Survival among Dually Infected HIV Patients Compared to HIV-1 Mono-Infected Patients Receiving ART in Senegal: A Twelve-Year Cohort Study
Assane Diouf1,2,3*, Amandine Cournil4, Sabrina Eymard-Duvernay4 and Louise Fortes-Deguenonvo3
1School of Public Health, Montreal University, Montreal, Canada
2Department of Infectious Diseases, Fann University Teaching Hospital, Dakar, Senegal
3Regional Research and Training Center on HIV and Associated Diseases, Dakar, Senegal
4UMI 233, Institut de Recherche pour le Développement, University of Montpellier, Montpellier, France
*Corresponding author: Assane Diouf, MD, MPH, PhD candidate, Department of Infectious Diseases/Regional Research and Training Center on HIV and Associated Diseases, Dakar, Senegal, E-mail: email@example.com
Int J Virol AIDS, IJVA-3-022, (Volume 3, Issue 2), Research Article; ISSN: 2469-567X
Received: April 25, 2016; Accepted: June 23, 2016; Published: June 27, 2016
Citation: Diouf A, Cournil A, Eymard-Duvernay S, Fortes-Deguenonvo L (2016) Survival among Dually Infected HIV Patients Compared to HIV-1 Mono-Infected Patients Receiving ART in Senegal: A Twelve-Year Cohort Study. Int J Virol AIDS 3:022.
Copyright: © 2016 Diouf A, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
HIV-2s: Human Immune Deficiency Virus type 2 single; HIV-1s: Human Immune Deficiency Virus type 1 single; HIV-D: Human Immune Deficiency Virus Dual; ART: Antiretroviral Therapy; ARV: Antiretroviral; NRTI: Nucleoside-Reverse Transcriptase Inhibitors; NNRTI: Non-Nucleoside-Reverse Transcriptase Inhibitor; PI: Protease Inhibitor; BMI: Body Mass Index; CDC: Center for Diseases Control and Prevention; IQR: Interquartile Range; PY: Person-Years; HR: Hazard Ratio
In West Africa, HIV-2 single infection (HIV-2s) and HIV-1 + HIV-2 dual infection (HIV-D) remain endemic but their morbidity is progressively decreasing [1-4]. Among HIV-D infected patients receiving antiretroviral therapy (ART), data on mortality are very scarce [5-8]. The purpose of this analysis was to compare survival of HIV-D infected with that of HIV-1 singly infected (HIV-1s) patients over twelve years of follow up after ART initiation.
A total of 403 HIV infected patients (10 HIV-D infected and 393 HIV-1s infected) who initiated ART in Senegal between 1998 and 2002 were included in a prospective cohort and followed until June 2010. Initial ART regimens combined two nucleoside-reverse transcriptase inhibitors (NRTI) plus either one non-nucleoside-reverse transcriptase inhibitor (NNRTI) or one protease inhibitor (PI). Clinical and biological assessments were performed at ART initiation and every semester thereafter. The data was censored at the date of the most recent visit and the survival function estimated by the Kaplan-Meier method. Cox proportional hazards models were used to identify risk factors of death among the baseline characteristics of the patients (age, sex, hemoglobin level, body mass index (BMI), CDC Stage, viral hepatitis B or C co-infection, HIV type, CD4 cell counts, HIV viral load, co-trimoxazole prophylaxis, ART regimen). Stata version 12.1 was used for analyses. The Senegalese national ethics committee approved this study and every participant signed an informed consent form after receiving a complete information sheet.
