Igho Ofotokun

Heart Failure in Patients With Human Immunodeficiency Virus Infection Epidemiology, Pathophysiology, Treatment, and Future Research

With the advent of highly active antiretroviral therapy (HAART), human immunodeficiency virus type 1 (HIV-1) infection has become a chronic disease with longer life expectancy.1 The HIV Outpatient Study showed that, with the addition of antiretroviral therapy (ART), mortality declined from 29.4 to 8.8 per 100 person-years.2 More recent data indicate that the proportions of patients expected to survive 5, 10, and 15 years after seroconversion in the HAART era are 99%, 93%, and 89%, respectively.3 With the increased life expectancy and decreased morbidity from opportunistic infections, the recognition and importance of chronic complications associated with HIV-1 infection are becoming more evident. Cardiac diseases are common complications found in these patients. The spectrum of heart diseases varies significantly between developed and developing countries and, in developed countries, between pre-HAART and post-HAART eras.4 Among them, HIV-associated cardiomyopathy, broadly defined as a decreased left ventricular (LV) ejection fraction or dilated LV by imaging studies, with or without symptoms of heart failure, is currently recognized as a major long-term complication of HIV-1 infection in developing countries; however, it is still prevalent in developed countries.4 Many questions regarding its pathogenesis and treatment remain unanswered. The epidemiology of HIV-associated cardiomyopathy has changed since the first report in 1986.5 The advent of HAART has significantly altered both the incidence and prevalence of this disease, and the definition of HIV-associated cardiomyopathy has also evolved from one of primarily systolic dysfunction to now reflect the growing recognition of diastolic dysfunction in these patients. The incidence of HIV-associated cardiomyopathy is difficult to ascertain because very few studies actually evaluated this measure. In the pre-ART era, HIV-associated cardiomyopathy was defined as symptomatic, systolic dysfunction with a dilated LV and was seen almost exclusively in patients with advanced HIV disease and AIDS. These older studies, …

HIV and metabolic, body, and bone disorders: what we know from low- and middle-income countries.

Abstract:Globally, the HIV epidemic is evolving. Life expectancy for HIV-infected individuals has been extended because of more effective and more widely available antiretroviral therapy. As a result, chronic noncommunicable diseases (NCDs) have become important comorbid conditions. In particular, HIV-infected persons are increasingly at risk of developing metabolic (diabetes, dyslipidemias), body composition (lipodystrophy, overweight/obesity) and bone mineral density abnormalities. We have summarized the published epidemiological and clinical literature regarding these HIV-NCD comorbidities in low- and middle-income countries (LMICs). We found important gaps in knowledge. Specifically, there are few studies that use standardized methods and metrics; consequently, prevalence or incidence data are not comparable. There are very little or no data regarding the effectiveness or cost-effectiveness of clinical monitoring or therapeutic interventions for metabolic disorders in HIV-infected individuals. Also, although NCDs continue to grow in the HIV-negative population of most LMICs, there are few data comparing the incidence of NCD comorbidities between HIV-infected and HIV-negative populations. To address these gaps, we describe potential research and capacity development priorities for the future.

Less Bone Loss With Maraviroc- Versus Tenofovir-Containing Antiretroviral Therapy in the AIDS Clinical Trials Group A5303 Study

