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 active antiretroviral therapy (HAART) compared with zidovudine (ZDV) plus single-dose nevirapine (sdNVP) on the emergence of viral resistance. Treatment was initiated at 34 weeks gestation and continued through 6 months of breastfeeding. Women whose CD4 counts were greater than 500 cells per cubic millimeter or less than 200 cells per cubic millimeter were referred elsewhere for additional evaluation. Allele-specific polymerase chain reaction assays identifying K103N and Y181C mutations showed low levels of resistant virus in 75% of women treated with ZDV/sdNVP and only 8% of women treated with HAART. This study, along with other recently published studies, a Cochran Review of prevention of mother-to-child transmission of HIV (PMTCT) clinical trials and additional 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 known about optimal prevention and prophylaxis and what should currently be considered optimal treatment in resource-limited countries to maximize efficacy and reduce the emergence of 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 pregnant women beginning at 14 to 34 weeks of gestation and given to formula-fed infants for 6 weeks after birth, reduced HIV transmission by 66%.6 Criticism of the study after its publication was based on ethical concerns regarding the use of a placebo-controlled clinical trial design for research studies in infants.7,8 The criticism was eventually superseded by the realization that the study results could profoundly impact millions of lives of HIV-infected pregnant women and their noninfected infants and could accelerate interventions for PMTCT in resource-limited countries.9 Despite optimism, specific obstacles had to be overcome-ZDV was expensive, monotherapy was associated with viral resistance, health care infrastructure and prenatal care were inadequate, antiretroviral (ARV) drugs were in short supply, and the need for breastfeeding resulted in continued infant exposure to HIV. Additional solutions were required, especially in populations where formula feeding could not be safely substituted for breastfeeding. In response, numerous clinical research studies were planned and executed to address the unique obstacles to prevent mother to child HIV transmission 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-sponsored study, HIVNET 012, demonstrated that sdNVP, given to HIV-infected pregnant women during labor and delivery, and a single dose to their infants shortly after delivery, could reduce HIV transmission by 50% even when breastfeeding was continued.11 Nevirapine was inexpensive, stable without refrigeration, and could be easily administered by midlevel health care workers, birth attendants, or HIV-infected mothers.12,13 The study results were not without controversy, however, as it was shown subsequently that sdNVP was associated with a high rate of drug resistance.14,15
Since 1994, more than 45 clinical trials have been conducted to evaluate maternal HIV treatment and prevention for PMTCT in resource-limited countries. Due to the economic and infrastructure constraints of resource-limited settings, many trials sought to identify the minimum short-course ARV administration necessary for PMTCT before efficacy was lost, a curious twist in the history of clinical research considering the magnitude and urgency of the HIV epidemic. One such study included an ultrashort ZDV regimen despite placing infants at high risk for HIV infection. Predictably, the ultrashort arm was found to be inferior to longer treatment and resulted in a higher rate of perinatal HIV transmission.16 Basically, a spectrum of studies included the evaluation of various short-course combinations of ARVs for PMTCT, when to initiate treatment during pregnancy, the preferred duration for treatment during pregnancy, and duration of ARVs for women and their infants after delivery while breastfeeding continued.
Retrospectively, as clinical studies identify the advantages of early uninterrupted treatment, ethical questions arise regarding the necessity for extensive clinical trials of various permutations of PMTCT regimen approaches, especially those using reduced treatment in resource-limited settings. The failure to apply the lessons learned from other clinical studies for treatment and prophylaxis for PMTCT and the overly cautious approaches of leaders in global health placed too many HIV-infected mothers and their HIV-exposed infants at risk for disease progression including, reduced efficacy of some ARVs due to viral resistance, continued high rates of viral resistance that may be transmitted to others, mother to child transmission rates that did not match those in developed countries, and unnecessarily high mortality rates in infants.
