Issouf Konate

Herpes simplex virus and HIV-1: deciphering viral synergy

Recent proof-of-concept randomised controlled trials have shown a causal relation between herpes simplex virus (HSV) type 2 infection and HIV-1 replication in co-infected individuals. We explore the mechanisms that may operate to enhance reciprocal viral replication. Direct interactions could involve HIV-1-related immune deficiency, disruption of mucosal barrier by HSV infection/reactivation, HSV-induced mucosal cell recruitment, transactivation of HIV-1 replication by HSV proteins, and immune modulation by HSV decoys. Indirect interactions might coexist through disturbances of the vaginal flora during HSV shedding and systemic immune activation. In co-infected individuals, suppressive HSV treatment reduces HIV-1 genital and systemic excretion. This finding is a likely result of efficacious prevention of HSV2 reactivations, and perhaps of other herpesviruses. Strategies to control HSV2 and other herpesviruses deserve urgent attention and should become part of the HIV-1 prevention and care package.

Human papillomavirus genotype distribution and cervical squamous intraepithelial lesions among high-risk women with and without HIV-1 infection in Burkina Faso

Human papillomavirus (HPV) infection and cervical squamous intraepithelial lesions (SILs) were studied in 379 high-risk women. Human papillomavirus DNA was detected in 238 of 360 (66.1%) of the beta-globin-positive cervical samples, and 467 HPV isolates belonging to 35 types were identified. Multiple (2–7 types) HPV infections were observed in 52.9% of HPV-infected women. The most prevalent HPV types were HPV-52 (14.7%), HPV-35 (9.4%), HPV-58 (9.4%), HPV-51 (8.6%), HPV-16 (7.8%), HPV-31 (7.5%), HPV-53 (6.7%), and HPV-18 (6.4%). Human immunodeficiency virus type 1 (HIV-1) seroprevalence was 36.0%. Human papillomavirus prevalence was significantly higher in HIV-1-infected women (87 vs 54%, prevalence ratio (PR)=1.61, 95% confidence interval (CI): 1.4–1.8). High-risk HPV types (71 vs 40%, PR=1.79, 95% CI: 1.5–2.2), in particular HPV-16+18 (22 vs 9%, PR=2.35, 95% CI: 1.4–4.0), and multiple HPV infections (56 vs 23%, PR=2.45, 95% CI: 1.8–3.3) were more prevalent in HIV-1-infected women. High-grade SIL (HSIL) was identified in 3.8% of the women. Human immunodeficiency virus type 1 infection was strongly associated with presence of HSIL (adjusted odds ratio=17.0; 95% CI 2.2–134.1, P=0.007) after controlling for high-risk HPV infection and other risk factors for HSIL. Nine of 14 (63%) HSIL cases were associated with HPV-16 or HPV-18 infection, and might have been prevented by an effective HPV-16/18 vaccine.

Impact of suppressive herpes therapy on genital HIV-1 RNA among women taking antiretroviral therapy: a randomized controlled trial

Objective:To demonstrate a causal relationship between herpes simplex virus 2 (HSV-2) and increased genital HIV-1-RNA shedding in women on HAART. Design:A randomized, double-blind, placebo-controlled trial of herpes-suppressive therapy (valacyclovir 500 mg twice a day) in HIV-1/HSV-2-infected women taking HAART in Burkina Faso. Methods:Participants were followed for a total of 12 biweekly visits before and after randomization. The presence and frequency of genital and plasma HIV-1 RNA, and of genital HSV-2 were assessed using summary measures, adjusting for baseline values. Random effect linear regression models were used to assess the impact of treatment on genital and plasma viral loads among visits with detectable virus. Results:Sixty women were enrolled into the trial. Their median CD4 lymphocyte count was 228 cells/μl, and 83% had undetectable plasma HIV-1 RNA at baseline. Valacyclovir reduced the proportion of visits with detectable genital HSV-2 DNA [odds ratio (OR) 0.37, 95% confidence interval (CI) 0.13, 1.05], but had no significant impact on the frequency (OR 0.90, 95% CI 0.31, 2.62) or quantity (reduction of 0.33 log copies/ml, 95% CI −0.81, 0.16) of genital HIV-1 RNA. However, according to pre-defined secondary analyses restricted to women who shed HIV-1 at least once in the baseline phase, valacyclovir reduced both the proportion of visits with detectable HIV-1 shedding (OR 0.27, 95% CI 0.07, 0.99) and the quantity of genital HIV-1 RNA during these visits (−0.71 log10 copies/ml, 95% CI −1.27, −0.14). Conclusion:HSV-2 facilitates residual genital HIV-1 replication among dually infected women taking HAART despite HIV-1 suppression at the systemic level.