BACKGROUND There is a need to prevent or minimize bone loss associated with antiretroviral treatment (ART) initiation. We compared maraviroc (MVC)- to tenofovir disoproxil fumarate (TDF)-containing ART. METHODS This was a double-blind, placebo-controlled trial. ART-naive subjects with human immunodeficiency virus type 1 RNA load (viral load [VL]) >1000 copies/mL and R5 tropism were randomized to MVC 150 mg or TDF 300 mg once daily (1:1), stratified by VL <100 000 or ≥100 000 copies/mL and age <30 or ≥30 years. All subjects received darunavir 800 mg, ritonavir 100 mg, and emtricitabine 200 mg daily. Dual-energy X-ray absorptiometry scanning was done at baseline and week 48. The primary endpoint was percentage change in total hip bone mineral density (BMD) from baseline to week 48 in the as-treated population. RESULTS We enrolled 262 subjects. A total of 259 subjects (130 MVC, 129 TDF) contributed to the analyses (91% male; median age, 33 years; 45% white, 30% black, 22% Hispanic). Baseline median VL was 4.5 log10 copies/mL and CD4 count was 390 cells/µL. The decline in hip BMD (n = 115 for MVC, n = 109 for TDF) at week 48 was less with MVC (median [Q1, Q3] of -1.51% [-2.93%, -0.11%] vs -2.40% [-4.30%, -1.32%] for TDF (P < .001). Lumbar spine BMD decline was also less with MVC (median -0.88% vs -2.35%; P < .001). Similar proportions of subjects in both arms achieved VL ≤50 copies/mL in as-treated and ITT analyses. CONCLUSIONS MVC was associated with less bone loss at the hip and lumbar spine compared with TDF. MVC may be an option to attenuate ART-associated bone loss. CLINICAL TRIALS REGISTRATION NCT01400412.

Contraceptive Methods and Risk of HIV Acquisition or Female-to-Male Transmission

Effective family planning with modern contraception is an important intervention to prevent unintended pregnancies which also provides personal, familial, and societal benefits. Contraception is also the most cost-effective strategy to reduce the burden of mother-to-child HIV transmission for women living with HIV who wish to prevent pregnancy. There are concerns, however, that certain contraceptive methods, in particular the injectable contraceptive depot medroxyprogesterone acetate (DMPA), may increase a woman’s risk of acquiring HIV or transmitting it to uninfected males. These concerns, if confirmed, could potentially have large public health implications. This paper briefly reviews the literature on use of contraception among women living with HIV or at high risk of HIV infection. The Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO) recommendations place no restrictions on the use of hormonal contraceptive methods by women with or at high risk of HIV infection, although a clarification recommends that, given uncertainty in the current literature, women at high risk of HIV who choose progestogen-only injectable contraceptives should be informed that it may or may not increase their risk of HIV acquisition and should also be informed about and have access to HIV preventive measures, including male or female condoms.

HIV-1 Genital Shedding is Suppressed in the Setting of High Genital Antiretroviral Drug Concentrations Throughout the Menstrual Cycle

BACKGROUND It is not known if fluctuations in genital tract antiretroviral drug concentrations correlate with genital virus shedding in human immunodeficiency virus (HIV)-infected women on antiretroviral therapy (ART). METHODS Among 20 HIV-infected women on ART (tenofovir [TFV], emtricitabine [FTC], and ritonavir-boosted atazanavir [ATV]) with suppressed plasma virus loads, blood and cervicovaginal samples collected twice weekly for 3 weeks were tested for antiretroviral concentrations, HIV-1 RNA, and proviral DNA. RESULTS Cervicovaginal:plasma antiretroviral concentration ratios were highest for FTC (11.9, 95% confidence interval [CI], 8.66-16.3), then TFV (3.52, 95% CI, 2.27-5.48), and ATV (2.39, 95% CI, 1.69-3.38). Within- and between-person variations in plasma and genital antiretroviral concentrations were observed. Low amounts of genital HIV-1 RNA (<50 copies/mL) were detected in 45% of women at 16% of visits. Genital HIV-1 DNA was detected in 70% of women at 35% of visits. Genital virus detection was associated with higher concentrations of mucosal leukocytes but not with genital antiretroviral concentrations, menstrual cycle phase, bacterial vaginosis, genital bleeding, or plasma virus detection. CONCLUSIONS Standard doses of ART achieved higher genital than plasma concentrations across the menstrual cycle. Therapeutic ART suppresses genital virus shedding throughout the menstrual cycle, even in the presence of factors reported to increase virus shedding.