Current international HIV treatment and prophylaxis guidelines recommend the use of HAART to maximize efficacy and prevent the emergence of drug-resistant HIV.17,18 Guidelines and publications also recommend early initiation of HAART at higher CD4 counts which has been shown in pediatric and adult studies to significantly reduce morbidity and mortality. Marked decreases in the cost and greater availability of ARVs along with persuasive clinical data shifted the criteria for initiating optimal ART in resource-limited countries toward earlier treatment at higher CD4 counts.
The change in recommendations was noted by those who perform mathematical modeling to predict what might happen if early diagnosis of HIV infection and more aggressive implementation of ART were to be initiated simultaneously.19 This model suggested that HIV transmission could be dramatically decreased and HIV seroprevalence reduced to <1% if HIV testing were coupled with immediate initiation of treatment regardless of CD4 count.19,20
Recent publication of guidelines by international organizations such as WHO have slowly shifted away from recommendations to initiate treatment in only the most advanced cases of HIV infection to recommendations that are more consistent with current clinical data demonstrating the compelling advantages of early treatment approaches. Other international organizations have been more aggressive, recommending initiation of HAART in asymptomatic individuals at higher CD4 counts.21 Current recommendations for optimal prophylaxis are well defined and consist of HAART administered for at least 4 weeks after exposure to HIV.22,23
At this point in the epidemic, there is consensus on the principles that define optimal treatment and prophylaxis of HIV infection, and it seems appropriate to ask whether participants in clinical trials for PMTCT in resource-limited countries are being offered the best available treatment.
1. HAART is the standard of care for the treatment of HIV infection for children and adults.21,24,25
2. HAART is the standard of care for post exposure prophylaxis of HIV infection.22,23
3. Suboptimal treatment (the use of fewer than 3 drugs) does not control HIV infection and increases viral resistance.21,26-28
4. Interrupted treatment increases the potential for drug resistance, viral rebound, opportunistic infection, mortality, and subsequent response to treatment.27-31
5. Delayed treatment, either by initiating treatment at low CD4 counts or waiting until the patient is symptomatic, is associated with increased morbidity and mortality which may persist for years.32
6. Early treatment with HAART and control of HIV infection decreases HIV transmission to sexual partners, lowers death rates, prevents opportunistic infections, and decreases HIV transmission at the population level.20,32-36
7. HAART reduces viral load, which is the major factor in HIV transmission.37
8. Continued use of ART while breastfeeding reduces HIV transmission and emergence of viral resistance.1,20,38,39
Clinical research studies for PMTCT have not aggressively incorporated these principles into their study design in resource-limited countries. Initially, implementation of PMTCT in resource-limited countries was hindered by the availability and expense of ARVs and inadequate infrastructure. As a result, clinical studies for PMTCT in breast-feeding populations continued to use suboptimal treatment and prophylaxis including the use of fewer than 3 drugs, interrupted treatment of mothers, shortened duration of treatment, shortened duration of prophylaxis, and initiation of treatment at more advanced stages of HIV infection.40-44 Results of these studies were predictable and confirmed what had been previously demonstrated-HIV transmission rates to infants increase with the use of suboptimal treatment for PMTCT and mono or dual prophylaxis results in a higher risk of HIV transmission and drug resistance.16,45-49