Long term virological, immunological and mortality outcomes in a cohort of HIV-infected female sex workers treated with highly active antiretroviral therapy in Africa

BackgroundConcerns have been raised that marginalised populations may not achieve adequate compliance to antiretroviral therapy. Our objective was to describe the long-term virological, immunological and mortality outcomes of providing highly active antiretroviral therapy (HAART) with strong adherence support to HIV-infected female sex workers (FSWs) in Burkina Faso and contrast outcomes with those obtained in a cohort of regular HIV-infected women.MethodsProspective study of FSWs and non-FSWs initiated on HAART between August 2004 and October 2007. Patients were followed monthly for drug adherence (interview and pill count), and at 6-monthly intervals for monitoring CD4 counts and HIV-1 plasma viral loads (PVLs) and clinical events.Results95 women, including 47 FSWs, were followed for a median of 32 months (interquartile range [IQR], 20-41). At HAART initiation, the median CD4 count was 147 cells/μl (IQR, 79-183) and 144 cells/μl (100-197), and the mean PVLs were 4.94 log10copies/ml (95% confidence interval [CI], 4.70-5.18) and 5.15 log10 copies/ml (4.97-5.33), in FSWs and non-FSWs, respectively. Four FSWs died during follow-up (mortality rate: 1.7 per 100 person-years) and none among other women. At 36 months, the median CD4 count increase was 230 cells/μl (IQR, 90-400) in FSWs vs. 284 cells/μl (193-420) in non-FSWs; PVL was undetectable in 81.8% (95% CI, 59.7-94.8) of FSWs vs. 100% (83.9-100) of non-FSWs; and high adherence to HAART (> 95% pills taken) was reported by 83.3% (95% CI, 67.2-93.6), 92.1% (95% CI, 78.6-98.3), and 100% (95% CI, 54.1-100) of FSWs at 6, 12, and 36 months after HAART initiation, respectively, with no statistical difference compared to the pattern observed among non-FSWs.ConclusionsClinical and biological benefits of HAART can be maintained over the long term among FSWs in Africa and could also lead to important public health benefits.

Effect of HIV-1 and antiretroviral therapy on herpes simplex virus type 2: a prospective study in African women.

Objectives: To document the natural history of herpes simplex virus type 2 (HSV-2) in relation to HIV and highly active antiretroviral therapy (HAART) in Africa, a longitudinal study was conducted of women in the placebo arms of two randomised controlled trials of HSV-suppressive therapy in Burkina Faso. Methods: 22 HIV-uninfected women (group 1), 30 HIV-1-infected women taking HAART (group 2), and 68 HIV-1-infected women not eligible for HAART (group 3) were followed over 24 weeks. HSV-2 DNA was detected on alternate weeks using real-time PCR from cervicovaginal lavages. Plasma HIV-1 RNA was measured every month. CD4 cell counts were measured at enrolment. Results: Ulcers occurred on 1.9%, 3.1% and 7.2% of visits in groups 1, 2 and 3 (p = 0.02). Cervicovaginal HSV-2 DNA was detected in 45.5%, 63.3% and 67.6% of women (p = 0.11), and on 4.3%, 9.7% and 15.5% of visits in the three groups (p<0.001). Among HIV-infected women, cervicovaginal HSV-2 DNA was detected more frequently during ulcer episodes (adjusted risk ratio (aRR) 2.79, 95% CI 2.01 to 3.86) and less frequently among women practising vaginal douching (aRR 0.60, 95% CI 0.40 to 0.91). Compared with women not taking HAART and with CD4 cell counts of 500 cells/μl or greater, women on HAART had a similar risk of HSV-2 shedding (aRR 0.95, 95% CI 0.52 to 1.73), whereas women with CD4 cell counts of 200–500 cells/μl were more likely to shed HSV-2 (aRR 1.71, 95% CI 1.02 to 2.86). Conclusions: HSV-2 reactivations occur more frequently among HIV-infected women, particularly those with low CD4 cell counts, and are only partly reduced by HAART. HSV therapy may benefit HIV-infected individuals during HAART.

