点击显示 收起
Division of Infectious Diseases, Columbia University Medical Center, New York, New York
Within the context of the historic development of drugs to treat HIV infection, there is perhaps no subject that has created more controversy than the use of these agents to interrupt the mother-to-child transmission (MTCT) of HIV-1. No one now takes issue with the fact that the AIDS Clinical Trials Group Protocol 076in which zidovudine (ZDV), given to the mother pre- and intrapartum and to the infant for the first 6 weeks of life, reduced MTCT of HIV-1 by 70%has been one of the most noteworthy advances in treatment of the past 20 years [1]. However, the development phase of that protocol was fraught with intense debate, particularly with respect to the ethics of the trial. The reduction in MTCT of HIV-1 from 25% to 8% immediately led to changes in public health policy in the developed world and, with the subsequent application of potent combinations of antiretroviral drugs for the mother and judicious use of caesarean section, neonatal HIV-1 infection is now a rare event in resource-unconstrained settings.
As with any new medical intervention, whether prophylactic or therapeutic, there are inevitable trade-offs. No major safety issues have arisen for mothers or infants who have received SD-NVP. However, the emergence of drug resistance in the setting of SD-NVP has created a gradually increasing challenge to the scientific, clinical research, and public health communities. In retrospect, it is not surprising that mutations associated with nonnucleoside reverse-transcriptase inhibitor (NNRTI) resistance would emerge with the administration of a drug for which the occurrence of rapid, single-step, high-level resistance and a prolonged half-life have been described for years [5]. It is also important to remember that the replication kinetics of HIV and the nature of reverse transcription result in a constant and inevitable mutation rate in the viral genome, such that drug resistanceassociated mutations occur in the absence of exposure to any drug. The occurrence of new mutations during and after exposure to a drug is greatly facilitated by the selective pressure of an antiretroviral agent, particularly if it is administered in a regimen that will not ensure full virologic suppression. Thus, the appearance of reports describing the relatively high proportions of NVPexposed mothers and infants with NNRTI-resistant viral strains was predictable [6].
Three articles in this issue of the Journal of Infectious Diseases extend our knowledge of the complexity of drug resistance that accompanies the administration of SD-NVP for the prevention of MTCT of HIV-1. Johnson et al. describe the application of a real-time polymerase chain reaction (PCR) assay to detect minority strains of HIV-1 possessing 1 of 2 key NNRTI-associated resistance mutations, K103N and Y181C, in 50 South African women who had received SD-NVP [7]. None of the women had detectable mutations before exposure to NVP. After exposure, 10 (20%) of the women were found to have the K103N mutation by standard sequencing assay. The real-time PCR assay detected the K103N mutation in an additional 16 (40%) of the remaining 40 women. For Y181C, none of 50 women had the mutation before exposure to NVP, 4 were found to have it by standard sequencing after exposure to NVP, and 5 (11%) of the remaining 46 were found to have it by the real-time PCR assay after exposure to NVP. Taken together, these data suggest that a majority of women (65%) exposed to NVP will have detectable NNRTI-associated resistance mutations 636 weeks postpartum.
Flys et al. explore the utility of sensitive assays for the detection of NNRTI-resistant mutants [8]. In this study, Flys et al. used available samples from 9 women and 5 infants obtained at 68 weeks and 1224 months after exposure to NVP in the HIVNET 012 trial. Standard sequencing techniques and 2 substantially more sensitive assaysLigAmp and TyHRTwere used. LigAmp involves oligonucleotide ligation and real-time PCR to interrogate specific regions of the viral genome. TyHRT is a labor-intensive assay that involves yeast transformation of the reverse-transcriptase gene from patient samples, the screening of colonies for phenotypic resistance to NVP, and clonal sequencing to define the mutations present. Standard sequencing analysis detected the K103N mutation in 8 of 9 women and 4 of 5 infants at 68 weeks after exposure to NVP but in none of the women or infants 12 months after exposure or later. In contrast, the LigAmp assay was able to detect the K103N mutation in 3 of 9 women at 14 months and in 1 of 5 infants at 12 months after exposure to NVP. Comparable, but not identical, results were obtained with the TyHRT assay. Given the small numbers and the selective nature of the study population, conclusions about the persistence of the K103N mutation in the overall HIVNET 012 population cannot be drawn, but the results are concordant with the findings of Johnson et al.
The technical achievements of Johnson et al. and Flys et al. illustrate, once again, that the more sensitive our virologic assays become, the more we will understand about HIV pathogenesis. Standard, population-based sequencing analysis generally cannot detect subpopulations of mutants that constitute <20% of the total viral population. In contrast, the real-time PCR assay described by Johnson et al. and the LigAmp assay described by Flys et al. have reported sensitivities of 0.2%0.3% and 0.1% of the total viral populations, respectively.
The obvious question that arises from these data is whether viral mutants circulating at low frequencies are clinically meaningful. Specifically, will the presence of these mutants after prophylaxis with SD-NVP at delivery and birth compromise the future treatment of mothers and children with NNRTI-based regimens when they are required to treat disease, and will the use of SD-NVP during subsequent pregnancies be effective in the prevention of MTCT of HIV-1 Prospective studies under way or planned will answer these questions, but evidence is already accumulating to suggest that viral mutants circulating at low frequencies are clinically relevant. In an observational study by Jourdain et al., women exposed to NVP who had detectable NNRTI-associated resistance mutations early during the postpartum period had an inferior virologic response to a subsequent NNRTI-based treatment regimen at 24 weeks of therapy, compared with that in women not exposed to NVP [9]. Women exposed to NVP who had no detectable resistance mutations early during the postpartum period had an intermediate-level virologic response, which suggests that NNRTI-resistant mutants were likely present at low frequencies and were possibly contributory to a less-than-ideal response to treatment. Importantly, the significance of NNRTI-resistant mutants circulating at low frequencies for subsequent virologic failure in adults receiving NNRTI-containing regimens has been reported by Mellors et al., who used 2 highly sensitive assays for the detection of mutants and phylogenetic analyses linking samples taken at baseline and during virologic failure [10].