The consequences of the use of a suboptimal treatment in clinical trials for the treatment of HIV-infected children was highlighted when a recent clinical trial was halted because the mortality in the deferred (suboptimal) treatment arm significantly exceeded that of the early treatment arm.50 The study is an example of a clinical trial design for treatment of HIV-infected children, which failed to acknowledge published evidence that delayed treatment was not the optimal means for controlling HIV disease progression.51 Studies of HIV-infected infants had demonstrated that HIV progressed more rapidly in children than adults; the mortality in untreated HIV-infected infants was 50% by 1 year old age; immune recovery after treatment was better in young infants; bacterial infections occurred at higher CD4 counts and are reduced by HAART; and growth and development, including neurologic development, are significantly greater when treatment is initiated early.51
Now that ARV treatment is more accessible in countries where research studies for PMTCT and treatment of children are performed, optimal treatment for PMTCT in clinical research studies should include early initiation of HAART for all HIV-infected pregnant women, and continuation of HAART during and after breastfeeding has ceased. Short courses of HAART, use of 1 or 2 ARVs, and premature discontinuation of HAART after exposure to HIV should be considered suboptimal treatment and prophylaxis. There is ample evidence at this time to conclude that single drug treatment and prophylaxis consistently results in drug resistance; delayed initiation of treatment and short duration of treatment consistently results in increased HIV transmission; and premature cessation of prophylaxis although HIV exposure continues results in increased HIV infection.3,16,52-55 Clinical research trials, conducted within countries supported by international programs that provide HAART for the general population or where optimal treatment of HIV infection is available, should be obligated to provide the best available treatment within clinical research studies. The transition from an economically based to an optimal efficacy-based rationale for PMTCT and treatment of children has not occurred quickly enough in clinical research trials, placing too many HIV-infected women and HIV-exposed infants at risk.56
At this juncture in the HIV epidemic, clinical research studies for PMTCT should conform to high ethical standards defined as the best available care and high efficacy standards defined as providing optimal treatment and prophylaxis as the minimal intervention.56 To do less, provides an unintentional signal to international organizations and National Ministries of Health that HIV-infected pregnant women and their infants need not receive the same level of treatment and prophylaxis as other HIV-infected or HIV-exposed individuals. Comparison interventions should consist of treatment and prevention arms that seek to enhance efficacy beyond current optimal treatment regimens although focusing on short-term and long-term safety evaluation of exposure to ARVs.39 Likewise, international research efforts should focus on improving the science of implementation and identify ways to improve diagnosis, access, adherence, and retention of women and infants while using the best available treatment and prophylactic regimens to reduce the continued unacceptably high numbers of perinatal HIV-infected infants in resource-poor settings.
1. Lehman DA, Chung MH, Mabuka JM, et al. Lower risk of resistance after short-course HAART compared with zidovudine/single-dose nevirapine used for prevention of HIV-1 mother-to-child transmission. J Acquir Immune Defic Syndr
2. Mofenson L. Overview of periantal intervention trials table. 2008. Available at: http://www.womenchildrenhiv.org/wchiv
?page=wx-resource&root=typ&cat=02&subcat=prov&rid=20-7854. Accessed March 10, 2009.
3. Chigwedere P, Seage GR, Lee TH, et al. Efficacy of antiretroviral drugs in reducing mother-to-child transmission of HIV in Africa: a meta-analysis of published clinical trials. AIDS Res Hum Retroviruses