Among the 403 patients, 220 were female. At baseline, median age was 37 years; interquartile range (IQR) = 31-43; 223 patients (55.3%) were at CDC stage C. The median values of BMI, hemoglobin level and CD4 cell counts were 19.9 kg/m2 (IQR = 17.9-22.4), 10.7 g/dl (IQR = 9.3-12.0) and 127 cells/μl (IQR = 53-217), respectively. A total of 169 patients (41.9%) were receiving PI based tritherapy. Among HIV-D infected patients, initial ART regimens combined 2 NRTI + either indinavir (seven patients) or one NNRTI (three patients). At baseline, HIV-D infected patients were more likely to be male (80% vs. 44.5%; P = 0.048); they had a higher mean age (49.5 vs. 37.8 years; P < 0.0001) and lower mean viral load (3.8 vs. 5.0 log copies/ml; P < 0.001) compared to HIV-1s infected patients (Table 1). As of June 30th 2010, mean follow up duration was 81.8 months (IC95% = 77.4-86.2); it was longer for HIV-1s (82.5 months; IC95% = 78.1-86.9) than for HIV-D patients (54.3 months; IC95% = 15.4-93.1); p = 0.05. A total of 126 deaths (31.3%) and 38 lost to follow up (9.4%) were notified resulting in a retention rate of 59.3%. During 2246.2 person-years (PY) of exposure time, overall mortality rate was 4.0/100 PY (95% CI = 3.5-4.5). Mortality rate decreased progressively from 13.2/100 PY (95% CI = 9.9-16.6) during the first year to 1.9/100 PY (95% CI = 0.3-2.8) after five years of ART. The mortality rate was 6.9/100 PY among HIV-D infected patients (95% CI = 4.8-9.1) versus 3.9/100 PY (95% CI = 3.4-4.4) among HIV-1s infected patients; log rank test: p = 0.001. Seven out of ten HIV-D patients died including two of three HIV-D patients who were receiving 2 NRTI + 1 NNRTI. HIV-D infection was a risk factor for death (adjusted hazard ratio (HR) = 4.6; 95% CI = 2.0-10.6) as well as hemoglobin level < 10 g/dl (adjusted HR = 1.5; 95% CI = 1.0-2.2), BMI < 18.5 kg/m2 (adjusted HR = 1.5; 95% CI = 1.-2.2) and CD4 cell counts < 200 cells/μl (adjusted HR = 2.2; 95% CI = 1.3-3.7) at baseline.
Table 1: Baseline characteristics of patients by HIV serotype. View Table 1
In this study, we found that HIV-D infected patients had a lower survival than HIV-1s infected patients receiving ART. The characteristics that might contribute to increased mortality among HIV-D infected patients were predominant male sex and advanced age  but their effects were controlled in multivariate analysis. Another factor was the use of suboptimal ART regimens. An adequate ART regimen for HIV-D infected people must include ARV drugs that are simultaneously active against HIV-1 and HIV-2. This condition excludes all the NNRTI, the fusion inhibitor and several PI . In our cohort, at baseline, three HIV-D infected patients were receiving 2 NRTI + 1 NNRTI although HIV-2 is naturally resistant to the NNRTI. Such suboptimal regimens were common in other West African cohorts [8,11-13] but might not impact treatment outcomes in the short term . The several studies that compared outcomes of ART in HIV-D infected and HIV-1s infected patients reported discordant results. Two previous studies conducted in Burkina Faso found a lower survival among HIV-D infected patients. The first one reported a crude HR of 1.27 (95% CI = 0.84-1.94) and the second one an adjusted HR of 1.26 (95% CI = 0.76-2.07) [6,8]. In Mumbai, India, over a three-year period, the risk of death was 50% among HIV-D infected patients versus 9% among HIV-1s infected patients . However, in Ivory Coast no difference was found: HR = 0.91 (95% CI = 0.59-1.40) . In these previous studies, the mean duration of ART was less than three years: this may explain their inability to detect a statistically significant difference in mortality although some reported poorer immunologic outcomes in HIV-D infected patients [5,7,12]. Other explanations are related to the limitations in the management of ART for such patients. There is a lack of adequate monitoring tools for HIV-2s infection: CD4 cell counts, viral load and drug resistance tests are not as clearly understood as for HIV-1s infection [14-20]; resistance selection appears earlier than in HIV-1s infection ; and the definition of therapeutic failure still remains unclear [20-23]. Hence, the suboptimal outcomes of ART in HIV-2 infected individuals are established [24,25]. Moreover, in resource-limited settings, the therapeutic options for HIV-2s infection and HIV-D infection are very limited, and the second line regimens do not automatically include a new class of ARV drug. These problems will mainly impact the long-term outcomes.
