Article

Analysis of nevirapine resistance in HIV-infected infants who received extended nevirapine or nevirapine/zidovudine prophylaxis

Department of Pathology, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD 21205, USA.
AIDS (London, England) (Impact Factor: 6.56). 04/2011; 25(7):911-7. DOI: 10.1097/QAD.0b013e328344fedc
Source: PubMed

ABSTRACT In the Post Exposure Prophylaxis of Infants (PEPI)-Malawi trial, infants received up to 14 weeks of extended nevirapine (NVP) or extended NVP with zidovudine (NVP + ZDV) to prevent postnatal HIV transmission. We examined emergence and persistence of NVP resistance in HIV-infected infants who received these regimens prior to HIV diagnosis.
Infant plasma samples collected at 14 weeks of age were tested using the ViroSeq HIV Genotyping System and a sensitive point mutation assay, LigAmp (for K103N and Y181C). Samples collected at 6 and 12 months of age were analyzed using LigAmp.
At 14 weeks of age, NVP resistance was detected in samples from 82 (75.9%) of 108 HIV-infected infants. Although the frequency of NVP resistance detected by ViroSeq was lower in the extended NVP + ZDV arm than in the extended NVP arm, the difference was not statistically significant (38/55 = 69.1% vs. 44/53 = 83.0%, P = 0.12). Similar results were obtained using LigAmp. Using LigAmp, the proportion of infants who still had detectable NVP resistance at 6 and 12 months was similar among infants in the two study arms (at 6 months: 17/20 = 85.0% for extended NVP vs. 21/26 = 80.8% for extended NVP + ZDV, P = 1.00; at 12 months: 9/16 = 56.3% for extended NVP vs.10/13 = 76.9% for extended NVP + ZDV, P = 0.43).
Infants exposed to extended NVP or extended NVP + ZDV had high rates of NVP resistance at 14 weeks of age, and resistant variants frequently persisted for 6-12 months. Frequency and persistence of NVP resistance did not differ significantly among infants who received extended NVP only vs. extended NVP + ZDV prophylaxis.

0 Bookmarks
 · 
92 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Considerable advances have been made in the effort to prevent mother-to-child HIV transmission (PMTCT) in sub-Saharan Africa. Clinical trials have demonstrated the efficacy of antiretroviral regimens to interrupt HIV transmission through the antenatal, intrapartum, and postnatal periods. Scientific discoveries have been rapidly translated into health policy, bolstered by substantial investment in health infrastructure capable of delivering increasingly complex services. A new scientific agenda is also emerging, one that is focused on the challenges of effective and sustainable program implementation. Finally, global campaigns to "virtually eliminate" pediatric HIV and dramatically reduce HIV-related maternal mortality have mobilized new resources and renewed political will. Each of these developments marks a major step in regional PMTCT efforts; their convergence signals a time of rapid progress in the field, characterized by an increased interdependency between clinical research, program implementation, and policy. In this review, we take stock of recent advances across each of these areas, highlighting the challenges-and opportunities-of improving health services for HIV-infected mothers and their children across the region.
    Current HIV/AIDS Reports 02/2013; DOI:10.1007/s11904-013-0154-z
  • [Show abstract] [Hide abstract]
    ABSTRACT: Achieving an AIDS-free generation will require elimination of postnatal transmission of HIV-1 while maintaining the nutritional and immunologic benefits of breastfeeding for infants in developing regions. Maternal/infant antiretroviral prophylaxis can reduce postnatal HIV-1 transmission, yet toxicities and the development of drug-resistant viral strains may limit the effectiveness of this strategy. Interestingly, in the absence of antiretroviral prophylaxis, greater than 90% of infants exposed to HIV-1 via breastfeeding remain uninfected, despite daily mucosal exposure to the virus for up to 2 y. Moreover, milk of uninfected women inherently neutralizes HIV-1 and prevents virus transmission in animal models, yet the factor(s) responsible for this anti-HIV activity is not well-defined. In this report, we identify a primary HIV-1-neutralizing protein in breast milk, Tenascin-C (TNC). TNC is an extracellular matrix protein important in fetal development and wound healing, yet its antimicrobial properties have not previously been established. Purified TNC captured and neutralized multiclade chronic and transmitted/founder HIV-1 variants, and depletion of TNC abolished the HIV-1-neutralizing activity of milk. TNC bound the HIV-1 Envelope protein at a site that is induced upon engagement of its primary receptor, CD4, and is blocked by V3 loop- (19B and F39F) and chemokine coreceptor binding site-directed (17B) monoclonal antibodies. Our results demonstrate the ability of an innate mucosal host protein found in milk to neutralize HIV-1 via binding to the chemokine coreceptor site, potentially explaining why the majority of HIV-1-exposed breastfed infants are protected against mucosal HIV-1 transmission.
    Proceedings of the National Academy of Sciences 10/2013; 110(45). DOI:10.1073/pnas.1307336110 · 9.81 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Oligonucleotide ligation assay (OLA) is a highly specific and relatively simple method to detect point mutations encoding HIV-1 drug-resistance, which can detect mutants comprising ≥2-5% of the viral population. Nevirapine (NVP), tenofovir (TDF) and lamivudine (3TC) are antiretroviral drugs (ARV) used worldwide for treatment of HIV infection and prevention of mother-to-child-transmission. Adapting the OLA to detect multiple mutations associated with HIV resistance to these ARV simultaneously would provide an efficient tool to monitor drug resistance in resource-limited settings. Known proportions of mutant and wild-type plasmids were used to optimize a multiplex OLA for detection of K103N, Y181C, K65R, and M184V in HIV subtypes B and C, and V106M and G190A in subtype C. Simultaneous detection of two mutations was impaired if probes annealed to overlapping regions of the viral template, but was sensitive to ≥2-5% when testing codons using non-overlapping probes. PCR products from HIV-subtype B and C-infected individuals were tested by multiplex-OLA and compared to results of single-codon OLA. Multiplex-OLA detected mutations at codon pairs 103/181, 106/190 and 65/184 reliably when compared to singleplex-OLA in clinical specimens. The multiplex-OLA is sensitive and specific and reduces the cost of screening for NVP, TDF and/or 3TC resistance.
    Journal of virological methods 05/2013; DOI:10.1016/j.jviromet.2011.11.030 · 2.13 Impact Factor

Full-text (2 Sources)

Download
35 Downloads
Available from
May 22, 2014