4. Sripipatana T, Spensley A, Miller A, et al. Site-specific interventions to improve prevention of mother-to-child transmission of human immunodeficiency virus programs in less developed settings. Am J Obstet 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. Cochrane Database Syst Rev
6. Connor EM, Sperling RS, Gelber R, et al. Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. N Engl J Med
7. Lurie P, Wolfe SM. Unethical trials of interventions to reduce perinatal transmission of the human immunodeficiency virus in developing countries. N Engl J Med
8. Bonkovsky FO. Ethical issues in perinatal HIV. Clin Perinatol
9. Rouse DJ, Owen J, Goldenberg RL, et al. Zidovudine for the prevention of vertical HIV transmission: a decision analytic approach. J Acquir Immune Defic Syndr Hum Retrovirol
10. Brocklehurst P, Volmink J. Antiretrovirals for reducing the risk of mother-to-child transmission of HIV infection. Cochrane Database Syst Rev
11. Jackson JB, Musoke P, Fleming T, et al. Intrapartum and neonatal single-dose nevirapine compared with zidovudine for prevention of mother-to-child transmission of HIV-1 in Kampala, Uganda: 18-month follow-up of the HIVNET 012 randomised trial. Lancet
12. Stringer JS, Chi BH. Extended nevirapine prophylaxis to prevent HIV transmission. Lancet
13. Welty TK, Bulterys M, Welty ER, et al. Integrating prevention of mother-to-child HIV transmission into routine antenatal care: the key to program expansion in Cameroon. J Acquir Immune Defic Syndr
14. Baldanti F, Paolucci S, Maga G, et al. Nevirapine-selected mutations Y181I/C of HIV-1 reverse transcriptase confer cross-resistance to stavudine. AIDS
15. Church JD, Omer SB, Guay LA, et al. Analysis of nevirapine (NVP) resistance in Ugandan infants who were HIV infected despite receiving single-dose (SD) NVP versus SD NVP plus daily NVP up to 6 weeks of age to prevent HIV vertical transmission. J Infect Dis
16. Lallemant M, Jourdain G, Le Coeur S, et al. A trial of shortened zidovudine regimens to prevent mother-to-child transmission of human immunodeficiency virus type 1. Perinatal HIV Prevention Trial (Thailand) Investigators. N Engl J Med
17. Working Group on Antiretroviral Therapy and Medical Management of HIV-Infected Children. Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection
. February 23, 2009:1-139. Available at: http://aidsinfo.nih.gov/contentfiles/PediatricGuidelines.pdf
. Washington, DC: DHHS; 2008. Accessed March 10, 2009.
19. Granich RM, Gilks CF, Dye C, et al. Universal voluntary HIV testing with immediate antiretroviral therapy as a strategy for elimination of HIV transmission: a mathematical model. Lancet
20. De Cock KM, Gilks CF, Lo YR, et al. Can antiretroviral therapy eliminate HIV transmission? Lancet
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
23. CDC releases detailed guidelines for PEP use. Agency focuses on nonoccupational exposure. AIDS Alert
26. Dybul M, Fauci AS, Bartlett JG, et al. Guidelines for using antiretroviral agents among HIV-infected adults and adolescents. Recommendations of the Panel on Clinical Practices for Treatment of HIV. MMWR Recomm Rep
27. Fox Z, Phillips A, Cohen C, et al. Viral resuppression and detection of drug resistance following interruption of a suppressive non-nucleoside reverse transcriptase inhibitor-based regimen. AIDS
28. Eron JJ. Managing antiretroviral therapy: changing regimens, resistance testing, and the risks from structured treatment interruptions. J Infect Dis
. 2008;197(Suppl 3):S261-S271.
29. Benson CA, Vaida F, Havlir DV, et al. A randomized trial of treatment interruption before optimized antiretroviral therapy for persons with drug-resistant HIV: 48-week virologic results of ACTG A5086. J Infect Dis
30. Danel C, Moh R, Minga A, et al. CD4-guided structured antiretroviral treatment interruption strategy in HIV-infected adults in west Africa (Trivacan ANRS 1269 trial): a randomised trial. Lancet
31. Holkmann Olsen C, Mocroft A, Kirk O, et al. Interruption of combination antiretroviral therapy and risk of clinical disease progression to AIDS or death. HIV Med
32. Lawn SD, Harries AD, Anglaret X, et al. Early mortality among adults accessing antiretroviral treatment programmes in sub-Saharan Africa. AIDS
