Immunovirological and therapeutic follow-up of HIV-1/HIV-2-dually seropositive patients
Landman, Rolanda; Damond, Florenceb,c; Gerbe, Juliettea; Brun-Vezinet, Francoiseb,c,d; Yeni, Patricka,d; Matheron, Sophiea,d
aAP-HP, Groupe hospitalier Bichat-Claude Bernard, Service de Maladies Infectieuses et Tropicales, France
bAP-HP, Groupe hospitalier Bichat-Claude Bernard, Laboratoire de Virologie, France
cINSERM U552, France
dUniversity Denis Diderot-Paris 7, Paris, France.
Received 24 October, 2008
Accepted 3 November, 2008
Among the 3700 HIV-infected patients followed in our institution, 17 with regular clinical, immunological and virological follow-up and identified as being dually seropositive for HIV-1 and HIV-2 were included in this study. Antiretroviral therapy seemed to be as effective, in terms of virological and immunological response, as in patients infected by HIV-1 alone. Nevertheless, the observed selection of HIV-2 protease resistance mutations in two cases underlines the importance of selecting drugs that are active on both viruses.
HIV-1 and HIV-2 both circulate in West Africa, where 0.3–1.0% of HIV-infected patients are estimated to be infected by both viruses [1–5]. Theoretically, HIV-1/HIV-2 dual infection should be defined by the presence of both HIV-1 and HIV-2 DNA or RNA by specific PCR, but as the rate of proviral DNA and plasma RNA HIV-2 detection in it is low [6–9], the diagnosis of such dual infections is complicated. Serology on the basis of specific synthetic peptides has provided useful informations for diagnosing dual seropositivity. In France, mandatory anonymous HIV case reporting was implemented in 2003 and includes routine virological monitoring and serological identification of the HIV type and group. Serological identification of the HIV type and group (HIV-1 groups M and O and HIV-2) is based on subtype serotyping enzyme-linked immunosorbant assay and is applied to all initial sera from newly diagnosed patients . Serological diagnosis of dual infection was based on similar high levels of antibody binding to both the immunodominant epitope of gp41 and the V3 region of both HIV-1 and HIV-2 .
Between January 2003 and June 2006, 10 184 new diagnoses of HIV infection with virological monitoring were reported. Of these, 186 involved patients infected by HIV-2, of whom 22 (0.2%; 95% confidence interval = 0.1–0.3) were probably dually seropositive .
Among the 3700 HIV-infected patients managed in our institution (Bichat Claude-Bernard Hospital, Paris), 36 have been identified as being dually seropositive for HIV-1 and HIV-2 by specific env (V3 and gp36) peptide serology and confirmed by western blots HIV-1 and HIV-2 since 1994. Among these 36 patients, 17 (10 women) with a regular clinical, immunological and virological follow-up of at least 1 year were included in this retrospective observational study. At diagnosis of the dual seropositivity, the patient's mean ± SD age was 38.1 ± 9.4 years, and nine patients were at Centers for Disease Control and Prevention stage C. The patients mostly originated from West Africa (Ivory Coast, n = 7; Ghana, n = 5; Benin, n = 2; Senegal, Mali and Cameroon, n = 1 each). Six out of the 17 patients had never received antiretroviral therapy (ART), and their 3.6 years of follow-up showed stable CD4 cell count and HIV-1 viral load. In all these patients, the HIV-2 plasma viral load remained undetectable.
Eleven patients received 1–7 different antiretroviral regimens. At the time of first line regimen, their median CD4 cell count was 130 cells/μl (16–290), the median HIV-1 viral load was 4.6 log copies/ml (2.8–5.8) and HIV-2 viral load was detectable in two patients (4.47 and 4.74 log copies/ml). After a median of follow-up of 2.6 years (0.3–7.6), the median CD4 cell count was 338 cells/μl (102–654), and plasma HIV-1 and HIV-2 RNA were undetectable in 10/11 cases. No clinical events were observed during follow-up. The ongoing treatment included lopinavir/ritonavir in nine cases (and two or three nucleoside reverse transcriptase inhibitors, n = 8 and saquinavir, n = 1); atazanavir/ritonavirtenofovir/emtricitabine, n = 1 and darunavir/ritonavir/tenofovir/raltegravir, n = 1. Detectable HIV-2 plasma RNA was observed in two out of the 11 patients during their follow-up. The first one had received five antiretroviral drug combinations between 1996 and 2007. HIV-1 plasma viral load became undetectable on zidovudine/abacavir/lamivudine, but HIV-2 plasma viral load never reached undetectability (2.24–4.78 log copies/ml) (Fig. 1). On the basis of reverse transcriptase and protease gene sequencing, which showed the presence of Q151M+M184V mutations in the reverse transcriptase gene and I54M+I82F in the protease gene, a tenofovir/darunavir/ritonavir/raltegravir combination was prescribed. HIV-2 plasma viral load became undetectable after 1 month and remained below 100 copies/ml for 6 months. The CD4 cell count rose from 102 to 314 cells/μl. The second patient had received didanosine/3TC/atazanavir/ritonavir, then didanosine/3TC/lopinavir/ritonavir combinations. Although HIV-1 viral load became undetectable, HIV-2 plasma viral load ranged from 2.63–4.59 log copies/ml. The HIV-2 reverse transcriptase gene could not be amplified in this patient. Protease gene sequencing showed the presence of the V47A mutation. The CD4 cell count remained stable in the range 315–386 cells/μl.
This is the first report on the response to ART in HIV-1 and HIV-2 dually seropositive patients. Treatment seemed to be as effective, in terms of virological and immunological response, as in patients infected by HIV-1 alone [13,14]. Nevertheless, the observed selection of HIV-2 protease inhibitor resistance mutations in the two cases with persistent HIV-2 viral load detectability underlines the importance of selecting drugs that are active on both viruses. These two patients had received atazanavir/ritonavir and did not respond to the subsequent lopinavir/ritonavir-based regimen. This is in keeping with French guidelines, which mention reduced HIV-2 sensitivity to several protease inhibitors, including atazanavir/ritonavir, fosamprenavir/ritonavir and tipranavir/ritonavir [15,16]. We observed the same good virological response to raltegravir combined with an active protease inhibitor (e.g. darunavir) as previously reported in HIV-2-monoinfected patients [17,18]. Immunological and virological follow-up of both HIV-1 and HIV-2 in dually seropositive patients is recommended. The efficacy of drugs on both viruses has to be taken into account for the choice of ART, and new regimens including an integrase inhibitor should be evaluated both in the northern countries and West Africa.
Roland Landman, Florence Damond and Sophie Matheron were responsible for the conception and design; Roland Landman, Florence Damond and Juliette Gerbe were responsible for the provision of study materials or patients; Roland Landman, Florence Damond, Sophie Matheron and Juliette Gerbe provided the statistical expertise and performed the analysis; Drafting of the article was carried out by Roland Landman, Florence Damond and Sophie Matheron; Interpretation of the data, critical revision of the article for important intellectual content, and final approval of the article was carried out by Roland Landman, Florence Damond, S. Matheron, Juliette Gerbe, Francoise Brun-Vezinet and Patrick Yeni.
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© 2009 Lippincott Williams & Wilkins, Inc.
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