Eshleman et al. compared the frequency of NNRTI-associated mutations after exposure to NVP at 68 weeks postpartum by standard sequencing analysis in women enrolled in HIVNET 012 and in the trial of NVP and ZDV in Malawi [11]. The critical finding was that the frequency of NNRTI-associated resistance mutations was significantly higher in women infected with HIV-1 subtype C (69.2%) than in those infected with subtype A (19.4%) or D (36.1%) (P < .0001 for both comparisons). Data reported by a number of investigators suggest that baseline viral polymorphisms can differ among subtypes and that the pathways of resistance and/or the facility with which a particular mutation or set of mutations develops may vary. These possibilities require extensive further research and careful evaluations of the fitness cost that mutations may or may not confer in one subtype of HIV-1 versus another. Viral fitness may well influence how long such mutants persist in the absence of selective drug pressure in the host, as well as their transmissibility to others [12, 13].
SD-NVP substantially reduces the MTCT of HIV-1, but the resultant transmission rates are still much higher than those seen in the developed world, where availability of potent combination antiretroviral therapy is commonplace, and what can be achieved, as was reported in a study in Thailand, with a combination of ZDV and NVP [14]. Thus, there is a moral imperative to continue to reduce the rate of MTCT of HIV-1 and to try to minimize the emergence of drug resistance in the process. The optimal management of antiretroviral resistance is to prevent its occurrence in the first place. In areas of the world where SD-NVP remains the principal practical option, the strategic use of nucleoside-analogue agents to reduce exposure to NVP alone is being studied [15]. As economics and health care infrastructures permit, the alternative approach of providing potent combinations of antiretroviral agents to pregnant women to achieve full virologic suppression has the potential to reduce neonatal HIV infection to the levels seen in the developed world while preventing drug resistance in the mothers. The articles by Johnson et al., Flys et al., and Eshleman et al. in this issue of the Journal of Infectious Diseases may help to bring us closer to this ultimate goal.
References
1. 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 1994; 331:117380. First citation in article
2. Guay LA, 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: HIVNET 012 randomised trial. Lancet 1999; 354:795802. First citation in article
3. 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 2003; 362:85968. First citation in article
4. Cohen J. HIV transmission: allegations raise fears of backlash against AIDS prevention strategy. Science 2004; 306:21689. First citation in article
5. Richman DD, Havlir D, Corbeil J, et al. Nevirapine resistance mutations of human immunodeficiency virus type 1 selected during therapy. J Virol 1994; 68:16606. First citation in article
6. 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 2001; 15:19517. First citation in article
7. Johnson JA, Li J-F, Morris L, et al. Emergence of drug-resistant HIV-1 after intrapartum administration of single-dose nevirapine is substantially underestimated. J Infect Dis 2005; 192:1623 (in this issue). First citation in article
8. Flys T, Nissley DV, Claasen CW, et al. Sensitive drug-resistance assays reveal long-term persistence of HIV-1 variants with the K103N nevirapine (NVP) resistance mutation in some women and infants after the administration of single-dose NVP: HIVNET 012. J Infect Dis 2005; 192:249 (in this issue). First citation in article
9. Jourdain G, Ngo-Giang-Huong N, Le Coeur S, et al. Intrapartum exposure to nevirapine and subsequent maternal responses to nevirapine-based antiretroviral therapy. N Engl J Med 2004; 351:22940. First citation in article
10. Mellors J, Palmer S, Nissley D, et al. Low-frequency NNRTI-resistant variants contribute to failure of efavirenz-containing regimens [abstract 39]. In: Proceedings of the 11th Conference on Retroviruses and Opportunistic Infections (San Francisco, CA, 2004). Alexandria, VA: Foundation for Retrovirology and Human Health, 2004:91. First citation in article
11. Eshleman SH, Hoover DR, Chen S, et al. Nevirapine (NVP) resistance in women with HIV-1 subtype C, compared with subtypes A and D, after the administration of single-dose NVP. J Infect Dis 2005; 192:306 (in this issue). First citation in article
12. Bezemer D, Jurriaans S, Prins M, et al. Declining trend in transmission of drug-resistant HIV-1 in Amsterdam. AIDS 2004; 18:15717. First citation in article
13. Turner D, Brenner B, Routy JP, et al. Diminished representation of HIV-1 variants containing select drug resistance-conferring mutations in primary HIV-1 infection. J Acquir Immune Defic Syndr 2004; 37:162731. First citation in article
14. Lallemant M, Jourdain G, Le Coeur S, et al. Single-dose perinatal nevirapine plus standard zidovudine to prevent mother-to-child transmission of HIV-1 in Thailand. N Engl J Med 2004; 351:21728. First citation in article
15. Cressey TR, Jourdain G, Lallemant MJ, et al. Persistence of nevirapine exposure during the postpartum period after intrapartum single-dose nevirapine in addition to zidovudine prophylaxis for the prevention of mother-to-child transmission of HIV-1. J Acquir Immune Defic Syndr 2005; 38:2838. First citation in article