Association of Macrophage Inflammation Biomarkers With Progression of Subclinical Carotid Artery Atherosclerosis in HIV-Infected Women and Men

Background Monocytes and monocyte-derived macrophages promote atherosclerosis through increased inflammation and vascular remodeling. This may be especially true in chronic human immunodeficiency virus (HIV) infection. Methods We examined 778 women (74% HIV+) in the Womens Interagency HIV Study and 503 men (65% HIV+) in the Multicenter AIDS Cohort Study who underwent repeated B-mode carotid artery ultrasound imaging in 2004-2013. We assessed baseline associations of the serum macrophage inflammation markers soluble (s)CD163, sCD14, galectin-3 (Gal-3), and Gal-3 binding protein (Gal-3BP) with carotid plaque formation (focal intima-media thickness >1.5 mm) over 7 years. Results Marker levels were higher in HIV+ persons versus HIV- persons. Presence of focal plaque increased over time: from 8% to 15% in women, and 24% to 34% in men. After adjustment for demographic, behavioral, and cardiometabolic factors, and CRP and interleukin-6, each standard deviation increase in sCD14 was associated with increased plaque formation (risk ratio [RR] 1.24, 95% confidence interval [CI] 1.07-1.43). This pattern was consistentby sex. sCD163 was associated with plaque formation in virally suppressed HIV+ men (RR 1.52, 95% CI 1.04-2.22); Gal-3BP and Gal-3 were not associated with increased plaque. Conclusions sCD14 and sCD163 may play important roles in atherogenesis among HIV+ persons.

Trends of and factors associated with live-birth and abortion rates among HIV-positive and HIV-negative women

BACKGROUND: Little is known about fertility choices and pregnancy outcome rates among HIV‐infected women in the current combination antiretroviral treatment era. OBJECTIVE: We sought to describe trends and factors associated with live‐birth and abortion rates among HIV‐positive and high‐risk HIV‐negative women enrolled in the Womens Interagency HIV Study in the United States. STUDY DESIGN: We analyzed longitudinal data collected from Oct. 1, 1994, through Sept. 30, 2012, through the Womens Interagency HIV Study. Age‐adjusted rates per 100 person‐years live births and induced abortions were calculated by HIV serostatus over 4 time periods. Poisson mixed effects models containing variables associated with live births and abortions in bivariable analyses (P < .05) generated adjusted incidence rate ratios and 95% confidence intervals. RESULTS: There were 1356 pregnancies among 2414 women. Among HIV‐positive women, age‐adjusted rates of live birth increased from 1994 through 1997 to 2006 through 2012 (2.85‐7.27/100 person‐years, P trend < .0001). Age‐adjusted rates of abortion in HIV‐positive women remained stable over these time periods (4.03‐4.29/100 person‐years, P trend = .09). Significantly lower live‐birth rates occurred among HIV‐positive compared to HIV‐negative women in 1994 through 1997 and 1997 through 2001, however rates were similar during 2002 through 2005 and 2006 through 2012. Higher CD4+ T cells/mm3 (≥350 adjusted incidence rate ratio, 1.39 [95% CI 1.03‐1.89] vs <350) were significantly associated with increased live‐birth rates, while combination antiretroviral treatment use (adjusted incidence rate ratio, 1.35 [95% CI 0.99‐1.83]) was marginally associated with increased live‐birth rates. Younger age, having a prior abortion, condom use, and increased parity were associated with increased abortion rates among both HIV‐positive and HIV‐negative women. CD4+ T‐cell count, combination antiretroviral treatment use, and viral load were not associated with abortion rates. CONCLUSION: Unlike earlier periods (pre‐2001) when live‐birth rates were lower among HIV‐positive women, rates are now similar to HIV‐negative women, potentially due to improved health status and combination antiretroviral treatment. Abortion rates remain unchanged, illuminating a need to improve contraceptive services.

