Correspondence

Primary Infection with Zidovudine-Resistant HIV

N Engl J Med 1993; 329:1123-1124October 7, 1993

Article

To the Editor:

Erice et al. (April 22 issue)1 described a patient with symptomatic human immunodeficiency virus type 1 (HIV-1) infection who had a primary infection with a virus resistant to zidovudine. We report the case of a homosexual man in whom clinical symptoms of acute HIV-1 infection developed in May 1992; tests for HIV-1 antibodies were positive in July 1992. His most recent negative HIV-1 test was in November 1991.

We studied the presence of genotypic mutations at codons 215 and 74 of the HIV pol gene -- those associated with reduced sensitivity to zidovudine and didanosine, respectively. We used the polymerase chain reaction as well as phenotypic properties to induce syncytium in MT2 cell lines2 in viral isolates from both the patient and his sexual partner, who had been given zidovudine for more than one year. In both isolates, genotypic mutations for zidovudine resistance were detected. The syncytium-inducer phenotype of the sexual partner did not appear to be transmitted to the patient, who had a non-syncytium-inducer strain.

In addition, we prospectively analyzed viral isolates from three consecutive patients who presented with acute primary HIV-1 infection. Isolates from two of the three patients revealed a mutation at position 215. No mutation at position 74 was detected in the two patients in whom sensitivity to didanosine was tested. Clinically, we did not notice a longer duration or greater severity of symptoms in these patients infected with primary zidovudine-resistant strains. So far, we find no evidence that isolates resistant to nucleoside analogues are associated with a higher virulence or a modified immune response, as suggested by Erice et al.

Our limited results also suggest that transmission of a genotypically mutant strain resistant to zidovudine is not associated with phenotypic transmission of the viral cytopathic properties as determined in vitro. The frequency of primary zidovudine-resistant strains remains undetermined3. Our data suggest that this problem is probably more frequent than was previously thought, and these findings have implications for the design of clinical trials.

P. Hermans, M.D.
Saint-Pierre University Hospital, 1000 Brussels, Belgium

S. Sprecher, Ph.D.
Institut Pasteur du Brabant, 1180 Brussels, Belgium

N. Clumeck, M.D.
Saint-Pierre University Hospital, 1000 Brussels, Belgium

3 References

1. 1

   Erice A, Mayers DL, Strike DG, et al. Primary infection with zidovudine-resistant human immunodeficiency virus type 1. N Engl J Med 1993;328:1163-1165
   Full Text | Web of Science | Medline

2. 2

   Boucher CA, Lange JM, Miedema FF, et al. HIV-1 biological phenotype and the development of zidovudine resistance in relation to disease progression in asymptomatic individuals during treatment. AIDS 1992;6:1259-1264
   CrossRef | Web of Science | Medline

3. 3

   Mohri H, Singh MK, Ching WT, Ho DD. Quantitation of zidovudine-resistant human immunodeficiency virus type 1 in the blood of treated and untreated patients. Proc Natl Acad Sci U S A 1993;90:25-29
   CrossRef | Web of Science | Medline

To the Editor:

We have characterized a zidovudine-resistant HIV-1 isolate from an infant born to an HIV-infected mother. The mother had been treated with zidovudine for 23 months before pregnancy and during the last 4 months of pregnancy. Two HIV-1 isolates were characterized phenotypically and genotypically: one from the mother at delivery and one from the infant at five months. The isolates were tested by the cell-free isolate sensitivity assay1 for their in vitro sensitivity to zidovudine, expressed as 50 percent and 90 percent inhibitory concentrations (IC₅₀ and IC₉₀) of zidovudine. Moreover, both isolates were directly sequenced after polymerase chain reaction into the pol gene. This was done to explore the genotype of a region of the reverse transcriptase gene that was involved in sensitivity to zidovudine. Further analysis was conducted by selective polymerase chain reaction at the codons of interest2-4.

The phenotypic and genotypic characteristics of the isolates are shown in Table 1Table 1Phenotypic and Genotypic Characteristics of HIV-1 Isolates from an HIV-1-Infected Mother and Her Infant.. Both isolates had intermediate values with regard to IC₅₀ and IC₉₀. The maternal isolate was mutated in the pol gene at positions 70 and 215, whereas the isolate from the infant was mutated at positions 41 and 215. The mutation at codon 215, crucial for zidovudine resistance, has usually been described in patients previously treated with the medication. The infant had neither been treated with zidovudine during the first months of life nor been breast-fed. We believe that the mutant strain was acquired from the mother.