Genital warts and infection with human immunodeficiency virus in high-risk women in Burkina Faso: a longitudinal study

BackgroundHuman papillomaviruses are the most common sexually transmitted infections, and genital warts, caused by HPV-6 and 11, entail considerable morbidity and cost. The natural history of genital warts in relation to HIV-1 infection has not been described in African women. We examined risk factors for genital warts in a cohort of high-risk women in Burkina Faso, in order to further describe their epidemiology.MethodsA prospective study of 765 high-risk women who were followed at 4-monthly intervals for 27 months in Burkina Faso. Logistic and Cox regression were used to identify factors associated with prevalent, incident and persistent genital warts, including HIV-1 serostatus, CD4+ count, and concurrent sexually transmitted infections. In a subset of 306 women, cervical HPV DNA was tested at enrolment.ResultsGenital wart prevalence at baseline was 1.6% (8/492) among HIV-uninfected and 7.0% (19/273) among HIV-1 seropositive women. Forty women (5.2%) experienced at least one incident GW episode. Incidence was 1.1 per 100 person-years among HIV-uninfected women, 7.4 per 100 person-years among HIV-1 seropositive women with a nadir CD4+ count >200 cells/μL and 14.6 per 100 person-years among HIV-1 seropositive women with a nadir CD4+ count ≤200 cells/μL. Incident genital warts were also associated with concurrent bacterial vaginosis, and genital ulceration. Antiretroviral therapy was not protective against incident or persistent genital warts. Detection of HPV-6 DNA and abnormal cervical cytology were strongly associated with incident genital warts.ConclusionsGenital warts occur much more frequently among HIV-1 infected women in Africa, particularly among those with low CD4+ counts. Antiretroviral therapy did not reduce the incidence or persistence of genital warts in this population.

Cervicovaginal HIV-1 shedding in women taking antiretroviral therapy in Burkina Faso: a longitudinal study

Background:Antiretroviral therapy (ART) reduces transmission of HIV-1. However, genital HIV-1 can be detected in patients on ART. We analyzed factors associated with genital HIV-1 shedding among high-risk women on ART in Burkina Faso. Methods:Plasma viral load (PVL) and enriched cervicovaginal lavage HIV-1 RNA were measured every 3–6 months for up to 8 years. Random-effects logistic and linear regression models were used to analyze associations of frequency and quantity of genital HIV-1 RNA with behavioral and biological factors, adjusting for within-woman correlation. The lower limit of detection of HIV-1 RNA in plasma and eCVL samples was 300 copies per milliliter. Results:One hundred and eighty-eight participants initiated ART from 2004 to 2011. PVL was detectable in 16% (171/1050) of visits, in 52% (90/174) of women. Cervicovaginal HIV-1 RNA was detectable in 16% (128/798) of visits with undetectable plasma HIV-1 RNA in 45% (77/170) of women. After adjusting for PVL, detectable cervicovaginal HIV-1 RNA was independently associated with abnormal vaginal discharge and use of nevirapine or zidovudine vs. efavirenz and stavudine, respectively; longer time on ART and hormonal contraception were not associated with increased shedding. The presence of bacterial vaginosis, herpes simplex virus-2 DNA, and the use of nevirapine vs efavirenz were independently associated with an increased quantity of cervicovaginal HIV-1 RNA. Conclusions:Certain ART regimens, abnormal vaginal discharge, bacterial vaginosis, and genital herpes simplex virus-2 are associated with HIV-1 cervicovaginal shedding or quantity in women on ART after adjusting for PVL. This may reduce the effectiveness of ART as prevention in high-risk populations.

Longitudinal effect following initiation of highly active antiretroviral therapy on plasma and cervico-vaginal HIV-1 RNA among women in Burkina Faso

Background: Highly active antiretroviral therapy (HAART) could decrease HIV-1 transmissibility by reducing genital and plasma HIV-1 RNA. Methods: We evaluated the effect of HAART on genital and plasma HIV-1 RNA in a cohort of 39 antiretroviral-naïve women in Burkina Faso. Cervico-vaginal lavages were collected before HAART initiation and at six visits over 28 weeks while on HAART. Blood samples were collected at baseline and at three and four visits for CD4 and plasma HIV-1 RNA measurements, respectively. Results: Before HAART, 72% of women had detectable genital HIV-1 RNA. After 18 weeks on HAART, only one woman (2.5%) had detectable plasma HIV-1 RNA and two women (5.1%) had detectable genital HIV-1 RNA. Similar results were observed at each follow-up visit. However, 16/34 (47%) women with consistently undetectable plasma HIV-1 RNA shed HIV-1 at least once between weeks 18 and 28. In samples with detectable genital HIV-1, the mean quantity of HIV-1 RNA decreased from 3.87 prior to HAART to 3.04 log10 copies/mL at last visit (median 29 weeks; a 6.8-fold decrease in absolute number of copies/mL) (p = 0.04). A significant median CD4 lymphocyte cell gain of 121 cells/μL (interquartile range 59 to 204) was measured between pre-HAART and last visit. Conclusion: These findings suggest that HAART could play a role in reducing HIV transmission in Africa; however, they underscore the need to emphasise safe sex practices with patients taking HAART.