Future desire for children among women living with HIV in Atlanta, Georgia

ABSTRACT Little is known regarding family planning desires among women living with HIV in the United States. This study aimed to identify factors influencing desire for children in the future among HIV-infected women in Atlanta, Georgia. HIV-infected women ages 18–45 completed an ACASI (audio computer-assisted self-interview) questionnaire. Chi-square, t-tests, and multivariate logistic regression evaluated factors associated with desire for future children. Of 181 participants, 62 (34.3%) expressed desire for children in the future, with increased desire among younger women (age <26) and those with seronegative partners. Concerns for horizontal and vertical HIV transmission were deterrents to future childbearing. Condom use and overall knowledge of transmission risk was low. Over a third of women desiring a child never discussed their desire with a physician. Misinformation regarding HIV transmission risks persists and is a notable concern influencing desire for children. Providers should reassess family planning desires regularly through integrated HIV care.

The Female Genital Tract Microbiome Is Associated With Vaginal Antiretroviral Drug Concentrations in Human Immunodeficiency Virus–Infected Women on Antiretroviral Therapy

Background The female genital tract (FGT) microbiome may affect vaginal pH and other factors that influence drug movement into the vagina. We examined the relationship between the microbiome and antiretroviral concentrations in the FGT. Methods Over one menstrual cycle, 20 human immunodeficiency virus (HIV)-infected women virologically suppressed on tenofovir (TFV) disoproxil fumarate/emtricitabine and ritonavir-boosted atazanavir (ATV) underwent serial paired cervicovaginal and plasma sampling for antiretroviral concentrations using high-performance liquid chromatography-tandem mass spectrometry. Analysis of 16S ribosomal RNA gene sequencing of cervicovaginal lavage clustered each participant visit into a unique microbiome community type (mCT). Results Participants were predominantly African American (95%), with a median age of 38 years. Cervicovaginal lavage sequencing (n = 109) resulted in a low-diversity mCT dominated by Lactobacillus (n = 40), and intermediate-diversity (n = 28) and high-diversity (n = 41) mCTs with abundance of anaerobic taxa. In multivariable models, geometric mean FGT:plasma ratios varied significantly by mCT for all 3 drugs. For both ATV and TFV, FGT:plasma was significantly lower in participant visits with high- and low-diversity mCT groups (all P < .02). For emtricitabine, FGT:plasma was significantly lower in participant visits with low- vs intermediate-diversity mCT groups (P = .002). Conclusions Certain FGT mCTs are associated with decreased FGT antiretroviral concentrations. These findings are relevant for optimizing antiretrovirals used for biomedical HIV prevention in women.

Characteristics of HIV target CD4 T cells collected using different sampling methods from the genital tract of HIV seronegative women

Background Understanding the immune profile of CD4 T cells, the primary targets for HIV, in the female genital tract (FGT) is critical for evaluating and developing effective biomedical HIV prevention strategies in women. However, longitudinal investigation of HIV susceptibility markers expressed by FGT CD4 T cells has been hindered by low cellular yield and risk of sampling-associated trauma. We investigated three minimally invasive FGT sampling methods to characterize and compare CD4 T cell yield and phenotype with the goal of establishing feasible sampling strategies for immune profiling of mucosal CD4 T cells. Methods and results FGT samples were collected bimonthly from 12 healthy HIV negative women of reproductive age in the following order: 1) Cervicovaginal lavage (CVL), 2) two sequential endocervical flocked swabs (FS), and 3) two sequential endocervical cytobrushes (CB1, CB2). Cells were isolated and phentoyped via flow cytometry. CD4 T cell recovery was highest from each individual CB compared to either CVL or FS (p < 0.0001). The majority of CD4 T cells within the FGT, regardless of sampling method, expressed CCR5 relative to peripheral blood (p < 0.01). Within the CB, CCR5+ CD4 T cells expressed significantly higher levels of α4β7, CD69, and low levels of CD27 relative to CCR5- CD4 T cells (all p < 0.001). We also identified CD4 Treg lineage cells expressing CCR5 among CB samples. Conclusions Using three different mucosal sampling methods collected longitudinally we demonstrate that CD4 T cells within the FGT express CCR5 and α4β7 and are highly activated, attributes which could act in concert to facilitate HIV acquisition. FS and CB sampling methods can allow for investigation of strategies to reduce HIV target cells in the FGT and could inform the design and interpretation microbicide and vaccine studies in women.