine to reduce perinatal HIV
transmission. J Acquir Immune Defic Syndr. 2008;48:220–223.
56. WMA. World Medical Association Declaration of Helsinki: ethical
41. Coffie PA, Ekouevi DK, Chaix ML, et al. Maternal 12-month response to
principles for medical research involving human subjects. Available at:
antiretroviral therapy following prevention of mother-to-child trans-
http://www.wma.net/e/policy/b3.htm. 2004. Accessed March 9, 2009.
Bacterial lysate in the prevention of acute exacerbation of COPD and in respiratory Abstract: Respiratory tract infections (RTIs) represent a serious problem because they are one of the most common cause of human death by infection. The search for the treatment of those diseases has therefore a great importance. In this study we provide an overview of the currently available treatments for
Dott. Stefano Muzi MEDICO DI MEDICINA GENERALE Studio Medico Convenzionato con il SSN per la Medicina Generale Viale Po 58 E Pomezia (Campoascolano) 00040 Roma In caso di trattamento dei disturbi del ritmo cardiaco, è necessario monitorare la tiroide. L'amiodarone è un farmaco che contiene molto iodio, ampiamente prescritto per le malattie cardiache e che può modificare il funzionam