Cervical infection with human papillomavirus (HPV) 6 or 11 in high-risk women in Burkina Faso.

Background Human papillomavirus (HPV) types 6 and 11 are known agents of genital warts but little is known about their epidemiology in Africa. Objective To present data on the prevalence of, and risk factors for, cervical HPV 6 and 11 in high-risk women in Burkina Faso. Methods 306 women were enrolled. HIV status and CD4+ counts were determined. Among other genital samples, a cervical swab (Cervex) was collected for liquid-based cytology and HPV genotyping using MY09/MY11 and GP5+/GP6+ PCRs, and INNO-LiPA genotyping v2. Risk factors were examined using logistic regression. Results HIV-1 seroprevalence was 40% (123/306). Cervical HPV DNA was detected in 55% (100/183) of HIV-uninfected women, 84% (78/93) of HIV-1 infected women with CD4+ T-cell counts >200 cells/μl and 97% (29/30) of HIV-1 infected women with CD4+ T-cell counts ≤200 cells/μl (ptrend<0.001). HPV 6 prevalence was 6% (18/306), HPV 11 prevalence 4% (13/306), and overall HPV 6/11 prevalence 9% (28/306), which increased with HIV infection and immunosuppression. Genital warts were associated with HPV 6 (adjusted OR=4.12, 95% CI 1.17 to 14.53) but not with HPV 11. Genital ulcerations were associated with HPV 6/11 but not with other HPV types. There was a protective effect for vaginal douching and the follicular phase of the menstrual cycle. Condom use, HIV-1 plasma viral load and sexually transmitted and other reproductive tract infections were not associated with HPV 6/11. Conclusions Prevalence of HPV 6/11 was high in this population, with predominance of HPV 6. HPV 6/11 were found more frequently in women with genital ulcers and in those with HIV-related immunosuppression.

Neisseria gonorrhoeae and Chlamydia trachomatis infection in HIV-1-infected women taking antiretroviral therapy: a prospective cohort study from Burkina Faso.

Objectives Neisseria gonorrhoeae (NG) and Chlamydia trachomatis (CT) are common sexually transmitted infections (STI). We assessed the cumulative risk of NG and CT in a cohort of HIV-1-infected high-risk women taking antiretrovirals over 4 years in Burkina Faso. Methods Between March 2007 and February 2011, participants were followed every 3–6 months. At each visit, participants underwent a gynaecological examination with collection of cervical and vaginal swabs. Random-effects logistic regression models were used to analyse associations of NG and CT infection with behavioural and biological factors. Results 172 women had samples tested for NG and CT during the study period, in a total of 1135 visits. NG was detected in 6.4% of women (11/172, 95% CI 2.7 to 10.1) at a rate of 2.76 cases (95% CI 1.53 to 4.99) per 100 person-years. CT was detected in 1.7% (3/172, 95% CI 0 to 3.7) of women at a rate of 0.75 cases (95% CI 0.24 to 2.34) per 100 person-years. The majority of women were asymptomatic (9/14). In the multivariable model, the presence of NG or CT was associated with tobacco use (aOR=11.85, 95% CI 1.13 to 124.17), and concurrent genital HIV-1 RNA shedding (aOR=4.78, 95% CI 1.17 to 19.46). Higher levels of education (aOR=0.17, 95% CI 0.03 to 0.92), and age greater than 35 years (aOR=0.07, 95% CI 0.01 to 0.92) were associated with lower odds of infection. Conclusions The risk of NG or CT infection remains low among high-risk women in Bobo-Dioulasso. This provides some evidence that antiretroviral use does not contribute to behavioural disinhibition. The asymptomatic nature of most infections underscores the need for regular screening and treatment of STIs in core groups.