Andrea Low

Natural Polymorphisms of Human Immunodeficiency Virus Type 1 Integrase and Inherent Susceptibilities to a Panel of Integrase Inhibitors

ABSTRACT We evaluated the human immunodeficiency virus type 1 (HIV-1) integrase coding region of the pol gene for the presence of natural polymorphisms in patients during early infection (AHI) and with triple-class drug-resistant HIV-1 (MDR). We analyzed selected recombinant viruses containing patient-derived HIV-1 integrase for susceptibility to a panel of strand transfer integrase inhibitors (InSTI). A pretreatment sequence analysis of the integrase coding region was performed for 112 patients identified during acute or early infection and 15 patients with triple-class resistance. A phenotypic analysis was done on 10 recombinant viruses derived from nine patients against a panel of six diverse InSTI. Few of the polymorphisms associated with in vitro InSTI resistance were identified in the samples from newly infected individuals or those patients with MDR HIV-1. We identified polymorphisms V72I, L74I, T97A, V151I, M154I/L, E157Q, V165I, V201I, I203M, T206S, and S230N. V72I was the most common, seen in 63 (56.3%) of the AHI samples. E157Q was the only naturally occurring mutation thought to contribute to resistance to elvitegravir, raltegravir, and L-870,810. None of the patient-derived viruses demonstrated any significant decrease in susceptibility to the drugs tested. In summary, the integrase coding region contains as much natural variation as that seen in protease, but mutations associated with high-level resistance to existing InSTI are rarely, if ever, present in integrase naïve patients, especially those being used clinically. Most of the highly prevalent polymorphisms have little effect on InSTI susceptibility in the absence of specific primary mutations. Baseline testing for integrase susceptibility in InSTI-naïve patients is not currently warranted.

Impact of Opioid Substitution Therapy on Antiretroviral Therapy Outcomes: a Systematic Review and Meta-Analysis

This meta-analysis provides strong evidence that opioid substitution therapy improves several key outcomes of the HIV care continuum among people who inject drugs, including recruitment onto antiretroviral therapy, retention in care, adherence, and viral suppression.

Transmitted Drug Resistance and Phylogenetic Relationships among Acute and Early HIV-1 Infected Individuals in New York City

Background:Transmitted drug resistance (TDR) is critical to managing HIV-1–infected individuals and being a public health concern. We report on TDR prevalence and include analyses of phylogenetic clustering of HIV-1 in a predominantly men who have sex with men cohort diagnosed during acute/recent HIV-1 infection in New York City. Methods:Genotypic resistance testing was conducted on plasma samples of 600 individuals with acute/recent HIV-1 infection (1995–2010). Sequences were used for resistance and phylogenetic analyses. Demographic and clinical data were abstracted from medical records. TDR was defined according to International AIDS Society–USA and Stanford HIV database guidelines. Phylogenetic and other analyses were conducted using PAUP*4.0 and SAS, respectively. Results:The mean duration since HIV-1 infection was 66.5 days. TDR prevalence was 14.3% and stably ranged between 10.8% and 21.6% (Ptrend = 0.42). Nucleoside reverse transcriptase inhibitors resistance declined from 15.5% to 2.7% over the study period (Ptrend = 0.005). M41L (3.7%), T215Y (4.0%), and K103N/S (4.7%) were the most common mutations. K103N/S prevalence increased from 1.9% to 8.0% between 1995 and 2010 (Ptrend = 0.04). Using a rigorous definition of clustering, 19.3% (112 of 581) of subtype B viral sequences cosegregated into transmission clusters and clusters increased over time. There were fewer and smaller transmission clusters than had been reported in a similar cohort in Montreal but similar to reports from elsewhere. Conclusions:TDR is stable in this cohort and remains a significant concern to both individual patient management and the public health.

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.

Incidence of Opportunistic Infections and the Impact of Antiretroviral Therapy Among HIV-Infected Adults in Low- and Middle-Income Countries: A Systematic Review and Meta-analysis

This meta-analysis provides strong evidence that antiretroviral therapy (ART) has led to a major reduction in the incidence of key opportunistic infections (OIs) in low- and middle-income countries. ART was estimated to have averted about a million cases of OIs in 2013.

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.

Incidence and prevalence of opportunistic and other infections and the impact of antiretroviral therapy among HIV-infected children in low and middle-income countries: a systematic review and meta-analysis

This meta-analysis demonstrates a substantial decrease in the risk of most opportunistic infections with antiretroviral therapy (ART) use in human immunodeficiency virus-infected children in low- and middle-income countries and estimated cost savings with earlier ART initiation.

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.

Potential impact of existing interventions and of antiretroviral use in female sex workers on transmission of HIV in Burkina Faso: a modeling study.

Background:The impact and cost-effectiveness of antiretroviral treatment (ART) as prevention is likely to vary depending on the local context. Burkina Faso has a concentrated mature HIV epidemic where female sex workers (FSW) are thought to have driven HIV transmission. Methods:A dynamic HIV transmission model was developed using data from the Yerelon FSW cohort in Bobo-Dioulasso and population surveys. Compared with current ART provision [status quo (SQ)], the model estimated the proportion of HIV infections averted or incremental life-years gained per additional person-year of ART over 20 years for ART targeting different subgroups or expanding eligibility to all HIV-infected individuals compared with SQ. Results:Modeling suggests that condom use within commercial sex has averted 40% of past HIV infections. Continuing SQ averts 35%–47% of new infections over 20 years compared with no ART. Expanding ART eligibility to all HIV-infected individuals and increasing recruitment (80% per year) could avert a further 65% of new infections, whereas targeting full-time FSW or all FSWs achieved less impact but was more efficient in terms of life-years gained per 100 person-years of ART. Local HIV elimination is possible with expanded ART provision to FSWs but requires condom use within commercial sex to be maintained at high levels. Conclusions:Increasing FSW recruitment onto ART could be a highly efficient method for reducing HIV transmission in concentrated epidemic settings but should not be undertaken at the expense of existing interventions for FSWs. Specialized clinics providing multiple interventions for FSWs should be a fundamental component of prevention in concentrated epidemics.