At the time that the isolate from the infant was obtained, the viral load in the infant was determined by end-point-dilution culture assay5. The viral titer in cells was ≥ 7000 median tissue-culture-infective doses (TCID₅₀) per million peripheral-blood mononuclear cells, and the titer in plasma was 14,000 TCID₅₀ per milliliter. The infant was treated with zidovudine with no noticeable clinical or biologic effect; HIV antigenemia was always detectable and the viral load, estimated three months after the start of therapy, was unchanged (viral titer in cells, 6987 TCID₅₀ per million peripheral-blood mononuclear cells; in plasma, 15,625 TCID₅₀ per milliliter).

Our observation suggests transmission of a zidovudine-resistant HIV-1 isolate from a treated mother to her infant. We suggest that the decision to treat a person infected with HIV with an antiviral drug should be preceded by an in vitro susceptibility assay of a corresponding HIV-1 isolate. In our patient there was no benefit of zidovudine treatment; the viral burden remained elevated. This could explain the rapid emergence of a mutant strain at position 74 one month after the therapeutic switch from zidovudine to didanosine (data not shown).

Bernard Masquelier, D.Pharm.
Emmanuelle Lemoigne, M.D.
Isabelle Pellegrin, M.D.
Danielle Douard, M.D.
Boris Sandler, M.D.
Herve J.A. Fleury, M.D., Ph.D.
Centre Hospitalier Universitaire de Bordeaux, 33076 Bordeaux, France

5 References

1. 1

   Brun-Vezinet F, Ingrand D, Deforges L, et al. HIV-1 sensitivity to zidovudine: a consensus culture technique validated by genotypic analysis of the reverse transcriptase. J Virol Methods 1992;37:177-188
   CrossRef | Web of Science | Medline

2. 2

   Larder BA, Kemp SD. Multiple mutations in HIV-1 reverse transcriptase confer high-level resistance to zidovudine (AZT). Science 1989;246:1155-1158
   CrossRef | Web of Science | Medline

3. 3

   Kellam P, Boucher CA, Larder BA. Fifth mutation in human immunodeficiency virus type 1 reverse transcriptase contributes to the development of high-level resistance to zidovudine. Proc Natl Acad Sci U S A 1992;89:1934-1938
   CrossRef | Web of Science | Medline

4. 4

   Larder BA, Kellam P, Kemp SD. Zidovudine resistance predicted by direct detection of mutations in DNA from HIV-infected lymphocytes. AIDS 1991;5:137-144
   CrossRef | Web of Science | Medline

5. 5

   Rouzioux C, Puel J, Agut H, et al. Comparative assessment of quantitative HIV viraemia assays. AIDS 1992;6:373-377
   CrossRef | Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: These letters confirm our findings that zidovudine-resistant HIV-1 can be transmitted and can cause primary infections. In contrast to the prolonged acute retroviral syndrome in our patient, the three patients described by Hermans et al. did not present with unusually severe clinical manifestations. In addition to the effect of possible differences in host factors and in the virulence of HIV-1 strains, treatment with zidovudine could have influenced the clinical course in our patient. As we suggested, the decision to treat primary HIV-1 infection should await the results of carefully designed prospective trials that incorporate susceptibility studies of HIV-1 isolates.

Masquelier et al. describe possible vertical transmission of a phenotypically and genotypically resistant HIV-1 strain from a zidovudine-treated infected mother to her infant. Their case was similar to ours in that the infant had a large viral load that did not change after three months of zidovudine therapy. The persistently elevated viral load and the rapid emergence of a didanosine-resistant mutant strain one month after therapy was changed indicates that the infection was caused by rapidly replicating virus and was possibly associated with a poor clinical outcome. Because zidovudine-resistant strains of HIV-1 have been isolated from vaginal washings,1 perinatal acquisition of the zidovudine-resistant virus is a possibility in this case. Recently, occupational transmission of a zidovudine-resistant HIV-1 strain has also been documented in the case of a health care worker after a percutaneous injury with a needle contaminated with blood from a zidovudine-treated patient with AIDS2. Taken together, these and other studies3 provide evidence of horizontal, occupational, and possibly vertical transmission of zidovudine-resistant HIV-1.

Although we agree in principle with Hermans et al. and Masquelier et al. that HIV-1 strains should be characterized before antiretroviral therapy is begun, this would represent a formidable and expensive approach. Simple, fast, and inexpensive laboratory methods of characterizing HIV-1 isolates are needed. Such methods would help determine the appropriate therapy for zidovudine-resistant infections. Meanwhile, careful virologic and clinical documentation of primary infections caused by HIV-1 resistant viruses should provide the missing natural-history data that are needed in order to make rational therapeutic recommendations.