To our knowledge, this is the first prospective cohort study to compare differences in mortality between HIV-D infected and HIV-1s infected patients under ART for such a long period. These differences may be explained, at least, in parts, by the insufficiencies in the management of ART for HIV-D infected individuals. However, these results must be interpreted with caution due to the limited sample size. Further research using adequate management of HIV-D infection is necessary to confirm whether HIV-2 co-infection is a risk factor for death among HIV-1 infected patients under ART. West African cohorts' collaboration can contribute to elucidate this question.
Ethics Approval and Consent to Participate
This study was approved by the “Conseil National d'Éthique pour la Rechercheen Santé” (CNERS). Before inclusion, every participant received complete information on the study and signed an informed consent form.
Availability of Data and Materials
For this manuscript, the data will not be shared due to the ownership rules. These data are under the responsibility of three agencies: « Conseil National de Lutte contre le Sida » (CNLS), « Agence Nationale de Recherches sur le Sida et les hépatites virales » et Institut de Recherche pour le Développement « IRD ».
The authors declare that they have no competing interests.
This work was funded by the « Agence Nationale de Recherches sur le Sida et les hépatites virales (ANRS) ».
Assane Diouf and Amandine Cournil conceived the work.
Assane Diouf and Sabrina Eymard-Duvernay coordinated data collection and quality control.
Assane Diouf, Amandine Cournil and Sabrina Eymard-Duvernay did the data analysis and interpretation.
Assane Diouf drafted the manuscript.
Amandine Cournil, Sabrina Eymard-Duvernay and Louise Fortes-Deguenonvo revised the consecutive drafts.
The authors acknowledge all the members of the ANRS 1215 Study Group, especially Pierre Debeaudrap and Eric Delaporte for their precious contribution as well as Gibril Ndow from Inperial College of London.
Chang LW, Osei-Kwasi M, Boakye D, Aidoo S, Hagy A, et al. (2002) HIV-1 and HIV-2 seroprevalence and risk factors among hospital outpatients in the Eastern Region of Ghana, West Africa. J Acquir Immune Defic Syndr 29: 511-516.
Heitzinger K, Sow PS, Dia Badiane NM, Gottlieb GS, N'Doye I, et al. (2012) Trends of HIV-1, HIV-2 and dual infection in women attending outpatient clinics in Senegal, 1990-2009. Int J STD AIDS 23: 710-716.
de Pina-Araujo II, Guimarães ML, Bello G, Vicente AC, Morgado MG (2014) Profile of the HIV epidemic in Cape Verde: molecular epidemiology and drug resistance mutations among HIV-1 and HIV-2 infected patients from distinct islands of the archipelago. PLoS One 9: e96201.
da Silva ZJ, Oliveira I, Andersen A, Dias F, Rodrigues A, et al. (2008) Changes in prevalence and incidence of HIV-1, HIV-2 and dual infections in urban areas of Bissau, Guinea-Bissau: is HIV-2 disappearing? AIDS 22: 1195-1202.
Toure S, Kouadio B, Seyler C, Traore M, Dakoury-Dogbo N, et al. (2008) Rapid scaling-up of antiretroviral therapy in 10,000 adults in Côte d'Ivoire: 2-year outcomes and determinants. AIDS 22: 873-882.
Kouanda S, Meda IB, Nikiema L, Tiendrebeogo S, Doulougou B, et al. (2012) Determinants and causes of mortality in HIV-infected patients receiving antiretroviral therapy in Burkina Faso: a five-year retrospective cohort study. AIDS Care 24: 478-490.