33. Williams BG, Dye C. Antiretroviral drugs for tuberculosis control in the era of HIV/AIDS. Science
34. Lawn SD, Myer L, Bekker LG, et al. Burden of tuberculosis in an antiretroviral treatment programme in sub-Saharan Africa: impact on treatment outcomes and implications for tuberculosis control. AIDS
35. Corbett EL, Marston B, Churchyard GJ, et al. Tuberculosis in sub-Saharan Africa: opportunities, challenges, and change in the era of antiretroviral treatment. Lancet
36. De Cock KM, Fowler MG, Mercier E, et al. Prevention of mother-to-child HIV transmission in resource-poor countries: translating research into policy and practice. JAMA
37. Janssen RS, Holtgrave DR, Valdiserri RO, et al. The serostatus approach to fighting the HIV epidemic: prevention strategies for infected individuals. Am J Public Health
38. Perez H, Vignoles M, Laufer N, et al. Low rate of emergence of nevirapine and lamivudine resistance after post-partum interruption of a triple-drug regimen. Antivir Ther
39. Gray GE, Saloojee H. Breast-feeding, antiretroviral prophylaxis, and HIV. N Engl J Med
40. Chi BH, Chintu N, Cantrell RA, et al. Addition of single-dose tenofovir and emtricitabine to intrapartum nevirapine to reduce perinatal HIV transmission. J Acquir Immune Defic Syndr
41. Coffie PA, Ekouevi DK, Chaix ML, et al. Maternal 12-month response to antiretroviral therapy following prevention of mother-to-child transmission of HIV type 1, Ivory Coast, 2003-2006. Clin Infect Dis
42. Tonwe-Gold B, Ekouevi DK, Viho I, et al. Antiretroviral treatment and prevention of peripartum and postnatal HIV transmission in West Africa: evaluation of a two-tiered approach. PLoS Med
43. Kilewo C, Karlsson K, Massawe A, et al. Prevention of mother-to-child transmission of HIV-1 through breast-feeding by treating infants prophylactically with lamivudine in Dar es Salaam, Tanzania: the Mitra Study. J Acquir Immune Defic Syndr
44. Kumwenda NI, Hoover DR, Mofenson LM, et al. Extended antiretroviral prophylaxis to reduce breast-milk HIV-1 transmission. N Engl J Med
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 transmission of HIV in Africa? AIDS
46. Phanuphak P. Ethical issues in studies in Thailand of the vertical transmission of HIV. N Engl J Med
47. Shaffer N, Chuachoowong R, Mock PA, et al. Short-course zidovudine for perinatal HIV-1 transmission in Bangkok, Thailand: a randomised controlled trial. Bangkok Collaborative Perinatal HIV Transmission Study Group. Lancet
48. Taha TE, Kumwenda NI, Hoover DR, et al. Nevirapine and zidovudine at birth to reduce perinatal transmission of HIV in an African setting: a randomized controlled trial. JAMA
49. Wade NA, Birkhead GS, Warren BL, et al. Abbreviated regimens of zidovudine prophylaxis and perinatal transmission of the human immunodeficiency virus. N Engl J Med
50. Violari A, Cotton M, Gibb D. Antiretroviral therapy initiated before 12 weeks of age reduces early mortality in young HIV-infected infants: evidence from the Children with HIV Early Antiretroviral Therapy (CHER) study. Abstract WESS103. Presented at: Fourth International AIDS Society Conference on HIV Treatment and Pathogenesis; July 22-27, 2007; Sydney, Australia.
51. Welch SB, Gibb D. When should children with HIV infection be started on antiretroviral therapy? PLoS Med
52. Dabis F, Bequet L, Ekouevi DK, et al. Field efficacy of zidovudine, lamivudine and single-dose nevirapine to prevent peripartum HIV transmission. AIDS
53. Eshleman SH, Mracna M, Guay LA, et al. Selection and fading of resistance mutations in women and infants receiving nevirapine to prevent HIV-1 vertical transmission (HIVNET 012). AIDS
54. Faye A, Le Chenadec J, Dollfus C, et al. Early versus deferred antiretroviral multidrug therapy in infants infected with HIV type 1. Clin Infect Dis
55. Suksomboon N, Poolsup N, Ket-Aim S. Systematic review of the efficacy of antiretroviral therapies for reducing the risk of mother-to-child transmission of HIV infection. J Clin Pharm Ther
56. WMA. World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. Available at: http://www.wma.net/e/policy/b3.htm
. 2004. Accessed March 9, 2009.