Alejo Erice, M.D.
Henry H. Balfour, Jr., M.D.
University of Minnesota Medical School, Minneapolis, MN 55455

3 References

1. 1

   Wainberg MA, Beaulieu R, Tsoukas C, Thomas R. Detection of zidovudine-resistant variants of HIV-1 in genital fluids. AIDS 1993;7:433-444
   CrossRef | Web of Science | Medline

2. 2

   HIV seroconversion after occupational exposure despite early prophylactic zidovudine therapyLancet 1993;341:1077-1078
   CrossRef | Web of Science | Medline

3. 3

   Mohri H, Singh MK, Ching WT, Ho DD. Quantitation of zidovudine-resistant human immunodeficiency virus type 1 in the blood of treated and untreated patients. Proc Natl Acad Sci U S A 1993;90:25-29
   CrossRef | Web of Science | Medline

Citing Articles (13)

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1. 1

   Ricardo Camacho, Eugénio Teófilo. (2011) Antiretroviral therapy in treatment-naïve patients with HIV infection. Current Opinion in HIV and AIDS 6, S3-S11
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   Lydia N Drumright, Simon DW Frost. (2008) Sexual networks and the transmission of drug-resistant HIV. Current Opinion in Infectious Diseases 21:6, 644-652
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3. 3

   Nitin K SAKSENA, Bin WANG, Megan STEAIN, Rong Ge YANG, Lin Qi ZHANG. (2005) Snapshot of HIV pathogenesis in China. Cell Research 15:11-12, 953-961
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   E Girardi, F N Lauria, G Ippolito. (2005) HIV/AIDS in 2004: the epidemiologist's point of view. Cell Death and Differentiation 12, 837-844
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   Karen P. Beckerman. 2005. Identification, Evaluation, and Care of the Human Immunodeficiency Virus–Exposed Neonate. , 475-494.
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   Suk-Yin Chan, Todd Hulgan, Richard T. D’Aquila. (2004) The role of baseline HIV-1 resistance testing in patients with established infection. Current Infectious Disease Reports 6:3, 243-249
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   P Hermans. (2001) Current review and clinical management of patients with primary HIV-1 infection: limits and perspectives. Biomedicine & Pharmacotherapy 55:6, 301-307
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8. 8

   Bernard Masquelier, Marie-Laure Chaix, Marianne Burgard, Jérome Lechenadec, Anne Doussin, François Simon, Jacqueline Cottalorda, Jacques Izopet, Catherine Tamalet, Danielle Douard, Hervé Fleury, Marie-Jeanne Mayaux, Stéphane Blanche, Christine Rouzioux. (2001) Zidovudine Genotypic Resistance in HIV-1–Infected Newborns in the French Perinatal Cohort. Journal of Acquired Immune Deficiency Syndromes 27:2, 99-104
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9. 9

   Bernard Masquelier, Marie-Laure Chaix, Marianne Burgard, Jérome Lechenadec, Anne Doussin, François Simon, Jacqueline Cottalorda, Jacques Izopet, Catherine Tamalet, Danielle Douard, Hervé Fleury, Marie-Jeanne Mayaux, Stéphane Blanche, Christine Rouzioux. (2001) Zidovudine Genotypic Resistance in HIV-1–Infected Newborns in the French Perinatal Cohort. JAIDS Journal of Acquired Immune Deficiency Syndromes 27:2, 99-104
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10. 10

    Deenan Pillay, Stephen Taylor, Douglas D. Richman. (2000) Incidence and impact of resistance against approved antiretroviral drugs. Reviews in Medical Virology 10:4, 231-253
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11. 11

    Amalia Rubio, Manuel Leal, Concha Rey, Juan Antonio Pineda, Armando Sanchez-Quijano, Eduardo Lissen. (1998) Short-term evolution of HIV-1 viraemia and CD4+ cell counts in patients who have a primary mutation to zidovudine. AIDS 12:4, 395-398
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12. 12

    A. van Vliet, J. van Roosmalen. (1997) Worldwide Prevention of Vertical Human Immunodeficiency Virus (HIV) Transmission. Obstetrical & Gynecological Survey 52:5, 301-309
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13. 13

    Marie-Louse Newell, Catherine S. Peckham. (1994) Working towards a European strategy for intervention to reduce vertical transmission of HIV. BJOG: An International Journal of Obstetrics and Gynaecology 101:3, 192-196
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