Chiara M, Rony Z, Homa M, Bhanumati V, Ladomirska J, et al. (2010) Characteristics, immunological response & treatment outcomes of HIV-2 compared with HIV-1 & dual infections (HIV 1/2) in Mumbai. Indian J Med Res 132: 683-689.
Harries K, Zachariah R, Manzi M, Firmenich P, Mathela R, et al. (2010) Baseline characteristics, response to and outcome of antiretroviral therapy among patients with HIV-1, HIV-2 and dual infection in Burkina Faso. Trans R Soc Trop Med Hyg 104: 154-161.
Balestre E, Eholié SP, Lokossue A, Sow PS, Charurat M, et al. (2012) Effect of age on immunological response in the first year of antiretroviral therapy in HIV-1-infected adults in West Africa. AIDS 26: 951-957.
Menéndez-Arias L, Alvarez M (2014) Antiretroviral therapy and drug resistance in human immunodeficiency virus type 2 infection. Antiviral Res 102: 70-86.
Sarfo FS, Bibby DF, Schwab U, Appiah LT, Clark DA, et al. (2009) Inadvertent non-nucleoside reverse transcriptase inhibitor (NNRTI)-based antiretroviral therapy in dual HIV-1/2 and HIV-2 seropositive West Africans: a retrospective study. J Antimicrob Chemother 64: 667-669.
Drylewicz J, Eholie S, Maiga M, Zannou DM, Sow PS, et al. (2010) First-year lymphocyte T CD4+ response to antiretroviral therapy according to the HIV type in the IeDEA West Africa collaboration. AIDS 24: 1043-1050.
Ekouevi DK, Balestre E, Coffie PA, Minta D, Messou E, et al. (2013) Characteristics of HIV-2 and HIV-1/HIV-2 Dually Seropositive Adults in West Africa Presenting for Care and Antiretroviral Therapy: The IeDEA-West Africa HIV-2 Cohort Study. PLoS One 8: e66135.
Camacho RJ (2012) Special aspects of the treatment of HIV-2-infected patients. Intervirology 55: 179-183.
Peterson K, Jallow S, Rowland-Jones SL, de Silva T (2011) Antiretroviral Therapy for HIV-2 Infection: Recommendations for Management in Low-Resource Settings. AIDS Res Treat 2011.
Costarelli S, Torti C, Rodella A, Baldanti F, Paolucci S, et al. (2008) Screening and Management of HIV-2-Infected Individuals in Northern Italy. AIDS Patient Care STDS 22: 489-494.
Charpentier C, Eholié S, Anglaret X, Bertine M, Rouzioux C, et al. (2014) Genotypic resistance profiles of HIV-2-treated patients in West Africa. AIDS 28: 1161-1169.
Ekouévi DK, Avettand-Fènoël V, Tchounga BK, Coffie PA, Sawadogo A, et al. (2015) Plasma HIV-2 RNA According to CD4 Count Strata among HIV-2-Infected Adults in the IeDEA West Africa Collaboration. PLoS One 10: e0129886.
New York State Department of Health AIDS Institute (2015) Human Immunodeficiency Virus Type 2 (HIV-2).
Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services.
WHO (2013) Consolidated Guidelines on the use of antiretroviral drugs for treating and preventing HIV infection - Recommendations for a public health approach.
Gilleece Y, Chadwick DR, Breuer J, Hawkins D, Smit E, et al. (2010) British HIV Association guidelines for antiretroviral treatment of HIV-2-positive individuals 2010. HIV Med 11: 611–619.
Ekouevi DK, Tchounga BK, Coffie PA, Tegbe J, Anderson AM, et al. (2014) Antiretroviral therapy response among HIV-2 infected patients: a systematic review. BMC Infect Dis 14: 461.
Okomo U, Togun T, Oko F, Peterson K, Townend J, et al. (2012). Treatment outcomes among HIV-1 and HIV-2 infected children initiating antiretroviral therapy in a concentrated low prevalence setting in West Africa. BMC Pediatr 12: 95.